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BR-PI0906181-B1 - KIT, METHOD FOR DETERMINING A THERAPEUTIC COMBINATION AND USE OF A THERAPEUTIC COMBINATION

Abstract

PHARMACEUTICAL COMPOSITION, ARTICLE OF MANUFACTURE, METHODS FOR DETERMINING COMPOUNDS AND FOR DETERMINING A THERAPEUTIC COMBINATION AND USE OF A THERAPEUTIC COMBINATION. The present invention relates to combinations of the antibody-drug conjugate, trastuzumab-MCC-DM1, and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, solvates, metabolites, and pharmaceutically acceptable salts thereof, which are useful for inhibiting the growth of tumor cells and for treating disorders such as HER2- and KDR-mediated (VEGFR receptor 1) cancer. Methods for using combinations for in vitro, in situ, and in vivo diagnosis, prevention, or treatment of these disorders in mammalian cells, or associated pathological conditions, are disclosed.

Inventors

  • Leanne Berry
  • GAIL LEWIS PHILLIPS
  • MARK X. SLIWKOWSKI

Assignees

  • GENENTECH, INC

Dates

Publication Date
20260317
Application Date
20090310
Priority Date
20080318

Claims (16)

  1. 1. A kit for the treatment of a hyperproliferative disorder, characterized by comprising a therapeutic combination administered to a mammal as a combined formulation, and comprising a therapeutically effective amount of trastuzumab-MCC-DM1, and a therapeutically effective amount of a chemotherapeutic agent selected from pertuzumab, lapatinib, docetaxel, GDC-0941 and GNE-390.
  2. 2. METHOD FOR DETERMINING A THERAPEUTIC COMBINATION, to be used for the treatment of cancer, characterized in that it comprises: (a) treating a tumor cell line in vitro with a therapeutic combination of trastuzumab-MCC-DM1 and a chemotherapeutic agent selected from pertuzumab, lapatinib, docetaxel, GDC-0941 and GNE-390; and (b) measuring a synergistic or non-synergistic effect; whereby a synergistic therapeutic combination for the treatment of cancer is determined.
  3. 3. USE OF A THERAPEUTIC COMBINATION, characterized in that it is for the manufacture of a medicament to treat a hyperproliferative dysfunction, wherein the therapeutic combination comprises a therapeutically effective amount of trastuzumab-MCC-DM1, and a therapeutically effective amount of a chemotherapeutic agent selected from pertuzumab, lapatinib, docetaxel, GDC-0941 and GNE-390.
  4. 4. USE, according to claim 3, characterized in that the HER2 dimerization inhibitor antibody is pertuzumab.
  5. 5. USE, according to claim 3, characterized in that the chemotherapeutic agent is lapatinib.
  6. 6. USE, according to claim 3, characterized in that the chemotherapeutic agent is docetaxel.
  7. 7. USE, according to claim 3, characterized in that the chemotherapeutic agent is GDC-0941.
  8. 8. USE, according to claim 3, characterized in that the chemotherapeutic agent is GNE-390.
  9. 9. USE, according to claim 3, characterized in that administration of the therapeutic combination results in a synergistic effect.
  10. 10. USE, according to claim 3, characterized in that hyperproliferative dysfunction is cancer.
  11. 11. USE, according to claim 10, characterized in that hyperproliferative dysfunction is a cancer that expresses ErbB2.
  12. 12. USE, according to claim 10, characterized in that the cancer is breast, ovarian, cervical, prostate, testicular, genitourinary tract, esophageal, laryngeal, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, squamous cell 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 and biliary tract carcinoma, renal carcinoma, pancreatic, myeloid dysfunctions, lymphoma, hairy cells, oral cavity, nasopharyngeal, pharynx, lip, tongue, mouth, small intestine, colorectal, large intestine, rectum, brain, central nervous system, Hodgkin's disease or leukemia.
  13. 13. USE, according to claim 3, characterized in that the amount of trastuzumab-MCC-DM1 and the amount of the chemotherapeutic agent are each from 1 mg to 1000 mg.
  14. 14. USE, according to claim 3, characterized in that the amount of trastuzumab-MCC-DM1 and the amount of the chemotherapeutic agent are in a ratio of 1:10 to 10:1, by weight.
  15. 15. USE, according to claim 3, characterized in that the mammal is a HER2-positive patient.
  16. 16. USE, according to claim 3, characterized in that the HER2-positive patient received therapy with trastuzumab or lapatinib.

