Combinations of an anti-her2 antibody-drug conjugate and chemotherapeutic agents, and methods of use

Abstract

Combinations of the antibody-drug conjugate trastuzumab-MCC-DM1 and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting tumor cell growth, and for treating disorders such as cancer mediated by HER2 and KDR (VEGFR receptor 1). Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

We claim: 
     
         1 . A method for the treatment of a hyperproliferative disorder comprising administering a therapeutic combination as a combined formulation or by alternation to a mammal, wherein the therapeutic combination comprises a therapeutically effective amount of trastuzumab-MCC-DM1, and a therapeutically effective amount of a chemotherapeutic agent selected from a HER2 dimerization inhibitor antibody, lapatinib, and docetaxel. 
     
     
         2 . The method of  claim 1  wherein the HER2 dimerization inhibitor antibody is pertuzumab. 
     
     
         3 . The method of  claim 1  wherein the chemotherapeutic agent is lapatinib. 
     
     
         4 . The method of  claim 1  wherein the chemotherapeutic agent is docetaxel. 
     
     
         5 . The method of  claim 1  wherein the therapeutically effective amount of trastuzumab-MCC-DM1 and the therapeutically effective amount of the chemotherapeutic agent are administered as a combined formulation. 
     
     
         6 . The method of  claim 1  wherein the therapeutically effective amount of trastuzumab-MCC-DM1 and the therapeutically effective amount of the chemotherapeutic agent are administered by alternation. 
     
     
         7 . The method of  claim 6  wherein the mammal is administered the chemotherapeutic agent and then subsequently administered trastuzumab-MCC-DM1. 
     
     
         8 . The method of  claim 5  wherein the combined formulation is administered at about three week intervals to a human subject with the hyperproliferative disorder. 
     
     
         9 . The method of  claim 6  wherein trastuzumab-MCC-DM1 is administered at intervals from about one week to three weeks to a human subject with the hyperproliferative disorder. 
     
     
         10 . The method of  claim 6  wherein trastuzumab-MCC-DM1 is administered at about three week intervals to a human subject with the hyperproliferative disorder. 
     
     
         11 . The method of  claim 1  wherein administration of the therapeutic combination results in a synergistic effect. 
     
     
         12 . The method of  claim 1  wherein the hyperproliferative disorder is cancer. 
     
     
         13 . The method of  claim 12  wherein the hyperproliferative disorder is a cancer expressing ErbB2. 
     
     
         14 . The method of  claim 13  wherein the cancer is breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, pancreatic, myeloid disorders, lymphoma, hairy cells, buccal cavity, nasopharyngeal, pharynx, lip, tongue, mouth, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's or leukemia. 
     
     
         15 . The method of  claim 14  wherein the cancer is breast, ovary or stomach cancer. 
     
     
         16 . The method of  claim 15  wherein the cancer is breast cancer. 
     
     
         17 . The method of  claim 1  wherein the amount of trastuzumab-MCC-DM1 and the amount of chemotherapeutic agent are each from about 1 mg to about 1000 mg. 
     
     
         18 . The method of  claim 1  wherein the amount of trastuzumab-MCC-DM1 and the amount of chemotherapeutic agent are in a ratio of about 1:10 to about 10:1 by weight. 
     
     
         19 . The method of  claim 1  wherein the mammal is a HER2 positive human subject. 
     
     
         20 . The method of  claim 19  wherein the hyperproliferative disorder is HER2 positive cancer. 
     
     
         21 . The method of  claim 20  wherein the cancer is HER2 positive breast, ovary or stomach cancer. 
     
     
         22 . The method of  claim 21  wherein the cancer is HER2 positive breast cancer. 
     
     
         23 . The method of  claim 22  wherein the breast cancer is metastatic breast cancer. 
     
     
         24 . The method of  claim 19  wherein the HER2 positive human subject has received trastuzumab or lapatinib therapy. 
     
