Antineoplastic Combinations with mTOR Inhibitor, Trastuzumab and/or HKI-272

Abstract

A combination of temsirolimus and trastuzumab in the treatment of cancer is provided. A combination of temsirolimus and HKI-272 is provided. A combination of a trastuzumab and a HKI-272 is also provided. Regimens and kits for treatment of metastatic breast cancer, containing trastuzumab, temsirolimus and/or HKI-272, optionally in combination with other anti-neoplastic agents, or immune modulators are described.

1 . A method of treating a neoplasm associated with overexpression or amplification of HER2 in a mammal in need thereof, which comprises providing to said mammal an effective amount of a combination of active components comprising a trastuzumab and a (E)-N-{4-[3-chloro-4-(2-pyridinyl methoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide (HKI-272). 
     
     
         2 . The method according to  claim 1 , wherein the combination further comprises an mTOR inhibitor. 
     
     
         3 . The method according to  claim 1 , wherein one or more of the active components is provided in subtherapeutically effective amounts. 
     
     
         4 . The method according to  claim 1 , wherein the neoplasm is selected from the group consisting of lung cancers, including bronchioalveolar carcinoma and non small cell lung cancer; breast cancers; myeloma; prostate cancers; head and neck cancer; transitional cell carcinoma; and small cell and large cell neuroendocrine carcinoma of the uterine cervix. 
     
     
         5 . The method according to  claim 4 , wherein the neoplasm is metastatic breast cancer. 
     
     
         6 . The method according to  claim 1 , wherein said combination further comprises another active component selected from the group consisting of one or more antineoplastic alkylating agent, one or more antimetabolite antineoplastic agents, one or more biochemical immune modulators, imatinib, one or more EGFR inhibitors, a multi-kinase inhibitor that targets serine/threonine and receptor tyrosine kinases in both the tumor cell and tumor vasculature or an interferon. 
     
     
         7 . The method according to  claim 6 , wherein said antineoplastic agents are selected from the group consisting of meclorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, thiotepa, mitomycin, busulfan, lomustine, carmustine, procarbazine, temozolomide, oxaliplatin, cisplatin, and carboplatin. 
     
     
         8 . The method according to  claim 6 , wherein the antimetabolite antineoplastic agent is selected from the group consisting of: 5-fluorouracil; floxuradine; thioguanine; cytarabine; fludarabine; 6-mercaptopurine; methotrexate; gemcitabine; capecitabine; taxanes; pentostatin; trimetrexatel; and cladribine. 
     
     
         9 . The method according to  claim 6 , wherein the biochemical modulating agent is selected from the group consisting of leucovorin and levofolinate. 
     
     
         10 . The method according to  claim 9 , wherein the combination further comprises a taxane. 
     
     
         11 . A regimen for treatment of breast cancer associated with overexpression or amplification of HER2, said method comprising:
 delivering a dosage amount of a trastuzumab; and   delivering a dose of a (E)-N-{4-[3-chloro-4-(2-pyrridinyl methoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide (HKI-272).   
     
     
         12 . The regimen according to  claim 11 , wherein the HKI-272 and/or the trastuzumab is delivered intravenously. 
     
     
         13 . The regimen according to  claim 11 , wherein the HKI-272 and/or the trastuzumab is delivered weekly. 
     
     
         14 . The regimen according to  claim 11 , wherein the HKI-272 and/or the trastuzumab is delivered orally. 
     
     
         15 . The regimen according to  claim 11 , wherein the trastuzumab is delivered for at least two weeks following at least one week off. 
     
     
         16 . The regimen according to  claim 11 , wherein the trastuzumab is delivered for a period of four weeks followed by two weeks off. 
     
     
         17 . The regimen according to  claim 11 , wherein the trastuzumab is delivered once every three to four weeks. 
     
     
         18 . The regimen according to  claim 11 , wherein the HKI-272 is delivered orally. 
     
     
         19 . A product containing a trastuzumab and a (E)-N-{4-[3-chloro-4-(2-pyridinyl methoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide (HKI-272) as a combined preparation for simultaneous, separate or sequential use in treating a neoplasm in a mammal. 
     
     
         20 . A pharmaceutical pack containing a course of an anti-neoplastic treatment for one individual mammal, wherein the pack contains (a) at least one unit of a trastuzumab and (b) at least one unit of a (E)-N-{4-[3-chloro-4-(2-pyridinyl methoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide (HKI-272) in unit dosage form. 
     
     
         21 . A pharmaceutical composition useful in treating a neoplasm in a mammal, the composition comprising (a) at least one unit of a trastuzumab and (b) at least one unit of a (E)-N-{4-[3-chloro-4-(2-pyridinyl methoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide (HKI-272), in unit dosage form, and at least one pharmaceutically acceptable carrier.