Description

Cross-referencing to related patent applications. [001] The present non-provisional application filed pursuant to 37 CFR §1.53 claims priority pursuant to 35 USC §119(e) of provisional patent application US 61/037,410, filed March 18, 2008, which is incorporated in full into the present application by reference. FIELD OF THE INVENTION [002] The present invention relates generally to pharmaceutical combinations of compounds with activity against hyperproliferative disorders such as cancer. The present invention also relates to methods of using combinations of compounds for in vitro, in situ and in vivo diagnosis, treatment of mammalian cells or associated pathological conditions. BACKGROUND OF THE INVENTION [003] The her2 tyrosine receptor (ErbB2) is a member of the epidermal growth factor transmembrane receptor (EGFR) family. HER2 overexpression is observed in approximately 20% of breast cancers and is involved in the aggressive growth and poor clinical response associated with these tumors (Slamon et al. (1987) Science 235:177-182). [004] Trastuzumab (CAS 180288-69-1, HERCEPTIN®, huMAb4D5-8, rhuMAb HER2, Genentech) is a humanized, recombinant DNA-derived IgG1 kappa monoclonal antibody, a version of the murine HER2 antibody that selectively binds with high affinity in a cell-based assay (Kd = 5 nM) to the extracellular domain of the epidermal growth factor receptor 2 protein, HER2 (ErbB2) (US patents 5677171, US 5821337, US 6054297, US 6165464, US 6339142, US 6407213, US 6639055, US 6719971, US 6800738, US 7074404; Coussens et al. (1985) Science 230:1132-9; Slamon et al. (1989) Science 244:707-12; Slamon et al. (2001) New Engl. J. Med. 344:783-792). Trastuzumab contains human framework regions with complementarity-determining regions of a murine antibody (4D5) that binds to HER2. Trastuzumab binds to the HER2 antigen and thereby inhibits the growth of cancer cells. Trastuzumab has been shown, in both in vitro and animal tests, to inhibit the proliferation of human tumor cells that overexpress HER2 (Hudziak et al. (1989) Mol Cell Biol 9:1165-72; Lewis et al. (1993) Cancer Immunol Immunother; 37:255-63; Baselga et al. (1998) Cancer Res. 58:2825-2831). Trastuzumab is an antibody-dependent cellular cytotoxicity mediator, ADCC (Lewis et al. (1993) Cancer Immunol Immunother 37(4):255-263; Hotaling et al. (1996) [abstract]. Proc. Annual Meeting Am Assoc Cancer Res; 37:471; Pegram MD, et al. (1997) [abstract]. Proc Am Assoc Cancer Res; 38:602; Sliwkowski et al. (1999) Seminars in Oncology 26(4), Suppl 12:60-70; Yarden Y. and Sliwkowski, M. (2001) Nature Reviews: Molecular Cell Biology, Macmillan Magazines, Ltd., Vol. 2:127-137). [005] HERCEPTIN® was approved in 1998 for the treatment of patients with metastatic breast cancer with ErbB2 overexpression (Baselga et al., (1996) J. Clin. Oncol. 14:737-744) who had previously received extensive anticancer therapy, and has already been used in more than 300,000 patients (Slamon DJ, et al. N Engl J Med 2001;344:783-92; Vogel CL, et al. J Clin Oncol 2002;20:719-26; Marty M, et al. J Clin Oncol 2005;23:4265-74; Romond EH, et al. T N Engl J Med 2005;353:1673-84; Piccart-Gebhart MJ, et al. N Engl J Med 2005;353:1659-72; Slamon D, et al. [abstract]. Breast Cancer Res Treat 2006, 100 (Suppl 1): 52). In 2006, the FDA approved HERCEPTIN® (trastuzumab, Genentech Inc.) as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant treatment of patients with HER2-positive, node-positive breast cancer. Although the development of HERCEPTIN® has provided a much better outcome for patients with HER2-positive tumors than chemotherapy alone, virtually every patient with HER2-positive metastatic breast cancer (MBC) will eventually progress with available therapies. Opportunities still exist to improve outcomes for breast cancer patients. Despite the diverse mechanisms of action of trastuzumab, many patients treated with trastuzumab have shown no response or have stopped responding after a period of treatment benefit. Some HER2+ (HER2-positive) tumors have failed to respond to HERCEPTIN®, and most patients whose tumors responded eventually progressed. There is a significant clinical need for the development of HER2-targeted cancer therapies for patients with HER2-overexpressing tumors, or other HER2-associated diseases that do not respond or respond poorly to HERCEPTIN® treatment. [006] An alternative approach to antibody-targeted therapies is the use of antibodies to deliver cytotoxic drugs specifically to cancer cells that express antigens. Maitansinoids, derived from the antimitotic drug maytansine, bind to microtubules in a manner similar to vinca alkaloid drugs (Issell BF et al. (1978) Cancer Treat. Rev. 5:199-207; Cabanillas F et al. (1979) Cancer Treat Rep, 63:507-9). Antibody-drug conjugates (ADCs) comprising the maytansinoid DM1 linked to trastuzumab have shown potent antitumor activity in trastuzumab-sensitive and trastuzumab-resistant tum