pancreatic cancer treatment methods

专利摘要:
USE OF A COMPOSITION UNDERSTANDING AN EFFECTIVE AMOUNT OF NANOPARTICLES THAT UNDERSTAND A TAXAN AND ALBUMIN.The present invention relates to methods and compositions for the treatment of pancreatic cancer in an individual who has previously been treated for pancreatic cancer (for example, based on gemcitabine) by administering a composition comprising nanoparticles comprising a taxane and a albumin. The invention also relates to methods of combination therapy for treating pancreatic cancer (for example, in an individual who has previously been treated for pancreatic cancer) comprising administering to an individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and another agent.
公开号:BR112012030909A2
申请号:R112012030909-9
申请日:2011-05-20
公开日:2020-08-18
发明作者:Neil P. Desai；Patrick Soon-Shiong
申请人:Abraxis Bioscience, Llc；
IPC主号:

专利说明:

Invention Patent Descriptive Report for "USE OF A COMPOSITION UNDERSTANDING AN EFFECTIVE AMOUNT OF NONPARTICLES THAT UNDERSTAND A TAXAN AND ALBUMIN".
CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority benefit to U.S. Provisional Patent Applications Nos. 61 / 351,846, deposited on June 4, 2010, 61 / 377,035, deposited on August 25, 2010 and 61 / 446,932, deposited on February 25, 2011, the content of each is incorporated by reference in your totality.
BACKGROUND Pancreatic cancer has one of the highest mortality rates among all types of cancer and is the fourth most common cause of adult cancer death in the United States, with an estimated 42,470 cases per year. See Nieto et al., The Oncologist, 13: 562-576 (2008); and Cancer Facts and Figures, American Cancer Society (2009). It accounts for about 3% of all cancers diagnosed in the United States each year. However, almost twice the number of patients, about 6%, die from pancreatic cancer. See Cancer Facts and Figures, American Cancer Society (2009). The high mortality rate from pancreatic cancer is a result of the high incidence of metastatic disease at the time of diagnosis. As a result, only 5% - 15% of patients are candidates who have tumors that are amenable to resection. See Nieto et al., The Oncologist, 13: 562-576 (2008). The standard first-line treatment for the treatment of pancreatic cancer is gemcitabine (eg GEMZARO), which was approved by the Food and Drug Administration ("FDA") in 1996. In a clinical study with 126 patients with locally advanced pancreatic cancer (63 treated with gemcitabine), gemcitabine was shown to be superior to 5-fluororouracil (5-FU) in terms of median overall survival (5.7 months for gemcitabine versus 4.2 months for 5-FU ), the median time to disease progression (2.1 months for gemcitabine versus 0.9 months for 5- FU) and clinical benefit responses. However, although gemcitabine has become a standard palliative therapy for the treatment of pancreatic cancer since its approval in 1996, there has been little improvement in the treatment of pancreatic cancer. For all stages of pancreatic cancer combined, the relative 5-year survival rate for pancreatic cancer between 1996 and 2004 was 5%, drastically lower than the survival rates for other types of cancer. See American Cancer Society, Surveillance and Health Policy Research (2009).
Several studies have been carried out, but have failed to identify an improved therapeutic regimen for the treatment of pancreatic cancer that combines gemcitabine with a second agent. The only exception to failed attempts to identify an effective combination therapy regimen was the 'combination of gemcitabine and erlotinib (eg TARCEVA ). See Mo- "ore et al., J. Clin. Oncol. 25: 1960-1966 (2007). The combination of gemrcitabi-” na / erlotinib improved median overall survival (6.4 months versus 6.0 months). 'ses) and median progression-free survival (3.8 months versus 3.5 months) compared to gemcitabine monotherapy, see id. Based on this very modest improvement in overall survival and progression-free survival (0.4 and 0.3 months, respectively), the FDA approved the gemcibabine / erlotinib combination in 2005. Despite its authorization, the gemcitabine / erlotinib combination has not been widely used as a standard of care for treatment pancreatic cancer due to the side effects associated with the combination of gemcitabine / erlotinib and the minimal improvement in survival compared to gemcitabine monotherapy, see Nieto et al., The Oncologist, 13: 562-576 (2008).
To date, no standard guidelines for treating second pancreatic cancer have been established. Data that support the use of second-line therapy compared to better supportive care are lacking. Benefits of second-line therapy appear to be modest, at the expense of drug toxicity. Almhanna et a / l., 2008, Oncology, vol. 22, No. 10. Taxanes have been investigated as a second-line treatment in gemcitabine-resistant pancreatic cancer patients. In a small study, weekly treatment with paclitaxel in 18 patients with recurrent disease produced a response rate of 6% and an average overall survival of 17.5 weeks. Almhanna et al., Oncology, 22: 10 (2008). In two small studies using a combination of docetaxel and gefitinib, the median overall survival was about 12 weeks. Capecitabine was also combined with docetaxel, with response rates ranging from 1% to 12% and an average survival of 13 weeks. In a study with 15 patients, the combination of docetaxel with mitomycin and irinotecan produced no response and the median overall survival was 24 weeks. Clinical benefits have not been reported in any of these studies. Almhanna et al., Oncology, 22: 10 (2008).
. : Albumin-bound paclitaxel (eg - ABRAXANES) in combination with gemcitabine was found to be well tolerated in advanced pancreatic cancer in a Phase I / ll study and showed evidence of "antitumor activity. See, for example, US Patent Application No.
2006/0263434; Maitra et al., Mol. Cancer Ther. 8 (12 Suppl): C246 (2009); Loehr et al., J. of Clinical Oncology 27 (158) (Supplement of May 20): 200, Abstract No. 4526 (2009); Von Hoff et al., J. of Clinical Oncology 27 (158S) (Supplement of May 20), Abstract No. 4525 (2009); and Kim et a /., Proc. Amer. Assoc. Cancer Res., 46, Abstract No. 1440 (2005).
Descriptions of all publications, patents, patent applications and patent applications published herein are hereby incorporated by reference in their entirety.
BRIEF SUMMARY OF THE INVENTION The present invention, in some embodiments, provides a method of treating pancreatic cancer (such as advanced pancreatic cancer) in an individual who needs the same that comprises (or consists of or essentially consists of) administration, to the individual , of an effective amount of a composition comprising nanoparticles comprising a taxane and albumin (hereinafter also referred to as "the nanoparticle composition" or "nanoparticle taxane composition"), in which the individual has previously been treated for cancer pancreatic (hereinafter also referred to as "prior therapy").
In some modalities, prior therapy comprises the administration of gemcitabine ("a gemcitabine-based therapy"). In some modalities, prior therapy is monotherapy with gemcitabine. In some embodiments, prior therapy includes the administration of gemcitabine eerbtinib. In some modalities, prior therapy includes the administration of gemcitabine and capecitabine. In some embodiments, prior therapy includes the administration of gemcitabine and 5-FU. In some modalities, prior therapy comprises the administration of gemcitabine, erlotinib, capecibabine and / or 5-FU. In some modalities, prior therapy is adjunctive therapy with gemcitabine. In some modalities, prior therapy is tera-: neoadjuvant sink with gemcitabine.
NO In some modalities, the individual progressed when he / she had previous treatment at the time of treatment. For example, the individual has progressed, within any of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after treatment with prior therapy. In some modalities, the individual is resistant or refractory to previous therapy. In some modalities, the individual has recurrent pancreatic cancer, that is, the individual initially responds to treatment with previous therapy, but develops pancreatic cancer after about any one of about 6, 7, 8, 9, 10, 11, 12.24 0 or 36 months when previous therapy was discontinued.
Although the description below describes individuals who have progressed when under prior therapy (for example, gemcitabine-based therapy) as exemplary modalities, it should be understood that the present description also applies to individuals who are resistant or refractory to prior therapy, individuals who are inadequate to continue with previous therapy (for example, due to a lack of response and / or toxicity), individuals who have recurrent pancreatic disease after previous therapy, individuals who are unresponsive to previous therapy, individuals who have a less desirable degree of responsiveness and / or individuals who exhibit an improved response. The methods described in the present invention include all second-line therapies for the treatment of pancreatic cancer that involve the administration of a composition comprising
giving albumin nanoparticles and comprising a taxane. The methods described herein also include all third-line therapies for the treatment of pancreatic cancer that involve the administration of a composition comprising albumin nanoparticles and which comprises mumtaxane.
Thus, in some embodiments, a method of treating pancreatic cancer (such as advanced pancreatic cancer) is provided in an individual who needs it, which comprises (or consists of or consists essentially of) administering to the individual a quantity effectiveness of a composition comprising nanoparticles comprising a taxane and an albumin, in which the individual has progressed on prior therapy (for example, progressed after any of about 3, 6, 9 or 12 months after the start prior therapy). In some cases, prior therapy is gemcitabine-based therapy, erlotinib-based therapy or 5-FU-based therapy. In some modalities, the method does not include the administration of gemcitabine. In some embodiments, the method comprises the administration of gemcitabine together with the nanoparticle composition. In some modalities, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some embodiments, the method does not include the administration of an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor). In some embodiments, the taxane is pa- clitaxel. In some embodiments, albumin is human serum albumin. In some embodiments, the nanoparticles comprise paclitaxel coated with albumin. In some embodiments, the average particle size of the nanoparticles in the nanoparticle composition is no more than about 200 nm (for example, less than about 200 nm). In some embodiments, the composition comprises the formulation of paclitaxel stabilized on albumin nanoparticles (Nab-paclitaxel (which is used as a synonym for the term "ABRAXANE )). In some embodiments, the composition is Nab-paclitaxel (ABRAXANE ) In some modalities, a method of
treatment of pancreatic cancer in an individual who needs it, including administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the taxane is coated with albumin, in which the individual progressed when under prior therapy (such as gemcitabine-based therapy). In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the Average particle size of the U nanoparticles in the nanoparticle composition is not greater than about 200 nm (such as less than about 200 nm), in which the individual has progressed under gemcitabine therapy.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in that taxane is coated with albumin, where the average particle size of the nanoparticles in the nanoparticle composition is not greater than about 200 nm (such as less than about 200 nm), where the individual progressed under gemcitabine-based therapy.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administering to the individual an effective amount of a composition comprising Nab-paclitaxel, in which the individual has progressed under therapy based on gemcitabine.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual an effective amount of Nab-paclitaxel, in which the individual has progressed under therapy based on gemcitabine.
In some modalities, the method does not include the administration of gemcitabine.
In some embodiments, the method comprises the administration of gemcitabine together with the nanoparticle composition.
In some
but modalities, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some modalities, the method does not include the administration of an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor).
In some modalities, the composition is administered intravenously. In some embodiments, the composition is administered intra-arterially. In some embodiments, the composition is administered intraperitoneally.
In some embodiments, the serum levels of CA19-9 (carbohydrate antigen 19-9) in the individual administered composition i comprising nanoparticles comprising a taxane and an albu-. mine are reduced by at least about 50% (for example, at least 'about any 60%, 70%, 80%, 90%, 95%) compared to "the serum levels of CA19-9 before treatment.
In some modalities, a method of treating an individual having locally advanced dutch pancreatic carcinoma, non-resectable or metastatic, is provided in which the individual has progressed within 6 months (as within any one of about 5, 4, 3, 2, 1 month) of gemcitabine-based therapy, comprising administering (such as intravenously) to the individual, an effective amount of a composition comprising nanoparticles comprising albumin and a taxane (such as as nanoparticles that comprise albumin and paclitaxel, for example ABRAXANEGO). In some modalities, the nanoparticle composition is administered weekly in a dose of 100 maolm . In some modalities, administration is carried out three every four weeks.
Combined therapy methods for the treatment of pancreatic cancer are also provided. Thus, for example, in some modalities, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual (a) an effective amount of a composition comprising nanoparticles which comprise taxane and albumin and (b) an effective amount of another agent. In some modalities, the individual progressed when under prior therapy (for example, he progressed after anyone about 3, 6, 9, or 12 months after the initiation of prior therapy). In some modalities, prior therapy is therapy based on gemcitabine, therapy based on erlotinib or therapy based on 5-FU. In some embodiments, the nanoparticle composition and the other agent are administered simultaneously or sequentially. In some embodiments, the nanoparticle composition and the other agent are administered at the same time. In some embodiments, the taxane is paclitaxel. In some embodiments, taxane is docetaxel. In some embodiments, albumin is Ô human serum albumin. In some embodiments, nanoparticles 2 comprise albumin-coated paclitaxel. In some modalities, the average particle size of the nanoparticles in the nanoparticle composition is no more than about 200 nm. In some modalities, the composition comprises the paclitaxel formulation stabilized in albumin nanoparticles (Nab- paclitaxel (ABRAXANEG). In some embodiments, the composition is Nab-paclitaxel (ABRAXANEG). In some embodiments of any of the above modalities related to combination therapy, the other agent is not gemcitabine. In some embodiments, the other agent it is not a platinum-based agent (such as carboplatin or cisplatin) In some embodiments, the method does not comprise the administration of an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor).
In some modalities of any of the above modalities related to the combination therapy, the other agent is an antimetabolite agent, a tyrosine kinase inhibitor (eg, an EGFR inhibitor), a matrix metalloproteinase inhibitor, an inhibitor of topoisomerase, a proteasome inhibitor, a platinum-based agent, a therapeutic antibody, a farnesyl transferase inhibitor, an anti-angiogenic agent and a macrolide. In some embodiments, the other agent is Vandetanib, 5-fluororouracil, erlotinib, gefitnib, marimastat, irinotecan, tipifarnib, pemetrexed, exactecane, capecitabine, raltitrexed, cetuximab, bevacizumab, borteac-
mib, rapamycin or gemcitabine.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin and ( b) an effective amount of erlotinib, in which the individual has progressed on gemcitabine-based therapy.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it including administration to the individual of (a) an effective amount of a composition comprising nanoparticles comprising ta- "xane and albumin and (b) an effective amount of a VEGFR2 and EGFR inhibitor (hereinafter referred to as the "VEGFR / EGFR inhibitor").: In some embodiments, a method of treating pancreatic cancer in an individual is provided which needs the same comprising administering, to the individual, (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin and (b) an effective amount of Vandetanib. In some embodiments, the individual has not been previously treated pancreatic cancer. In some modalities, the individual was previously treated for pancreatic cancer. In some modalities, the individual was unsuccessful with gemcitabine-based therapy. Pancreatic diseases that can be treated with the methods described in the present invention include, but are not limited to, exocrine pancreatic cancers and endocrine pancreatic cancers. Exocrine pancreatic cancers include, but are not limited to, adenocarcinomas, acinar cell carcinomas, adenosquamous carcinomas, colloid carcinomas, undifferentiated osteoclast-like giant cells, hepatoid carcinoma, intraduate papillary mucous neoplasms, cystic neoplasms, pancreatoblastomas, serous cystadenomas, ring cell carcinomas, solid and pseudopapillary tumors, dutch pancreatic carcinomas and undifferentiated carcinoma. In some modalities
exocrine pancreatic cancer is dutch pancreatic carcinoma.
Endocrine pancreatic cancers include, but are not limited to, insulinomas and glucagon.
In some modalities, pancreatic cancer is any form of early-stage pancreatic cancer, non-metastatic pancreatic cancer, primary pancreatic cancer, pancreatic cancer that has undergone resection, advanced pancreatic cancer, locally advanced pancreatic cancer, metastatic pancreatic cancer, non-passable pancreatic cancer resection, pancreatic cancer in remission, recurrent pancreatic cancer, pancreatic cancer in an adjuvant context or pancreatic cancer in a neoadjuvant environment. In some modalities, pancreatic cancer is locally advanced and pancreatic cancer, pancreatic cancer that is not amenable to resection, or metastatic dutch pancreatic carcinoma. In some modalities, pancreatic cancer is resistant to gemcitabine-based therapy. In some modalities, pancreatic cancer is refractory to gemcitabine-based therapy.
The methods described here can be used for any one or more of the following purposes: relief of one or more symptoms of pancreatic cancer, delayed progression of pancreatic cancer, decrease in size of the pancreatic cancer tumor, interruption (such as destruction) of pancreatic cancer stroma, inhibition of pancreatic cancer tumor growth, prolongation of overall survival, prolongation of disease-free survival, prolongation of time for progression of | in pancreatic cancer, prevention or delay of tumor metastasis 25. pancreatic cancer, reduction (such as eradication) of pre-existing pancreatic cancer tumor metastasis, reduction of the incidence or burden of pre-existing pancreatic cancer tumor metastasis, prevention of pancreatic cancer recurrence and / or enhancement of clinical benefit pancreatic cancer.
Compositions (such as pharmaceutical compositions), medicaments, kits and unit dosages useful for the methods described herein are also provided.
Here, methods of treating pancreatic cancer are provided in an individual who needs it comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the individual progressed under gemcitabine-based therapy.
In some modalities, the progression is within less than about 12 months.
In some embodiments, gemcitabine-based therapy still comprises erlotinib.
In some modalities, gemcitabine-based therapy is monotherapy.
Methods for treating resistant or refractory pancreatic cancer are provided here in an individual who needs the same not comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin.
In some embodiments, prior therapy has been discontinued for at least 6 months when an effective amount of a composition comprising - nanoparticles comprising a taxane and albumin is administered to the individual.
In some embodiments, prior therapy is gemcitabine-based therapy.
In some embodiments, gemcitabine-based therapy still comprises deerlotinib.
In some modalities, gemcitabine-based therapy is monotherapy.
Methods of treating recurrent pancreatic cancer in an individual who need it are provided here comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin.
In some embodiments, prior therapy has been interrupted for at least 6 months when administration of an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin to the subject begins.
In some modalities, prior therapy is a therapy based on gemcitabine.
In some modalities, gemcitabine-based therapy still comprises erlotinib.
In some modalities, gemcitabine-based therapy is monotherapy.
Methods are provided here for treating pancreatic cancer in an individual who needs it comprising administering, to the individual, (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin and (b) an effective amount of another agent, in which the individual has progressed on gemcitabine-based therapy. In some embodiments, the nanoparticle composition and the other agent are administered simultaneously or sequentially. In some embodiments, the nanoparticle composition and the other agent are administered at the same time. In some modalities, the other agent is selected from the group consisting of 5-fluoro- 'ruracil, erlotinib, gefitnib, marimastat, irinotecan, tipifarnib, pemetrexed, in exactecane, capecitabine, raltitrexed, cetuximab, bevacizumab, rap, bortezizibiz, rap, vandetanib and gemcitabine.
'Methods of treating pancreatic cancer in an individual who need it are provided here comprising administering, to the individual, (a) an effective amount of a composition comprising - nanoparticles comprising a taxane and an albumin and (b) an effective amount of vandetanib. In some embodiments, the nanoparticle composition and vandetanib are administered simultaneously or sequentially. In some modalities, the nanoparticle composition and vandetanib are administered concomitantly. In any of the modalities described here, pancreatic cancer is exocrine pancreatic cancer or endocrine pancreatic cancer. In any of the modalities described here, exocrine pancreatic cancer is dutch pancreatic carcinoma. In any of the modalities described here, pancreatic cancer is locally advanced pancreatic cancer, pancreatic cancer that cannot be resected, or metastatic dutch pancreatic carcinoma. In any of the embodiments described herein, the composition comprising nanoparticles comprising taxane and albumin is administered parenterally. In any of the modalities described here, the composition comprising nanoparticles comprising taxane and albumin is administered intravenously or intraarterially.
mind. In any of the embodiments described here, the taxane is paclibutable. In any of the embodiments described here, the nanoparticles in the composition have an average diameter of no more than about 200 nm. In any of the embodiments described here, the nanoparticles in the composition have an average diameter of less than about 200 nm. In any of the modalities described here, the taxane in the nanoparticles is coated with albumin. In any of the modalities described here, the individual is a human being. In any of the modalities described here, the serum levels of CA19-9 (carbohydrate antigen 19-9) in the individual are reduced by at least about 50% compared to the serum levels of CA19-9 before treatment. “These and other aspects and advantages of the present invention will become apparent from the subsequent detailed description and the appended claims. It is to be understood that one, some or all of the properties of the various embodiments described herein can be combined to form other embodiments of the present invention. - BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the early response, in a target lesion, to the baseline level and after 2 treatment cycles with a paclitaxel formulation stabilized in albumin nanoparticles (eg Nab-paclitaxel) . Figure 2 is a Kaplan-Meier curve showing progression-free survival (figure 2A) and overall survival (figure 2B) after Nab-paclitaxel treatments in patients with stage pancreatic cancer |! | and IV. Figure 3 is a correlation between SPARC (Secreted Protein Rich in Cysteine), IHC (Immunohistochemistry - Immunohistochemistry) and PFS (Progression-Free Survival). SD: Stable disease; PR: Partial response. Figure 4 is a SPARC immunohistochemistry of two different patients with pancreatic cancer.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides methods and compositions for the treatment of pancreatic cancer (such as advanced pancreatic cancer) in a subject as a second-line treatment (for example, an individual who has previously been treated for pancreatic cancer) measured before administering a composition comprising nanoparticles comprising a taxane and an albumin. The method can be monotherapy or combination therapy.
In a phase | l clinical trial in a population of patients with locally advanced, nonresponsive or metastatic pancreatic carcinoma that progressed under gemcitabine-based therapy, a nanoparticle-stabilized paclitaxel formulation was found to] albumin, namely Nab-paclitaxel, conferred clinical benefit (partial response 2 or stabilization of the disease) in about 37% of treated patients and about 21% of patients remained on therapy for at least 6 months. Serum CA19-9 levels were also found to decrease by about 52% in patients who had stable disease or a partial response compared to a decrease of about 18% in - patients with progressive disease.
In one aspect, a method of treating pancreatic cancer (such as advanced pancreatic cancer) is provided in an individual who is needed even though administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the individual was previously treated for pancreatic cancer.
In another aspect, a method of treating pancreatic cancer (such as advanced pancreatic cancer) is provided in an individual who needs it comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin and (b) an effective amount of another agent, in which the individual was previously treated for pancreatic cancer.
In another aspect, a method of treating pancreatic cancer (such as advanced pancreatic cancer) is provided in an individual who needs it comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin and (b) an effective amount of van-detanib. In some modalities, the individual was previously treated for pancreatic cancer. In some modalities, the individual was not previously treated for pancreatic cancer.
Compositions (such as pharmaceutical compositions), medicaments, kits and unit dosages useful for the methods described herein are also provided.
Definitions: Á As used here, "treatment" or "treating" is an approach 2 to obtain beneficial or desired results, including clinical results. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: relief of more symptoms resulting from the disease, decrease in the extent of the disease, stabilization of the disease (for example, prevention or delay of disease), prevention or delay of spread (for example, metastasis) of the disease, prevention or delay of disease recurrence, prevention or delay of disease progression, improvement of disease status, remission (partial or total) of the disease, reduction of the dose of one or more other medications necessary to treat the disease, delay in the progression of the disease, increase or improvement in quality of life, increase in weight gain and / or prolongation of survival. Also covered by "treatment" is a reduction in the pathological consequence of pancreatic cancer. The methods of the present invention consider any or more of these aspects of treatment. | The term "individual" refers to a mammal and includes, but is not limited to, humans, horses, cattle, felines, rodents, canines or primates.
"Prior therapy" used here refers to a therapeutic regimen - which is different from and was instituted before the methods of administering the nanoparticle compositions. Prior therapy, in general, but not necessary
it does not necessarily involve administering the composition to taxane nanoparticles.
It should be understood that prior therapy may involve some (s) of the same therapeutic agent (s) as the methods described herein.
As used herein, an "at risk" individual is an individual who is at risk of developing pancreatic cancer.
An "at risk" individual may or may not have a detectable disease and may or may not have a detectable disease exhibited before the treatment methods described here. "At risk" denotes that an individual has one or more of the so-called risk factors, which are measurable parameters that correlate with the development of pancreatic cancer, which are described here.
An individual having one or more of these factors. risk factors are more likely to .. develop cancer than an individual without these risk factors. "Adjuvant environment" refers to a clinical environment in which: an individual has had a history of pancreatic cancer and has generally (but not necessarily) been responsive to therapy which includes, but is not limited to, surgery (for example, resection surgery), radiotherapy and chemotherapy.
However, because of their history of pancreatic cancer, these individuals are considered to be at risk of developing the disease.
Treatment or administration in an "adjuvant environment" refers to a subsequent mode of treatment.
The degree of risk (for example, when an individual in the adjuvant environment is considered to be "high risk" or "low risk") depends on several factors, most usually the extent of the disease when first treated. "Neoadjuvant environment" refers to a clinical environment in —which method is performed before primary / definitive therapy.
As used here, "delay" in the development of pancreatic cancer means to postpone, prevent, reduce, delay, stabilize and / or postpone the development of the disease.
This delay can be for different periods of time, depending on the history of the disease and / or the individual being treated.
As is evident to those versed in the field, a sufficient or significant delay can, in effect, include prevention because the individual does not develop the disease.
A method that "slows down"
development of pancreatic cancer is a method that reduces the likelihood of disease development in a certain period of time and / or reduces the extent of the disease in a certain period of time when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of individuals. The development of pancreatic cancer can be detectable using standard methods including, but not limited to, computed tomography (CT Scan, for example, helical spiral CT), endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP) , laparoscopy or biopsy (for example, percutaneous needle biopsy or fine needle aspiration). Development may also refer to the progression of pancreatic cancer that can be initially detected and includes recurrence.
: As used herein, by "combination therapy" is meant that a first agent is administered in conjunction with another agent. "In conjunction with" refers to the administration of one treatment modality - in addition to another treatment modality, such as the administration of one. nanoparticle composition described herein in addition to the administration of another agent to the same individual. As such, "together with" refers to the administration of one treatment modality before, during or after the distribution of the other treatment modality to the individual.
The term "effective amount", as used herein, refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease, such as relief, palliation, decrease and / or delay one or more of your symptoms. In reference to pancreatic cancer, an effective amount comprises an amount sufficient to cause a tumor to slow and / or to slow the growth rate of the tumor (such as to suppress tumor growth) or prevent or delay the proliferation of other unwanted cells in pancreatic cancer. In some embodiments, an effective amount is an amount sufficient to delay the development of pancreatic cancer. In some embodiments, an effective amount is a quantity greater than
sufficient to prevent or delay recurrence. An effective amount can be administered in one or more administrations. In the case of pancreatic cancer, the effective amount of the drug or composition can: (i) reduce the number of pancreatic cancer cells; (ii) reducing the size of the tube; (iii) inhibit, delay, reduce to a certain extent and, preferably, stop the infiltration of pancreatic cancer cells in peripheral organs; (iv) inhibit (that is, reduce to some extent and, preferably, cease) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay the occurrence and / or recurrence of a tumor; (vii) relieving, to some extent, one or more of the symptoms associated with pancreatic cancer; and / or (viii) interrupting (such as destroying) the pancreatic cancer stroma.
Cs The term "simultaneous administration", as used here, means that a first therapy and a second therapy in a combined therapy are administered with an interval of no more than about 15 minutes, such as no more than about any of 10, 5 or 1 minute. When the first and second therapies are administered simultaneously, the first and second therapies can be contained in the same composition (for example, a composition comprising the first and second therapies) or in separate compositions (for example, a first therapy in one composition and a second therapy is contained in another composition).
As used here, the term "sequential administration" means that the first therapy and the second therapy in a combined therapy are administered with an interval of more than about 15 minutes, such as about any of 20, 30, 40, 50, 60 or more minutes. Both the first therapy and the second therapy can be administered first. The first and second therapies are contained in separate compositions, which can be contained in the same or different packages or kits.
As used here, the term "concurrent administration" means that the administration of the first therapy and that of a second therapy in a combination therapy overlap each other.
As used herein, by "pharmaceutically acceptable" or "pharmacologically compatible" is meant a material that is not biologically or otherwise undesirable, for example, the material can be incorporated into a pharmaceutical composition administered to a patient without causing any harm. significant or inter-biological undesirable effects. rotate in a deleterious way with any of the other components of the composition in which it is contained. Pharmaceutically acceptable vehicles or excipients should preferably meet the required toxicological testing and manufacturing standards and / or be included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
It should be understood that the aspects and modalities of the invention "as described in the present invention include aspects and modalities" that consist of "and / or" that consist essentially of ".
'Reference to "about" a value or parameter includes (and describes) variations that are directed at that value or parameter per se. For example- Description, description of "about X" includes description of "X".
- As used herein and in the appended claims, the forms in the singular "one", "one", "o" and "a" include references in the plural, unless the context clearly indicates otherwise.
Where aspects or modalities of the invention are described in terms of a Markush group or other grouping of alternatives, the present invention encompasses not only the entire group listed as a whole, but each individual group member and all possible subgroups of the main group, but also the main group without one or more of the group members. The present invention also provides for the express exclusion of one or more of any of the group members in the claimed invention.
Pancreatic Cancer Treatment Methods The invention provides methods of treating pancreatic cancer (such as advanced pancreatic cancer) in an individual (for example, human) that comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the subject has previously been treated for pancreatic cancer (also referred to as "prior therapy").
The present invention also provides methods of treating pancreatic cancer (such as advanced pancreatic cancer) in an individual (e.g., human) that comprises administering to the individual a) an effective amount of a composition comprising nanoparticles that comprise a taxane and albumin and b) an effective amount of another agent, in which the individual has previously been treated for pancreatic cancer. ] It should be understood that reference to and description of the methods or treatment of pancreatic cancer below is exemplary and that the present description applies equally to and includes methods for the treatment of pancreatic cancer using combination therapy. In addition, although the description below describes individuals who have progressed when under prior therapy (for example, gemcitabine based therapy) as - exemplary modalities, it should be understood that the present description also applies to individuals who are resistant or refractory previous therapy, individuals who are not suitable to continue with previous therapy (for example, due to a lack of response and / or because of toxicity), individuals who have recurrent pancreatic disease after previous therapy, individuals who do not respond to previous therapy, individuals who require a less desirable degree of responsiveness and / or individuals who require an enhanced responsiveness. As used here, responsiveness can be determined by levels of CA19-9, RECIST, computed tomography, biopsy, immunohistochemistry and the like. The methods described in the present invention include all second-line therapies for the treatment of pancreatic cancers that involve the administration of a composition comprising nanoparticles comprising albumin and ataxane. The methods described herein also include all third-line therapies for the treatment of pancreatic cancers that involve the administration of a composition comprising albumin nanoparticles and which comprise a taxane.
In some modalities, the individual progressed under prior therapy at the time of treatment. For example, the individual has progressed within any one of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months when treating with prior therapy. In some modalities, the individual is resistant or refractory to previous therapy. In some modalities, the individual is not suitable to continue with previous therapy (for example, due to a lack of response and / or due to toxicity). In some modalities, the individual failed to respond to previous therapy. In some modalities, the individual is unresponsive to prior therapy. In some modalities, the individual is partially responsive to previous therapy. In some modalities, the individual exhibits a less desirable degree of responsiveness. In some modalities, the individual has an intensified responsibility. In some modalities, the individual has recurrent pancreatic cancer, that is, the individual is initially responsive to treatment with previous therapy, but develops pancreatic cancer after about "anyone of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months when interrupting previous therapy.
In some embodiments, prior therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6.7, 8, 9 or 10 months) when the methods of the present invention are started. In some modalities, previous therapy was not interrupted when the methods of the present invention were started.
In some modalities, the method still comprises a step of selecting patients for treatment. For example, in some embodiments, a method of treating pancreatic cancer is provided in an individual who has been treated with prior therapy, the method comprising: a) determining whether the individual has progressed under previous therapy (eg, gemcitabine-based therapy); and b) administering an effective amount of a composition comprising nanoparticles comprising albumin and a taxane to the individual. In some modalities, a method of treating pancreatic cancer is provided in an individual who has been treated with prior therapy, the method comprising: a) selecting the individual who is unresponsive to prior therapy (such as therapy based on gemcitabine); and b) administering an effective amount of a composition comprising nanoparticles comprising albumin and a taxane to the individual.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who has been treated with prior therapy (such as gemcitabine-based therapy), the method comprising administering an effective amount of a composition comprising nanoparticles comprising albumin and a taxane to the subject, wherein said subject is selected for treatment based on determining whether the subject has progressed during prior therapy.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who has been treated with prior therapy (such as gemcitabine based therapy), the method comprising administering an effective amount of a composition comprising nanoparticles that - comprise albumin and a taxane to the individual, in which said individual is selected based on non-responsiveness to previous therapy.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who has been treated with prior therapy (such as gemcitabine-based therapy), the method comprising: a) determining whether the individual is suitable for the continued treatment with previous therapy (for example, due to lack of responsiveness and / or toxicity); and b) administering an effective amount of a composition comprising nanoparticles comprising albumin and a taxane to the individual.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who has been treated with prior therapy (such as gemcitabine based therapy), the method comprising administering an effective amount of a composition comprising nanoparticles comprising albumin and a taxane to the individual, wherein said individual is selected based on the determination of whether the individual is unsuitable
for continuous treatment with previous therapy (for example, due to lack of responsiveness and / or toxicity). An individual may also be unsuitable for ongoing treatment with prior therapy if the individual has less than desirable responsiveness or has undesirable symptoms associated with prior therapy.
In some modalities, a method of treating pancreatic cancer is provided in an individual who has been treated with prior therapy, the method comprising: a) determining whether the individual is resistant or refractory to previous therapy (for example, gemcitabine therapy); and b) administering an effective amount of a composition comprising nanoparticles comprising albumin and a taxane to the individual. In some embodiments, a method of treating pancreatic cancer is provided to an individual who has been: treated with prior therapy , the method comprising administering an effective amount of a composition comprising nanoparticles comprising albumin and a taxane to the individual, wherein said individual is selected based on the determination of whether the individual is resistant or refractory to prior therapy (for example, gemcitabin-based therapy) In some embodiments, the method does not include the administration of an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor).
