Carboplatin and Paclitaxel With or Without Sorafenib Tosylate in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This randomized phase III trial studies carboplatin, paclitaxel, and sorafenib tosylate to see how well they work compared to carboplatin and paclitaxel in treating patients with stage III or stage IV melanoma that cannot be removed by surgery. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafenib tosylate 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. It is not yet known whether giving carboplatin and paclitaxel together with sorafenib tosylate is more effective than carboplatin and paclitaxel in treating melanoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the overall survival of patients with unresectable stage III or stage IV melanoma treated with carboplatin, paclitaxel and placebo versus carboplatin, paclitaxel and sorafenib (sorafenib tosylate). II. To compare progression-free survival, response rate, and safety of patients with unresectable stage III or stage IV melanoma treated with carboplatin, paclitaxel and placebo versus carboplatin, paclitaxel and sorafenib. III. To analyze the pharmacokinetic and pharmacogenetic properties of sorafenib including angiogenesis, monooxygenases polymorphisms and multidrug resistance (MDR). IV. To assess the association of expression markers in the patient tumor with clinical outcome. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30 minutes on day 1. Patients also receive sorafenib tosylate orally (PO) twice daily (BID) (approximately every 12 hours) on days 2-19. Arm II: Patients receive paclitaxel and carboplatin as in Arm I. Patients also receive placebo PO BID (approximately every 12 hours) on days 2-19. In both arms, treatment repeats every 21 days for 10 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease or who achieve a partial response or complete response may continue to receive sorafenib tosylate or placebo alone BID (approximately every 12 hours) on days 1-21. Courses with sorafenib tosylate or placebo repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years.

Official Title
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A Double-Blind, Randomized, Placebo-Controlled Phase III Trial of Carboplatin, Paclitaxel and Sorafenib Versus Carboplatin, Paclitaxel and Placebo in Patients With Unresectable Locally Advanced or Stage IV Melanoma

Conditions
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Mucosal Melanoma, Recurrent Melanoma, Stage IIIA Skin Melanoma, Stage IIIB Skin Melanoma, Stage IIIC Skin Melanoma, Stage IV Skin Melanoma

Intervention / Treatment
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* Drug: Carboplatin
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Other: Pharmacological Study
* Other: Placebo
* Drug: Sorafenib Tosylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological confirmed melanoma that is metastatic or unresectable; patients must have a history of cutaneous, mucosal or unknown primary site Patients who have received prior systemic cytotoxic chemotherapy for treatment of melanoma are ineligible; the following groups are eligible with regard to prior systemic therapy either in the adjuvant or metastatic disease setting: No prior therapy Immunotherapy consisting of interferon, interleukin-2, granulocyte macrophage colony-stimulating factor (GM-CSF) or vaccine One prior investigational therapy (cannot be chemotherapy or an inhibitor of rat sarcoma [Ras], serine/threonine kinase [Raf], or mitogen-activated protein kinase kinase [MEK]) NOTE: Chemotherapy given via isolated limb perfusion is allowed Prior radiation therapy is allowed; however, if radiation has been administered to a lesion, there must be radiographic evidence of progression of that lesion in order for that lesion to constitute measurable disease or to be included in the measured target lesions All sites of disease must be evaluated within 4 weeks of registration; patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 White blood count >= 3,000/mm^3 Absolute granulocyte count >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Serum creatinine =< 2.0 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 40 ml/min (neither drug is cleared by the kidney) Total bilirubin =< 1.5 x ULN (< 3.0 x ULN in the presence of Gilbert's disease) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5.0 ULN in the presence of liver metastases) International normalized ratio (INR) =< 1.5 and a partial thromboplastin time (PTT) within normal limits (patients who are on therapeutic anticoagulation with warfarin should have documentation of a normal prothrombin time [PT]/PTT prior to initiating that therapy) Patients must not have ocular melanoma Patients must have discontinued immunotherapy or radiation therapy at least 4 weeks prior to initiation of treatment and recovered from adverse events due to those agents Patients must not receive any other investigational agents during the period on study or the four weeks prior to initiation of treatment Patients must not have a history or clinical evidence of brain metastasis; patients must be evaluated with a head magnetic resonance imaging (MRI) within 4 weeks prior to enrollment Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for >= 5 years prior to the time of randomization Patients must not have any evidence of bleeding diathesis Patients must not have a serious intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics, clinically significant cardiovascular disease (e.g. uncontrolled hypertension, myocardial infarction, unstable angina), New York Heart Association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or grade II or greater peripheral vascular disease within 1 year prior to study entry, or psychiatric illness/social situations that would limit compliance with study requirements Patients must not be taking cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or phenobarbital), rifampin or St. John's Wort Women must not be pregnant or breast-feeding All females of childbearing potential must have a blood test or urine study within 4 weeks prior to registration to rule out pregnancy Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant while participating in this study, she should inform her treating physician immediately; if a man impregnates a woman while participating in this study, he should inform his treating physician immediately as well Human immunodeficiency virus (HIV)-positive patients are excluded from the study

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (paclitaxel, carboplatin, sorafenib tosylate)<br>Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Patients also receive sorafenib tosylate PO BID (approximately every 12 hours) on days 2-19. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Sorafenib Tosylate<br>* Given PO<br>* Other names: sorafenib;|
| Active Comparator: Arm II (carboplatin, paclitaxel, placebo)<br>Patients receive paclitaxel and carboplatin as in Arm I. Patients also receive placebo PO BID (approximately every 12 hours) on days 2-19. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Pharmacological Study<br>* Correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as time from study entry to death from any cause. The comparison of overall survival was conducted in intention-to-treat population. | Survival was assessed every 3 months if patient is < 2 years from study entry. Every 6 months is patient is 2-5 years from study entry. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival was defined as time from study entry to disease progression or death from any cause, whichever occurred first. Patients without disease progression were censored at last date of assessment. Disease progression was assessed by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. | Tumor response was assessed after every 2 cycles during cycle 1 through 10, and every 3 cycles after cycle 10. Survival was assessed every 3 months if patient is < 2 years from study entry, and every 6 months if 2-5 years from study entry. | 
| Objective Response (Complete and Partial Response) Rate | Tumor response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. Objective response =complete response (CR) + partial response (PR). Complete response is defined as disappearance of all target lesions. Partial response is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum of longest diameters. | Tumor response was assessed after every 2 cycles during cycle 1 through 10. After cycle 10, tumor response was assessed after every 3 cycles. |