Combination Therapy with an Antitumor Alkaloid

Abstract

The present invention relates to the combination of PM01183 with several anticancer drugs, in particular other anticancer drugs selected from antitumor platinum coordination complexes, antimetabolites, mitotic inhibitors, anticancer antibiotics, topoisomerase I and/or II inhibitors, proteasome inhibitors, histone deacetylase inhibitors, nitrogen mustard alkylating agents, nitrosourea alkylating agents, nonclassical alkylating agents, estrogen antagonists, androgen antagonists, mTOR inhibitors, tyrosine kinase inhibitors, and other agents selected from aplidine, ET-743, PM02734 and PM00104, and the use of these combinations in the treatment of cancer.

1 . A method of treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of PM01183, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of another anticancer drug selected from antimetabolites, proteasome inhibitors, nonclassical alkylating agents, mTOR inhibitors, tyrosine kinase inhibitors, histone deacetylase inhibitors, anticancer antibiotics, antitumor platinum coordination complexes, mitotic inhibitors, topoisomerase I and/or II inhibitors, nitrogen mustard alkylating agents, nitrosourea alkylating agents, estrogen antagonists, androgen antagonists, and other agents selected from aplidine, ET-743, PM02734 and PM00104. 
     
     
         2 . A method of increasing the therapeutic efficacy of an anticancer drug selected from antimetabolites, proteasome inhibitors, nonclassical alkylating agents, mTOR inhibitors, tyrosine kinase inhibitors, histone deacetylase inhibitors, anticancer antibiotics, antitumor platinum coordination complexes, mitotic inhibitors, topoisomerase I and/or II inhibitors, nitrogen mustard alkylating agents, nitrosourea alkylating agents, estrogen antagonists, androgen antagonists, and other agents selected from aplidine, ET-743, PM02734 and PM00104 in the treatment of cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of PM01183, or a pharmaceutically acceptable salt thereof, in conjunction with said anticancer drug. 
     
     
         3 - 38 . (canceled) 
     
     
         39 . The method according to  claim 1 , wherein the cancer to be treated is selected from lung cancer, sarcoma, malignant melanoma, bladder carcinoma, prostate cancer, pancreas carcinoma, thyroid cancer, gastric carcinoma, ovarian cancer, hepatoma, breast cancer, colorectal cancer, kidney cancer, esophageal cancer, neuroblastoma, brain cancer, cervical cancer, anal cancer, testicular cancer, leukemia, multiple myeloma and lymphoma. 
     
     
         40 . The method according to  claim 39 , wherein PM01183, or a pharmaceutically acceptable salt thereof, and the other anticancer drug selected from antimetabolites, proteasome inhibitors, nonclassical alkylating agents, mTOR inhibitors, tyrosine kinase inhibitors, histone deacetylase inhibitors, anticancer antibiotics, antitumor platinum coordination complexes, mitotic inhibitors, topoisomerase I and/or II inhibitors, nitrogen mustard alkylating agents, nitrosourea alkylating agents, estrogen antagonists, androgen antagonists, and other agents selected from aplidine, ET-743, PM02734 and PM00104 form part of the same medicament. 
     
     
         41 . The method according to  claim 39 , wherein PM01183, or a pharmaceutically acceptable salt thereof, and the other anticancer drug selected from antimetabolites, proteasome inhibitors, nonclassical alkylating agents, mTOR inhibitors, tyrosine kinase inhibitors, histone deacetylase inhibitors, anticancer antibiotics, antitumor platinum coordination complexes, mitotic inhibitors, topoisomerase I and/or II inhibitors, nitrogen mustard alkylating agents, nitrosourea alkylating agents, estrogen antagonists, androgen antagonists, at and other agents selected from aplidine, ET-743, PM02734 and PM00104 are provided as separate medicaments for administration at the same time or at different times. 
     
     
         42 . The method according to  claim 41 , wherein PM01183, or a pharmaceutically acceptable salt thereof, and the other anticancer drug selected from antimetabolites, proteasome inhibitors, nonclassical alkylating agents, mTOR inhibitors, tyrosine kinase inhibitors, histone deacetylase inhibitors, anticancer antibiotics, antitumor platinum coordination complexes, mitotic inhibitors, topoisomerase I and/or II inhibitors, nitrogen mustard alkylating agents, nitrosourea alkylating agents, estrogen antagonists, androgen antagonists, and other agents selected from aplidine, ET-743, PM02734 and PM00104 are provided as separate medicaments for administration at different times. 
     
     
         43 . The method according to  claim 42 , wherein the other anticancer drug combines with PM01183, or a pharmaceutically acceptable salt thereof, is an antimetabolite. 
     