In some modalities, prior therapy comprises administration of gemcitabine ("gemcitabine-based therapy"). In some modalities, previous therapy is monotherapy with gemcitabine. In some modalities, prior therapy includes the administration of gemcitabine and erlotinib. In some modalities, prior therapy includes the administration of gemcitabine and capecitabine. In some embodiments, prior therapy includes the administration of gemcitabine and 5-FU. In some embodiments, prior therapy comprises administration of gemcitabine, erlotinib, capecitabine and / or 5-FU. In some modalities, prior therapy is adjuvant therapy with gemcitabine. In some modalities, prior therapy is neoadjuvant therapy with gemcitabine. In some modalities, prior therapy comprises surgery.
In some embodiments, the method described herein comprises administering the taxane nanoparticle composition together with one or more of the same agent (s) used in the prior therapy. In some embodiments, the method described herein comprises administering the taxane nanoparticle composition in conjunction with the agent (s) that is not used in the prior therapy.
In some embodiments, the method comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, wherein the taxane in the nanoparticles is coated with albumin, in which the individual has progressed when on therapy previous (for example, progressed after any E of about 3, 6, 9 or 12 months when starting previous therapy). In some embodiments, prior therapy is gemcite-based therapy, erlotinib based therapy or 5-FU based therapy. In some embodiments, the method does not include administration of gemcitabine. Ã In some embodiments, the method comprises administration of gemcibacterine in conjunction with the nanoparticle composition. In some modalities, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some embodiments, the taxane is paclitaxel. In some embodiments, albumin is human serum albumin. In some embodiments, the nanoparticles comprise albumin-coated paclitaxel. In some modalities, size. particle average of the nanoparticles in the nanoparticle composition is no more than about 200 nm (for example, less than about 200 nm). In some embodiments, the composition comprises the formulation of paclitaxel stabilized on albumin nanoparticles (Nab-paclitaxel (A-BRAXANES)). In some embodiments, the composition is Nab-paclitaxel (A-BRAXANES). In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the method comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the taxane in the nanoparticles is coated with albumin and in which the individual is resistant or refractory to a previous therapy. In some embodiments, prior therapy is therapy based on gemcitabine, therapy based on emerlkotinibou therapy based on 5-FU. In some modalities, the method does not include administration of gemcitabine. In some modalities, the method comprises administration of gemcitabine together with the nanoparticle composition. In some embodiments, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some embodiments, the taxane is paclitaxel. In some embodiments, albumin is human serum albumin. In some NC modalities, nanoparticles comprise albumin-coated paclitaxel. In some embodiments, the average particle size of the nanoparticles in the nanoparticle composition is no more than about 200 nm (for example, less than about 200 nm). In some modes, the composition comprises the formulation of stabilized paclitaxel and albumin nanoparticles (Nab-paclitaxel (ABRAXANEG)). In some embodiments, the composition is Nab-paclitaxel (ABRAXANEG). In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the method comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, wherein the. taxane in nanoparticles is coated with albumin and in which the individual has failed to respond to previous therapy. In some modalities, prior therapy is gemcitabine-based therapy, erlotinib-based therapy or 5-FU-based therapy. In some embodiments, the method does not include administration of gemcitabine. In some embodiments, the method comprises administration of gemcitabine in conjunction with the nanoparticle composition. In some embodiments, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some embodiments, the taxane is paclitaxel. In some embodiments, albumin is human serum albumin.
In some modalities, nanoparticles comprise albumin-coated paclitaxel.
In some embodiments, the average particle size of the nanoparticles in the nanoparticle composition is no more than about 200 nm (for example, less than about 200 nm). In some embodiments, the composition comprises the formulation of paclitaxel stabilized in nanoparticles of albumin (Nab-paclitaxel (ABRAXANEG)). In some modes, the composition is Nab-paclitaxel (ABRAXANEG). In some ways, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer. ] In some embodiments, the method comprises administering, "to the individual, an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the 'taxane in the nanoparticles is coated with albumin and in which the individual exhibits a less desirable degree of responsiveness to prior therapy.
In some modalities, prior therapy is therapy based on gemcitabine, therapy based on erlotinib or therapy based on 5-FU.
In some embodiments, the method does not include administration of gemcitabine.
In some embodiments, the method comprises administration of gemcibine in conjunction with the nanoparticle composition.
In some modalities, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some embodiments, the taxane is paclitaxel.
In some embodiments, albumin is human serum albumin.
In some embodiments, the nanoparticles comprise albumin-coated paclitaxel.
In some embodiments, the average particle size of the nanoparticles in the nanoparticle composition is no more than about 200 nm (for example, less than about 200: nm). In some embodiments, the composition comprises the formulation of paclitaxel stabilized on albumin nanoparticles (Nab-paclitaxel (A- —BRAXANEÔ)). In some embodiments, the composition is Nab-paclitaxel (A-BRAXANE9). In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has pancreatic cancer
primary tactic.
In some embodiments, the method comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, where the taxane in the nanoparticles is coated with albumin and in which the individual has recurrent pancreatic cancer (for example, example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5,6,7,8, 9, 10, 11, 12, 24 or 36 months when previous therapy is stopped). In some embodiments, prior therapy is therapy based on gemcitazine, therapy based on erlotinib or therapy based on 5-FU. In some modalities, the method does not include administration of gemcitabine. "o In some embodiments, the method comprises administration of gemcibacterine in conjunction with the nanoparticle composition. In some modalities, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some embodiments, the taxane is paclitaxel In some embodiments, the albumin is human serum albumin In some embodiments, the nanoparticles comprise the albumin-coated pacilitaxel In some embodiments, the average particle size of the nanoparticles in the nanoparticle composition is no more than about 200 nm (for example, less than about 200 nm). In some embodiments, the composition comprises the formulation of paclitaxel stabilized on albumin nanoparticles (Nab-paclitaxel (A-BRAXANEG)). the composition is Nab-paclitaxel (ABRAXANEO) .In some modalities, the individual has pancreatic cancer metastatic. In some modalities, the individual has pancreatic cancer primary.
In some embodiments, the method comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the taxane in the nanoparticles is coated with albumin and in which previous therapy has been discontinued (for example , for at least 1, 2, 3, 4, 5, 6,7, 8, 9 or 10 months) when the administration of the effective amount of the composition comprising nanoparticles comprising a taxane and an albumin to the subject begins. In some embodiments, prior therapy is gemcitabine-based therapy, erlotinib-based therapy or 5-FU-based therapy. In some modalities, the method does not include gemcitabine administration. In some embodiments, the method comprises administering gemcitabine together with the nanoparticle composition. In some embodiments, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some embodiments, the taxane is paclitaxel. In some modalities, albumin is human serum albumin. In some embodiments, the nanoparticles comprise albumin-coated paclitaxel. In some embodiments, the average particle size of the nanoparticles in the nanoparticle composition is no more than about 200 nm (for example, less than about 200 nm). In some embodiments, the composition comprises the formulation of paclitaxel stabilized on albumin nanoparticles (Nab-paclitaxel (ABRAXANEG)). In some modalities, the composition is Nab-paclitaxel (ABRAXANEG). In some modalities, the individual has non-metastatic pancreatic cancer. In some ways, the individual has primary pancreatic cancer.
In some embodiments, the method comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the taxane is coated with albumin, in which the individual has progressed when under prior therapy (for example, gemcitabine-based therapy). In some cases, a method of treating pancreatic cancer is provided in an individual who needs it including ad- | administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, wherein the average particle size of the nanoparticles in the nanoparticle composition is not greater than about 200 nm (such as less than about 200 nm), in which the individual progressed under gemcitabine therapy. In some modalities, a method is provided
treatment of pancreatic cancer in an individual who needs it including administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the taxane is coated with albumin , where the average particle size of the nanoparticles in the nanoparticle composition is not greater than about 200 nm (for example, less than about 200 nm), in which the individual progressed under gemcitabine-based therapy. In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administering to the individual an effective amount of a composition comprising Nab-paclitaxel, in which the individual is duo progressed under gemcitabine-based therapy. In some modalities, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual an effective amount of Nab-paclitaxel, in which the individual has progressed under gemcitabine therapy . In some embodiments, - the method does not include administration of gemcitabine. In some modalities, the method comprises administration of gemcitabine in conjunction with the nanoparticle composition. In some embodiments, the method did not include administration of a platinum-based agent (such as carboplatin or cisplatin). In some modalities, the method does not comprise administration of an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor). In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the method comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the taxane is coated with albumin and in which the individual is resistant or refractory to a previous therapy (eg gemcitabine-based therapy). In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the size particle mean of the nanoparticles in the nanoparticle composition is not greater than about 200 nm (such as me- in the 200-nm range), in which the individual is resistant or refractory to previous therapy (such as therapy based on gemcitabine). In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in] that the taxane is coated with albumin, where the average nanoparticle particle size in the nanoparticle composition is not greater than about 200 nm (for example, less than about 200 nm), in Í that the individual is resistant or refractory to previous therapy (such as therapy based on gemcitabine). In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs the same comprising administering to the individual an effective amount of a composition comprising Nab-paclitaxel, wherein the individual is resistant or refractory to previous therapy (eg gemcitabine based therapy). In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual an effective amount of Nab-paclitaxel, in which the individual is resistant or refractory to previous therapy. (for example, gemcitabine-based therapy). In some modalities, the method does not include administration of gemcibacterine.
In some embodiments, the method comprises administering gemcitabine together with the nanoparticle composition.
In some embodiments, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some modalities, the method does not include administration of an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor). In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities
the individual has primary pancreatic cancer.
In some embodiments, the method comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the taxane is coated with albumin and in which the individual has failed to respond to previous therapy (such as o gemcitabine based therapy). In some embodiments, a cancer treatment method is provided - pancreatic in an individual who needs it comprising administering, to the individual, an effective amount of a composition comprising nanoparticles comprising a taxane and an albu-] mine, in which the average particle size of the nanoparticles in the nanoparticle composition is not greater than about 200 nm (such as less than about 200 nm), in which the individual has failed to respond to an IS therapy prior (such as gemcitabine-based therapy). In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administering, to the individual, an effective amount of a composition comprising nanoparticles comprising a taxane and a albumin, where the taxane is coated with albumin, where the average size of nanoparticle particles in the nanoparticle composition is not greater than about 200 nm (for example, less than about 200 nm), where the individual has failed to respond to previous therapy (such as gemcitabine based therapy) .In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs — even comprising administering to the individual an amount of effectiveness of a composition comprising Nab-paclitaxel, in which the individual has failed to respond to a previous therapy (such as gemcitabine-based therapy). In some embodiments, a method is provided whole treatment of pancreatic cancer in an individual who needs it including administration to the individual of an effective amount of Nab-paclitaxel, in which the individual has failed to respond to previous therapy (such as gemcitabine based therapy). In some embodiments, the method does not include administration of gemcitabine.
In some modes, the method comprises administration of gemcitabine in conjunction with the nanoparticle composition.
In some embodiments, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some modalities, the method does not comprise administration of an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor). In some modalities, the individual has pancreatic cancer. non-metastatic.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the method comprises administering, to the individual, an effective amount of a composition comprising E nanoparticles comprising a taxane and an albumin, in which the taxane is coated with albumin and in which the individual has pancreatic cancer. recurrent (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5.6, 7, 8, 9, 10, 11, 12, 24 or  36 months from interruption therapy based on gemcitabine. In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the size average particle size of the nanoparticles in the nanoparticle composition is not greater than about 200 nm (such as less than about 200 nm), in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer a- —Percent of anyone of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months when gemcitabine-based therapy is discontinued). In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, wherein the taxane is is coated with albumin, where the average particle size of the nanoparticles in the nanoparticle composition is not greater than about 200 nm (for example, less than about 200 nm), in which the individual has pancreatic cancer recurrent (for example, the individual develops pancreatic cancer after about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months after interruption - —addition of therapy based on gemcitabine). In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual an effective amount of a composition comprising Nab-paclitaxel, in which the individual has recurrent pancreatic cancer ( for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months from the start disruption of gemcitabine-based therapy). In some modalities, a method of treating pancreatic cancer in. an individual who needs it including administering to the individual an effective amount of Nab-paclitaxel, in which individual f has recurrent pancreatic cancer (for example, the individual develops - pancreatic cancer after about any of about 2 , 3, 4,5,6,7,8, 9, 10, 11, 12, 24 or 36 months after the interruption of gemcitabine therapy). In some embodiments, the method comprises administration of gemcitabine in conjunction with the nanoparticle composition. In some embodiments, the method does not include the administration of a platinum-based agent (such as carboplatin or cisplatin). In some modalities, the method does not include administration of an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor). In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the method comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the taxane is coated with albumin and in which a prior therapy (for example, a therapy based on gemcitabine) has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when the effective amount of the composition comprising comprise a taxane and albumin to the individual.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, wherein the average particle size of the nanoparticles in the nanoparticle composition is not greater than about 200 nm (such as less than about 200 nm), in which a previous therapy (for example, a therapy based on gemcitabine) has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when administration of the effective amount of the composition comprising nanoparticles comprising a taxane and albumin to the individual.
In some fashion, a method of treating pancreatic cancer is provided in an individual who needs the same comprising administering to the individual an effective amount of a composition comprising - nanoparticles comprising a taxane and an albumin, wherein taxane is coated with albumin, where the average particle size of the nanoparticles in the nanoparticle composition is not greater than about 200 nm (for example, less than about 200 nm), in which a previous therapy (for example example, a gemcitabine based therapy) was stopped (for example, for at least 1, 2, 3, 4, 5.6, 7, 8, 9 or 10 * - months) when the effective amount of composition comprising nanoparticles comprising a taxane and an albumin to the individual.
In some embodiments, a method of treating pancreatic cancer is provided to an individual who needs it, including administering to the individual an effective amount of a composition comprising Nab-paclitaxel, in which a prior therapy (for example, example, gemcitabine-based therapy) was interrupted (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when effective amount of the composition comprising nanoparticles comprising a taxane and an albumin
mine to the individual.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it even comprising administering to the individual an effective amount of Nab-paclitaxel, in which prior therapy (for example, therapy with gemcitabine base) has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6.7, 8, 9 or 10 months) when the administration of the: effective amount of the composition comprising nanoparticles that comprise a taxane and albumin to the individual.
In some modalities, the method does not include administration of gemcitabine.
In some embodiments, the method comprises administration of gemcitabine in conjunction with the nanoparticle composition.
In some embodiments, the "method does not include administration of a platinum-based agent (such as carboplatin or cisplatin). In some embodiments, the method does not include administration of an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor). In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has - primary pancreatic cancer.
In some embodiments, the serum levels of CA 19-9 in the individual to whom the composition of the present invention was administered decrease significantly.
In some embodiments, serum levels of CA 19-9 in the individual administered the composition comprising nanoparticles comprising a taxane and an albumin are reduced by at least about 20% (including, for example, at least about any of 20%, 30%, 40%, 50%, 52%, 53%, 55%, 57%, 59%, 60%, 70%, 80%, 90%, 95% or 100%) in comparison with serum levels of CA 19-9 before treatment.
In some embodiments, serum CA 19-9 levels in the individual administered the composition comprising nanoparticles comprising a taxane and albumin are reduced by at least about 50% compared to serum CA 19-9 levels prior to treatment .
In some embodiments, the method is for the treatment of an individual who has locally advanced dutch pancreatic carcinoma, not amenable to resection or metastatic, in which the individual has progressed within 6 months (as within any of about 5, 4 , 3, 2, 1 month) under gemcitabine based therapy comprising administering (such as intravenously) to the individual an effective amount of a composition comprising nanoparticles comprising albumin and a taxane (such as nanoparticles comprising al - bumina and paclitaxel, for example, ABRAXANE9). In some embodiments, the nanoparticle composition is administered weekly at a dose of 100 mg / m . In some modalities, administration is carried out three every four weeks.
Í In some modalities, pancreatic cancer is exocrine pancreatic cancer or endocrine pancreatic cancer.
Exocrine pancreatic cancer includes, but is not limited to, adenocarcinomas, carcinomas of inar cells, adenosquamous carcinomas, colloid carcinomas, non-differentiated carcinomas with giant cells similar to osteoclasts, hepatoid carcinoma, intraductal papillary mucous neoplasms, cystic neoplasms: cystic, pancreatoblastomas, serous cystadenomas, ring cell carcinomas, solid and pseudopapillary tumors, dutch pancreatic carcinomas and undifferentiated carcinoma.
In some modalities, exocrine pancreatic cancer is dutral pancreatic carcinoma.
Pancreatic endocrine cancer includes, but is not limited to, insulinomas and glucagon.
In some modalities, pancreatic cancer is early-stage pancreatic cancer, non-metastatic pancreatic cancer, primary pancreatic cancer, advanced pancreatic cancer, locally advanced pancreatic cancer, metastatic pancreatic cancer, non-resectable pancreatic cancer, cancer pancreatic remission or recurrent pancreatic cancer.
In some modalities, pancreatic cancer is locally advanced pancreatic cancer, nonresectable pancreatic cancer, or metastatic dutch pancreatic carcinoma.
In some modalities, pancreatic cancer is resistant to gemcitabine-based therapy.
In some modalities, pancreatic cancer is refractory to gemcitabine-based therapy. In some modalities, pancreatic cancer is amenable to resection (that is, tumors that are confined to a part of the pancreas or have already spread beyond it that allow complete surgical removal) or locally advanced (not amenable to resection) (ie, localized tumors may not be amenable to resection due to the impact or invasion of local vessels by the tumor). In some modalities, pancreatic cancer is, according to the American Joint Committee on Cancer (AJCC) TNM classifications, a tumor in stage O (the tumor is confined to the upper layers of cells of the pancreatic duct and has not invaded deeper tissue and has not spread outside the pancreas (eg, pancreatic carcinoma in situ or pancreatic intraepithelial neoplasia 11), ras a stage IA tumor (the tumor is confined to the pancreas and is less than 2 cm in size and that has not spread to lymph nodes or 'distinct sites', a tumor in stage IB (the tumor is confined to the pancreas are more than 2 cm in size and has not spread to nearby or distant lymph nodes) , a tumor in stage IIA (the tumor: it is growing outside the pancreas, but not in large blood vessels and has not spread to nearby or distant lymph nodes), tumor in stage! IB (the tumor is confined to the pancreas or is growing out of bread ncreas, but not in large nearby blood vessels or important nerves and has spread to nearby lymph nodes, but not distant sites) or stage III tumor (the tumor is growing outside the pancreas in large nearby blood vessels or important nerves and it may or may not have spread to nearby lymph nodes. It did not spread to distant sites) or stage IV tumor (the cancer spread to distant sites).
The methods provided here can be used to treat an individual (eg, human) who has been diagnosed with pancreatic cancer and has progressed when on prior therapy (eg, gemcitabine-based, erlotinib-based or based on 5-fluorouracil). In some modalities, the individual is resistant to treating pancreatic cancer with gemcitabine-based therapy (for example, gemcitabine monotherapy or combined therapy with gemcitabine) and has progressed after treatment (for example, pancreatic cancer was refractory ). In some modalities, the individual is initially responsive to treatment of pancreatic cancer with gemcitabine-based therapy (for example, gemcitabine monotherapy or gemcitabine combination therapy), but has progressed after treatment.
In some modalities, the individual is a human being.
In some embodiments, the individual is at least about anyone aged 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 or 85 years of age.
In some modalities, the individual has a family history of pancreatic cancer (for example, at least two first-degree relatives affected with pancreatic cancer, with no accumulation of other cancers or family diseases). In some modalities, the individual has one or more hereditary pancreatic cancer syndromes including, but not limited to, BRCA2 mutation, atypical soft familial multiple melanoma (FAMMM), Peutz-Jeghers syndrome and hereditary pancreatitis.
In some modalities, the individual is a long-term smoker (for example, - over 10, 15 or 20 years). In some modalities, the patient has diabetes starting in adulthood.
In some modalities, the individual is a man.
In some modalities, the individual is a woman.
In some modalities, the individual has early pancreatic cancer, non-metastatic pancreatic cancer, primary pancreatic cancer, pancreatic cancer that has undergone resection, advanced pancreatic cancer, pancreatic cancer -
locally advanced, metastatic pancreatic cancer, pancreatic cancer - not amenable to resection, pancreatic cancer in remission or recurrent pancreatic cancer.
In some modalities, the individual has pancreatic cancer in Stage 0, IA, IB, IA, IIB, Ill or IV according to the AJCC (American Joint Commission on Cancer) TNM classification criteria. In some modalities, the individual has an ECOG / WHO / Zubrod score of O (asymptomatic), 1 (symptomatic, but completely outpatient), 2 (symptomatic, <50% in bed during the day), 3 (symptomatic, > 50% in bed, but not confined to bed) or 4 (confined to bed). In some modalities, the individual has a single injury when presenting.
In some fashion-
the individual has multiple injuries when presenting. In some modalities, the individual is a human being who exhibits one or more symptoms associated with pancreatic cancer. In some N modalities, the individual is in an early stage of pancreatic cancer In some modalities, the individual is in an advanced stage of pancreatic cancer. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some modalities, the individual is genetically predisposed or otherwise (for example, having a risk factor) to the development of pancreatic cancer. These risk factors include, but are not limited to, age, sex, race, diet, previous history of “pancreatic cancer, presence of hereditary pancreatic cancer syndrome (eg, BRCA2, atypical soft familial multiple melanoma, 'Peutz syndrome -Jeghers, hereditary pancreatitis), genetic considerations (for example, familial pancreatic cancer) and environmental exposure. In some ways, individuals at risk for pancreatic cancer include, for example, - those who have at least two first-degree relatives who have had pancreatic cancer without accumulating other cancers or family diseases and those whose risk is determined by analyzing genetic or biochemical markers (for example, BRCA2, p16, STK11 / LKB1 or PRSS1 gene). In some embodiments, the individual is positive for SPARC expression (for example based on the IHC standard). In some modalities, the individual is negative for the expression of SPARC. The methods provided here can be practiced in an adjuvant environment. In some modalities, the method is practiced in a necadjuvant environment, that is, the method can be performed before primary / definitive therapy.
The methods described here are useful for various aspects of pancreatic cancer treatment. In some embodiments, a method is provided for inhibiting the proliferation of pancreatic cancer cells (such as pancreatic cancer tumor growth) in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the individual has progressed under gem-cytabine therapy. In some embodiments, at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of cell proliferation are inhibited. In some modes, taxane is paclitaxel. In some embodiments, taxane in the nanoparticle composition is administered through intravenous administration.
In some embodiments, a method of inhibiting pancreatic cancer tumor metastasis is provided in an individual comprising administering to the individual an effective amount of a ... composition comprising nanoparticles comprising a taxane and an albumin , in which the individual progressed under gem- 'citabine-based therapy. In some modalities, at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of metastases are inhibited. In. some modality-. However, a method of inhibiting metastasis to one or more lymph nodes is provided. In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered through intravenous administration.
In some embodiments, a method of inhibiting pancreatic cancer tumor metastasis in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and wherein the individual is resistant or refractory to gemcitabine-based therapy. In some modalities, at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of metastases are inhibited. In some embodiments, a method of inhibiting metastasis to one or more lymph nodes is provided. In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of inhibiting pancreatic cancer tumor metastasis in an individual is comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin in which the individual failed to respond to gemcitabine-based therapy. In some modalities, at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of metastases are inhibited. In some embodiments, a method of inhibiting metastasis to one or more lymph nodes is provided. In some embodiments, the taxane is] pacilitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration. | In some embodiments, a method of inhibiting pancreatic cancer tumor metastasis is provided in an individual comprising the administration, to the individual, of an effective amount of a composition comprising nanoparticles comprising a taxane and - an albumin and in which the individual exhibits a less desirable degree of responsiveness to gemcitabine-based therapy. In some modali- -.
At least about 10% (including, for example, at least about any 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of metastases are inhibited. In some embodiments, a method of inhibiting metastasis to one or more lymph nodes is provided. In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of inhibiting pancreatic cancer tumor metastasis in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and wherein the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months when interruption of gemcitabine-based therapy). In some modalities, at least about 10% (including, for example, at least about 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) metastases are inhibited. In some embodiments, a method of inhibiting: 5 - metastasis to one or more lymph nodes is provided. In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of inhibiting pancreatic cancer tumor metastasis is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and in that gemcitabine-based therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when administration of the quantity effectiveness of the composition comprising nanoparticles comprising a taxane and an albumin to the subject. In some modalities, at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of metastases are inhibited. In some embodiments, a method of inhibiting metastasis to one or more lymph nodes is provided. In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration. In some embodiments, a method of reducing (such as eradicating) preexisting pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the individual has progressed under emgemcitabine based therapy. In some modalities, at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of metastases are reduced. In some modalities, a metastasis reduction method for the lymph node is provided. In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of reducing (such as eradicating) preexisting pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and in which the individual is resistant or refractory to gemcitabine-based therapy. In some modalities, at least -. about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%; 70%, 80%, 90% or 100%) of metastases are reduced. In some modalities, a metastasis reduction method for the lymph node is provided. In some embodiments, the taxane is Á paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of reducing (such as eradicating) preexisting pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and in which the individual has failed to respond to gemcitabine-based therapy. In some modalities, at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of metastases are reduced .
In some modalities, a metastasis reduction method for the lymph node is provided. In some embodiments, the taxane is paclitic. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of reducing (such as eradicating) preexisting pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and in which the individual exhibits a less desirable degree of responsiveness to gemcitabine based therapy.
In some modalities, at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of metastases are reduced.
In some modalities, a metastasis reduction method for the lymph node is provided.
In some embodiments, the taxane is paclitaxel.
In some embodiments, the taxane in the nanoparticle composition is administered via intravenous Fm administration.
In some embodiments, at least about 10% (including, for example, at least about 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of metastases are reduced.
In some modalities, a metastasis reduction method for the lymph node is provided.
In some embodiments, the taxane is paclitaxel.
In some embodiments, taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of reducing (such as eradicating) a pre-existing pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months when gemcitabine-based therapy is discontinued). In some modalities, at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) of metastases are reduced.
In some modalities, a metastasis reduction method for the lymph node is provided.
In some embodiments, the taxane is paclitaxel.
In some embodiments, taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of reducing (such as eradicating) a pre-existing pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and in which gemcitabine-based therapy has been discontinued (for example, at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when administration of the effective amount of the composition begins, comprising nanoparticles comprising a taxane and albumin a to the subject.
In some modalities, at least about 10% (including, for example, at least about any of 20%, 30%, 40%,: 60%, 70%, 80%, 90% or 100%) metastases are reduced.
In some embodiments, a method of metastasis reduction for the lymph node is provided.
In some embodiments, the taxane is paclitaxel.
In some embodiments, taxane in the nanoparticle composition is administered by: intravenous administration.
In some embodiments, a method of reducing the incidence or burden of pre-existing pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the individual has progressed under gemcitabine-based therapy.
In some embodiments, the taxane is paclitaxel.
In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of reducing the incidence or burden of pre-existing pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles that comprise a size
xane and albumin and in which the individual is resistant or refractory to gemcitabine-based therapy. In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of reducing the incidence or burden of pre-existing pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and in which the individual has failed to respond to gemcitabine-based therapy. In some embodiments, the taxane is paclite-PE xel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration. : In some embodiments, a method of reducing the incidence or burden of preexisting pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual - comprising administering to the individual an effective amount de: a composition comprising nanoparticles comprising a taxane and an albumin and in which the individual exhibits a less desirable degree of responsiveness to gemcitabine-based therapy. In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of reducing the incidence or burden of pre-existing pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles that comprise a taxane and an albumin and in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months when gemcitabine-based therapy is discontinued). And bad-
In some embodiments, the taxane is paclitaxel.
In some embodiments, the tax in the nanoparticle composition is administered through intravenous administration.
In some embodiments, a method of reducing the incidence or burden of pre-existing pancreatic cancer tumor metastasis (such as metastasis to the lymph node) is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising taxan and albumin and where gemcitabine-based therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when the administration of the effective amount of the composition starts -. comprising nanoparticles comprising a taxane and an albumin to the individual.
In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method of reducing the size of the pancreatic cancer tumor in an individual is provided - comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in that the individual has progressed under gem-based therapy. 20 cytabine.
In some embodiments, the size of the tumor is reduced by at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%). In some modes, taxane is paclitaxel.
In some embodiments, taxane in the nanoparticle composition is administered through intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer. . In some embodiments, a method of reducing the size of the pancreatic cancer tumor is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and wherein the individual is resistant or refractory to gemcitabine-based therapy. In some embodiments, the size of the tumor is reduced by at least about 10% (including, for example, at least about 20%, 30%, 40%, 60%, 70%, 80%, 90) % or 100%). In some embodiments, the taxane is paclitaxel. In some embodiments, the nanoparticle composition taxanone is administered via intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of reducing the size of the pancreatic cancer tumor in an individual is provided by administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and in that the individual failed to respond to gemcitabine-based therapy. In some embodiments, the size of the tumor is reduced by at least about 10% (including, for example, at least about À of any 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%). In some modalities, the taxane is paclitaxel. In some embodiments, taxane in the nanoparticle composition is administered via intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of reducing the size of the pancreatic cancer tumor is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and in which the individual exhibits a less desirable degree of responsiveness to gemcitabine-based therapy. In some modalities, the size of the tumor is reduced by at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90 % or 100%). In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration. In some modalities
the individual has non-metastatic pancreatic cancer.
In some ways, the individual has primary pancreatic cancer.
In some embodiments, a method of reducing the size of the pancreatic cancer tumor is provided in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and wherein the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months after inter - disruption of therapy based on gemcitabine). In some modalities, the size of the tumor is reduced by at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80 %, 90%, or 100%). In some embodiments, the taxane is paclitaxel. fa In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some fashion-. the individual has primary pancreatic cancer.
In some embodiments, a method of reducing the size of the pancreatic cancer tumor in an individual is provided, comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin and wherein the gemcitabine-based therapy was discontinued (for example, at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when the effective amount of the composition comprising —nanoparticles comprising a taxane and albumin to the individual.
In some embodiments, the size of the tumor is reduced by at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%). In some embodiments, the taxane is paclitaxel.
In some embodiments, the taxane in the —nanoparticle composition is administered via intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some modalities, a method is provided to prolong the time for the progression of pancreatic cancer disease (for example, progression-free survival) in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the individual has progressed under gemcitabine-based therapy. In some modalities, the method prolongs the time for disease progression by at least any one, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks. In some modalities, the method prolongs the time for disease progression by at least 1, 0, 1,2, 1,4, 1,6, 1,8,2,0,2,2,2,4, ' 2,6,2,8,3,0,3,2,3,4,3,6,3,8,4,0,4,2,4,4,4,6,4,8,5, 0,5,2,5,4,5, o 6, 5, 8,6, O, 6, 2, 6,4, 6,6,6,8,7,0,7,2,7,4 , 7,6,7,8,8,0,8,2,8,4,8,6, 8, 8, 9, 0, 9, 2, 9,4, 9,6, 9,8, 10 , 0, 10.2, 10.4, 10.6, 10.8, 11.0, 11.2, 11.4, '11.6, 11.8, 12.0, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54,60,66 or 72 months. In some embodiments, the taxane is paclitaxel. In É some modalities, the taxane in the nanoparticle composition is administered through intravenous administration.
