Bevacizumab and Temozolomide or Bevacizumab and Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Carboplatin 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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RATIONALE: Drugs used in chemotherapy, such as temozolomide, paclitaxel albumin-stabilized nanoparticle formulation, and carboplatin, 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. It is not yet known whether bevacizumab is more effective when given together with temozolomide or paclitaxel albumin-stabilized nanoparticle formulation and carboplatin in killing malignant melanoma cells. PURPOSE: This randomized phase II trial is studying the side effects of giving temozolomide together with bevacizumab and to see how well it works compared with giving bevacizumab together with paclitaxel albumin-stabilized nanoparticle formulation and carboplatin in treating patients with stage IV malignant melanoma that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To assess the anti-tumor activity, in terms of the percentage of patients who are treated with these regimens and who are progression-free at 6 months. To assess the safety profile of each treatment regimen. Secondary To estimate the response rate in patients treated with these regimens. To estimate the distribution of progression-free survival time and overall survival time of patients treated with these regimens. Tertiary To examine the impact of therapy on angiogenesis and immune homeostasis. OUTLINE: Patients are stratified according to ECOG performance status (0 vs 1) and location of metastatic disease (M1a [skin or subcutaneous tissue or lymph node only] vs M1b [lung] vs M1c [other visceral sites]) and randomized to 1 of 2 treatment arms. Arm I: Patients receive oral temozolomide on days 1-5 and bevacizumab IV over 30-90 minutes on days 1 and 15. (closed to accrual 8/21/09) Arm II: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. In both arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection periodically for VEGF plasma levels and analysis of changes in immune homeostasis. Beginning at study entry, patients are followed up every 3 months for 2 years and then every 6 months for up to 3 years.

Official Title
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A Randomized Phase II Trial of Temozolomide (TMZ) and Bevacizumab or ABI-007 (ABX)/Carboplatin (CBDCA) and Bevacizumab in Patients With Unresectable Stage IV Malignant Melanoma

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Biological: bevacizumab
* Drug: carboplatin
* Drug: paclitaxel albumin-stabilized nanoparticle formulation
* Drug: temozolomide


Participation Criteria
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Eligibility Criteria
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Histologic confirmed diagnosis of malignant melanoma Stage IV disease Not amenable tosurgery Measurable disease with at least one lesion whose longest diameter canbe measured as ≥ 20 mm by CT or MRI scans OR ≥ 10 mm by spiral CT No disease that is measurable by physical examination only No brain metastases per MRI or CT No radiographically documented invasion of adjacent organs(duodenum, stomach, etc.) or tumor invading major blood vessels ECOG performance status 0-1 Life expectancy ≥ 4 months ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9 g/dL (transfusion allowed) Creatinine ≤ 1.5 times upper limit of normal (ULN) Total bilirubin ≤ 1.5 mg/dL (unless Gilbert syndrome) AST ≤ 2.5 times ULN Alkaline phosphatase ≤ 2.5 times ULN Urine protein:creatinine ratio < 1.0 at screening ORproteinuria < 2+ by urine dipstick or protein ≤ 1 g by 24-hour urine collection Negative serum pregnancy test Not pregnant or nursing Fertile patients must use effective contraception Active infection requiring parenteral antibiotics Poorly controlled high blood pressure (≥ 150 mm Hg systolic and/or100 mm Hg diastolic) despite treatment NYHA class II-IV congestive heart failure Serious cardiac arrhythmia requiring medication Myocardial infarction or unstable angina within the past 6 months Clinically significant peripheral vascular disease Deep venous thrombosis or pulmonary embolus within the past year Active bleeding or pathological conditions that carry high risk of bleeding (e.g., known esophageal varices) Serious, non-healing wound (including wounds healing by secondary intention), ulcer or bone fracture Abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within the past 6 months History of CNS disease (e.g., primary brain tumor, vascular abnormalities, etc.) Clinically significant stroke or TIA within the past 6 months Seizures not controlled with standardmedical therapy Peripheral neuropathy ≥ grade 2 History of other malignancy within the past 5 years except basal cell or squamous cell carcinoma of the skin treatable with local resection only or carcinoma in situ of the cervix Significant traumatic injury within the past 4 weeks History of hypertensive crisis or hypertensive encephalopathy Active or recent (≤ 30 days) history of hemoptysis (≥ ½ teaspoon of bright red blood per episode) Known hypersensitivity to any of the components of bevacizumab Known to be HIV positive Current or known history of hepatitis Prior adjuvant chemotherapy and/or immunotherapy for this cancer allowed No prior treatment with agents disrupting VEGF activity (i.e., bevacizumab,VEGF-trap, anti-VEGFR Mab) No ongoing need for full-dose oral or parenteral anticoagulation No ongoing anti-platelet treatment other than low-dose aspirin(i.e., aspirin 81 mg daily) No other investigational agents within the past 4 weeks No major surgical procedure or open biopsy within the past 4 weeks No fine needle aspirations or core biopsies within the past 7 days No prior chemotherapy in the metastatic setting No prior treatment with sunitinib malate or sorafenib No prior treatment with any taxane-based chemotherapy Patients who have had > 25% of their functional bone marrow irradiated are not eligible for this trial No adjuvant radiation therapy within the past 4 weeks More than 2 weeks since prior and no concurrent palliative radiation therapy No concurrent major surgical procedure No concurrent participation in another clinical study for procedures or agents that treat the same primary study malignancy

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<br>Patients receive oral temozolomide on days 1-5 and bevacizumab IV over 30-90 minutes on days 1 and 15. | Biological: bevacizumab<br>* Given IV over 30-90 minutes<br>Drug: temozolomide<br>* Oral temozolomide on days 1-5<br>|
| Experimental: Arm II<br>Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. | Biological: bevacizumab<br>* Given IV over 30-90 minutes<br>Drug: carboplatin<br>* Given IV over 30 minutes<br>Drug: paclitaxel albumin-stabilized nanoparticle formulation<br>* Given IV over 30 minutes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival at 6 Months | The primary endpoint is the 6 month post registration Progression-free survival (PFS) rate. Progression-free survival time is defined as the time from registration to documentation of disease progression using the RECIST criteria. Patients who died without documentation of disease progression will be considered to have progressed at death unless there is sufficient documented evidence to conclude no progression occurred prior to death. All patients, who meet the eligibility criteria, sign a consent form, and start treatment will be included in the evaluation of the 6 month PFS rate. | at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response Rate, Calculated as a Percentage Along With it's 95% Confidence Interval | A confirmed tumor response is defined to be a Complete Response or Partial Response noted > as the objective status on 2 consecutive evaluations at least 8 > weeks apart. The proportion of tumor responses will be > estimated by the number of confirmed tumor responses divided > by the total number of evaluable patients. > Complete Response (CR): Disappearance of all target lesions > Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD. > Progression (PD): At least a 20% increase in the sum of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. > Stable Disease (SD): Neither sufficient shrinkage to Qualify for PR nor sufficient increase to Qualify for PD taking as reference the smallest sum LD. responses will be calculated assuming that the number of > confirmed tumor responses follows a binomial distribution. | Up to 5 years | 
| Overall Survival | Overall survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier. | Up to 5 years | 

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