Carboplatin, Paclitaxel, and Bevacizumab in Treating Patients With Stage IV Melanoma That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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This phase II trial is studying how well giving carboplatin and paclitaxel together with bevacizumab works in treating patients with 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. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving carboplatin and paclitaxel together with bevacizumab may kill more tumor cells.

Detailed Description
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OBJECTIVES: Primary I. Determine the anti-tumor activity of carboplatin, paclitaxel, and bevacizumab, in terms of progression-free survival, in patients with unresectable stage IV melanoma. II. Determine the toxicity profile of this regimen in these patients. Secondary I. Determine the distribution of overall survival times in patients treated with this regimen. II. Determine the response rate in patients treated with this regimen. III. Determine the changes in blood levels of vascular endothelial growth factor in patients treated with this regimen. IV. Determine the changes in immune homeostasis in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive carboplatin IV over 30 minutes on day 1, paclitaxel IV over 1 hour on days 1, 8, and 15, and bevacizumab IV over 30-90 minutes on days 1 and 15. 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 5 years. PROJECTED ACCRUAL: A total of 47 patients will be accrued for this study.

Official Title
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Phase II Trial of Carboplatin, Weekly Paclitaxel and Biweekly Bevacizumab in Patients With Unresectable Stage IV Melanoma

Conditions
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Recurrent Melanoma, Stage IV Melanoma

Intervention / Treatment
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* Drug: carboplatin
* Drug: paclitaxel
* Biological: bevacizumab
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed melanoma Unresectable stage IV disease Evidence of metastatic disease Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan No radiologically confirmed invasion of adjacent organs (e.g., duodenum or stomach) No tumor invasion of major blood vessels No history of primary brain tumor or other CNS disease No brain metastases by MRI or CT scan Performance status - ECOG 0-2 More than 4 months Absolute granulocyte count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9 g/dL (transfusion allowed) No active bleeding Bilirubin ≤ 1.5 mg/dL AST ≤ 3 times upper limit of normal (ULN) Alkaline phosphatase ≤ 3 times ULN INR ≤ 1.5 times ULN PTT normal No known esophageal varices Creatinine ≤ 1.5 times ULN Urine protein creatinine ratio ≤ 0.5 Urine protein < 1 g/24-hr urine collection No New York Heart Association class II-IV congestive heart failure No serious cardiac arrhythmia requiring medication No myocardial infarction within the past 6 months No unstable angina within the past 6 months No clinically significant peripheral vascular disease No uncontrolled hypertension (i.e., blood pressure ≥ 150/90 mmHg despite antihypertensive therapy) No clinically significant stroke within the past 6 months No deep vein thrombosis within the past year No other vascular abnormality No pulmonary embolus within the past year No history of abdominal fistula No gastrointestinal perforation No intra-abdominal abscess within the past 4 weeks Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after completion of study therapy No other pathological condition that would confer a high risk of bleeding No active infection requiring parenteral antibiotics No serious nonhealing wound (including wounds healing by secondary intention), ulcer, or bone fracture No peripheral neuropathy ≥ grade 2 No history of allergic reaction attributed to compounds of similar chemical or biological composition to the study drugs No uncontrolled seizures No other uncontrolled illness No significant traumatic injury within the past 4 weeks No prior antivascular endothelial growth factors (VEGF), including any of the following: Bevacizumab VEGF Trap Anti-VEGF receptor monoclonal antibody Small molecular tyrosine kinase inhibitors of VEGF receptors No more than 1 prior systemic chemotherapy regimen No prior carboplatin or paclitaxel No other concurrent chemotherapy More than 4 weeks since prior radiotherapy No prior radiotherapy to > 25% of bone marrow No concurrent radiotherapy At least 4 weeks since prior major surgical procedure or open biopsy At least 1 week since prior fine-needle aspiration or core biopsy No concurrent major surgery More than 4 weeks since prior systemic therapy No concurrent full-dose oral or parenteral anticoagulation No concurrent antiplatelet therapy except low-dose aspirin (i.e., 81 mg of oral aspirin daily) allowed No other concurrent experimental drugs

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, bevacizumab)<br>Patients receive carboplatin IV over 30 minutes on day 1, paclitaxel IV over 1 hour on days 1, 8, and 15, and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Constructed using the properties of the binomial distribution. Estimated using the Kaplan-Meier method. | Time from registration to documentation of disease progression, assessed up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed tumor response (complete response or partial response) | A ninety percent confidence interval for the true proportion of confirmed tumor responses will be calculated assuming that the number of confirmed tumor responses follows a binomial distribution. | Up to 5 years | 
| Clinical response rate | A ninety percent confidence interval for the true clinical response rate will be calculated. | Up to 5 years | 
| Overall survival | The distribution of survival time will be estimated using the method of Kaplan-Meier. | Time is defined as the time from registration to death due to any cause, assessed up to 5 years |