In some embodiments, a method is provided to extend the overall survival of an individual with pancreatic cancer, comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in which the individual progressed on gemcitabine-based therapy. In some modalities, the method prolongs the individual's survival by at least anyone from 1, 0, 1, 2, 1, 4, 1.6, 1.8, 2.0,2,2,2, 4 , 2,6,2,8,3,0,3,2,3,4,3,6,3,8,4,0,4,2,4,4,4,6,4,8,5 , 0,5,2,5, 4,5,6,5,8,6, 0, 6, 2,6,4,6,6,6,8,7,0,7,2,7,4 , 7,6,7,8,8,0,8,2,8,4, 8,6,8,8,9,0,9,2,9,4, 9,6, 9,8, 10 , 0, 10.2, 10.4, 10.6, 10.8, 11.0, 11.2, 11.4, 11.6, 11.8, 12.0, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, 66 or 72 months. In some embodiments, the taxane is pacli- taxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration. In some modalities, a method is provided for information
break out (as well as destroy) the pancreatic cancer stroma of an individual who has pancreatic cancer comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, wherein the individual progressed under gemcitabine therapy.
In some modalities, the pancreatic cancer stroma is ruptured or destroyed by at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%). In some modes, taxane is paclitaxel.
In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some modalities, the individual has pancreatic and non-metastatic cancer.
In some modalities, the individual has primary pancreatic cancer. 'In some embodiments, a method is provided to disrupt (such as destroy) the pancreatic cancer stroma of an individual who has pancreatic cancer comprising administration, to the individual | duo, an effective amount of a composition comprising nanoparticles comprising a taxane and albumin and in which the individual is resistant or refractory to gemcitabine based therapy.
In some modalities, the pancreatic cancer stroma is ruptured or destroyed by at least about 10% (including, for example, at least about 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%). In some embodiments, the taxane is paclitaxel.
In some embodiments, taxane in the nanoparticle composition is administered via intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method is provided to disrupt (such as destroy) the pancreatic cancer stroma of an individual who has pancreatic cancer comprising administering to the individual an effective amount of a composition comprising nanoparticles that comprise a taxane and albumin and in which the individual
duo failed to respond to gemcitabine-based therapy. In some modalities, the pancreatic cancer stroma is ruptured or destroyed by at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70 %, 80%, 90% or 100%). In some embodiments, the taxane is paclitaxel. In some embodiments, taxane in the nanoparticle composition is administered via intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some modalities, a method is provided to disrupt (such as destroy) an individual's pancreatic cancer stroma. a pancreatic cancer patient comprising administering to the individual an effective amount of a composition comprising nano- particles comprising a taxane and an albumin and in which the individual exhibits a less desirable degree of responsiveness to therapy with It is based on gemcitabine. In some modalities, the pan- stroma of cancer. crematorium is disrupted or destroyed by at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%). In some embodiments, the taxane is paclitaxel. In some embodiments, taxane in the nanoparticle composition is administered through intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, a method is provided to disrupt (such as destroy) the pancreatic cancer stroma of an individual who has pancreatic cancer comprising administering to the individual an effective amount of a composition comprising nanoparticles which comprise a taxane and albumin and in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5,6,7,8, 9 , 10, 11, 12, 24 or 36 months when interrupting therapy based on gemcitabine). In some modalities, the stroma of pancreatic cancer
crematorium is disrupted or destroyed by at least about 10% (including, for example, at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%). In some embodiments, the taxane is paclitaxel. In some embodiments, taxane in the nanoparticle composition is administered — administered via intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method is provided to disrupt (such as destroy) the pancreatic cancer stroma of an individual who has pancreatic cancer, comprising administering to the individual an effective amount of a composition comprising nano- particles comprising a taxane and an albumin and in which gemcitabine-based therapy has been discontinued (for example, for "at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when administering the effective amount of the composition comprising nanoparticles comprising a taxane and albumin to the individual In some ways, the pancreatic cancer stroma is disrupted or destroyed by at least about 10% (including, for example) , at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%). In some modalities, taxane is paclitaxel. in the composition in nanoparticles is administered through administration - + intravenous osa. In some. modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of improving one or more clinical benefits of an individual who has pancreatic cancer is provided, comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin , in which the individual progressed under gemcitabine therapy. Clinical benefits include, but are not limited to, improved / better quality of life, improved / better control of pancreatic cancer symptoms and weight gain. In some modalities
the individual has an improved quality of life, improved control of symptoms and increased weight gain. In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane in the nanoparticle composition is administered via intravenous administration.
In some embodiments, a method is provided for alleviating one or more symptoms of an individual who has pancreatic cancer comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in that the individual has progressed under gemcitabine-based therapy. In some embodiments, taxane in the nanoparticle composition is administered via intravenous administration.
LAS In some modalities, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition that comprises ABRAXANES, in which the individual has progressed under therapy based on gemcitabine and where ABRAXANEº is administered weekly or. weekly for three out of four weeks, at a dose ranging between about 80 mg / m at about 150 mg / m (e.g., about 100 mg / m ). In some modalities, ABRAXANEº is administered through intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, a method of treating pancreatic cancer in an individual is provided, comprising administering to the individual an effective amount of a composition that com- | includes ABRAXANEº, where ABRAXANE "is administered weekly or weekly for three out of four weeks, in a dose ranging from about 80 mg / m to about 150 mg / m (for example, about 100 mg / m ) and in which the individual is resistant or refractory to gemcitabine-based therapy In some modalities, ABRAXANEG is administered via intravenous administration In some modalities, the individual has non-metastatic pancreatic cancer. In some fashion-
| 55/129, the individual has primary pancreatic cancer. 'In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising- ABRAXANES, in which ABRAXANES is administered weekly or weekly for three out of four weeks, at a dose ranging from about 80 mg / m at about 150 mg / m (for example, about 100 mg / m ) and where the individual has failed to respond to gemcitabine-based therapy.
In some modalities, ABRAXANEG is administered through intravenous administration.
In some modalities, the 'F individual has non-metastatic pancreatic cancer.
In some modalities ll. the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANEº, in which ABRAXANEG is administered weekly. te or weekly for three out of four weeks, at a dose ranging from about 80 mg / m at about 150 mg / m (eg, about 100 mg / m ) and where the individual exhibits a less desirable degree of responsiveness to gemcitabine based therapy.
In some modali- | activities, ABRAXANEº is administered through intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some modalities, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANES, in which ABRAXANEº is administered weekly or weekly for three every four weeks, in one dose | 30 - which ranges from about 80 mg / m at about 150 mg / m (for example, about 100 mg / m ) and where the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any one of about 2, 3, 4, 5, 6, 7 , 8, 9, 10, 11, 12, 24 or 36 months when discontinuing gemcitabine therapy). In some modalities, ABRAXANEº is administered through intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some modalities, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANE , in which ABRAXANEº is administered weekly. or weekly for three out of four weeks, at a dose ranging from about 80 mg / m at about 150 mg / m (for example, about 100 ma / m ) and where a gemcitabine based therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when the administration of the effective amount of the composition comprising ABRAXANEº to the individual begins. In some modalities, - ABRAXANEº is administered through intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer in an individual is provided comprising administering to the individual an effective amount of a composition comprising ABRAXANE , in which the individual has progressed under therapy based on: in gemcitabine and in which ABRAXANEº is administered once every three weeks at a dose ranging from about 200 mg / m at about 300 mg / m (e.g., about 260 mg / m ). In some modalities, ABRAXANEG is administered through intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer in an individual is provided, comprising administering to the individual an effective amount of a composition that comprises
do you understand ABRAXANEº, where ABRAXANEº is administered once every three weeks, in a dose that varies between about 200 mg / m about 300 mg / m (eg, about 260 mg / m ) and where the individual is resistant or refractory to gemcitabine-based therapy. In some modalities, ABRAXANEº is administered through intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some modalities, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition that comprises ABRAXANEº, in which ABRAXANE ”is administered once at every three weeks, at a dose ranging between about 200 mg / m about 300 mg / m (for example, about 260 mg / m ) and where the individual has failed to respond to gemcitabine-based therapy. In some i modalities, ABRAXANEº is administered through in- administration. mischievous. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANE º, in which ABRAXANEGO is administered once at every three weeks, at a dose ranging between about 200 mo / m about 300 mg / m (for example, about 260 mg / m ) and where the individual exhibits a less desirable degree of responsiveness to gemcitabine-based therapy. In some modalities, ABRAXANESº is administered through intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. : In some modalities, a method of treating pancreatic cancer is provided in an individual comprising administration
tion, to the individual, of an effective amount of a composition comprising ABRAXANES, in which ABRAXANE ”is administered once every three weeks, in a dose that varies between about 200 mg / m about 300 mg / m (for example, about 260 mg / m ) and where the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5,6,7, 8, 9, 10, 11, 12, 24 or 36 months when gemcitabine-based therapy is discontinued). In some modalities, ABRAXANES is administered through intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. *. In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising: ABRAXANEº, in which ABRAXANEQO is administered once every three weeks, at a dose ranging between about 200 mg / m about 300 mg / m (for example, about 260 mg / m ) and where gemcitabine-based therapy has been discontinued (for example, for at least 1, 2,3,4,5,6,7,8, 9 or 10 months ) when the administration of the effective amount of the composition comprising ABRAXANESº to the individual begins. In some modalities, ABRAXANES is administered through intravenous administration. In some “modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANEº, in which the individual has progressed under gemcitabine therapy and where ABRAXANEº is administered weekly or weekly for three out of four weeks at a dose of around 150 mg / m2. In some modalities, ABRAXANEº is administered through intravenous administration. In some modalities, the individual
duo has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some modalities, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANES, in which ABRAXANEº is administered weekly or weekly for three every four weeks, at a dose of about 150 mg / m and where the individual is resistant or refractory to gemcitabine-based therapy.
In some modalities, ABRAXA-NEº is administered through intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANEº, in which ABRAXANES is administered weekly. or weekly for three out of four weeks, at a dose of about 150 mg / m and in which the individual failed to respond to gemcitabine-based therapy.
In some modalities, ABRAXANEº is administered through intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some ways, the individual has primary pancreatic cancer.
In some embodiments, a working method is provided. treatment of pancreatic cancer in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANES, in which ABRAXANES * is administered weekly or weekly for three out of four weeks, in one dose about 150 mg / m and where the individual exhibits a less desirable degree of responsiveness to gemcitabine-based therapy.
In some modalities, ABRAXANEº is administered through intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has pancreatic cancer
primary tactic.
In some modalities, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANESº, in which ABRAXANEº is administered weekly or weekly for three every four weeks, at a dose of about 150 mg / m and where the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months when discontinuing gemcitabine therapy). In some modalities, ABRAXANESº is administered through intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
'15 In some modalities, a method of treating pancreatic cancer is provided in an individual comprising administering, to the individual, an effective amount of a composition comprising ABRAXANESº, in which ABRAXANEG is administered weekly. - you or weekly for three out of four weeks, at a dose of around 150 mg / m and where gemcitabine-based therapy has been discontinued (for example for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when the effective amount is started comprising the composition of ABRAXANESº to the individual: In some modalities, ABRAXANEº is administered through intravenous administration. In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANEº, in which the individual has progressed under gemcitabine therapy and where ABRAXANESº is administered once every three weeks at a dose of around 260 mg / m . In some modalities
However, ABRAXANEº is administered through intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANEG, in which ABRAXANEG is administered once every three weeks, at a dose of about 260 mg / m and in which the individual is resistant or refractory to gemcitabine-based therapy.
In some modalities, ABRAXANEQG is administered through intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer. í In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANEG, in which ABRAXANEG is administered once every three weeks, at a dose of about 260 mg / m and in which the individual failed to respond to gemcitabine-based therapy.
In some modalities, ABRAXANEO is administered through intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some modalities, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition comprising ABRAXANEG, in which ABRAXANEGO is administered once every three weeks, at a dose of about 260 mg / m and in which the individual exhibits a less desirable degree of responsiveness to gemcitabine based therapy.
In some modalities, ABRAXANEQG is administered through intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities
the individual has primary pancreatic cancer. : In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering, to the individual, an effective amount of a composition comprising- ABRAXANEG, in which ABRAXANEG is administered once at every three weeks, at a dose of about 260 mg / m and in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3,4,5,6,7,8, 9, 10, 11, 12, 24 or 36 months at the end of gemcitabine therapy). In some embodiments, ABRAXANEG is administered via intravenous administration.
In some modalities, the individual Fei has non-metastatic pancreatic cancer.
In some modalities, the individual | duo has primary pancreatic cancer. In some embodiments, a method of treating pancreatic cancer is provided in an individual comprising administering to the individual an effective amount of a composition that com- does ABRAXANEG, in which ABRAXANEG is administered once every three weeks, at a dose of about 260 mg / m and where gemcitabine based therapy has been discontinued (for example, for at least 1,2,3,4,5,6,7,8,9 or 10 months) when administration of the effective amount of the composition comprising ABRAXANEGO to the individual.
In some modalities, ABRAXANEG is administered through intravenous administration.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
It should be understood that any of the modalities described in this section apply to the modalities provided in the "Combined Therapy Methods" section. For example, in some embodiments, a method is provided to relieve one or more symptoms in an individual who has pancreatic cancer comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane and albumin; and b) an effective amount of another agent, in which the other agent is not gemcitabine, in which the individual has progressed under gemcitabine based therapy and in which the nanoparticle composition and the other agent are administered concurrently.
Combination Therapy Methods The methods of administering the composition comprising nanoparticles comprising a taxane and an albumin, in some embodiments, are performed in conjunction with the administration of another person to an individual.
In some modalities, the individual was not previously treated for pancreatic cancer.
In some modalities, the individual was previously treated for pancreatic cancer.
Methods of administering the composition comprising "the nanoparticles comprising a taxane and an albumin, in some embodiments, are carried out in conjunction with the administration of another: agent, for example, in an individual who has previously been treated for cancer D 15 pancreatic.
In some embodiments, a working method is provided. treatment of pancreatic cancer in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of another agent, in which the individual has progressed when under prior therapy (for example, he has progressed after any of about 3, 6, 9 or 12 months when initiation of therapy | prior). In some embodiments, prior therapy is gemcitabine-based therapy, erlotinib-based therapy or 5-FU-based therapy.
In some embodiments, the nanoparticles comprise albumin-coated paclitaxel.
In some embodiments, the average particle size of the nanoparticle compositions is not greater than about | 200 nm (for example, less than about 200 nm). In some modes, the composition comprises Nab-paclitaxel (ABRAXANEG). In some modalities, the composition is Nab-paclitaxe! (ABRAXANEG). In some embodiments, the nanoparticle composition and the other agent have a synergistic effect in the treatment of pancreatic cancer.
In some
dalities, the other agent sensitizes pancreatic cancer cells to treatment with the nanoparticle composition. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of another agent and in which the individual is resistant or refractory to prior therapy. In some modalities, prior therapy is gemcitabine-based therapy, erlotinib-based therapy or 5-FU-based therapy. In some embodiments, the nanoparticles comprise albumin-coated paclitaxel. In some embodiments, the average particle size of the D 15 compositions — nanoparticles is not greater than about 200 nm (for example, less than about 200 nm). In some modalities, the composition comprises. of Nab-paclitaxel (ABRAXANEG). In some embodiments, the composition is Nab-paclitaxel (ABRAXANEGO). In some embodiments, the nanoparticle composition and the other agent have a synergistic effect in the treatment of pancreatic cancer. In some embodiments, the other agent sensitizes pancreatic cancer cells to treatment with the nanoparticle composition. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of another agent and in which the individual has failed to respond to previous therapy. In some modalities, prior therapy is gemcitabine-based therapy, erlotinib-based therapy or 5-FU-based therapy. In some modalities
nities, the nanoparticles comprise albumin-coated paclitaxel. In some embodiments, the average particle size of the nanoparticle compositions is no greater than about 200 nm (for example, less than about 200 nm). In some embodiments, the composition comprises Nab-paclitaxel (ABRAXANEG). In some embodiments, the composition is Nab-paclitaxel (ABRAXANEG). In some modalities, the composition in nanoparticles and the other agent have a synergistic effect in the treatment of pancreatic cancer. In some modalities, the other agent sensitizes pancreatic cancer cells to treatment with the nanoparticle composition. In some modalities, the individual has non-metastatic pancreatic cancer. In some embodiments, the individual has primary pancreatic cancer.
In some modalities, a method of treating pancreatic cancer is provided in an individual who needs it; 15 comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising ta- and xane and albumin; and (b) an effective amount of another agent and in which the individual exhibits a less desirable degree of responsiveness to prior therapy. In some embodiments, prior therapy is gemcitabine-based therapy, erlotinib-based therapy or 5-FU-based therapy. In some embodiments, the nanoparticles comprise albumin-coated paclitaxel. In some embodiments, the average particle size of the nanoparticle compositions is not greater than. than about 200 nm (for example, less than about 200 nm). In some modes, the composition comprises Nab-paclitaxel (ABRAXANEG). In some modalities, the composition is Nab-paclitaxel (ABRAXANEG). In some embodiments, the nanoparticle composition and the other agent have a synergistic effect in the treatment of pancreatic cancer. In some modalities, the other agent sensitizes pancreatic cancer cells to treatment with the nanoparticle composition. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of another agent and in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5,6,7 , 8, 9, 10, 11, 12, 24 or 36 months when interrupting a previous therapy). In some embodiments, prior therapy is gemcitabine-based therapy, erlotinib-based therapy, or 5-FU-based therapy.
In some embodiments, the nanoparticles comprise albumin-coated paclite-Foo xel.
In some embodiments, the average particle size of the nanoparticle compositions is not greater than about 200 nm (for example, less than about 200 nm). In some fashion and 15 styles, the composition comprises Nab-paclitaxel (ABRAXANEG). In some modalities, the composition is Nab-paclitaxel (ABRAXANEO). In . some modalities, the composition in nanoparticles and the other agent have a synergistic effect in the treatment of pancreatic cancer.
In some modalities, the other agent sensitizes pancreatic cancer cells to treatment with the nanoparticle composition.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities
the individual has primary pancreatic cancer.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of another agent and in which previous therapy has been discontinued (for example for at least 1,2, 3, 4, 5,6,7,8, 9 or 10 months) when administering the effective amount of the composition comprising nanoparticles comprising taxane and albumin and the effective amount of another agent for the individual.
In some modalities, prior therapy is therapy based on gemcitabine,
erlotinib-based therapy or 5-FU-based therapy.
In some embodiments, the nanoparticles comprise albumin-coated paclitaxel.
In some embodiments, the average particle size of the nanoparticle compositions is not greater than about 200 nm (for example, less than about 200 nm). In some embodiments, the composition comprises Nab-paclitaxel (ABRAXANEG). In some modes, the composition is Nab-paclitaxel (ABRAXANEG). In some ways, the nanoparticle composition and the other agent have a synergistic effect in the treatment of pancreatic cancer.
In some embodiments, the other agent sensitizes pancreatic cancer cells to treatment with the nanoparticle composition.
In some embodiments, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer. In some embodiments, the serum levels of CA 19-9 in the individual to which the nanoparticle composition was administered and the other agent of the present invention decrease significantly.
In some . embodiments, serum CA 19-9 levels are reduced by at least about 20% (including, for example, at least about any of about 20%, 30%, 40%, 50%, 52%, 53% , 55%, 57%, 59%, 60%, 70%, 80%, 90% or 100%) compared to serum CA 19-9 levels before therapy.
In some embodiments, serum CA 19-9 levels are reduced by at least about 50% compared to serum CA 19-9 levels prior to therapy.
In some embodiments, the other agent is not gemcitabine.
In some embodiments, the other agent is not a platinum-based agent (such as carboplatin or cisplatin). In some modalities, the method does not include administration of an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor). In some embodiments, the other agent is an antimetabolite agent, a tyrosine kinase inhibitor (eg, an EGFR inhibitor), a matrix metalloproteinase inhibitor, a topoisomerase inhibitor, a proteasome inhibitor, a base agent platinum, a therapeutic antibody
a farnesyl transferase inhibitor, an anti-angiogenic agent and a macrolide.
In some modalities, the chemotherapeutic agent is any one (and, in some modalities, selected from the group consisting of) selected from the group consisting of vandetanib (for example, Zactima &), 5-fluororouracil (for example, CARACGE or EFUDEXO), erlincinib (eg TARCEVAG), gefitinib IRESSAG), marimastat, cisplatin, carboplatin, satraplatin, irinotecan (eg CAMTOSARG), typifarnib (eg ZARNESTRAG), oxaliplatin (eg ELOXATING), pemetrexed (for example, ALIMTAG), exactecane, capecitabine (for example, XELODAG), raltitrexed (for example, TOMUDEXG), cetuximab (ERBIORA TUXO), bevacizumab (for example, AVASTING), bortezomib example, VELCADEOG), rapamycin or gemcitabine. In some modalities, the chemotherapeutic person is any one (and, in some modalities, selected from the group consisting of) selected from the group consisting of 5-fluororouracil (for example, CARACG or EFUDEXO ), erlotinib (eg "TARCEVAG), gefitinib (IRESSAS), marimastat, irinotecan (eg CAMTOSARG), tipifamnib (eg ZARNESTRAG), pemetrexed (eg ALIMTAG), exactecane, capecitabine (eg , XE-LODAG), raltittexed (for example, TOMUDEXO), cetuximab (ERBITUXO), bevacizumab (for example, AVASTING), bortezomib (for example, VELCA-DEG), rapamycin or gemcitabine. In some embodiments, the other chemotherapeutic agent is an antimetabolite agent An antimetabolite agent is an agent which is structurally similar to a metabolite, but cannot be used by the body in a productive way Many antimetabolite agents interfere with the production of nucleic acids, RNA and DNA. antimetabolite can be a nucleoside analog which includes, but is not limited to, 5-fluororuracil (eg, CARACG or EFUDEXO), gemcitabine (GEM-ZARO), pemetrexed (eg, ALIMTAG), raltitrexed (eg, TO-MUDEXOG) and capecitabine (by example, XELODAG). Thus, in some modalities, a method of treating pancreatic cancer is provided.
* typical in an individual who needs it, including administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of an antimetabolite agent, in which the individual has progressed under gemcitabine-based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some modalities, the an- timetabolite is 5-fluorouracil, pemetrexed, raltitrexed, gemcitabine or capecitabine. In some embodiments, the antimetabolite agent is not gemcitabine | ] In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it including administration to the individual of (a) an effective amount of a composition comprising nanoparticles comprising ta; 15 xane and albumin; and (b) an effective amount of an antimetabolite agent and in which the individual is resistant to or refractory to therapy based on. gemcitabine. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the antimetabolite is 5-fluorouracil, pemetrexed, raltitrexed, gemcitabine or capecitabine. In some modalities, the antimetabolite agent is not gemcitabine.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of an antimetabolite agent and in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2,3,4,5,6,7 , 8, 9, 10, 11, 12, 24 or 36 months when discontinuing gemcitabine-based therapy). In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some modalities, the
timetabolite is 5-fluorouracil, pemetrexed, raltitrexed, gemcitabine or capecitabine.
In some embodiments, the antimetabolite agent is not gemcitabine.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of an antimetabolite agent and in which gemcitabine-based therapy has been discontinued (for example, for at least 1.2, 3,4,5,6,7,8,9 or 10 months) when administering the effective amount of the composition comprising nanoparticles comprising "taxane and albumin and the effective amount of the anti-metabolite agent to the individual.
In some modalities, the individual has non-metastatic pan-crematory cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the antimetabolite is 5-fluorouracil, pemetrexed, raltitrexed, gemcitabine or capecitabine.
In some embodiments, the antimetabolite agent is not gemcitabine.
In some embodiments, the other chemotherapeutic agent is a tyrosine kinase inhibitor (eg, EGFR). Suitable tyrosine kinase inhibitors include, but are not limited to, vandetanib (eg Zactima &), erlotinib (eg TARCEVAG) and gefitinib IRESSAG). Thus, in some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a tyrosine kinase inhibitor, in which the individual has progressed under gemcitabine-based therapy.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, tyrosine kinase inhibitors are vandetanib, erlotinib or gefitinib.
In some modalities, a treatment method is provided
treatment of pancreatic cancer in an individual who needs it, including administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a kinase tyrosine inhibitor that the individual is resistant to or refractory to gemcitabine-based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, tyrosine kinin inhibitors are vandetanib, erlotinib or gefitinib.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin ; and (b) an effective amount of a kinase tyrosine inhibitor that the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months when a therapy based on gemcitabine is interrupted). In some modalities, the individual has non-metastatic pancreatic cancer. In some ways, the individual has primary pancreatic cancer. In some modalities, tyrosine kinase inhibitors are vandetanib, erlotinib or gefitinib. In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administration, to the individual, of (a) an effective amount of a composition comprising nanoparticles comprising ta-. xane and albumin; and (b) an effective amount of a tyrosine kinase inhibitor and in which gemcitabine-based therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8 , 9 or 10 months) when administering the effective amount of the composition comprising nanoparticles comprising taxane and albumin and the effective amount of the tyrosine kinase inhibitor to the individual. In some modalities, the individual has | non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, tyrosine kinase inhibitors are vandetanib, erlotinib or gefitinib. In some embodiments, the other chemotherapeutic agent is a matrix metalloproteinase inhibitor. Suitable matrix metalloproteinase inhibitors include, but are not limited to, marimastat. Thus, in some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administering, to the individual, (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a matrix metalloproteinase inhibitor, wherein] the subject has progressed under gemcitabine-based therapy. In some - modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the matrix metalloproteinase inhibitor is marimastat. In some modalities, a method of treating pancreatic cancer is provided in an individual who needs it. comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a matrix metalloproteinase inhibitor, in which the individual is resistant or refractory to gemcitabine-based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the matrix metalloproteinase inhibitor is marimastat.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a matrix metalloprotein inhibitor, in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 24 or 36 months when discontinuing gemcitabine therapy). In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some modalities, the matrix metalloproteinase inhibitor is marimastat.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a matrix metalloproteinase inhibitor, on which gemcitabine based therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) -. when administering the effective amount of the composition comprising 'nanoparticles comprising taxane and albumin and the effective amount' of the matrix metalloproteinase inhibitor to the subject. In some modalities, the individual has non-metastatic pancreatic cancer. In some Ki modalities, the individual has primary pancreatic cancer. In some mo-. dalities, the matrix metalloproteinase inhibitor is marimastat.
In some embodiments, the other chemotherapeutic agent is a topoisomerase inhibitor. Suitable topoisomerase inhibitors include, but are not limited to, irinotecan (eg, CAMTOSARG). Thus, in some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and = albumin; and (b) an effective amount of a topoisomerase inhibitor, in which the individual has progressed under gemcitabine based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the topoisomerase inhibitor is irinotecan.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a topoisomerase inhibitor, in which the individual is resistant or refractory to gemcitabine-based therapy. In some modalities, the individual has pancreatic metastatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the topoisomerase inhibitor is irinotecan. In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering, to the individual, (a) an effective amount of a composition comprising nanoparticles comprising taxan and albumin; and (b) an effective amount of a topoisome-: rase inhibitor, in which the individual has recurrent pancreatic cancer (for example, the 'individual develops pancreatic cancer after about anyone from about 15 to 2,3,4, 5,6,7,8, 9,10, 11,12, 24 or 36 months when gemcitabine-based therapy is discontinued). In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the topoisomerase inhibitor is irinotecan.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a topoisomerase inhibitor, in which gemcitabine based therapy has been discontinued (for example for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when administering the effective amount of the composition comprising nanoparticles comprising taxane and albumin and the effective amount of the topoisomerase inhibitor to the individual. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the topoisomerase inhibitor is irinotecan.
In some embodiments, the other chemotherapeutic agent is a proteasome inhibitor. Suitable proteasome inhibitors include, but are not limited to, bortezomib (eg, VELCADEGO). Thus, in some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it including the administration, to the individual, of (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a proteasome inhibitor, in which the individual has progressed under gemcitabine-based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, IF the proteasome inhibitor is bortezomib. In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it: 15 comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising ta-. xane and albumin; and (b) an effective amount of a proteasome inhibitor, in which the individual is resistant or refractory to gemcitabine-based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the proteasome inhibitor is bortezomib.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a proteasome inhibitor, in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any number of cells2,3,4,5,6, 7,8,9,10,11,12,24 or 36 months when gemcitabine-based therapy is discontinued). In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities,
the individual has primary pancreatic cancer.
In some modalities, the | proteasome inhibitor is bortezomib.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a proteasome inhibitor, in which gemcitabine based therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when administering the effective amount of the composition comprising nanoparticles comprising taxane and albumin and the effective amount of the proteasome EN inhibitor to the individual.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has: primary pancreatic cancer.
In some embodiments, the protein inhibitor. 15 assoma is bortezomib.
In some embodiments, the other chemotherapeutic agent is - a platinum-based agent.
Suitable platinum-based agents include, but are not limited to, carboplatin, cisplatin, oxaliplatin (for example, ELOXATINO) and satraplatin.
Thus, in some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a platinum-based agent, and, wherein the individual has progressed under gemcitabine-based therapy.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the platinum-based agent is carboplatin, cisplatin, oxaliplatin or satraplatin.
In some embodiments, the platinum-based agent is not carboplatin, cisplatin, oxaliplatin or satraplatin.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a platinum-based one, in which the individual is resistant or refractory to an emgemcitabine-based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the platinum-based agent is carboplatin, cisplatin, oxaliplatin or satraplatin. In some modalities, the platinum-based agent is not carboplatin, cisplatin, oxaliplatin or satraplatin.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administration to the individual of (a) an effective amount: of a composition comprising nanoparticles comprising ta-. 15 xane and albumin; and (b) an effective amount of a platinum-based one, in which the individual has recurrent pancreatic cancer (eg, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months when interrupting a gemcitabine-based therapy). In some modalities. 20 des, the individual has non-metastatic pancreatic cancer. In some ways, the individual has primary pancreatic cancer. In some modalities, the platinum-based agent is carboplatin, cisplatin, oxaliplatin or saplatin. In some embodiments, the platinum-based agent is not carboplatin, cisplatin, oxaliplatin or satraplatin.
25. In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a platinum-based one, where the gemcitabine-based therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when the effective amount of the nanoparticle composition is administered
particles comprising taxane and albumin and the effective amount of the platinum-based agent to the individual.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the platinum-based agent is carboplatin, cisplatin, oxaliplatin or satraplatin.
In some embodiments, the platinum-based agent is not carboplatin, cisplatin, oxaliplatin or satraplatin.
In some embodiments, the other chemotherapeutic agent is a therapeutic antibody.
Suitable therapeutic antibodies include, but are not limited to, anti-VEGF antibody (such as bevacizumab (for example, AVASTINO)) and anti-HER2 (such as cetuximab (for example, ERBIOR TUXO)). Thus, in some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a therapeutic antibody, wherein the subject has progressed on gemcitabine based therapy.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the therapeutic antibody is bevacizumab or cetuximab.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a therapeutic antibody, in which the individual is resistant or refractory to gemcitabine-based therapy.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the therapeutic antibody is bevacizu- —maboucetuximab.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering, to the individual, (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a therapeutic antibody, in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5,6, 7,8, 9, 10, 11, 12, 24 or 36 months when gemcitabine-based therapy is discontinued). In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some modalities, the therapeutic antibody is bevacizumab or cetuximab.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it comprising administration to the individual of (a) an effective amount of a composition comprising nanoparticles comprising such | 15 xane and albumin; and (b) an effective amount of a therapeutic antibody, in which gemcitabine based therapy has been discontinued (e.g., for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when administering the effective amount of the composition comprising nanoparticles comprising taxane and albumin and the effective amount of the therapeutic antibody, to the individual.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the therapeutic antibody is bevacizumab or cetuximab.
In some embodiments, the other chemotherapeutic agent is - a farnesi inhibitor! transferase.
Suitable farnesyl transferase inhibitors include, but are not limited to, tipifarnib (eg ZARNES-TRA'Y). Thus, in some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a farnesyl transferase inhibitor, in which the individual has progressed under gemci-