     
         25 . The method of any one of  claims 8 - 10  wherein the trastuzumab-MCC-DM1 is administered at a dose of 2.4, 3.0 or 3.6 mg/kg intravenously. 
     
     
         26 . The method of  claim 19  wherein the trastuzumab-MCC-DM1 is administered at a dose of 2.4, 3.0 or 3.6 mg/kg intravenously. 
     
     
         27 . The method of  claim 21  or  claim 22  wherein the trastuzumab-MCC-DM1 is administered at a dose of 2.4, 3.0 or 3.6 mg/kg intravenously. 
     
     
         28 . The method of  claim 27  wherein the trastuzumab-MCC-DM1 is administered at a dose of 3.6 mg/kg intravenously. 
     
     
         29 . A pharmaceutical composition comprising trastuzumab-MCC-DM1, a chemotherapeutic agent selected from a HER2 dimerization inhibitor antibody, lapatinib, and docetaxel, and one or more pharmaceutically acceptable carrier, glidant, diluent, or excipient. 
     
     
         30 . The pharmaceutical composition of  claim 29  comprising a pharmaceutically acceptable glidant selected from silicon dioxide, powdered cellulose, microcrystalline cellulose, metallic stearates, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, corn starch, magnesium carbonate, asbestos free talc, stearowet C, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof. 
     
     
         31 . The pharmaceutical composition of  claim 29  wherein the amount of trastuzumab-MCC-DM1 and the amount of chemotherapeutic agent are each present from about 1 mg to about 1000 mg. 
     
     
         32 . The pharmaceutical composition of  claim 29  wherein the amount of trastuzumab-MCC-DM1 and the amount of chemotherapeutic agent are present in a ratio of about 1:10 to about 10:1 by weight. 
     
     
         33 . An article of manufacture for treating a hyperproliferative disorder comprising:
 a) a therapeutic combination administered to a mammal as a combined formulation or by alternation, and comprising a therapeutically effective amount of trastuzumab-MCC-DM1, and a therapeutically effective amount of a chemotherapeutic agent selected from a HER2 dimerization inhibitor antibody, lapatinib, and docetaxel; and   b) instructions for use.   
     
     
         34 . A method for determining compounds to be used in combination for the treatment of cancer comprising:
 a) administering a therapeutic combination of trastuzumab-MCC-DM1 and a chemotherapeutic agent selected from a HER2 dimerization inhibitor antibody, lapatinib, and docetaxel, to HER2-amplified breast cancer cells, and   b) measuring inhibition of cellular proliferation wherein nonmalignant and malignant mammary cells are discriminated by cell viability.   
     
     
         35 . The method of  claim 34  wherein the HER2-amplified breast cancer cells are BT-474. 
     
     
         36 . A method for determining a synergistic therapeutic combination to be used for the treatment of cancer comprising:
 a) treating an in vitro tumor cell line with a combination of trastuzumab-MCC-DM1, and a chemotherapeutic agent selected from a HER2 dimerization inhibitor antibody, lapatinib, and docetaxel, and   b) measuring a synergistic or non-synergistic effect;   whereby a synergistic therapeutic combination for the treatment of cancer is determined.   
     
     
         37 . A method for the treatment of a cancer expressing ErbB2 comprising administering trastuzumab-MCC-DM1 intravenously once every three weeks to a patient having the cancer at a dose of 2.4 mg/kg, 3.0 mg/kg, or 3.6 mg/kg. 
     
     
         38 . The method of  claim 37 , wherein the trastuzumab-MCC-DM1 is administered at a dose of 3.6 mg/kg intravenously. 
     
     
         39 . The method of  claim 37 , wherein the cancer expressing ErbB2 is breast cancer. 
     
     
         40 . The method of  claim 39 , wherein the breast cancer is metastatic breast cancer. 
     
     
         41 . The method of  claim 37 , wherein the patient is a HER2 positive patient. 
     
     
         42 . The method of  claim 41 , wherein the HER2 positive patient has received trastuzumab or lapatinib therapy.