     
         44 . The method according to  claim 43 , wherein the antimetabolite is selected from 5-fluorouracil, gemcitabine, cytarabine, capecitabine, decitabine, floxuridine, fludarabine, aminopterin, methotrexate, pemetrexed, raltitrexed, cladribine, clofarabine, mercaptopurine, pentostatin, and thioguanine. 
     
     
         45 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is a proteasome inhibitor. 
     
     
         46 . The method according to  claim 45 , wherein the proteasome inhibitor is selected from bortezomib, disulfiram, epigallocatechin gallate, and salinosporamide A. 
     
     
         47 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is a nonclassical alkylating agent. 
     
     
         48 . The method according to  claim 47 , wherein the nonclassical alkylating agent is selected from procarbazine, dacarbazine, temozolomide and altretamine. 
     
     
         49 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is an mTOR inhibitor. 
     
     
         50 . The method according to  claim 49 , wherein the mTOR inhibitor is selected from sirolimus, temsirolimus, everolimus, ridaforolimus, KU-0063794 and WYE-354. 
     
     
         51 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is a tyrosine kinase inhibitor. 
     
     
         52 . The method according to  claim 51 , wherein the tyrosine kinase inhibitor is selected from erlotinib, sorafenib, axitinib bosutinib, cediranib crizotinib, dasatinib, gefitinib, imatinib, canertinib, lapatinib, lestaurtinib, neratinib, nilotinib, semaxanib, vatalanib and vandetanib. 
     
     
         53 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is a histone deacetylase inhibitor. 
     
     
         54 . The method according to  claim 53 , wherein the histone deacetylase inhibitor is selected from romidepsin, panobinostat, vorinostat, mocetinostat, belinostat, entinostat, resminostat, PCI-24781 AR-42, CUDC-101 and valproic acid. 
     
     
         55 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is an anticancer antibiotic. 
     
     
         56 . The method according to  claim 55 , wherein the anticancer antibiotic is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pixantrone, valrubicin, mitomycin C, Neomycin, actinomycin A and mithramycin. 
     
     
         57 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is an antitumor platinum coordination complex. 
     
     
         58 . The method according to  claim 57 , wherein the antitumor platinum coordination complex is selected from cisplatin, oxaliplatin, carboplatin, triplatin tetranitrate, satraplatin, tetraplatin, ormiplatin, iproplatin, nedaplatin and lobaplatin. 
     
     
         59 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is a mitotic inhibitor. 
     
     
         60 . The method according to  claim 59 , wherein the mitotic inhibitor is selected from paclitaxel, docetaxel, vinblastine, vincristine, vindesine, and vinorelbine. 
     
     
         61 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or al pharmaceutically acceptable salt thereof, is a topoisomerase I and/or II inhibitor. 
     
     
         62 . The method according to  claim 61 , wherein the topoisomerase I and/or II inhibitor is selected from topotecan, SN-8, irinotecan, camptothecin, rubitecan, etoposide, amsacrine and teniposide. 
     
     
         63 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is a nitrogen mustard alkylating agent. 
     
     
         64 . The method according to  claim 63 , wherein the nitrogen mustard alkylating agent is selected from melphalan, ifosfamide, chlorambucil, cyclophosphamide, mechlorethamine, uramustine, estramustine and bendamustine. 
     
     
         65 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is a nitrosourea alkylating agent. 
     
     
         66 . The method according to  claim 65 , wherein the nitrosourea alkylating agent is selected from lomustine, semustine, carmustine, fotemustine and streptozotocin. 
     
     
         67 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is an estrogen antagonist. 
     
     
         68 . The method according to  claim 67 , wherein the estrogen antagonist is selected from toremifene, fulvestrant, tamoxifen and nafoxidine. 
     
     
         69 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is an androgen antagonist. 
     
     
         70 . The method according to  claim 69 , wherein the androgen antagonist is selected from bicalutamide, flutamide, MDV3100 and nilutamide. 
     
     
         71 . The method according to  claim 42 , wherein the other anticancer drug combined with PM01183, or a pharmaceutically acceptable salt thereof, is selected from aplidine, ET-743, PM02734 and PM00104. 
     
     
         72 . A kit for use in the treatment of cancer which comprises a dosage form of PM01183, or a pharmaceutically acceptable salt thereof, and/or a dosage form of another anticancer drug selected from antimetabolites, proteasome inhibitors, nonclassical alkylating agents, mTOR inhibitors, tyrosine kinase inhibitors, histone deacetylase inhibitors, anticancer antibiotics, antitumor platinum coordination complexes, mitotic inhibitors, topoisomerase I and/or II inhibitors, nitrogen mustard alkylating agents, nitrosourea alkylating agents, estrogen antagonists, androgen antagonists, and other agents selected from aplidine, ET-743, PM02734 and PM00104, and instructions for the use of both drugs in combination.