80/129 | tabina. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the farnesyl transferase inhibitor is tipharnib.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a farnesyl transferase inhibitor, wherein the individual is resistant or refractory to gemcitabine-based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the farnesyl] transferase inhibitor is tipifarnib. BD 15 In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it - comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a farnesyl transferase inhibitor, in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any one of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months when gemcitabine-based therapy is discontinued). In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some modalities, the farnesyl transferase inhibitor is tipifarnib.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a farnesyl transferase inhibitor, where gemcitabine-based therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6,7, 8, 9 0u 10 months ) when administering the effective amount of the composition comprising nanoparticles comprising taxane and albumin and the effective amount of the farnesyl transferase inhibitor to the individual. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the farnesyl transferase inhibitor is tipifarnib.
In some embodiments, the other chemotherapeutic agent is an inhibitor of the Hedgehog signaling pathway (a Hedgehog inhibitor). Home | Suitable hedgehog binders include, but are not limited to, vismode- gib and cyclopamide. Thus, in some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) a quantity. effective effectiveness of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a Hedgehog inhibitor, in which the individual has progressed under gemcite-based therapy. bina. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the Hedgehog inhibitor is vismodegib. In some embodiments, the Hedgehog inhibitor is cyclopamide.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a hedgehog inhibitor, in which the individual is resistant or refractory to gemcibabine-based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the Hedgehog inhibitor is vismodegib.
In some embodiments, the Hedgehog inhibitor is cyclopamide.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a hedgehog inhibitor, in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6,7, 8 , 9, 10, 11, 12, 24 or 36 months when discontinuing gemcitabine therapy). In some modalities, the individual - has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the Hedgehog inhibitor is vismodegib.
In some embodiments, the Hedge- 'hog inhibitor is cyclopamide. o In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it 'comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin ; and (b) an effective amount of a hedgehog inhibitor, in which gemcitabine based therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when administering the effective amount of the composition comprising nanoparticles comprising taxane and albumin and the effective amount of the Hedgehog inhibitor to the individual.
In some modalities, the individual has non-metastatic pancreatic cancer.
In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the Hedgehog inhibitor is vismodegib.
In some modalities, the Hedgehog inhibitor is cyclopamine. In some modalities, the other chemotherapeutic agent is an anti-angiogenic agent.
The anti-angiogenic agent can be naturally occurring or non-naturally occurring.
In some embodiments, the chemotherapeutic agent is a synthetic antiangiogenic peptide.
In some embodiments, the antiangiogenic agent is different from an anti-VEGF antibody (such as bevacizumab (eg, AVASTING)) Thus, in some embodiments, a method of treating pancreatic cancer is provided in an individual who needs thereof comprising administering to the individual (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of an anti-angiogenic agent, in which the individual progresses with — gemcitabine-based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it including administration to the individual of: (a) an effective amount of a composition comprising nanoparticles comprising .-. taxane and albumin; and (b) an effective amount of an anti-angiogenic agent, in which the individual is resistant or refractory to gemcitabine-based therapy. In some modalities, the individual has pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
r In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of an anti-angiogenic agent, in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any | about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24 or 36 months when gemcitabine-based therapy is discontinued). In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
) In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it including administration to the individual of: (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin ; and (b) an effective amount of an anti-angiogenic agent
gene therapy, where gemcitabine-based therapy was discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when the effective amount of the composition comprising the nanoparticle- | including taxane and albumin and the effective amount of the anti-angiogenic agent to the individual. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer.
In some embodiments, the other chemotherapeutic agent is a macrolide, such as rapamycin. Thus, in some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it including administration, to the individual, of: (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a macrolide, in which the subject has progressed under therapy based on y 15 gemcitabine. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the macrolide is rapamycin.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a macrolide, in which the individual is resistant or refractory to gemcitabine based therapy. In some modalities, the individual has non-metastatic pancreatic cancer In some modalities, the individual has primary pancreatic cancer. In some embodiments, the macrolide is rapamycin.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a macrolide, in which the 'individual has recurrent pancreatic cancer (for example, the individual must
develops pancreatic cancer after about any of about 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 24 or 36 months when a gemcitabine-based therapy is stopped) . In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the macrolide is rapamycin.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of a macrolide, in which * gemcitabine based therapy has been discontinued (for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months) when the effective amount of the composition comprising nanoparticles comprising y 15 comprises taxane and albumin and the effective amount of the macrolide is administered to the individual. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some embodiments, the macrolide is rapamycin.
The other agents described herein can be the agents themselves, their pharmaceutically acceptable salts and pharmaceutically acceptable esters, as well as stereoisomers, enantiomers, racemic mixtures and the like. The other agent or agents, as described, can be administered, as well as a pharmaceutical composition containing the agent (s), wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier vehicle or the like.
In some embodiments, two or more chemotherapeutic agents are administered in addition to taxane in the nanoparticle composition. These two or more chemotherapeutic agents may belong (but not necessarily) to different classes of chemotherapeutic agents. E- —examples of these combinations are provided here. Other combinations are also considered.
Thus, for example, in some embodiments, a method of treating pancreatic cancer, in an individual comprising administering, to the individual, is provided: a) an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, b) an effective amount of 5-fluorouracil; and c) an effective amount of erlotinib, in which the individual progressed on gemcitabine-based therapy. In some modalities, the individual has non-metastatic pancreatic cancer. In some modalities, the individual has primary pancreatic cancer. In some modalities, the individual is resistant or refractory to previous therapy. In some modalities, the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 24 or 36 months after the end of previous therapy). In some modalities, previous therapy was interrupted (for example, for at least 1, 2,3,4,5,6,7,8, 9 or 10 months) when the methods of the present "15 invention are started - In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it including administration to the individual of: (a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and (b) an effective amount of a VEGFR / EFGR inhibitor.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as as paclitaxel) and an albumin; and (b) an effective amount of vandetanib.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it - comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles, which comprise a taxane (such as paclitaxel), coated with albumin; and (b) an amount
effectiveness of a VEGFR / EFGR inhibitor.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles, which comprise a taxane (such as paclitaxel), coated with albumin; and (b) an effective amount of vandetanib.
In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual: (a) an effective amount of a composition comprising nanoparticles, comprising F a taxane (such as paclitaxel), coated with albumin; and (b) an effective amount of a VEGFR / EFGR inhibitor; wherein the nanoparticles of the present composition have an average diameter of no more than about 200 nm (U, for example, less than about 200 nm). In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual: (a) an effective amount of a composition comprising nanoparticles, comprising a taxane (such as paclitaxel), coated with albumin; and (b) an effective amount of vandetanib; wherein the nanoparticles of the present composition have an average diameter of no more than about 200 nm (for example, less than about 200 nm). In some modalities, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual: (a) an effective amount of ABRAXANEG and (b) an effective amount of a VEGFR / EFGR inhibitor. In some modalities, a method of treating pancreatic cancer is provided in an individual who needs it, which comprises (a) intravenously, administering to the individual an effective amount of ABRAXANEG and (b) administer orally to the individual an effective amount of an inhibitory VEGFR / EFGR.
In some modalities, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual: (a) an effective amount of ABRAXANEO and (b) an effective amount of vandetanib . In some modalities, a method of treating pancreatic cancer is provided in an individual who needs it, which comprises (a) administering to the individual intravenously an effective amount A-BRAXANEPO and (b) oral administration of an amount effective of vandeta-nib.
In some modalities, a method of treating pancreatic cancer is provided in an individual who needs it. comprising administering to the individual: (a) an effective amount of ABRAXANEG (b) an effective amount of vandetanib; where 'ABRAXANEO is administered (for example, weekly or weekly for three weeks of three weeks) at a dose ranging between about 80 mg / m about 150 mg / m (eg, about 100 mg / m ) and where vandetanib - is administered daily in a dose ranging from about 100 mg to about 300 mg (for example, about 300 mg). In some modalities, a method of treating pancreatic cancer is provided in an individual who needs it, which comprises (a) intravenously, administering to an individual the effective amount of ABRAXANEG (b) administering orally to the individual an amount effective of vandetanib; where ABRAXANEO is administered (for example, weekly or weekly for three out of four weeks) at a dose ranging between about 80 mg / m at about 150mg / m (eg, about 100 mg / m ) and where vandetanib is administered in a daily dose ranging from about 100 mg to about 300 mg (for example, about 300 mg). In some modalities, a method of treating pancreatic cancer is provided in an individual who needs it, including administering to the individual: (a) an effective amount of ABRAXANEG and (b) an effective amount of vandetanib ; where ABRAXANEOG is administered (for example, once every three weeks)
at a dose of about 200 mg / m at about 300 mg / m (eg, about 260 mg / m ) and where vandetanib is administered daily at a dose ranging from about 100 mg to about 300 mg (for example, about 300 mg). In some embodiments, a method of treating pancreatic cancer is provided in an individual who needs it, comprising (a) intravenously, administering to the individual an effective amount of ABRAXANEG and (b) administering orally to the individual an amount effective of vandetanib; where ABRAXANEG is administered (for example, once every three weeks) at a dose of around 200 mg / m at about 300 mg / m (eg, about 260 mg / m ) and where vandetanib is administered daily at a dose ranging from about 100 mg to about 300 mg (for example, about 300 mg). In some embodiments, the nanoparticle composition and the VEGFR / EGFR inhibitor (such as vandetanib) are administered simultaneously or sequentially. In some embodiments, the nanoparticle composition and the VEGFR / EGFR inhibitor (such as vandetanib) are administered concurrently. In some embodiments, at least one treatment cycle (including, for example, 2, 3, 4, 5, 6 or more) comprises administration of the nanoparticle composition and the VEG-FR / EGFR inhibitor (such as vandetanib).
i Combination therapy methods with the nano-particle composition and the VEGFR / EGFR inhibitor are useful for the treatment of individuals with pancreatic cancer, including individuals who have previously been treated for pancreatic cancer and individuals who have not previously treated for pancreatic cancer. In some modalities, the individual has not been previously treated for pancreatic cancer. In some modalities, the individual was previously treated for pancreatic cancer. In some modalities, the individual has progressed when under prior therapy (for example, gemcitabine-based therapy). In some modalities, the individual is resistant or refractory to previous therapy. In some modalities, the individual is not suitable to continue with previous therapy (for example, due to a lack of response and / or due to toxicity).
In some modalities, the individual has recurrent pancreatic disease after previous therapy. In some modalities, the individual is unresponsive to previous therapy. In some modalities, the individual exhibits a desirable degree of less responsiveness to previous therapy. In some modalities, the individual has an intensified responsiveness to previous therapy. Pharmaceutical compositions comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin) are also provided for use in any of the methods of treating pancreatic cancer described herein. It should be understood that any of the methods of treating pancreatic cancer described here (as in the section "Methods of Treating Pancreatic Cancer" above) apply to and include the description of combination therapies. In some embodiments, a lower amount of each pharmaceutically active compound is used as part of a combined therapy compared to the amount normally used for an individual therapy. In some embodiments, the same or (a superior therapeutic benefit is achieved using a combined therapy than using any of the individual compounds alone. In some embodiments, the same or a superior therapeutic benefit is achieved using a smaller amount ( for example, a lower dose or a less frequent dosing schedule) of a pharmaceutically active compound in a combination therapy than the amount normally used for an individual therapy, eg the use of a small amount of compound pharmaceutically active can result in a reduction in the number, severity, frequency or duration of one or more side effects associated with the compound.
In some embodiments of the method of any of the above, the method of treating pancreatic cancer in an individual who needs it comprises administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin, in that the individual has progressed under gemcitabine-based therapy. In some modalities, progression is within less than about 12 months.
In some embodiments, gemcitabine-based therapy still comprises erlotinib.
In some modalities, gemcitabine-based therapy is monotherapy.
In some embodiments of the method of any of the above, the method of treating pancreatic cancer in an individual who needs it comprises administering, to the individual, (a) an effective amount of a composition comprising nanoparticles comprising taxane and albumin; and (b) an effective amount of another agent, in which the individual has progressed under gemcitabine-based therapy.
In some modalities, the nanoparticle composition and the other agent can be administered simultaneously or sequentially.
In some embodiments, the “nanoparticle composition and the other agent are administered concurrently.
In some embodiments, the other agent is selected from the group consisting of vandetanib, 5-fluororouracil, erlotinib, gefitnib, marimas-: 15 tat, irinotecan, tipifamib, pemetrexed, exactecan, capecitabine, raltittexed, cetuximab, bevacizumab, bevacizumab , rapamycin and gemcitabine.
In som-. but modalities, the other agent is vandetanib and the individual has not received any previous treatment for pancreatic cancer.
In some modalities of the method of any of the above, pancreatic cancer is exocrine pancreatic cancer or endocrine pancreatic cancer.
In some modalities, exocrine pancreatic cancer is dutch pancreatic carcinoma.
In some modalities, pancreatic cancer is locally advanced pancreatic cancer, pancreatic cancer not amenable to resection, or metastatic Dutch pancreatic carcinoma.
In some embodiments of the method of any of the above, the composition comprising nanoparticles comprising taxane and albumin is administered parenterally.
In some embodiments, the composition comprising nanoparticles comprising taxane and albumin is administered intravenously or intraarterially.
In some embodiments of the method of any of the above, the taxane is paclitaxel.
In some embodiments, the nanoparticle compositions have an average diameter of no more than about 200 nm.
In some embodiments, the nanoparticle compositions have an average diameter of less than about 200 nm. In some embodiments, the taxane in the nanoparticles is coated with albumin.
In some modalities of the method of any of the above, —the individual is a human being.
In some modalities of the method of any of the above, the serum levels of CA19-9 (carbohydrate antigen 19-9) in the individual are reduced by at least about 50% compared to the serum levels of CA19-9 before treatment.
Dosing regimens for the methods described here are also provided below. F Dosage and Method of Administration of the Nanoparticle Compositions The dose of the taxane nanoparticle compositions administered to an individual (such as a human being) may vary with the particular composition, mode of administration and type of pancreatic cancer to be treated. In some embodiments, the amount of the composition is effective in eliciting an objective response (such as a partial response, a complete response or a stable disease). In some embodiments, the amount of the taxane nanoparticle composition is sufficient to result in a complete response in the individual. In some embodiments, the amount of the taxane nanoparticle composition is sufficient to result in a partial response in the individual. In some embodiments, the amount of the taxane nanoparticle composition is sufficient to result in a stable disease (i.e., pancreatic cancer) in the individual. In some embodiments, the amount of taxane nanoparticle composition administered (for example, when administered alone) is sufficient to produce a total response rate of more than about 25%, 30%, 32%, 35%, 36%, 37%, 38%, 39%, 40%, 50%, 60%, 65% or 70% among a population of individuals treated with the compound in taxane ranoparticles. An individual's responses to treatment with one of the methods described here can be determined, for example, based on RECIST levels.
In some modalities, the amount of composition is sufficient to prolong the individual's progression-free survival. In some modalities, the amount of composition is sufficient to prolong the individual's overall survival. In some embodiments, the amount of the composition (for example, when administered together) is sufficient to produce the clinical benefits of more than about 25%, 30%, 32%, 35%, 36%, 37%, 38 %, 39%, 40%, 50%, 60%, 65% or 70% among a population of individuals treated with the taxane nanoparticle composition. In some embodiments, the amount of the composition, the first therapy, second therapy or combination therapy is sufficient to decrease the size of a tumor, decrease the number of cancer cells or decrease the growth rate of a tumor at least 'about any 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, D 15 95% or 100% compared to the size of the tumor, the number of pancreatic cancer cells or corresponding tumor growth rates in the same individual before treatment or compared with the corresponding activity in other individuals who did not receive treatment. Standard methods can be used to measure the magnitude of this effect, such as in vitro assays with purified enzyme, cell-based assays,. animal models or testing with humans.
In some embodiments, the amount of taxane (eg, paclitaxel) in the composition is below the level that induces a toxic effect (ie, an effect above a clinically acceptable level of toxicity) or is at a level wherein a potential side effect can be controlled or tolerated when the composition is administered to the individual.
In some embodiments, the amount of the composition is close to a maximum tolerated dose (Maximum Tolerated Dose - BAT) of the composition following the same dosage regimen. In some modalities, the amount of the composition is more than about 80%, 90%, 95% or 98% of the BAT. In some embodiments, the amount of a taxane (for example,
example, paclitaxel) in the composition is included in any of the following ranges: from about 0.1 mg to about 500 mg, about 0.1 mg to about 2.5 mg, about 0.5 to about 5 mg, about 5 to about 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25 about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg.
In some embodiments, the amount of a taxane (for example, paclitaxel) in the effective amount of the composition (for example, a "unit dosage form) is in the range of about 5 mg to about 500 and 15 mg, as such as about 30 mg to about 300 mg or about 50 mg to about 200 mg.
In some embodiments, the concentration of taxane (for example, paclitaxel) in the composition is diluted (about 0.1 mg / ml) or concentrated (about 100 mg / ml) including, for example, any of about deO0.1 to about 50 mg / ml, about 0.1 to about 20 mg / ml, about 1 to about 10 mg / ml, about 2 mg / ml to about 8 mg / ml, about 4 to about 6 mg / ml or about 5 mg / ml.
In some embodiments, the taxane concentration (eg, paclitaxel) is at least about any of 0.5 mg / ml, 1.3 mg / ml, 1.5 mg / ml, 2 mg / ml, 3 mg / ml ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30mg / ml 40 mg / ml or 50 mg / ml.
Examples of effective amounts of a taxane (e.g., paclitaxel) in the nanoparticle composition include, but are not limited to, at least about any of 25 mga / m , 30 mg / m , 50 mg / m , 60 mgim , 75 mg / m , 80 mg / m , 100 mg / m , 120 mg / m , 125 mg / m , 150 mg / m , 160 mg / m , 175 mg / m , 180 mg / m , 200 mg / m , 210 mg / m , 220 mg / m , 250 mg / m , 260 mg / m , 300 mg / m , 350 mg / m , 400 mg / m , 500 mg / m , 540 mg / m , 750 mg / m , 1000 mg / m or 1080 mg / m and a taxane
95/129.
(e.g., paclitaxel). In some embodiments, the amount of taxane (e.g., paclitaxel) per administration is less than about any of 350 mg / m , 300 mg / m , 250 mg / m , 200 mg / m , 150 mg / m , 120 mg / m , 100 mg / m , 90 mg / m , 50 mg / m or 30 mg / m . In some modalities, the amount of taxane (eg, paclitaxel) per administration is less than about any one of 25 mg / m , 22 mg / m , 20 mg / mº , 18 mg / m , 15 mg / m , 14 mg / m , 13 mg / m , 12 ma / m , 11 mg / m , 10 mg / m , 9 mg / m , 8 ma / m , 7 mg / m, 6 mg / m, 5 mg / m, 4 mg / m, 3 mg / m, 2 mg / m or 1 mg / m . In some embodiments, the effective amount of a taxane (e.g., paclitaxel) in the composition is included in any of the following ranges: about 1 to about 5 mg / m2, about 5 to about 10. mg / m ", about 10 to about 25 mg / m", about 25 to about 50 mg / m ", about 50 to about 75 ma / m", about 75 to about 100 mg / m , about: 100 to about 125 mg / m , about 125 to about 150 mg / m , about 150 to about 175 mg / m , about 175 to about 200 mg / m , about 200 to about 225 mg / m , about 225 to about 250 mg / m , about "250 to about 300 mg / m , about 300 to about 350 ma / m or about 350 to about 400 mg / m 2. In some embodiments, the effective amount of a taxane (e.g., paclitaxel) in the composition is about 5 to about 300 mg / m 2, such as about 100 at about 150 mg / m ", about 120 mg / m", about 130 mg / m "or about 140 mg / m". In some ways, the effective amount of a taxane (for example, paclitaxel ) in the composition is about 100 mg / m . In some embodiments of any of the above, the effective amount of a taxane (e.g., paclitaxel) in the composition includes at least about any of 1 mg / kg, 2.5 mg / kg, 3.5 mg / kg, 5 mg / kg, 6.5 mg / kg, 7.5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg or 60 mg / kg. In various embodiments, the effective amount of a taxane (e.g., paclitaxel) in the composition includes less than about 350 mg / kg, 300 mg / kg, 250 mg / kg, 200 mg / kg, 150 mg / kg, 100 mg / kg, 50 mg / kg, 25 mg / kg, 20 mg / kg, 10 mg / kg, 7.5 mg / kg, 6.5 mg / kg, 5 mg / kg, 3.5 mg / kg, 2.5 mg / kg or 1 mg / kg of a taxane (for example, paclitaxel). In some embodiments, the effective amount of paclitaxel in the composition is at least about 2 mg / kg, 2.5 mg / kg, 2.7 mg / kg, 5 mg / kg, 6.5 mg / kg , 7.5 mg / kg or 10 mg / kg administered on days 1.8 and 15 in a 28-day cycle.
In some embodiments, the effective amount of paclitaxel in the composition is about 2.7 mg / kg administered on days 1, 8 and 15 of a 28-day cycle.
In some modalities, the composition is administered intravenously over 30 minutes.
Examples of dosing frequencies for administering the nanoparticle compositions include, but are not limited to, every two days, every three days, every four days, every five days. in five days, every six days, weekly, without interruption, three every four weeks, once every three weeks, once every two weeks, or two every three weeks.
In some modalities, the com-: 15 position is administered about once every 2 weeks, once every three weeks, once every 4 weeks, once every 6 weeks. or once every 8 weeks.
In some embodiments, the composition is administered at least about any of 1x, 2x, 3x, 4x, 5x, 6x or 7x (i.e., daily) per week.
In some embodiments, the interval between administration is less than about any 6 months, 3 months, 1 month, 28 days, 20 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, nine days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or one day.
In some modalities, the interval between each administration is more than about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months or 12 months.
In some modalities, there is no disruption in the dosing schedule.
In some embodiments, the interval between each administration is no more than about a week.
In some modalities, the frequency of administration is once every two days once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times and 11 times.
In some modalities, the frequency of administration is once every two days five times.
In some embodiments, taxane (for example, paclitaxel) is administered over a period of at least ten days, in which the interval between each administration is no more than about two days and in which the dose of taxane (for example, paclitaxel) for each administration is about 0.25 mg / m at about 250 mg / m , about - 5 0.25 mg / m at about 150 mg / m , about 0.25 mg / m at about 75 mg / m , such as about 0.25 mg / m at about 25 mg / m or about 25 mg / m at about 50 mg / m . In some embodiments, taxane (eg, paclitaxel) is administered on days 1, 8 and 15 in a 28-day cycle, where the dose of taxane (eg, paclitaxel) with each administration is about 100 mg / m , 125 mg / m , 150 mg / m , 175 mg / m and 200 mg / m . In some fashion-. lities, taxane (eg paclitaxel) is administered intravenously over 30 minutes on days 1, 8 and 15 in a 28-day cycle, where the taxane dosage (eg paclitaxel) with each administration is of about: 15 100 mg / m, 125 mg / m, 150 mg / m, 175 mg / m and 200 mg / m . In some embodiments, the taxane is paclitaxel.
- The administration of the composition can be extended over an extended period of time, such as from about one month to about seven years. In some embodiments, the composition is administered over a period of at least about any of 2, 3, 4, 5, 6,7,8, 9,10, 11, 12, 18, 24, 30, 36 , 48, 60, 72 or 84 months. : In some embodiments, the dosage of a taxane (eg, paclitaxel) in a nanoparticle composition can be in the range of 5-400 mg / m When administered on a 3-week schedule or 5-250 —mg / m (e.g. 80 - 150 mg / m , for example 100-120 mg / m ), when administered on a weekly schedule. For example, the amount of a taxane (for example, paclitaxel) is about 60 to about 300 mg / m (for example, about 260 maim ), on a four-week schedule. Other exemplary dosing schedules for administering the nanoparticle composition (for example, the nanoparticle composition of paclitaxel / albumin) include, but are not limited to, 100 mg / m , Weekly, without interruption; 75 mg / m weekly, 3 in each
4 weeks; 100 mg / m , Weekly, 3 of 4 weeks; 125 mg / m ” , weekly, 3 of 4 weeks; 125 mg / m , Weekly, 2 for 3 weeks; 130 mg / m , Weekly, without interruption; 175 mg / m , Once every 2 weeks; 260 mg / m , Once every 2 weeks; 260 mMg / m , Once every 3 weeks; 180-300 mg / m , every three weeks, 60-175 mg / mº, weekly, without interruption; 20-150 mg / m twice a week and 150-250 mg / m twice a week.
The dosage frequency of the composition can be adjusted over the course of treatment based on the judgment of the administering physician.
In some embodiments, the individual is treated for at least about any one, two, three, four, five, six, seven, eight,. nine or ten treatment cycles.
The compositions described herein allow the infusion of the composition to an individual during an infusion period that is shorter than: 15 about 24 hours.
For example, in some embodiments, the composition is administered over an infusion period of less than about - either 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes , 20 minutes or 10 minutes.
In some embodiments, the composition is administered over an infusion period of about 30 minutes. : Other exemplary doses of taxane (paclitaxel in some embodiments) in the nanoparticle composition include, but are not limited to, about 50 mg / m , 60 mg / m , 75 ma / m , 80 mg / m m , | 90 mg / m , 100 ma / m , 120 mg / m , 160 mg / m , 175 mg / m , 200 mg / m , 210 —mgo / m 220 mg / m , 260 mg / m , and 300 mg / m . For example, can the dosage of paclitaxel in a nanoparticle composition be in the range of about 100-400 mg / m when administered on a 3-week schedule or about 50-250 mg / m when administered on a weekly basis.
Nanoparticle compositions can be administered to an individual (e.g., human) via a variety of routes including, for example, intravenous, intrathecal, intraarterial, intraperitoneal, intrapulmonary, oral, inhalation, intravesicular, intramuscular, intratracheal, subcutaneous
taneous, intraocular, transmucosal and transdermal. In some embodiments, a formulation with continuous controlled release of the composition can be used. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered intra-arterially. In some embodiments, the composition is administered intraperitoneally. | Modes of Administration of Combination Therapies The dosage regimens described in the section above apply to monotherapy and combination therapy environments. The modes of administration for the combined therapy methods are further described below. “In some embodiments, the nanoparticle composition and the other agent (including the specific chemotherapeutic agents described here) are administered simultaneously. When drugs are administered simultaneously, the drug in the nanoparticles and the other agent may be contained in the same composition (for example, a composition comprising the nanoparticles and the other agent) or in separate compositions (for example, example, nanoparticles are contained in one composition and the other agent is contained in another composition). In some embodiments, the nanoparticle composition and the other agent are administered sequentially. The nanoparticle composition or the other agent can be administered first. The nanoparticle composition and the other agent are contained in separate compositions, which can be contained in the same or in different packages.
In some modalities, the administration of the nanoparticle composition and the other agent are concurrent, that is, the period of administration of the nanoparticle composition and that of other agents overlap each other. In some embodiments, the nanoparticle composition is administered for at least one cycle (for example, at least any of 2, 3 or 4 cycles), prior to administration of the other agent. In some embodiments, the other agent is given at least any one, two, three or four weeks. In some embodiments, administrations of the nanoparticle composition and the other agent are initiated at approximately the same time (as within any 1, 2, 3, 4, 5, 6 or 7 days). In some embodiments, administrations of the nanoparticle composition and the other agent are terminated at approximately the same time (such as within any one, 2, 3, 4, 5, 6 or 7 days). In some modalities, the administration of the other agent continues (for example, for about any of 1,2,3,4,5,6,7,8, 9,10, 11 or 12 months) after termination administration of the composition in nanoparticles. In some modalities, the administration of the other agent is initiated after (for example, after about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months) the start of the administration of the composition in nanoparticles. In some embodiments, administrations of the nanoparticle composition and the other agent are initiated: 15 doses are completed at approximately the same time. In some modalities, administrations of the nanoparticle composition and the other person are initiated. approximately the same time and administration of the other agent continues (for example, for about any 1, 2,3,4,5,6,7,8, 9, 10, 11 or 12 months) after the end of the administration of the nanoparticle composition In some embodiments, the administration of the nanoparticle composition and the other agent ends at approximately the same time and the administration of the other agent begins after (for example, after about any one of 2 , 3, 4, 5,6, 7, 8,9, 10, 11 or 12 months) the beginning of the administration of the composition in nanoparticles.
In some embodiments, the administration of the nanoparticle composition and the other agent is non-concurrent. For example, in some embodiments, the administration of the nanoparticle composition is terminated before the other agent is administered. In some embodiments, the administration of the other agent is terminated before the nanoparticle composition is administered. The time period between the two simultaneous administrations can vary from about two to eight weeks, as well as about four weeks.
The frequency of administration of the composition in nanoparticles containing the drug and the other agent can be adjusted throughout the course of treatment, based on the judgment of the doctor who performs the administration. When administered separately, the nanoparticle composition containing the drug and the other agent can be administered at a different dosing frequency or intervals. For example, the drug-containing nanoparticle composition can be administered weekly, while a chemotherapeutic agent can be administered more or less frequently. In some embodiments, a formulation with sustained sustained release of the nanoparticles containing the drug and / or the. chemotherapeutic agent can be used. Various formulations and devices for obtaining controlled release are known in the art. A 'combination of administration settings described here can also be used. . The nanoparticle composition and the other agent can be administered using the same route of administration or different routes of administration. In some embodiments (for simultaneous and sequential administration), the taxane in the nanoparticle composition and the other agent are administered in a predetermined proportion. For example, in some embodiments, the weight ratio of taxane in the nanoparticle composition and the other agent is about 1 to 1. In some modes, the weight ratio can be between about 0.001 to about from about 1 to about 1000 to about 1 or between about 0.01 to about 1 and about 100 to 1. In some embodiments, the weight ratio of taxane in the nanoparticle composition and the other agent is less than about any one of 100: 1, 50: 1, 30: 1, 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: 1, 3: 1,2 : 1 and 1: 1 In some embodiments, the weight ratio of taxane in the nanoparticle composition and the other agent is more than about 1: 1.2: 1.3: 1.4: 1.5 : 1,6: 1,7: 1,8: 1, 9: 1, 30: 1, 50: 1, 100: 1. Other proportions are considered. The doses required for taxane and / or the other agent may
(but not necessarily) be smaller than is normally required when each agent is administered alone. Thus, in some modalities, a subtherapeutic amount of the drug in the nanoparticle composition and / or the other agent is administered. "Subthera- therapeutic amount" or "subtherapeutic level" refers to an amount that is less than the therapeutic amount, that is, less than the amount normally used when the drug in the nanoparticle composition and / or the another agent is administered alone. The reduction can be reflected in terms of the amount administered in a given administration and / or the amount administered over a given period of time (reduced frequency).
. In some embodiments, enough chemotherapeutic agent is administered to allow a reduction in the normal dose of the drug in the nanoparticle composition necessary to obtain the same degree of treatment in at least about 5%, 10%. , 20%, 30%, 50%, 60%, 70%, 80%, 90% or more. In some modalities, the drug “. enough of the nanoparticle composition is administered in order to allow a reduction in the normal dose of the other agent required to obtain the same degree of treatment by at least about any of 5%, 10%, 20%, 30%, 50% , 60%, 70%, 80%, 90% or more. In some embodiments, the dose of taxane in the nanoparticle composition and the other agent is reduced when compared to the corresponding normal dose for each when administered alone. In some embodiments, taxane in the nanoparticle composition and —the other agent are administered at a subtherapeutic level, that is, reduced. In some embodiments, the dose of the nanoparticle composition and / or the other agent is substantially less than the established maximum toxic dose (BAT). For example, the dose of the nanoparticle composition and / or the other agent is less than about 50%, 40%, 30%, 20% or 10% of the MDT. | A combination of administration settings described here can be used. The combination therapy methods described herein can be performed alone or in conjunction with another therapy, such as chemotherapy, radiation therapy, surgery, hormone therapy, therapy | genetics, immunotherapy, chemo-immunotherapy, hepatic artery based therapy, cryotherapy, ultrasound therapy, liver transplantation, a-localblative therapy, radio frequency ablation therapy, photodynamic therapy and - - similar.
In addition, a person at greater risk of developing pancreatic cancer may receive treatments to inhibit or and / or delay the development of the disease.
The other agent described herein can be administered to an individual (e.g., human) via several routes, such as parenterally, including intravenous, intra-arterial, intraperitoneal, intrapulmonary,. oral, by inhalation, intravesicular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal or transdermal.
In some embodiments, the other 'agent is administered intravenously.
In some embodiments, the com- B 15 —position in nanoparticles is administered orally.
The dosage frequency of the other agent can be the same or. different from that of nanoparticle composition.
Exemplary frequencies are provided above.
As another example, the other agent can be administered three times a day, twice a day, daily, six times a week, five times a week, four times a week, three times a week, twice a week, weekly.
In some embodiments, the other agent is administered twice a day or three times a day.
Exemplary amounts of another agent include, but are not limited to, any of the following ranges: from about 0.5 to about 5 mg, about 10 mg, about 10 to about 15 mg, about 15 about 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, - about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg or about 450 to about 500 mg.
For example, the other agent can be administered at a dose of about 1 mg / kg to about 200 mg / kg (including, for example, about 1 mg / kg to about 20 mg / kg, about 20 mg / kg) kg to about 40 mg / kg, about 40 mg / kg to about 60 mg / kg, about 60 mg / kga to about 80 mg / kg, about 80 mg / kg to about 100 mg / kg, about 100 mg / kg to about 120 mg / kg, about 120 mg / kg to about
140 mg / kg, about 140 mg / kg to about 200 mg / kg). In some embodiments the other agent is vandetanib.
In some embodiments, the effective amount of vandetanib is about 100 mg, about 100 mg to about 200 mg, about 200 mg, about 200 mg to about 300 mg, about 300 mg.
In some embodiments, vandetanib. is administered orally.
In some modalities, vandetanib is administered daily.
In some modalities, vandetanib is administered
'daily for three weeks of a 28-day cycle.
B 15 In some embodiments, the effective amount of taxane in the nanoparticle composition is between about 45 mg / m2 to about - 350 mg / m and the effective amount of the other agent is from about 1 mg / kg to about 200 mg / kg (for example, including about 1 mg / kg to about 20 mg / kg, about 20 mg / kg to about 40 mg / kg, about 40 mg / kg to about 60 mg / kg, about 60 mg / kg to about 80 mg / kg, about 80 mg / kg and about 100 mg / kg, about 100 mg / kg to about 120 mg / kg, about 120 mg / kg to about 140 mg / kg, about 140 mg / kg to about 200 mg / kg). In some embodiments, is the effective amount of taxane in the nanoparticle composition between about 80 mg / m at about 350 mg / m 2 and the effective amount of the other agent is from about 1 mg / kg to about 200 mg / kg (for example, including about 1 mg / kg to about 20 mg / kg, about 20 mg / kg to about 40 mg / kg, about 40 mg / kg to about 60 mg / kg, about 60 mg / kg to about 80 mg / kg, about 80 mg / kg and about 100 mg / kg, about 100 mg / kg to about 120 mg / kg, about 120 mg / kg (about 140 mg / kg, about 140 mg / kg to about 200 mg / kg). In some embodiments, the effective amount of taxane in the nanoparticle composition is between about 80 mg / m at about 300 mg / m and the effective amount of the other agent is from about 1 mg / kg to about 200 mg / kg (for example, including about 1 mg / kg to about 20 mg / kg, about 20 mg / kg to about 40 mg / kg, about 40 mg / kg to about 60 mg / kg,
about 60 mg / kg to about 80 mg / kg, about 80 mg / kg and about 100 mg / kg, about 100 mg / kg to about 120 mg / kg, about 120 mg / kg to about 140 mg / kg, about 140 mg / kg to about 200 mg / kg). In some
but modalities, the effective amount of taxane in the nanoparticle composition
