Part 2 of Phase 1 Study of GC1008 to Treat Advanced Melanoma (Part 2 Will Only Accept and Treat Patients With Advanced Malignant Melanoma)

BACKGROUND: Transforming growth factor-beta (TGFBeta) is a member of a large family of evolutionarily conserved proteins with broad activity. Paradoxically, TGFBeta is involved in both preventing malignant transformation of cells and promoting tumor progression by enhancing the proteolysis of extracellular matrix, stimulating tumor cell migration, tumor invasiveness, angiogenesis and inhibiting the immune response to tumor. GC1008 is a human IgG4 monoclonal antibody that neutralizes all isoforms of TGFBeta. GC1008 reduced metastatic burden and enhanced immune responses against cancers in preclinical studies. OBJECTIVES: To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety of GC1008 in patients with locally advanced of metastatic renal cell carcinoma or malignant melanoma. To obtain pharmacokinetic (PK) and pharmacodynamic data on GC1008. To evaluate tumor response as a preliminary assessment of clinical activity. To assess possible surrogate markers that might predict clinical efficacy by obtaining tumors and blood samples for exploratory biomarker analysis. ELIGIBILITY: Adult patients with locally advanced, surgically inoperable metastatic renal cell carcinoma or malignant melanoma. The Part 2 cohort expansion will accrue only malignant melanoma patients. Patients must have failed greater than or equal to 1 prior therapy. Patients must have a hemoglobin greater than or equal to 10.0 gm/dL granulocyte count (ANC) of greater than or equal to 1500/miocroliter and platelets greater than or equal to 100,000/microliter; creatinine less than or equal to 2 mg/dL, serum bilirubin less than or equal to 1.5 x ULN, meet criteria for AST/ALT and have a normal PT/PTT. Measurable disease by RECIST criteria. Patients must test negative for hepatitis B virus, hepatitis C virus and human immune deficiency virus (HIV). Patient must be greater than 4-weeks since major surgery, radiation therapy or chemotherapy. DESIGN: Part 1: Cohorts of 3-6 patients will be treated with a single intravenous dose of GC1008 at doses of 0.1 to 15 mg/kg as prescribed by the protocol (This part has been completed). Part 2: A cohort expansion will treat an additional 6 subjects with GC1008 15 mg/kg to estimate the frequency of unacceptable skin adverse events (e.g., keratoacanthomas, etc). If an unacceptable frequency of skin adverse events are observed, an additional 6 subjects will be treated at the lower dose of 10 mg/kg to determine the phase II dose. Patients will then be observed for adverse events and PK studies obtained for 4-weeks. Patients will then receive three additional doses of GC1008 at same dose every 2-weeks. Responding patients and those with stable disease may receive additional treatments.