A Randomized Phase II Trial of BAY 43-9006 (Sorafenib; NSC-724772) with Either CCI-779 (Temsirolimus; NSC-683864) or R115777 (Tipifarnib; NSC-702818) in Metastatic Melanoma

Pts must have biopsy-proven diagnosis of malignant melanoma of cutaneous or mucosal origin. Pts must have St IV measurable, unresectable disease and LDH measurement. Measurable lesions to be assessed by physical exam, CT, MRI or X-Ray w/i 28 days. Non-measurable disease to be assessed w/i 42 days. If PET/CT used for any disease assessment, designate those lesions as non-target. Baseline PET w/i 7 days, baseline correlative CT or MRI w/i 7 days prior to start of tx. Pts must have negative brain CT or MRI w/i 42 days. Pts must not have: ocular melanoma, history of brain mets, received prior systemic therapy for St IV disease, inability to swallow pills, allergy to imidazoles or other compound similar to R115777. Must send blood, H&E stained slides, tumor block or unstained slides correlative studies, if pts have consented and specimens are available. Pts must have PS 0-1, 18 years or older. Prior adjuvant therapy is allowed, cytotoxic agent exposure must be at least 90 days. Pts must not have received BAY-43-9006 or any other agents targeting the MAPkinase pathway or VEGF/VEGFR, or CCI-779 or R115777 or any other agents targeting farnesyl transferase. Pts must not plan to rec�v drugs which induce or suppress hepatic enzymes responsible for metabolism of the study drugs. Pts may have rec�d prior RT completed at least 28 days prior. Prior St IV sx completed at least 28 days prior to registration is permitted; residual tumor at site of incomplete resection may be included only as non-measurable disease. Pts must have adequate hepatic function: bili </= 1.5 x IULN and SGOT or SGPT </= 2.5 x IULN; adequate renal function: serum creat </= 1.5 x IULN, ANC >/= 1,5000, platelet >/= 100,000, and hgb >/= 9. No symptomatic neuropathy-sensory > Grade 2. Pts must have fasting cholesterol </= 350 and triglycerides </= 300 and not be on lipid-lowering agents. No pts with HIV+ rec�ving HAART therapy. No hypertension with >140 / >90; well controlled hypertension allowed. Pts must not be on full-dose anticoagulation and not have bleeding diathesis or coagulopathy. Pts must be able tolerate/complete tx/grant reliable informed consent. Pts must not have > Grade 3/4 cardiac problems (NY Heart Ass.) w/i 2 months. No severe or uncontrolled concurrent disease or infection. No pregnant or nursing women. No other prior malignancy except: treated basal cell or squamous cell skin ca, in situ cervical, Stage I or II ca in complete remission; disease-free from any ca for 5 years.