Sorafenib and Temozolomide in Treating Patients With Stage III or Stage IV Melanoma

Study Overview
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Brief Summary
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RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with temozolomide may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of giving sorafenib together with temozolomide in treating patients with stage III or stage IV melanoma.

Detailed Description
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OBJECTIVES: Primary Determine the safety profile and the maximum tolerated dose of sorafenib tosylate and temozolomide in patients with stage III-IV melanoma. (Phase I) Evaluate progression-free survival at 12 weeks. (Phase II) Secondary Evaluate tumor response according to RECIST criteria. Evaluate overall and progression-free survival. Evaluate the effect of treatment on tumor vascularization. Compare the pharmacokinetic profile of temozolomide with and without sorafenib tosylate. Evaluate the number and the role of lymphocytes. Correlate tumor response rate with BRAF mutation status. Correlate response rate with MGMT activity. Compare the efficacy of genomics and proteomics as a means of discovery of serum biomarkers. Study the prognostic and predictive value of circulating endothelial cells and circulating endothelial progenitors. OUTLINE: This is a phase I dose-escalation study followed by a phase II study. Patients receive oral sorafenib tosylate twice daily on days 1-28 (days 8-28 of course 1) and oral temozolomide once daily on days 1-7 and 15-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with accessible tumors (cutaneous or sub-cutaneous) undergo biopsies at baseline and day 28 for analysis of BRAF mutations and MGMT expression.

Official Title
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Open-label, Single Center, Uncontrolled Phase I/II Study Evaluating the Safety and Maximum Tolerated Dose of Daily Sorafenib Administered in Combination With Prolonged Temozolomide in Patients With Metastatic Melanoma

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Drug: sorafenib tosylate
* Drug: temozolomide
* Genetic: gene expression analysis
* Genetic: mutation analysis
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Procedure: biopsy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of unresectable or metastatic melanoma Stage III or IV disease Previously treated or untreated metastatic disease At least one unidimensionally measurable lesion by RECIST criteria by scan or MRI No concurrent brain or CNS metastases PATIENT CHARACTERISTICS: WHO performance status 0-1 Life expectancy ≥ 3 months ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin > 9 g/dL PT, INR, and PTT < 1.5 times upper limit of normal (ULN) Transaminases < 2.5 times ULN (< 5 in the case of liver metastases) Amylase and lipase < 1.5 times ULN Bilirubin ≤ 1.5 times ULN Serum creatinine < 1.5 times ULN Normal respiratory, cardiac, and neurological function Not pregnant or nursing No history of any of the following cardiac conditions: NYHA class II-IV heart failure Coronary disease Myocardial infarction within the past 6 months Cardiac arrhythmia requiring treatment with something other than beta-blockers or digoxin Severe uncontrolled hypertension No severe active infection > grade 2 No epilepsy requiring medical treatment No other cancer except for carcinoma in situ of the cervix, basal cell carcinoma, superficial bladder tumors, or curatively treated cancer > 3 years ago No HIV or hepatitis B or C positivity No lactase or galactokinase deficiency, galactose intolerance, or disease accompanied by malabsorption of glucose or galactose No allergy to the study drugs or to dacarbazine Able to swallow medications No patients deprived of liberty No psychological, familial, social, or geographic conditions that would preclude clinical follow up PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior organ transplantation No prior temozolomide or sorafenib tosylate More than 30 days since other prior antitumor chemotherapy, immunotherapy, hormonal therapy, or investigational agent More than 30 days since prior study drugs More than 3 weeks since prior radiotherapy More than 3 weeks since prior biological response modifiers (i.e., filgrastim [G-CSF])

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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: sorafenib tosylate|nan|
|Drug: temozolomide|nan|
|Genetic: gene expression analysis|nan|
|Genetic: mutation analysis|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacological study|nan|
|Procedure: biopsy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (Phase I) |  |  | 
| Progression-free survival at 12 weeks (Phase II) |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV melanoma, stage III melanoma, recurrent melanoma