particles is between about 150 mg / m at about 350 mg / m and the amount
effectiveness of the other agent is from about 1 mg / kg to about 200 mg / kg
(for example, including about 1 mg / kg to about 20 mg / kg, about 20 mg / kg to about 40 mg / kg, about 40 mg / kg to about 60 mg / kg, about
- from 60 mg / kg to about 80 mg / kg, about 80 mg / kg and about 100 mg / kg,
about 100 mg / kg to about 120 mg / kg, about 120 mg / kg to about
140 mg / kg, about 140 mg / kg to about 200 mg / kg). In some modalities
. 15, the effective amount of taxane in the nanoparticle composition is
is it around 80 mg / m at about 150 mg / m and the effective amount of
- another agent is from about 1 mg / kg to about 200 mg / kg (for example, including
including about 1 mg / kg to about 20 mg / kg, about 20 mg / kg to about
40 mg / kg, about 40 mg / kg to about 60 mg / kg, about 60 mg / kg about
where 80 mg / kg, about 80 mg / kg and about 100 mg / kg, about 100 mg / kg to about 120 mg / kg, about 120 mg / kg to about 140 mg / kg,
about 140 mg / kg to about 200 mg / kg). In some embodiments, the effective amount of taxane (e.g., paclitaxel) in the nanoparticle composition is about 100 mg / m 2. In some embodiments, is the effective amount of taxane in the nanoparticle composition between about 170 mg / m at about 200 mg / m and the effective amount of the other agent is from about 1 mg / kg to about 200 mg / kg (for example, including about
1 mg / kg to about 20 mg / kg, about 20 mg / kg to about 40 mg / kg, about 40 mg / kg to about 60 mg / kg, about 60 mg / kg to about 80 mg / kg,
about 80 mg / kg and about 100 mg / kg, about 100 mg / kg about
120 mg / Kkg, about 120 mg / kg to about 140 mg / kg, about 140 mg / kg to about 200 mg / kg). In some modalities, the effective amount of
xan in the nanoparticle composition is between about 200 mgim at about 350 mg / m and the effective amount of the other agent is from about 1 mg / kg to about 200 mg / kg (for example, including about 1 mg / kg to about 20 mg / kg, about 20 mg / kg to about 40 mg / kg, about 40 mg / kg - about 60 mg / kg, about 60 mg / kg to about 80 mg / kg, about 80 mg / kg and about 100 mg / kg, about 100 mg / kg to about 120 mg / kg, about 120 mg / kg to about 140 mg / kg, about 140 mg / kg to about 200 mg / kg). In some embodiments, the effective amount of taxane (e.g., paclitaxel) in the nanoparticle composition is about 260 mg / m 2. In some embodiments of any of the above methods, the effective amount of the other agent is about 20-30 mg / kg, about 30-. 40 mg / kg, about 40-50 mg / kg, about 50-60 mg / kg, about 60-70 mg / kg, about 70-80 mg / kg, about 80-100 mg / kg or about 100-120 'mg / kg. : 15 In some embodiments, the effective amount of taxane (eg, paclitaxel) in the nanoparticle composition is between about - 30 and about 300 mg / m and the effective amount of the other agent is between about 100 to about 5000 mg / m2. In some embodiments, the effective amount of taxane (for example, paclitaxel) in the nanoparticle composition is about any of 30, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275 or 300 mg / m and the effective amount of the other agent is about any of 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3250 , 3500, 3750, 4000, 4250, 4500, 4750 or 5000 mg / m . In some embodiments, the effective amount - of nanoparticle composition is about 30 to about 300 mgIm and the effective amount of the other agent is about 100 to about 5000 mg / m , wherein the nanoparticle composition and the other agent are both administered weekly to the individual who has previously been treated for pancreatic cancer.
In some embodiments, the effective amount of the nanoparticle composition is about 30 to about 300 mg / m and the effective amount of the other agent is about 100 to about 5000 mg / m , wherein the nanoparticle composition and the other agent are both administered less frequently than weekly to the individual who has previously been treated for cancer pancreatic. In some embodiments, the effective amount of the nanoparticle composition is about 30 to about 300 mg / m and the effective amount of the other agent about 100 to about 5000 mg / m , in which the nanoparticle composition and the other agent are both administered intravenously, for 30 minutes, on days 1, 8 and 15 in a cycle 28 days to the individual who has previously been treated for pancreatic cancer (for example, the individual who has progressed on gemcitabine-based therapy). In some modalities, the appropriate doses of other agents are approximately those already used in clinical therapies where. the other agent is administered alone or in combination with other agents. Nanoparticle Compositions: The compositions described herein comprise nanoparticles comprising (in various embodiments consisting essentially of) a taxane (such as paclitaxel) and albumin (such as human serum albumin). Nanoparticles of poorly water-soluble drugs (such as taxane) have been described, for example, in U.S. Patent Nos.
5,916,596; 6,506,405; 6,749,868 and 6,537,579; 7,820,788 and US Patent Publications Nos. 2006/0263434 and 2007/0082838; PCT Patent Application WOO8 / 137148, each of which is incorporated herein by reference in its entirety. i In some embodiments, the composition comprises 25 nanoparticles: particles with an average or median diameter of no more than about 1000 nanometers (nm), as well as no more than about any of 900, 800, 700, 600 , 500, 400, 300, 200 and 100 nm. In some embodiments, the average or median diameter of the nanoparticles is not greater than about 200 nm. In some embodiments, the average or median diameter of —nanoparticles is not greater than about 150 nm. In some modalities, the average or median diameter of the nanoparticles is not greater than about 100 nm. In some embodiments, the average or median diameter of the nanoparticles is about 20 to about 400 nm. In some modes, the average or median diameter of the nanoparticles is about 40 to about 200 nm. In some embodiments, the nanoparticles are filtered sterile.
In some embodiments, the nanoparticles in the nanoparticle composition described herein have an average diameter of no more than about 200 nm including, for example, no more than about any of 190, 180, 170, 160, 150, 140 , 130, 120, 110, 100, 90, 80, 70 or 60 nm. In some embodiments, at least about 50% (for example, at least about any of 60%, 70%, 80%, 90%, 95% or 99%) of the nanoparticles in the nanoparticle composition have a diameter -. no greater than about 200 nm including, for example, no more than about any of 190, 180, 170, 160, 150, 140, 130, 120, 110, "100, 90, 80, 70 or 60 nm In some embodiments, at least about 50% (for example, at least any of 60%, 70%, 80%, 90%, 95% | or 99%) of the nanoparticles in the nanoparticle composition is within ' in the range of about 20 to about 400 nm including, for example, about to about 200 nm, about 40 to about 200 nm, about 30 to about 180 nm and any of about 40 at about 150, about 50 20 about 120 and about 60 at about 100 nm.
In some embodiments, albumin has suifidral groups that can form disulphide bridges. In some embodiments, at least about 5% (including, for example, at least about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90%) of the albuminized nanoparticle portion of the composition is cross-linked (for example, cross-linked through one or more disulfide bonds).
In some embodiments, the nanoparticles comprise taxane (such as paclitaxel) coated with an albumin (for example, human serum alumina). In some embodiments, the composition comprises taxane in the forms of nanoparticles and non-nanoparticles, in which at least about any of 50%, 60%, 70%, 80%, 90%, 95% or 99% of the taxane in the composition are in the form of nanoparticles. In some embodiments, the taxane in nanoparticles constitutes more than about any of 50%, 60%, 70%, 80%, 90%, 95% or 99% of the nanoparticles by weight. In some embodiments, the nanoparticles have a non-polymeric matrix. In some embodiments, nanoparticles comprise a taxane core that is substantially free of polymeric materials (such as polymeric matrix).
In some embodiments, the composition comprises albumin in the nanoparticle and non-nanoparticle portions of the composition, wherein at least about any of 50%, 60%, 70%, 80%, 90%, 95% or 99% of the albumin in the composition are in the non-nanoparticles part of the composition. . In some embodiments, the weight ratio of albumin (such as human serum albumin) and taxane in the nanoparticle composition is about 18: 1 or less, such as about 15: 1 or less, for example U 15 example, about 10: 1 or less. In some embodiments, the weight ratio of albumin (such as human serum albumin) and taxane in the composition is within the range of anyone from about 1: 1 to about 18: 1, about 2: 1 about 15: 1, about 3: 1 to about 13: 1, about 4: 1 to about 12: 1, about 5: 1 to about 10: 1. In some embodiments, the weight ratio of albumin and taxane in the nanoparticle portion of the composition is about any one of 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 15 or less. In some embodiments, the weight ratio of albumin (such as human serum alumina) and taxane in the composition is any of the following: about 1: 1 to about 18: 1, about 1: 1 to about 15: 1, about 1: 1 to — about 12: 1, about 1: 1 to about 10: 1, about 1: 1 to about 9: 1, about 1: 1 to about 8: 1, about 1: 1 to about 7: 1, about 1: 1 to about 6: 1, about 1: 1 to about 5: 1, about 1: 1 to about 4: 1, about 1: 1a about 3: 1, about 1: 1 to about 2: 1, about 1: 1 to about 1: 1. In some embodiments, the nanoparticle composition comprises one or more of the characteristics mentioned above.
The nanoparticles described here can be present in a dry formulation (such as a lyophilized composition) or suspended in a biocompatible medium. Suitable biocompatible media include, but are not limited to, water, aqueous buffered medium, saline, buffered saline, optionally buffered amino acid solutions, optionally buffered protein solutions, optionally buffered sugar solutions, buffered vitamin solutions, optionally buffered solutions of synthetic polymers, emulsions containing lipids and the like.
In some embodiments, the pharmaceutically acceptable carrier comprises human serum albumin. Human serum albumin (Human Serum Albumin - HSA) is a highly soluble globular protein of Mr 65K and consists of 585 amino acids. HSA is the most abundant protein in plasma and represents 70-80% of the colloidal osmotic pressure of human plasma. The HSA amino acid sequence contains a total of 17 dis- "sulfide bridges, a free thiol (Cys 34) and a single tryptophan (Trp 214). Intravenous use" 15 of the HSA solution has been indicated for the prevention and treatment of hypovolemic shock (see, for example, Tullis, JAMA, 237, 355-360, 460-463, - (1977)) and Houser et al., Surgery, Gynecology and Obstetrics, 150, 811-816 (1980)) and in together with exchange transfusion in the treatment of neonatal hyperbyrilubremia (see, for example, Finlayson, Seminars in Thrombosis andHemostasis, 6, 85-120, (1980)). Other albumin is considered, such as bovine serum albumin. such non-human albumin may be appropriate, for example, in the context of use of these compositions in non-human mammals, such as in veterinary medicine (including domestic animals and agricultural context). Human serum albumin (HSA) has multiple sites of hydrophobic bond (a total of eight for fatty acids, an endogenous HSA ligand) and bonds to a diverse set of taxanes, especially neutral and negatively charged hydrophobic compounds (Goodmãâán et al, The Pharmacological Basis of Therapeutics, 9th ed, McGraw-Hill New York (1996)). Two high affinity binding sites have been proposed in HSA subdomains 1IA and IIIA, which are highly elongated hydrophobic bags with lysine and arginine residues loaded close to the surface,
which act as attachment points for binders with polar characteristics (see, for example, Fehske et al., Biochem.
Pharmcol., 30, 687-92 (198a), Vorum, Dan.
Med.
Bull., 46, 379-99 (1999), Kragh-Hansen, Dan.
Med.
Bull., 1441, 131-40 (1990), Curry et al., Nat.
Struct.
Biol., 5, 827-35 (1998), Sugio et al, Protein.
Eng., 12, 439-46 (1999), He et al., Nature, 358, 209-15 (199b) and Carter et al., Adv.
Protein.
Chem., 45, 153-203 (1994)). Paclitaxel and propofol have been shown to bind to HSA (see, for example, Pa-.: Al et al., Eur. J.
Biochem., 268 (7), 2187-91 (200a), Purcell et al., Biochim.
Biophys.
Acta, 1478 (a), 61-8 (2000), Altmayer et al., Arzneimittelforschung, 45,1053-6 (1995) and Garrido et al., Rev.
Esp.
Anestestiol.
Reanim., 41, 308-12 (1994)). In addition, docetaxel has been shown to bind to pro-. human plasma proteins (see, for example, Urien et al., Invest.
New
Drugs, 14 (b), 147-51 (1996)). 'Albumin (such as human serum albumin) in composition D 15 generally serves as a vehicle for taxane, that is, albumin in the composition makes taxane more readily susceptible to suspension in an aqueous medium or helps to maintain suspension when compared to compositions do not comprise an albumin.
This can avoid the use of toxic solvents (or surfactants) to solubilize the taxane and thus can reduce one or more side effects of taxane administration to an individual (such as a human). Thus, in some embodiments, the composition described herein is substantially free (such as free) of surfactants, such as Cremophor (including Cremophor ELG & (BASF)). In some embodiments, the nanoparticle composition is substantially free (as well as free) of surfactants.
The composition is "substantially free of Cremophor" or "substantially free of surfactant" if the amount of Cremophor or surfactant in the composition is not sufficient to cause one or more side effects in an individual when the nanoparticle composition is administered to the individual .
In some modes, the nanoparticle composition contains less than about 20%, 15%, 10%, 7.5%, 5%, 2.5% or 1% organic solvent or surfactant.
The amount of albumin in the composition described here may vary, depending on other components in the composition. In some instances, the composition comprises albumin in an amount sufficient to stabilize the taxane in an aqueous suspension, for example, in the form of a stable colloidal suspension (such as a stable suspension of nanoparticles). In some embodiments, albumin is in an amount that reduces the rate of sedimentation of taxane in an aqueous medium. For compositions containing particles, the amount of albumin also depends on the size and density of the nanoparticles in the taxane.
A taxane is "stabilized" in an aqueous suspension if it - remains suspended in an aqueous medium (such as without visible precipitation or sedimentation) for an extended period of time such as: for example, for at least about any one of 0.1, 0.2, 0.25, 0.5,1,2,3,4,5,6,7,8,9,10, 11.12, 24, 36, 48, 60 or 72 hours . The suspension is generally (but not necessarily) suitable for administration to - an individual (for example, a human being). The stability of the suspension is generally (but not necessarily) assessed at storage temperature (such as room temperature (such as 20-25 ° C) or refrigeration conditions (eg 4 ° C)). For example, a suspension is stable at a storage temperature if it does not exhibit flocculation or agglomeration of particles visible to the naked eye or when viewed under an optical microscope 1000 times about 15 minutes after preparing the suspension. Stability can also be assessed under accelerated testing conditions, such as at a temperature that is above about 40ºC.
In some embodiments, albumin is present in an amount that is sufficient to stabilize the taxane in an aqueous suspension at a certain concentration. For example, the concentration of taxane in the composition is about 0.1 to about 100 mg / ml including, for example, any one of about 0.1 to about 50 mg / ml, about 0.1 about 20 mg / ml, about 1 to about 10 mg / ml, about 2 mg / ml to about 8 mg / ml, about 4 to about 6 mg / ml, about 5 mg / ml. In some
but embodiments, the taxane concentration is at least about any of 1.3 mg / ml, 1.5 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 40 mg / ml and 50 mg / ml. In some embodiments, albumin is present in an amount that prevents the use of surfactants (such as Creophor), so that the composition is free or substantially free of surfactant (such as Cremophor). In some embodiments, the composition, in liquid form, comprises from about 0.1% to about 50% (weight / v) (for example, about 0.5% (weight), about 5% (weight / v), about 10% (weight / v), about 15% (weight / v), about 20% (weight / v), about 30% (weight / v), about 40%. (weight / v) or about 50% (weight / v)) of albumin. In some embodiments, the composition, in liquid form, comprises about 0.5% to about 5% (weight / v) albumin.
. 15 In some embodiments, the weight ratio of albumin, for example, albumin to taxane in the nanoparticle composition, is - such that a sufficient amount of taxane binds to or is transported by a cell. Although the weight ratio of albumin to taxane has to be optimized for different combinations of albumin and taxane, in general, the weight ratio of albumin, for example, albumin, to taxane (weight / weight) is about 0, 01: 1 to about 100: 1, about 0.02: 1 to about 50: 1, about 0.05: 1 to about 20: 1, about 0.1: 1 to about 20: 1 , about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 to about 10: 1, about 5: 1 to about 9: 1 or about 9: 1. In some embodiments, the weight-to-ratio ratio of albumin is about 18:01 or less, 15: 1 or less, 14: 1 or less, 13: 1 or less, 12: 1 or less , 11: 1 or less, 10: 1 or less, 9: 1 or less, 8: 1 or less, 7: 1 or less, 6: 1 or less, 5: 1 or less, 4: 1 or less and 3 : 1 or less. In some embodiments, the weight ratio of - albumin (such as human serum albumin) and taxane in the composition is any of the following: about 1: 1 to about 18: 1, about 1: 1 to about 15: 1, about 1: 1 to about 12: 1, about 1: 1 to about 10: 1,
about 1: 1 to about 9: 1, about 1: 1 to about 8: 1, about 1: 1 to about 7: 1, about 1: 1 to about 6: 1, about 1: 1 to about 5: 1, about 1: 1 to about 4: 1, about 1: 1 to about 3: 1, about 1: 1 to about 2: 1, about 1: 1 to about 1: 1. |
In some embodiments, albumin allows the composition to be administered to an individual (such as a human being) without significant side effects.
In some embodiments, albumin (such as human serum albumin) is in an amount that is effective in reducing one or more side effects of administering taxane to a human.
The term "reduction of one or more side effects of taxane administration" refers to reducing, alleviating, eliminating or preventing one or more in- effects. desirable effects caused by taxane, as well as side effects caused by distribution vehicles (such as solvents that make taxanes a-: suitable for injection) used for taxane distribution.
These side effects include, for example, neurotoxicity, myelosuppression, hypersensitivity, inflammation, venous irritation, phlebitis, pain, skin irritation, peripheral neuropathy, febrile neutropenia, anaphylactic reactions, venous thrombosis, extravasation and combinations thereof .
These side effects, however, are merely exemplary and other side effects or a combination
side effects associated with taxanes can be reduced.
In some embodiments, the nanoparticle composition comprises ABRAXANEG (Nab-paciitaxel). In some embodiments, the nanoparticle composition is ABRAXANEQ (Nab-paclitaxel). ABRAXANEGO is a paclitaxel formulation stabilized by USP human albumin, which can be dispersed in a directly injectable saline solution.
When dispersed in a suitable aqueous medium, such as 0.9% sodium chloride injection or 5% dextrose injection, ABRAXANEG forms a stable colloidal suspension of paclitaxel.
The average particle size of the nanoparticles in colloidal suspension is about 130 nanometers.
Since HSA is freely soluble in water, ABRAXANEG can be reconstituted with a wide range of concentrations ranging from dilute (0.1 mg paclitaxel / ml) to concentrate (paclitaxel 20 mg / ml) including, for example ,
about 2 mg / ml to about 8 mg / ml, about 5 mg / ml.
Methods for preparing nanoparticle compositions are known in the art. For example, nanoparticles containing taxanes (such as paclitaxel) and albumin (such as human serum albumin) can be prepared under conditions of high shear forces (for example, ultrasound, high pressure homogenization or the like). These methods are described, for example, in U.S. Patent Nos. 5,916,596; 6,506,405;
6,749,868; 6,537,579. 7,820,788 and also in U.S. Patent Publication No. 2007/0082838, PCT Applications 2006/0263434 and WOO08 / 137148. Briefly, the taxane (such as paclitaxel) is dissolved in an organic solvent and the solution can be added to a solution of. albumin. The mixture is subjected to homogenization at high pressure. The organic solvent can then be removed by evaporation. The dispersion: obtained can also be lyophilized. Suitable organic solvents include, for example: ketones, esters, ethers, chlorinated solvents and other solvents known in the field. For example, the organic solvent can be methylene chloride or chloroform / ethanol (for example, in a ratio of 1: 9, 1: 8, 1: 7, 1: 6, 1: 5, 1: 4, 1: 3, 1: 2, 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1 or 9: 1 Other Components of Nanoparticle Compositions The nanoparticles described here can be present in a composition that includes other agents, excipients or stabilizers.For example, to increase stability by increasing the negative zeta potential of nanoparticles, certain negatively charged components can be added: Such negatively charged components include, but are not limited to, bile salts of bile acids consisting of glycolic acid, cholic acid, chenodeoxycholic acid, taurocholic acid, glyochochodeodeoxicolic acid, taurochenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, dehydrocholic acid and others; phospholipids lecithin (egg yolk), which includes phospholipids based on the following phosphatidylcholine: palmitoyl oleoyl phosphatidyl choline, palmitoyl linoleoyl phosphatidyl choline, stearoyl oleoyl phosphatidyl choline, stearoyl linoleoyl phosphatidyl choline, stearyl arachidoyl phosphatidyl choline and dipalmitoyl phosphatidyl choline. Other phospholipids
media, including L-α-dimiristoyl phosphatidyl choline (DMPC), dioleoyl phosphatidyl choline (DOPC), distearoyl phosphatidyl choline (DSPC), hydrogenated soy phosphatidyl choline (HSPC) and other related compounds. Negatively charged surfactants or emulsifiers are also suitable as additives, for example, cholesterol, sodium sulfate and the like.
In some modalities, the composition is suitable for administration to a human being. In some embodiments, the composition is suitable for administration to a mammal, such as, in the veterinary context, domestic animals and agricultural animals. There is a wide variety of suitable formulations of the nanoparticle composition (see, for example, U.S. Patent Nos. 5,916,596; 6096331; 7820788). The formulations and - methods below are for illustration only and are in no way limiting. Formulations suitable for oral administration may consist of (a) liquid solutions, such as an effective amount of the compound dis-. 15 —solved in diluents such as water, saline or orange juice; (b) capsules, sachets or tablets each containing a predetermined amount of one of the active ingredients as solids or granules; (c) suspensions in an appropriate liquid; and (d) suitable emulsions. Tablet forms can include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, gum arabic, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc; magnesium stearate, stearic acid and other excipients, dyes, diluents, buffering agents, wetting agents, preservatives, flavoring agents and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavoring, usually sucrose and acacia or tragacanth, as well as lozenges comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia, emulsions, gels and the like containing, in addition to active ingredient, excipients as are known in the art. Examples of suitable vehicles, excipients and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol starch, mannitol, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, silica.
calcium, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, saline, water, syrup, methylcellulose, methyl and propyl hydroxy benzoates, talc, magnesium stearate and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying agents and suspending agents, preserving agents, sweetening agents or flavoring agents.
Formulations suitable for parenteral administration include aqueous and non-aqueous solutions, isotonic sterile injectable solutions that may contain antioxidants, buffers, bacteriostats and solutes that make the formulation compatible! with the blood of the intended recipient and sterile aqueous and non-aqueous solutions and suspensions that may include - suspending agents, solubilizers, thickening agents, stabilizers and preservatives. The formulations can be presented in containers with a single dose or multiple doses, such as ampoules and bottles, and can be stored in a dry condition by freezing (lyophilized) requiring only the addition of a liquid - sterile excipient, for example, water, for injections, just before use. Extemporaneous injectable solutions and suspensions can be prepared from sterile powders, granules and tablets of the type previously described. Injectable formulations are preferred.
In some embodiments, the composition is formulated to have a pH range of about 4.5 to about 9.0 including, for example, pH ranges of anywhere from about 5.0 to about 8, 0, about 6.5 to about 7.5 and about 6.5 to about 7.0. In some embodiments, the pH of the composition is formulated to be no less than about 6 including, for example, no less than about any of 6.5, 7 or 8 (such as about 8). The composition can also be made to be isotonic with the blood by adding a suitable tonicity modifier, such as glycerol.
Medicament Kits and Compositions The invention also provides kits, medications, compositions and | unit dosage forms for use in any of the methods described herein.
Kits of the present invention include one or more containers comprising nanoparticle compositions containing taxane (or unit dosage forms and / or articles of manufacture) and / or other agent (for example, the agents described herein) and, in some modalities, it also includes instructions for use according to any of the methods described here. The kit may also include a description of a selection of suitable individuals or treatments. Instructions provided in kits - of the invention are typically instructions written on a label or package insert (for example, a sheet of paper included in the kit), but computer-readable instructions (for example, instructions written on a storage disk - magnetic or optical) are also acceptable. For example, in some embodiments, the kit comprises: a): a composition comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin); and b) instructions for administering the nanoparticle composition for treatment. pancreatic cancer in an individual who has previously been treated for pancreatic cancer (for example, who has progressed under previous therapy). In some embodiments, the kit comprises: a) a composition comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin); and b) instructions for administering the nanoparticle composition for the treatment of pancreatic cancer in an individual who has progressed on gemcitabine-based therapy (for example, | gemcitabine monotherapy or combined therapy with gememe and erlenminib, gemcitabine and capecitabine or gemcitabine and 5-FU). In some modalities, the kit comprises: a) a composition comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin); b) an effective amount of another agent; and c) instructions for administering the nanoparticle composition and the other agents for treating pancreatic cancer in an individual who has previously been treated for pancreatic cancer (for example, who has progressed under previous therapy). In some modalities, the kit comprises: a) a composition
a position comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin); b) an effective amount of another agent; and c) instructions for administering the nanoparticle composition and the other agents for treating pancreatic cancer in an individual who has progressed on gemcitabine-based therapy (for example, gemcitabine monotherapy or combination therapy with gemcitabine and erlotinib, gemcitabine and capecitabine or gemcitabine and 5-FU). In some modalities, prior therapy comprises administration of gemcitabine ("gemcitabine-based therapy"). Nanoparticles and other agents can be present in separate containers or in a single container.
For example, the kit may comprise a different composition. or two or more compositions, one composition comprising a nanoparticle composition and the other comprising another agent. In some embodiments, the kit comprises: a) a composition comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin); b) an effective amount of - a VEGFR / EGFR inhibitor (such as vandetanib); and c) instructions for administering the nanoparticle composition and the VEG-FR / EGFR inhibitor (such as vandetanib) for the treatment of pancreatic cancer in an individual.
The nanoparticles and the VEGFR / EGFR inhibitor (such as vandetanib) are present in separate containers or in a single container.
For example, the kit can comprise a different composition or two or more compositions, one composition comprising the nanoparticles and the other the VEGFR / EGFR inhibitor (such as vandetanib). The kits of the invention are in a suitable packaging.
Suitable packaging includes, but is not limited to, ampoules, bottles, jars, flexible packaging (Mylar, for example, sealed plastic bags) and the like.
Kits can optionally provide additional components, such as tampons and interpretive information.
The present patent application, therefore, also provides articles of manufacture which include vials (such as sealed vials), bottles, jars, flexible packaging and the like.
The instructions regarding the use of the nanometer compositions
Particles generally include information about the dosage, dosage regimen and route of administration for the intended treatment.
The containers can be unit doses, bulky packages (for example, multi-dose packs) or sub-unit doses.
For example, kits that contain sufficient dosages of taxane (such as taxane) may be provided, as disclosed herein, to provide effective treatment of an individual over an extended period, such as any one week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.
Kits can also include multiple unit doses of pharmaceutical compositions. and taxane and instructions for use and can be packaged in sufficient quantities for storage and use in pharmacy, for example,
"hospital hospitals and handling pharmacies.
B 15 Medicines, compositions and unit dosage forms useful for the methods described herein are also provided.
In some embodiments, a drug (or composition) is provided for use in the treatment of pancreatic cancer in an individual who has progressed on gemcitabine based therapy comprising nanoparticles comprising a taxane and an albumin (such as serum albumin) human). In some embodiments, a drug (or composition) is provided for use in the treatment of pancreatic cancer in an individual, in which the individual is resistant to or refractory to gemcitabine-based therapy comprising nanoparticles comprising a taxane and a al- albumin (such as human serum albumin). In some embodiments, a medication (or composition) is provided for use in the treatment of pancreatic cancer in an individual, in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any one of about 2,3, 4,5,6,7,8, 9, 10, 11, 12, 24 —or36 months when gemcitabine-based therapy is discontinued) comprising nanoparticles comprising a taxane and an albumin (such as as human serum albumin). In some embodiments, a medication (or composition) is provided for use in the treatment of pancreatic cancer in an individual, in which gemcitabine-based therapy has been discontinued (for example, for at least 1,2,3,4,5, 6, 7, 8, 9 or 10 months) when starting treatment with the drug comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin). In some embodiments, a drug (or composition or unit dosage form) is provided for use in the treatment of pancreatic cancer in conjunction with another agent in an individual who has progressed a gem-cytabine therapy comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin). In some modalities, a drug (or composition or unit dosage form) is provided for use in the treatment of pancreatic cancer in conjunction with another agent in an individual, where the individual is resistant or 'refractory'. to a gemcitabine-based therapy comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin). In some embodiments, a drug (or composition or unit dosage form) is provided for use in the treatment of pancreatic cancer in conjunction with another agent in an individual, in which the individual has recurrent pancreatic cancer (for example, the individual develops pancreatic cancer after about any of about 2, 3, 4, 5,6,7, 8, 9, 10, 11, 12, 24 or 36 months when interrupting a gemcitabine based therapy) comprising nanoparticles that you buy - they end up with a taxane and albumin (such as human serum albumin). In some embodiments, a drug (or composition or unit dosage form) is provided for use in the treatment of pancreatic cancer in conjunction with another agent in an individual, where gemcitabine-based therapy has been discontinued (eg, for at least 1, 2,3,4,5,6,7,8, 9 or 10 months) when starting treatment with the medication comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin ). In some modalities, a drug (or composition or unit dosage form) is provided for use in the treatment of pancreatic cancer comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin) and another agent . In some modalities, the other agent is not gemcitabine. In some embodiments, a medicament (or composition or unit dosage form) is provided for use in the treatment of pancreatic cancer comprising nanoparticles comprising a taxane and an albumin (such as human serum albumin) and a VEGFR / inhibitor. EGFR (such as vandetanib). The examples, which are intended to be merely exemplary of the invention and should therefore not be considered as limiting the invention in any way, also describe and detail aspects and modalities of the invention discussed above. The preceding examples and detailed description are offered by way of illustration and not by way of limitation. All publications, patent applications and patents cited in this specification are incorporated herein by reference as if each publication, patent application or individual patent were specifically and individually indicated as being incorporated by reference. In particular, all publications cited herein are expressly incorporated herein by reference in order to describe and disclose compositions and methods that can be used in connection with the invention. Although the foregoing invention has been described in detail by way of illustration and example for the sake of clarity of understanding, it will be readily apparent to those skilled in the field, in light of the teachings of the present invention, that certain changes and modifications can be made without departing from the spirit or scope of the appended claims.
EXAMPLES Example 1. Phase I clinical trial of Nab-paclitaxel in patients with advanced pancreatic cancer who progressed on gemcitabine-based therapy This example demonstrates that Nab-paclitaxel was well tolerated and provided a clinical benefit in patients who had progressed on therapy with gemcitabine based.
Materials and Methods In the Phase II open-label trial, patients with locally advanced dutch pancreatic carcinoma, not amenable to resection or metastatic (ECOG 0-2) that evolved within 6 months of gemcitabine-based therapy, received Nab- paclitaxel at 100 mg / m intravenously for 30 minutes on days 1, 8 and 15 in a 28-day cycle.
The patients were at least 18 years old with good organ function.
Contrast CT (Computed Tomography - Computed Tomography) was assessed at the beginning of the study and every 2 cycles.
The primary endpoint was 6-month overall survival (OS - Overall Survival).
The secondary objectives were rate - response according to the RECIST (Response Evaluation Criteria In Solid Tumors) criteria, progression-free survival (PFS - Progression-Free Survival), safety and tolerability and toxicity profile.
CA19-9 levels were '15 measured at baseline and every two cycles.
SPARC immunohistochemistry on available pre-treatment tumor samples was also performed.
Results Of the 20 patients enrolled, 1 patient never received study therapy and was excluded from the analysis.
The average age was 61 years, 9 (47%) were male, 18 (95%) had stage IV disease and 15 (79%) had a PS ECOG (Performance Status) of 0-1. The 6-month OS (survival = | global) was 58% (95% CI, 33% - 76%) and the median OS was 7.3 months (95% CI, 2.8 -13.3 ). Median PFS (progression-free survival) was 1.6 months (95% CI 1.5-3.4). One patient had a confirmed partial response (PR) and 6 (32%) had stable disease (DS) as their best response.
The remaining 12 patients (63%) had progressive disease (PD) on or before the first response assessment.
Five patients were alive, with a mean follow-up of 12.7 months (range 9.6-16.3), including one with DS in cycle 15 of therapy.
After two cycles, the median levels of CA 19-9 decreased by 52% in patients who had DS or PR versus an 18% decrease in patients with PD.
Studies related to the expression of SPARC are also carried out.
Non-hematological toxicities were mild in general, with grade 1 or 2 nausea, anorexia, vomiting and hypocalcemia occurring in 63%, 47%, 37% and 26% of patients, respectively.
Grade 3 or 4 neutropenia, neutral fever — pollen and anemia occurred in 32%, 11% of patients, respectively.
There were no cases of grade 3 or 5 neuropathy. Tables 1-6 provide experimental data and detailed results.
Table 1: Patient Characteristics (N = 19) N% Age (years) Median (range) 61 (24-80) Ú Gender Female 10 52.6 Male 9 47.4: - Internship. mm 1 5.3 'DA 18 94.7 State of Performance' o 3 15.8 1 12 63.2 | 2 4 21.1 Other therapies Adjuvant chemoradiation 5 26.3 previous | Any - chemotherapy 1 57.9 post-study Status at the time of reporting Patient 15 78.9 Active, in study 1 5.3 Live, out of study 3 15.8
Table 2: Best Response by the RECIST Criteria (N = 19)
NO O PC Time point Survival without progression Overall survival (months) (95% CI) (95% CI) 3 31.6% (12.9 - 52.2) 73.7% (47.9-88 , 1) 6 15.8% (3.9 - 34.9) 57.9% (33.2-76.3) - 9 5.3% (0.4 - 21.4) 47.4% ( 24.4-67.3) 12 5.3 (0.4-21.4) 36.8% (16.5-57.5) Í Median 1.6 months (1.5 to 3.4 7.3 months (2.8 to 15.8; | N No. of points with decrease> 50% in CA1I9-9 * PD 12 2 (16.6% i Table 5: Correlation between CA19-9 after 2 cycles and survival (N = 19 [ow jPrseMO) —josesmen - | 50% sr Ear 50% NA) FESP RN RC POP
Jemiano Co - jeausanco | | Hematorogenic [Thrombocytopenia— [aa fo | | Neutropenic fever - lo "fas | | Non-nematetogicals [Do = leen lo | [Nausea = een fo [alopeeia = l16an Jo | '[anorexia - lean - lo | | [vamto = jdsesan do: [Newropata = Ílsasaã jo | Conclusion 'Nab-paclitaxel was well tolerated in patients with advanced pancreatic cancer who had progressed on gemcibabine therapy.37% of patients treated in this phase study obtained clinical benefit (partial response or disease stabilization) ) and 21% remained on therapy for at least 6 months, suggesting that Nab-paclitaxel has antitumor activity in this situation.
There was a tendency for CA19-9 to be a prognosis for clinical benefit, PFS and OS, but this did not reach statistical significance.
Other studies have suggested that SPARC expression is associated with a higher response rate to Nab-paclitaxel (Von Hoff et al., J.
Clin Oncol 27 (155): 4525 (2009)). The correlation of ex-. SPARC pressure with response or survival is under further analysis.
Example 2. A phase study | of two different regimens of Nab- —Paclitaxel with rising doses of vandetanib with expansion in patients with pancreatic cancer This example reports a Phase study | two different schemes
Nab-paclitaxel fer- ents with rising doses of vandetanib with expansion in patients with pancreatic cancer.
A main objective was to determine the maximum tolerated dose (BAT) of the combination of Nab-paclitaxel and vandetanib.
A secondary objective was to assess the preliminary efficacy in patients with pancreatic cancer.
Materials and Methods Patients were randomly assigned to one of two groups.
Doses of Nab-paclitaxel for Group A were set at 100 mga / m of Nab-paclitaxel intravenously, weekly for three weeks in a 28-day cycle.
Doses of Nab-paclitaxel for Group B were fixed at 260 mg / m of Nab-paclitaxel intravenously in a scheme of - three weeks.
Vandetanib was administered to patients in doses of 100 mg, 200 mg or 300 mg orally, daily, for each group.
A 3 + 3 de- 'sign was used.
Expansion in the maximum tolerated dose (BAT) for 15 D 15 patients was planned for both groups.
The expansion of Group A is es-; was restricted to patients with pancreatic cancer who failed therapy and based on gemcitabine.
Two polymorphisms of a single nucleotide, SPARC rs1059829 and SPARC rs3210714, were evaluated by PCR-RFLP in 25 patients.
Results An indication of dose-limiting toxicity (DLT - Dose Limiting Toxicity) was reported at each dose level in Group A, including grade 3 rash in two patients and grade 4 neutropenia in one patient (Table 7) . No indication of DLTs was recorded for patients in Group B. AMTD was 100 mg / m of Nab-paclitaxel administered intravenously per week for three of four weeks in combination with 300 mg of vandetanib administered per day (Group A). The BAT was 260 mg / m of Nab-paclitaxel administered intravenously every three weeks in combination with 300 mg of vandetanib administered daily (Group B). Twenty nine pancreatic cancer patients were treated: nine from Group A (dose escalation), 15 from Group A (dose expansion) and five from group B.
The average age of patients was 62 years.
There were 16 men and 13 women.
The median number of previous treatments for Group A was two (range 1-4). Twenty-two patients with pancreatic cancer had responses that could be evaluated: six (27.5%) of these patients were considered partial responders (PR), 10 (45%) had stable disease (DS) and six presented (27.5%) disease progression.
Median progression-free survival (PFS) was 5.3 months (95% CI: 3.7-7.3) and median overall survival (OS) was 8.2 months (95% CI: 6.2 - 11.5). No statistically significant association was found between SNPs in clinical results and SPARC.
Table 7 presents a summary of grade 3 and grade 4 adverse events. Table 7. Adverse events | %% | : [iareia Pago go [Leucopenia a as | “Oo [Rreshaonefome - | as | 8 | [Fatigue a | [Hypertension Rg [rotonated arch [Thrombosis A [Artieutar pain | Pain museutar [anorexia [tramples the [| o | [Nausea PR [Prurigo Conclusion Both Nab-paclitaxel and vandetanib regimens are safe and well tolerated.
BAT for both groups is the maximum tolerated dose. Although the preceding invention has been described in detail by way of illustration and example for the sake of clarity of understanding, it will be apparent to those skilled in the field that certain minor changes and modifications can be made. practiced.
Therefore, the description and examples should not be interpreted as limiting the scope of the invention.

