This randomized phase II trial is studying how well giving sorafenib together with either temsirolimus or tipifarnib works in treating patients with stage IV melanoma that cannot be removed by surgery. Sorafenib, temsirolimus, and tipifarnib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib and tipifarnib may also stop the growth of tumor by blocking blood flow to the tumor. It is not yet known whether sorafenib is more effective when given together with temsirolimus or tipifarnib in treating patients with malignant melanoma.

PRIMARY OBJECTIVES:

I. Compare the response rate (confirmed and unconfirmed and complete and partial) in patients with unresectable stage IV malignant melanoma treated with sorafenib in combination with either temsirolimus or tipifarnib.

II. Compare the 4-month progression-free survival rate of patients treated with these regimens.

III. Compare the safety and tolerability of these regimens, with an emphasis on long-term side effects and toxic effects, in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to metastatic (M) stage (M1a/b vs M1c). Patients are randomized to 1 of 2 treatment arms.

ARM I (reopened to accrual as of 8/15/2009): Patients receive oral sorafenib twice daily on days 1-28 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.

ARM II (closed to accrual as of 8/15/2009): Patients receive oral sorafenib as in arm I and oral tipifarnib twice daily on days 1-21.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 3 years.

Criteria:

• Histologically confirmed malignant melanoma of cutaneous origin
• Patients with unknown primary allowed
• Stage IV disease
• Measurable disease by physical examination, CT scan, MRI or plain x-ray
• Unresectable disease
• Residual or recurrent disease after prior surgery for stage IV disease allowed
• Residual tumor at the site of incomplete resection may be included only as nonmeasurable disease
• Must have serum lactate dehydrogenase (LDH) levels measured
• Must have tissue specimens available
• Negative brain CT scan or MRI within the past 42 days
• Creatinine =< 1.5 times ULN
• Absolute neutrophil count >= 1,000/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 9.0 g/dL
• Fasting cholesterol =< 350 mg/dL (lipid-lowering agents allowed)
• Triglycerides =< 300 mg/dL (lipid-lowering agents allowed)
• No symptomatic sensory neuropathy >= grade 2
• No evidence of bleeding diathesis or coagulopathy
• No congestive heart failure
• No myocardial infarction within the past 2 months
• No New York Heart Association class III or IV heart disease
• No condition that impairs the ability to swallow pills (e.g., gastrointestinal tract disease resulting in an inability to take oral medication, requirement for IV alimentation, prior surgical procedure affecting absorption, or active peptic ulcer disease)
• No known allergy to imidazoles (e.g. clotrimazole, ketoconazole, miconazole, or econazole)
• No history of allergic reaction to compounds of similar chemical or biologic composition as tipifarnib
• No hypertension with systolic blood pressure (BP) > 140 mm Hg or diastolic BP > 90 mm Hg
• Patients with well-controlled hypertension allowed
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled diabetes
• No uncontrolled diabetes
• No active uncontrolled infection
• No other severe or uncontrolled medical disease
• No psychologic or medical condition that would preclude study treatment or compliance
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, adequately treated stage I or II cancer that is in complete remission, or carcinoma in situ of the cervix
• At least 90 days since prior adjuvant therapy, including cytotoxic agents
• At least 28 days since prior radiotherapy
• At least 28 days since prior surgery to remove the tumor
• No prior systemic therapy for stage IV melanoma
• No prior therapy with agents targeting farnesyl transferase, the MAP kinase pathway, or vascular endothelial growth factors (VEGF) or receptors (VEFGR), including drugs such as sorafenib, temsirolimus, or tipifarnib
• Concurrent lipid-lowering agents allowed
• Not requiring full-dose anticoagulation for recent thrombotic event
• No concurrent highly active antiretroviral therapy (HAART) in HIV-positive patients
• No concurrent use of any of the following: dilantin; carbamazepine; Phenobarbital; rifampin; hypericum perforatum (St. John's wort); ketoconazole; itraconazole; ritonavir; cyclosporine; phenytoin; grapefruit juice
• Bilirubin =< 1.5 times upper limit of normal (ULN)
• SGOT or SGPT =< 2.5 times ULN (5 times ULN if hepatic metastases)
• No history of brain metastases
• Zubrod performance status 0-1