Sorafenib, Carboplatin, and Paclitaxel in Treating Patients With Stage IV Melanoma of the Eye

Study Overview
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Brief Summary
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This phase II trial is studying how well sorafenib works when given together with carboplatin and paclitaxel in treating patients with stage IV melanoma of the eye. 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 may help carboplatin and paclitaxel work better by making tumor cells more sensitive to the drugs. Sorafenib may also stop the growth of melanoma by blocking some of the enzymes needed for tumor cell growth and by blocking blood flow to the tumor. Giving sorafenib together with carboplatin and paclitaxel may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the response rate (confirmed and unconfirmed, complete and partial response) of patients with stage IV uveal melanoma treated with sorafenib, carboplatin, and paclitaxel. SECONDARY OBJECTIVES: I. Determine the overall and progression-free survival of patients treated with this regimen. II. Determine the toxic effects of this regimen in these patients. III. Determine, preliminarily, the relationship between clinical outcomes and baseline microvessel density (MVD) in tumor specimens, changes in vascular endothelial growth factor (VEGF) levels in plasma and urine, changes in MVD, changes in VEGF receptor-2 phosphorylation in tumor, and/or changes in ERK 1/2 phosphorylation in stimulated lymphocytes and tumor. OUTLINE: This is a non-randomized, open-label, multicenter study. Patients receive carboplatin IV and paclitaxel IV once on day 1 and oral sorafenib twice daily on days 2-19. Treatment repeats every 21 days for up to 6 courses.* After 6 courses, patients continue to receive oral sorafenib alone twice daily in the absence of disease progression or unacceptable toxicity. [Note: *If sorafenib is discontinued prior to course 6, patients may continue to receive carboplatin and paclitaxel for up to 6 courses; if carboplatin and paclitaxel are discontinued prior to course 6, patients may continue to receive sorafenib alone twice daily on days 1-21 of each course 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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Phase II Trial of BAY 43-9006 (Sorafenib; NSC-724772) in Combination With Carboplatin and Paclitaxel in Patients With Metastatic Uveal Melanoma

Conditions
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Ciliary Body and Choroid Melanoma, Medium/Large Size, Extraocular Extension Melanoma, Iris Melanoma, Metastatic Intraocular Melanoma, Recurrent Intraocular Melanoma

Intervention / Treatment
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* Drug: carboplatin
* Drug: paclitaxel
* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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Criteria: Histologically proven uveal melanoma Must have documented disease progression during or after =< 1 prior systemic treatment Measurable disease, defined as >= 1 unidimensionally measurable lesion >= 20 mm by conventional techniques or >= 10 mm by spiral CT scan No tumor involving major vessels Zubrod performance status 0-1 Absolute neutrophil count > 1,500/mm^3 Platelet count > 100,000/mm^3 Creatinine =< 2 times upper limit of normal (ULN) Bilirubin =< 2 times ULN SGOT or SGPT =< 2 times ULN (5 times ULN if hepatic metastasis present) INR in range (usually between 2 and 3) No active bleeding No bleeding diathesis, active coagulopathy, or pathological condition that carries a high risk of bleeding No condition (e.g., gastrointestinal tract disease) affecting ability to take oral medication or requiring IV alimentation Not pregnant or nursing Fertile patients must use effective contraception No prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer for which the patient is currently in complete remission, or any other cancer for which the patient has been disease-free for 5 years At least 28 days since prior systemic treatment for this disease comprising 1 of the following: single chemotherapy agent/regimen; single immunotherapy agent/regimen; single investigational treatment agent/regimen At least 21 days since prior major surgery No prior sorafenib or any other agents targeting raf kinase or vascular endothelial growth factor (VEGF) or VEGF receptor No prior surgical procedures affecting absorption No concurrent systemic corticosteroid therapy Topical and/or inhaled steroids are allowed No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, and phenobarbital), rifampin, or Hypericum perforatum (St. John's wort) No prophylactic granulocyte/platelet colony-stimulating factors during the first course of treatment Concurrent full-dose oral anticoagulants (e.g., warfarin) are allowed provided all of the following criteria are met: in-range INR ; stable dose of oral anticoagulant; no active bleeding or high risk of bleeding Stage IV disease No known varices No uncontrolled hypertension with systolic blood pressure (BP) > 140 mm Hg or diastolic BP > 90 mm Hg No significant traumatic injury within the past 21 days No active, uncontrolled peptic ulcer disease

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (carboplatin, paclitaxel, sorafenib)<br>Patients receive carboplatin IV and paclitaxel IV once on day 1 and oral sorafenib twice daily on days 2-19. Treatment repeats every 21 days for up to 6 courses.* After 6 courses, patients continue to receive oral sorafenib alone twice daily in the absence of disease progression or unacceptable toxicity. [Note: *If sorafenib is discontinued prior to course 6, patients may continue to receive carboplatin and paclitaxel for up to 6 courses; if carboplatin and paclitaxel are discontinued prior to course 6, patients may continue to receive sorafenib alone twice daily on days 1-21 of each course in the absence of disease progression or unacceptable toxicity. ] | Drug: carboplatin<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>Drug: sorafenib tosylate<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Complete and Partial Response) | 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 6 weeks for the first 8 cycles of therapy, then every three cycles (9 weeks) until progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year Overall Survival | Measured from date of registration to study until death due to any caused with observations last known to be alive censored at the date of last contact | Every 6-9 weeks until progression, after progression every six months for first two years and annually thereafter up to 3 for up to 3 years after registration or until death | 
| 6-month Progression-free Survival | Measured from the date of registration to the first of progression or death due to any cause with patients last known to be alive and progression-free censored at the date of last contact | Every 6 weeks for the first 8 cycles of therapy, and then every 9 weeks until disease progression for up to 3 years after registration or until death | 
| Toxicity | Number of patients with Grade 3-5 adverse events that are related to study drug by given type of adverse event | Weekly during the first cycle of therapy, then prior to each cycle (one cycle = 3 weeks) |