权利要求:
Claims (29)
[1]
1. Use of a composition comprising an effective amount of nanoparticles comprising a taxane and an albumin, characterized by the fact that it is in the preparation of a drug to treat pancreatic cancer in an individual in need of it, in which the individual progressed on gemcitabine-based therapy.
[2]
2. Use according to claim 1, characterized by the fact that the progression is within less than about 12 months.
[3]
3. Use of a composition comprising an effective amount of nanoparticles comprising a taxane and an albumin, characterized by the fact that it is in the preparation of a drug to treat resistant, refractory or recurrent pancreatic cancer in an individual in need of it .
[4]
4. Use of a composition comprising an effective amount of nanoparticles comprising a taxane and an albumin, characterized by the fact that it is in the preparation of a drug to treat recurrent pancreatic cancer in an individual in need of it.
[5]
5. Use according to claim 3 or 4, characterized by the fact that previous therapy has been interrupted for at least 6 months when the administration of an effective amount of a composition comprising nanoparticles comprising a taxane to the individual begins. and an albumin.
[6]
6. Use according to claim 5, characterized by the fact that the previous therapy is a therapy based on gemcitabine.
[7]
Use according to claim 1, 2 or 6, characterized by the fact that gemcitabine-based therapy still comprises erlotinib.
[8]
8. Use according to claim 1, 2 or 6, characterized by the fact that gemcitabine-based therapy is monotherapy.
[9]
9. Use of a composition comprising nanoparticles comprising a taxane and an albumin, characterized by the fact that it is in the preparation of a drug to treat pancreatic cancer in an individual in need of it, in which the individual has progressed under
based on gemcitabine, and where the treatment is in combination with an effective amount of another agent.
[10]
10. Use according to claim 9, characterized by the fact that the nanoparticle composition and the other agent are administered simultaneously or sequentially.
[11]
11. Use according to claim 9, characterized by the fact that the nanoparticle composition and the other agent are administered concurrently.
[12]
12. Use according to any one of claims 9 to 11, characterized in that the other agent is selected from the group consisting of 5-fluororouracil, erlotinib, gefitnib, marimastat, irinotecan, tipifarnib, pemetrexed, exactecane, capecitabine , raltitrexed, cetuximab, bevaci- zumab, bortezomib, rapamycin, vandetanib and gemcitabine.
[13]
13. Use of a composition comprising nanoparticles comprising a taxane and an albumin, characterized by the fact that it is in the preparation of a drug to treat pancreatic cancer in an individual in need of it, where the treatment is in combination with a effective amount of vandetanib.
[14]
Use according to claim 11, characterized by the fact that the nanoparticle composition and vandetanib are administered simultaneously or sequentially.
[15]
Use according to claim 11, characterized by the fact that the nanoparticle composition and vandetanib are administered concomitantly.
[16]
16. Use according to any one of claims 1 to 15, characterized by the fact that the cancer is exocrine pancreatic cancer or endocrine pancreatic cancer.
[17]
17. Use according to claim 16, characterized by the fact that exocrine pancreatic cancer is dutch pancreatic carcinoma.
[18]
18. Use according to any one of claims 1 to 17, characterized by the fact that the cancer is locally advanced pancreatic cancer, non-resectable pancreatic cancer or pancreatic cancer
metastatic duttic crematorium.
[19]
19. Use according to any one of claims 1 to 18, characterized in that the composition comprising nanoparticles comprising taxane and albumin is administered parenterally.
[20]
20. Use according to claim 19, characterized by the fact that the composition comprising nanoparticles comprising taxane and albumin is administered intravenously or intraarterially.
[21]
21. Use according to any one of claims 1 to 20, characterized in that the taxane is paclitaxel.
[22]
22. Use according to any one of claims 1 to 21, characterized in that the nanoparticles in the nanoparticle composition have an average diameter of no more than about 200 nm.
[23]
23. Use according to claim 22, characterized by the fact that the nanoparticles in the nanoparticle composition have an average diameter of less than about 200 nm.
[24]
24. Use according to any one of claims 1 to 23, characterized in that the taxane in the nanoparticles is coated with albumin.
[25]
25. Use according to any one of claims 1 to 24, characterized in that the albumin is human albumin.
[26]
26. Use according to any one of claims 1 to 24, characterized in that the albumin is human serum albumin.
[27]
27. Use according to any one of claims 1 to 26, characterized by the fact that the individual is a human being.
[28]
28. Use according to any one of claims 1 to 27, characterized in that the serum levels of CA19-9 (carbohydrate antigen 19-9) in the individual are reduced by at least about 50% compared to the levels serum CA19-9 before treatment.
[29]
29. Invention, in any form of its embodiments or in any applicable category of claim, for example, of product or process or use encompassed by the matter initially described, revealed or illustrated in the patent application.

