Sorafenib With Either Temsirolimus or Tipifarnib in Treating Patients With Stage IV Malignant Melanoma That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Recurrent Melanoma, Stage IV Melanoma

Intervention / Treatment
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* Drug: sorafenib tosylate
* Drug: tipifarnib
* Drug: temsirolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (sorafenib, temsirolimus)<br>Patients receive oral sorafenib twice daily on days 1-28 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. | Drug: sorafenib tosylate<br>* Given orally<br>* Other names: SFN;Drug: temsirolimus<br>* Given IV<br>* Other names: Torisel;|
| Experimental: Arm II (sorafenib, tipifarnib)<br>Patients receive oral sorafenib as in arm I and oral tipifarnib twice daily on days 1-21 | Drug: sorafenib tosylate<br>* Given orally<br>* Other names: SFN;Drug: tipifarnib<br>* Given orally<br>* Other names: Zarnestra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Complete and Partial) | Complete response corresponds to complete disappearance of all measurable and non-measurable lesions with no new lesions. Partial response corresponds to greater than or equal to 30ﬁ decrease of sum of longest diameter of all target measurable lesions with no new lesion and non unequivocal progression of non-measurable disease. | Every 8 weeks until progression | 
| 4-month Progression-free Survival | Progression was defined as one or more of the following: 20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed, unequivocal progression of non-measurable disease, appearance of any new lesions, death due to disease without prior documentation of progression and without symptomatic deterioration. | 4 months after registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year Overall Survival |  | One year after registration | 
| Toxicity | Number of patients with Grade 3-5 adverse events that are related to study drug by given type of adverse event | Weekly during first cycle, every two weeks during the second cycle, and once a cycle further cycles (one cycle = 4 weeks). |