类似技术:

---

公开号 | 公开日 | 专利标题

---

AU2018200347B2|2020-03-19|Methods of treatment of pancreatic cancer

---

JP2019081790A|2019-05-30|Methods of treating pancreatic cancer

---

US20200246275A1|2020-08-06|Combination therapy comprising nanoparticles of a taxane and albumin with abt-263 in methods for treating cancer

---

US20160374952A1|2016-12-29|Methods of treatment of hepatocellular carcinoma

---

JP2016172777A|2016-09-29|Method and composition for treating recurrent cancer

---

JP2013527232A|2013-06-27|How to treat bladder cancer

---

US20200129469A1|2020-04-30|Methods of treating biliary tract cancer

同族专利:

---

公开号 | 公开日

---

JP2013527233A|2013-06-27|

---

US20170049711A1|2017-02-23|

---

AU2016202815B2|2018-02-08|

---

US20140079788A1|2014-03-20|

---

CR20120625A|2014-05-07|

---

ZA201208821B|2014-01-29|

---

IL223189D0|2013-02-03|

---

US9820949B2|2017-11-21|

---

AU2018200347B2|2020-03-19|

---

AU2016202815A1|2016-05-26|

---

WO2011153010A1|2011-12-08|

---

US20130202709A1|2013-08-08|

---

CN103140225A|2013-06-05|

---

US9399071B2|2016-07-26|

---

RU2576609C2|2016-03-10|

---

RU2012156275A|2014-07-20|

---

CA2801645A1|2011-12-08|

---

EP2575804A4|2013-10-23|

---

KR20130088116A|2013-08-07|

---

MX347225B|2017-04-19|

---

US9399072B2|2016-07-26|

---

IL223189A|2018-01-31|

---

JP6257324B2|2018-01-10|

---

MY162903A|2017-07-31|

---

AU2018200347A1|2018-02-15|

---

NZ604031A|2015-05-29|

---

KR20180049180A|2018-05-10|

---

KR20190130050A|2019-11-20|

---

AU2011261685B2|2016-02-11|

---

NI201200179A|2013-02-06|

---

JP2016172771A|2016-09-29|

---

EP2575804A1|2013-04-10|

---

CO6670567A2|2013-05-15|

---

MX2012013910A|2013-02-21|

---

AU2011261685A1|2013-01-10|

---

NZ706745A|2017-01-27|

---

CN106924219A|2017-07-07|

---

SG186112A1|2013-01-30|

---

KR20190038684A|2019-04-08|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US5470571A|1988-01-27|1995-11-28|The Wistar Institute|Method of treating human EGF receptor-expressing gliomas using radiolabeled EGF receptor-specific MAB 425|

---

FR2660556B1|1990-04-06|1994-09-16|Rhone Poulenc Sante|MICROSPHERES, THEIR PREPARATION PROCESS AND THEIR USE.|

---

IL98528D0|1990-06-21|1992-07-15|Merck & Co Inc|Pharmaceutical compositions containing hybrid for killing bladder cancer cells|

---

AU658396B2|1991-03-06|1995-04-13|Merck Patent Gesellschaft Mit Beschrankter Haftung|Humanized and chimeric monoclonal antibodies|

---

US5981568A|1993-01-28|1999-11-09|Neorx Corporation|Therapeutic inhibitor of vascular smooth muscle cells|

---

US6491938B2|1993-05-13|2002-12-10|Neorx Corporation|Therapeutic inhibitor of vascular smooth muscle cells|

---

US6306421B1|1992-09-25|2001-10-23|Neorx Corporation|Therapeutic inhibitor of vascular smooth muscle cells|

---

US6515009B1|1991-09-27|2003-02-04|Neorx Corporation|Therapeutic inhibitor of vascular smooth muscle cells|

---

CA2086874E|1992-08-03|2000-01-04|Renzo Mauro Canetta|Methods for administration of taxol|

---

US6441026B1|1993-11-08|2002-08-27|Aventis Pharma S.A.|Antitumor compositions containing taxane derivatives|

---

US5811447A|1993-01-28|1998-09-22|Neorx Corporation|Therapeutic inhibitor of vascular smooth muscle cells|

---

US5650156A|1993-02-22|1997-07-22|Vivorx Pharmaceuticals, Inc.|Methods for in vivo delivery of nutriceuticals and compositions useful therefor|

---

US5665383A|1993-02-22|1997-09-09|Vivorx Pharmaceuticals, Inc.|Methods for the preparation of immunostimulating agents for in vivo delivery|

---

US8853260B2|1997-06-27|2014-10-07|Abraxis Bioscience, Llc|Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof|

---

US6537579B1|1993-02-22|2003-03-25|American Bioscience, Inc.|Compositions and methods for administration of pharmacologically active compounds|

---

US6528067B1|1993-02-22|2003-03-04|American Bioscience, Inc.|Total nutrient admixtures as stable multicomponent liquids or dry powders and methods for the preparation thereof|

---

US5439686A|1993-02-22|1995-08-08|Vivorx Pharmaceuticals, Inc.|Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor|

---

US6749868B1|1993-02-22|2004-06-15|American Bioscience, Inc.|Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof|

---

US8137684B2|1996-10-01|2012-03-20|Abraxis Bioscience, Llc|Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof|

---

US6096331A|1993-02-22|2000-08-01|Vivorx Pharmaceuticals, Inc.|Methods and compositions useful for administration of chemotherapeutic agents|

---

DE69433723T3|1993-02-22|2008-10-30|Abraxis Bioscience, Inc., Los Angeles|PROCESS FOR IN VIVO ADMINISTRATION OF BIOLOGICAL SUBSTANCES AND COMPOSITIONS USED THEREFROM|

---

US5665382A|1993-02-22|1997-09-09|Vivorx Pharmaceuticals, Inc.|Methods for the preparation of pharmaceutically active agents for in vivo delivery|

---

US6753006B1|1993-02-22|2004-06-22|American Bioscience, Inc.|Paclitaxel-containing formulations|

---

WO1999000113A1|1997-06-27|1999-01-07|Vivorx Pharmaceuticals, Inc.|Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof|

---

CA2684454A1|1999-05-21|2000-11-18|American Bioscience, Llc.|Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof|

---

US5997904A|1993-02-22|1999-12-07|American Bioscience, Inc.|Total nutrient admixtures as stable multicomponent liquids or dry powders and methods for the preparation thereof|

---

US5916596A|1993-02-22|1999-06-29|Vivorx Pharmaceuticals, Inc.|Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof|

---

US20030068362A1|1993-02-22|2003-04-10|American Bioscience, Inc.|Methods and formulations for the delivery of pharmacologically active agents|

---

US5362478A|1993-03-26|1994-11-08|Vivorx Pharmaceuticals, Inc.|Magnetic resonance imaging with fluorocarbons encapsulated in a cross-linked polymeric shell|

---

KR20080043375A|1993-07-19|2008-05-16|더 유니버시티 오브 브리티쉬 콜롬비아|Anti-angiogenic compositions, a stent coated with the anti-angiogenic compositions and a method for manufacturing the stent|

---

US5716981A|1993-07-19|1998-02-10|Angiogenesis Technologies, Inc.|Anti-angiogenic compositions and methods of use|

---

EP0739203A4|1994-01-14|2000-12-20|Cell Therapeutics Inc|Method for treating diseases mediated by cellular proliferation in response to pdgf, egf, fgf and vegf|

---

US5626862A|1994-08-02|1997-05-06|Massachusetts Institute Of Technology|Controlled local delivery of chemotherapeutic agents for treating solid tumors|

---

US5662883A|1995-01-10|1997-09-02|Nanosystems L.L.C.|Microprecipitation of micro-nanoparticulate pharmaceutical agents|

---

US5534270A|1995-02-09|1996-07-09|Nanosystems Llc|Method of preparing stable drug nanoparticles|

---

US5510118A|1995-02-14|1996-04-23|Nanosystems Llc|Process for preparing therapeutic compositions containing nanoparticles|

---

US5609629A|1995-06-07|1997-03-11|Med Institute, Inc.|Coated implantable medical device|

---

US6565842B1|1995-06-07|2003-05-20|American Bioscience, Inc.|Crosslinkable polypeptide compositions|

---

AU716005B2|1995-06-07|2000-02-17|Cook Medical Technologies Llc|Implantable medical device|

---

US5744460A|1996-03-07|1998-04-28|Novartis Corporation|Combination for treatment of proliferative diseases|

---

ES2258790T3|1996-03-12|2006-09-01|Pg-Txl Company, L.P.|WATERPROOF PACLITAXEL PROFARMACOS IN WATER.|

---

US6441025B2|1996-03-12|2002-08-27|Pg-Txl Company, L.P.|Water soluble paclitaxel derivatives|

---

ES2182112T3|1996-07-30|2003-03-01|Novartis Ag|PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF THE REJECTION OF TRANSPLANTS AND OF AUTOIMMUNE OR INFLAMMATORY STATES, THAT INCLUDE CYCLOSPORIN A AND 40-O- -RAPAMICINE.|

---

WO1998007410A1|1996-08-19|1998-02-26|Vivorx Pharmaceuticals, Inc.|Methods for the production of protein particles useful for delivery of pharmacological agents|

---

US6495579B1|1996-12-02|2002-12-17|Angiotech Pharmaceuticals, Inc.|Method for treating multiple sclerosis|

---

MXPA01011981A|1999-05-24|2003-09-04|Sonus Pharma Inc|Emulsion vehicle for poorly soluble drugs.|

---

US6143276A|1997-03-21|2000-11-07|Imarx Pharmaceutical Corp.|Methods for delivering bioactive agents to regions of elevated temperatures|

---

EP1325932B9|1997-04-07|2006-07-19|Genentech, Inc.|Anti-vegf antibodies|

---

US6884879B1|1997-04-07|2005-04-26|Genentech, Inc.|Anti-VEGF antibodies|

---

US20030199425A1|1997-06-27|2003-10-23|Desai Neil P.|Compositions and methods for treatment of hyperplasia|

---

US6258084B1|1997-09-11|2001-07-10|Vnus Medical Technologies, Inc.|Method for applying energy to biological tissue including the use of tumescent tissue compression|

---

RS49779B|1998-01-12|2008-06-05|Glaxo Group Limited,|Byciclic heteroaromatic compounds as protein tyrosine kinase inhibitors|

---

DK1071440T3|1998-04-16|2007-05-14|Eurovita As|New synergistic compositions containing aromatic compounds and terpenoids present in Alpinia galanga|

---

EP1100494A1|1998-07-30|2001-05-23|Novopharm Biotech, Inc.|Pharmaceutically composition comprising an aqueous solution of paclitaxel and albumin|

---

US6682758B1|1998-12-22|2004-01-27|The United States Of America As Represented By The Department Of Health And Human Services|Water-insoluble drug delivery system|

---

US6537585B1|1999-03-26|2003-03-25|Guilford Pharmaceuticals, Inc.|Methods and compositions for treating solid tumors|

---

CA2369740A1|1999-04-22|2000-11-02|American Biosciences, Inc.|Long term administration of pharmacologically active agents|

---

JP2003527337A|1999-11-12|2003-09-16|エントレメッドインコーポレイテッド|Administration method of therapeutic agent based on anti-angiogenic schedule|

---

US7740841B1|2000-01-28|2010-06-22|Sunnybrook Health Science Center|Therapeutic method for reducing angiogenesis|

---

MXPA02009984A|2000-04-10|2004-09-10|Teva Pharma|Method and composition for treating cancer by administration of apoptosis inducing chemotherapeutic agents.|

---

ITMI20001107A1|2000-05-18|2001-11-18|Acs Dobfar Spa|METHOD FOR TREATMENT OF SOLIC TUMORS BY INCORPORATING PACLITAXEL MICROPARTICLES OF ALBUMIN|

---

NZ522989A|2000-06-30|2005-06-24|Glaxo Group Ltd|Quinazoline ditosylate salt compounds|

---

AU2001292548B2|2000-07-28|2005-06-16|Sloan-Kettering Institute For Cancer Research|Methods for treating cell proliferative disorders and viral infections|

---

PL366100A1|2000-09-22|2005-01-24|Bristol-Myers Squibb Company|Method for reducing toxicity of combined chemotherapies|

---

US20040033271A1|2001-12-03|2004-02-19|Seth Lederman|Methods for contemporaneous administration of levamisole and 5-fluorouracil|

---

ES2236481T3|2001-01-16|2005-07-16|Glaxo Group Limited|PHARMACEUTICAL COMBINATION CONTAINING A 4-QUINAZOLINAMINE AND PACLITAXEL, CARBOPLATIN OR VINORELBINE FOR CANCER TREATMENT.|

---

US6548531B2|2001-02-09|2003-04-15|Hoffmann-La Roche Inc.|Method for cancer therapy|

---

GB0103668D0|2001-02-15|2001-03-28|Biointeractions Ltd|Methods and clinical devices for the inhibition or prevention of mammalian cell growth|

---

US20040143004A1|2002-02-26|2004-07-22|Joseph Fargnoli|Metronomic dosing of taxanes|

---

YU69903A|2001-03-06|2006-08-17|Bristol-Myers Squibb Company|Method and dosage form for treating tumors by the administration of tegafur, uracil, folinic acid, paclitaxel and carboplatin|

---

WO2002069949A2|2001-03-06|2002-09-12|Prendergast Patrick T|Combination therapy for reduction of toxycity of chemotherapeutic agents|

---

US6752922B2|2001-04-06|2004-06-22|Fluidigm Corporation|Microfluidic chromatography|

---

US7638161B2|2001-07-20|2009-12-29|Applied Materials, Inc.|Method and apparatus for controlling dopant concentration during BPSG film deposition to reduce nitride consumption|

---

US6872715B2|2001-08-06|2005-03-29|Kosan Biosciences, Inc.|Benzoquinone ansamycins|

---

ITMI20020681A1|2002-03-29|2003-09-29|Acs Dobfar Spa|PROCEDURE FOR THE PRODUCTION OF PACLITAXEL AND ALBUMINA NANOPARTICLES|

---

ITMI20020680A1|2002-03-29|2003-09-29|Acs Dobfar Spa|IMPROVED ANTI-TUMOR COMPOSITION BASED ON PACLITAXEL AND METHOD FOR ITS OBTAINING|

---

US20040126400A1|2002-05-03|2004-07-01|Iversen Patrick L.|Delivery of therapeutic compounds via microparticles or microbubbles|

---

US7794743B2|2002-06-21|2010-09-14|Advanced Cardiovascular Systems, Inc.|Polycationic peptide coatings and methods of making the same|

---

US7038071B2|2002-07-16|2006-05-02|Sonus Pharmaceuticals, Inc.|Platinum compounds|

---

DE60336485D1|2002-08-19|2011-05-05|Pfizer|COMBINATION THERAPY AGAINST HYPERPROLIFERATIVE DISEASES|

---

US20040047835A1|2002-09-06|2004-03-11|Cell Therapeutics, Inc.|Combinatorial drug therapy using polymer drug conjugates|

---

US20050095267A1|2002-12-04|2005-05-05|Todd Campbell|Nanoparticle-based controlled release polymer coatings for medical implants|

---

KR20140027554A|2002-12-09|2014-03-06|아브락시스 바이오사이언스, 엘엘씨|Compositions and methods of delivery of pharmacological agents|

---

DK1585548T3|2002-12-09|2018-09-03|Abraxis Bioscience Llc|COMPOSITIONS AND PROCEDURES FOR THE DELIVERY OF PHARMACOLOGICAL AGENTS|

---

MXPA05007382A|2003-01-10|2005-11-23|Threshold Pharmaceuticals Inc|Treatment of cancer with 2-deoxyglucose.|

---

US7056338B2|2003-03-28|2006-06-06|Conor Medsystems, Inc.|Therapeutic agent delivery device with controlled therapeutic agent release rates|

---

US20060165744A1|2003-05-22|2006-07-27|Neopharm, Inc|Combination liposomal formulations|

---

CA2526085A1|2003-05-30|2005-01-06|Genentech, Inc.|Treatment with anti-vegf antibodies|

---

AR046510A1|2003-07-25|2005-12-14|Regeneron Pharma|COMPOSITION OF A VEGF ANTAGONIST AND AN ANTI-PROLIFERATIVE AGENT|

---

CA2538570A1|2003-09-18|2005-03-31|Combinatorx, Incorporated|Combinations of drugs for the treatment of neoplasms|

---

MXPA06003163A|2003-09-23|2006-06-05|Novartis Ag|Combination of a vegf receptor inhibitor with a chemotherapeutic agent.|

---

WO2005039533A1|2003-10-15|2005-05-06|Medigene Ag|Method of administering cationic liposomes comprising an active drug|

---

US20080045559A1|2003-10-29|2008-02-21|Sonus Pharmaceuticals, Inc.|Tocopherol-modified therapeutic drug compounds|

---

US7223770B2|2003-10-29|2007-05-29|Sonus Pharmaceuticals, Inc.|Tocopherol-modified therapeutic drug compounds|

---

WO2005090372A2|2004-03-15|2005-09-29|Sonus Pharmaceuticals, Inc.|Platinum carboxylate anticancer compounds|

---

US20060003931A1|2004-05-06|2006-01-05|Genentech, Inc.|Crystal structure of the hepatocyte growth factor and methods of use|

---

US8420603B2|2004-05-14|2013-04-16|Abraxis Bioscience, Llc|SPARC and methods of use thereof|

---

JP4689666B2|2004-05-14|2011-05-25|アブラクシスバイオサイエンスリミテッドライアビリティーカンパニー|Therapy using albumin binding protein as a target|

---

JP5234734B2|2004-06-01|2013-07-10|ジェネンテック，インコーポレイテッド|Antibody-drug conjugates and methods|

---

CA2566979A1|2004-06-04|2005-12-15|Genentech, Inc.|Use of a cd20 antibody in treatment of multiple sclerosis|

---

SV2006002143A|2004-06-16|2006-01-26|Genentech Inc|USE OF AN ANTIBODY FOR THE TREATMENT OF CANCER RESISTANT TO PLATINUM|

---

US8772269B2|2004-09-13|2014-07-08|Eisai R&D Management Co., Ltd.|Use of sulfonamide-including compounds in combination with angiogenesis inhibitors|

---

US8735394B2|2005-02-18|2014-05-27|Abraxis Bioscience, Llc|Combinations and modes of administration of therapeutic agents and combination therapy|

---

CA2902071C|2005-02-18|2019-10-08|Neil P. Desai|Combination chemotherapy regimens using albumin/paclitaxel nanoparticles and nucleoside analogs|

---

AU2006237613A1|2005-02-18|2006-10-26|Abraxis Bioscience, Inc.|Q3 SPARC deletion mutant and uses thereof|

---

US20070166388A1|2005-02-18|2007-07-19|Desai Neil P|Combinations and modes of administration of therapeutic agents and combination therapy|

---

JPWO2006090928A1|2005-02-28|2008-07-24|エーザイ・アール・アンド・ディー・マネジメント株式会社|Novel combination of sulfonamide compounds with angiogenesis inhibitors|

---

WO2006117220A2|2005-05-04|2006-11-09|Medigene Ag|Method of administering a cationic liposomal preparation comprising paclitaxel|

---

US20080221135A1|2005-05-13|2008-09-11|Bristol-Myers Squibb Company|Combination therapy|

---

CA2609299A1|2005-05-20|2006-11-23|Array Biopharma Inc.|Raf inhibitor compounds and methods of use thereof|

---

JP5368093B2|2005-08-31|2013-12-18|アブラクシスバイオサイエンス，エルエルシー|Compositions and methods of preparation of poorly water-soluble drugs with increased stability|

---

NZ566696A|2005-08-31|2012-03-30|Abraxis Bioscience Llc|Compositions comprising poorly water soluble pharmaceutical agents and antimicrobial agents|

---

WO2007059116A2|2005-11-14|2007-05-24|Abraxis Bioscience, Inc.|Geldanamycin derivatives and pharmaceutical compositions thereof|

---

WO2007107305A2|2006-03-22|2007-09-27|Medigene Ag|Treatment of triple receptor negative breast cancer|

---

US20080086337A1|2006-08-10|2008-04-10|Patrick Soon-Shiong|Web based integrated information system for sharing patient medical information cross-organizationally|

---

US20080280987A1|2006-08-31|2008-11-13|Desai Neil P|Methods of inhibiting angiogenesis and treating angiogenesis-associated diseases|

---

CN101568332A|2006-08-31|2009-10-28|阿布拉科斯生物科学公司|Methods of inhibiting angiogenesis and treating angiogenesis-associated diseases|

---

PT2117520T|2006-12-14|2018-12-04|Abraxis Bioscience Llc|Breast cancer therapy based on hormone receptor status with nanoparticles comprising taxane|

---

FR2912839B1|2007-02-16|2009-05-15|Soitec Silicon On Insulator|IMPROVING THE QUALITY OF COLD CLEANING INTERFACE BY COLD CLEANING AND HOT COLLAGE|

---

MX2009009537A|2007-03-07|2009-09-16|Abraxis Bioscience Llc|Nanoparticle comprising rapamycin and albumin as anticancer agent.|

---

EP3326630A3|2007-05-03|2018-08-29|Abraxis BioScience, LLC|Methods and compositions for treating pulmonary hypertension|

---

ES2435452T3|2007-06-01|2013-12-19|Abraxis Bioscience, Llc|Methods and compositions to treat recurrent cancer|

---

WO2009009587A2|2007-07-09|2009-01-15|Board Of Regents Of The University Of Nebraska|Apoptosis-modulating protein therapy for proliferative disorders and nanoparticles containing the same|

---

WO2009089098A1|2008-01-03|2009-07-16|Musc Foundation For Research Development|Methods for the treatment of cancers|

---

CA2721153C|2008-04-10|2018-10-02|Abraxis Bioscience, Llc|Compositions of hydrophobic taxane derivatives and uses thereof|

---

RU2010145529A|2008-04-10|2012-05-20|АБРАКСИС БАЙОСАЙЕНС ЭлЭлСи |COMPOSITIONS OF HYDROPHOBIC DERIVATIVES OF TAXANA AND THEIR APPLICATION|

---

CA2746129A1|2008-12-11|2010-06-17|Abraxis Bioscience, Llc|Combination chemotherapy of nanoparticulate taxanes and inhibitors of pro-survival and/or inflammatory signals|

---

EP2405750B1|2009-03-13|2018-05-09|Abraxis BioScience, LLC|Combination therapy with thiocolchicine derivatives|

---

AU2010233097B2|2009-04-10|2016-04-07|Abraxis Bioscience, Llc|Nanoparticle formulations and uses thereof|

---

JP5781500B2|2009-04-15|2015-09-24|アブラクシス バイオサイエンス， エルエルシー|Nanoparticle compositions and methods without prions|

---

WO2011025838A1|2009-08-25|2011-03-03|Abraxis Bioscience, Llc|Combination therapy with nanoparticle compositions of taxane and hedgehog inhibitors|

---

US20110118298A1|2009-11-13|2011-05-19|Infinity Pharmaceuticals, Inc.|Compositions, kits, and methods for identification, assessment, prevention, and therapy of cancer|

---

DK2552438T3|2010-03-26|2016-07-04|Abraxis Bioscience Llc|METHOD FOR THE TREATMENT OF hepatocellular carcinomas|

---

BR112012024442A2|2010-03-29|2017-03-21|Abraxis Bioscience Llc|cancer treatment methods|

---

MX369728B|2010-03-29|2019-11-20|Abraxis Bioscience Llc|Methods of enhancing drug delivery and effectiveness of therapeutic agents.|

---

MX343671B|2010-06-02|2016-11-16|Abraxis Bioscience Llc |Methods of treating bladder cancer.|

---

JP2013530166A|2010-06-03|2013-07-25|アブラクシスバイオサイエンスリミテッドライアビリティーカンパニー|Use of SPARC microenvironment signatures in cancer treatment|

---

MX347225B|2010-06-04|2017-04-19|Abraxis Bioscience Llc |Methods of treatment of pancreatic cancer.|

---

CN103037846B|2010-06-07|2016-03-02|阿布拉科斯生物科学有限公司|The combinational therapeutic methods for the treatment of proliferative disease|

---

CN103648521A|2011-04-28|2014-03-19|阿布拉科斯生物科学有限公司|Intravascular delivery of nanoparticle compositions and uses thereof|

---

CN109771377A|2011-12-14|2019-05-21|阿布拉科斯生物科学有限公司|The polymeric excipient for being lyophilized or freezing for particle|

---

US9149455B2|2012-11-09|2015-10-06|Abraxis Bioscience, Llc|Methods of treating melanoma|

---

US20140186447A1|2012-12-28|2014-07-03|Abraxis Bioscience, Llc|Nanoparticle compositions of albumin and paclitaxel|

---

US20140199404A1|2013-01-11|2014-07-17|Abraxis Bioscience, Llc|Method for treating cancer based on level of a nucleoside transporter|

---

US20140199405A1|2013-01-11|2014-07-17|Abraxis Bioscience, Llc|Method for treating cancer based on mutation status of k-ras|

---

US9511046B2|2013-01-11|2016-12-06|Abraxis Bioscience, Llc|Methods of treating pancreatic cancer|

---

KR102191311B1|2013-03-12|2020-12-15|아브락시스 바이오사이언스, 엘엘씨|Methods of treating lung cancer|

---

EP2968253A4|2013-03-13|2016-11-02|Abraxis Bioscience Llc|Methods of treatment of pediatric solid tumor|

---

AU2014236802B2|2013-03-14|2019-01-03|Abraxis Bioscience, Llc|Methods of treating bladder cancer|US8853260B2|1997-06-27|2014-10-07|Abraxis Bioscience, Llc|Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof|

---

DK1585548T3|2002-12-09|2018-09-03|Abraxis Bioscience Llc|COMPOSITIONS AND PROCEDURES FOR THE DELIVERY OF PHARMACOLOGICAL AGENTS|

---

CA2902071C|2005-02-18|2019-10-08|Neil P. Desai|Combination chemotherapy regimens using albumin/paclitaxel nanoparticles and nucleoside analogs|

---

US8735394B2|2005-02-18|2014-05-27|Abraxis Bioscience, Llc|Combinations and modes of administration of therapeutic agents and combination therapy|

---

NZ566696A|2005-08-31|2012-03-30|Abraxis Bioscience Llc|Compositions comprising poorly water soluble pharmaceutical agents and antimicrobial agents|

---

PT2117520T|2006-12-14|2018-12-04|Abraxis Bioscience Llc|Breast cancer therapy based on hormone receptor status with nanoparticles comprising taxane|

---

MX2009009537A|2007-03-07|2009-09-16|Abraxis Bioscience Llc|Nanoparticle comprising rapamycin and albumin as anticancer agent.|

---

ES2435452T3|2007-06-01|2013-12-19|Abraxis Bioscience, Llc|Methods and compositions to treat recurrent cancer|

---

JP5781500B2|2009-04-15|2015-09-24|アブラクシス バイオサイエンス， エルエルシー|Nanoparticle compositions and methods without prions|

---

DK2552438T3|2010-03-26|2016-07-04|Abraxis Bioscience Llc|METHOD FOR THE TREATMENT OF hepatocellular carcinomas|

---

BR112012024442A2|2010-03-29|2017-03-21|Abraxis Bioscience Llc|cancer treatment methods|

---

MX369728B|2010-03-29|2019-11-20|Abraxis Bioscience Llc|Methods of enhancing drug delivery and effectiveness of therapeutic agents.|

---

MX347225B|2010-06-04|2017-04-19|Abraxis Bioscience Llc |Methods of treatment of pancreatic cancer.|

---

CN103037846B|2010-06-07|2016-03-02|阿布拉科斯生物科学有限公司|The combinational therapeutic methods for the treatment of proliferative disease|

---

CN103648521A|2011-04-28|2014-03-19|阿布拉科斯生物科学有限公司|Intravascular delivery of nanoparticle compositions and uses thereof|

---

CN109771377A|2011-12-14|2019-05-21|阿布拉科斯生物科学有限公司|The polymeric excipient for being lyophilized or freezing for particle|

---

PL2833905T3|2012-04-04|2019-01-31|Halozyme, Inc.|Combination therapy with hyaluronidase and a tumor-targeted taxane|

---

AU2013202947B2|2012-06-13|2016-06-02|Ipsen Biopharm Ltd.|Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan|

---

US9149455B2|2012-11-09|2015-10-06|Abraxis Bioscience, Llc|Methods of treating melanoma|

---

US9511046B2|2013-01-11|2016-12-06|Abraxis Bioscience, Llc|Methods of treating pancreatic cancer|

---

KR102191311B1|2013-03-12|2020-12-15|아브락시스 바이오사이언스, 엘엘씨|Methods of treating lung cancer|

---

AU2014236802B2|2013-03-14|2019-01-03|Abraxis Bioscience, Llc|Methods of treating bladder cancer|

---

CN105792845A|2013-07-26|2016-07-20|施瑞修德制药公司|Treatment of pancreatic cancer with a combination of a hypoxia-activated prodrug and a taxane|

---

WO2015018380A2|2014-07-03|2015-02-12|Cspc Zhongqi Pharmaceutical TechnologyCo., Ltd.|Therapeutic nanoparticles and the preparation methods thereof|

---

US10705070B1|2015-03-05|2020-07-07|Abraxis Bioscience, Llc|Methods of assessing suitability of use of pharmaceutical compositions of albumin and poorly water soluble drug|

---

US10527604B1|2015-03-05|2020-01-07|Abraxis Bioscience, Llc|Methods of assessing suitability of use of pharmaceutical compositions of albumin and paclitaxel|

---

CN108024999A|2015-06-29|2018-05-11|阿布拉科斯生物科学有限公司|The method for treating epithelioid cell's tumour|

---

PT3337467T|2015-08-20|2021-01-25|Ipsen Biopharm Ltd|Combination therapy using liposomal irinotecan and a parp inhibitor for cancer treatment|

---

US9943505B2|2016-09-09|2018-04-17|Corcept Therapeutics, Inc.|Glucocorticoid receptor modulators to treat pancreatic cancer|

---

EA201990979A1|2016-11-02|2019-09-30|Ипсен Биофарм Лтд.|METHODS FOR TREATING GASTROINTESTINAL CANCER USING COMBINATION TYPES OF THERAPY CONTAINING LIPOSOMAL IRINOTECAN AND OXALALPLATIN|

---

EP3873445A1|2018-10-30|2021-09-08|Institute For Cancer Research d/b/a The Research Institute of Fox Chase Cancer Center|Combination therapies for treating cancer|

---

RU2706346C1|2019-07-24|2019-11-18|ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "РОССИЙСКИЙ НАУЧНЫЙ ЦЕНТР РАДИОЛОГИИ И ХИРУРГИЧЕСКИХ ТЕХНОЛОГИЙ ИМЕНИ АКАДЕМИКА А.М. ГРАНОВА" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ / ФГБУ "РНЦРХТ им. ак. А.М. Гранова" Минздрава России|Method of treating operable gastric adenocarcinoma|

---

RU2706786C1|2019-07-24|2019-11-21|ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "РОССИЙСКИЙ НАУЧНЫЙ ЦЕНТР РАДИОЛОГИИ И ХИРУРГИЧЕСКИХ ТЕХНОЛОГИЙ ИМЕНИ АКАДЕМИКА А.М. ГРАНОВА" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ / ФГБУ "РНЦРХТ им. ак. А.М. Гранова" Минздрава России|Method of treating inoperable pancreatic adenocarcinoma with liver metastases|

---

RU2706347C1|2019-07-24|2019-11-18|ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "РОССИЙСКИЙ НАУЧНЫЙ ЦЕНТР РАДИОЛОГИИ И ХИРУРГИЧЕСКИХ ТЕХНОЛОГИЙ ИМЕНИ АКАДЕМИКА А.М. ГРАНОВА" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ / ФГБУ "РНЦРХТ им. ак. А.М. Гранова" Минздрава России|Method of treating operable pancreatic head adenocarcinoma|

---

RU2706341C1|2019-07-24|2019-11-18|ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "РОССИЙСКИЙ НАУЧНЫЙ ЦЕНТР РАДИОЛОГИИ И ХИРУРГИЧЕСКИХ ТЕХНОЛОГИЙ ИМЕНИ АКАДЕМИКА А.М. ГРАНОВА" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ / ФГБУ "РНЦРХТ им. ак. А.М. Гранова" Минздрава России|Method of treating inoperable pancreatic head adenocarcinoma|

法律状态:
2020-09-01| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2020-09-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

---

2021-09-08| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO EM FUNCAO DA REVOGACAO DO ART. 229-C DA LEI NO 9.279, DE 1996, POR FORCA DA LEI NO 14.195, DE 2021 |

---

2021-09-14| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

---

2021-12-28| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|

优先权:

---

申请号 | 申请日 | 专利标题

---

US35184610P| true| 2010-06-04|2010-06-04|

---

US61/351,846|2010-06-04|

---

US37703510P| true| 2010-08-25|2010-08-25|

---

US61/377,035|2010-08-25|

---

US201161446932P| true| 2011-02-25|2011-02-25|

---

US61/446,932|2011-02-25|

---

PCT/US2011/037462|WO2011153010A1|2010-06-04|2011-05-20|Methods of treatment of pancreatic cancer|

---