Combination Chemotherapy With or Without Bevacizumab in Treating Patients With Malignant Mesothelioma

Study Overview
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Brief Summary
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This randomized phase II trial is to see if combination chemotherapy works better with or without bevacizumab in treating patients who have malignant mesothelioma. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them. It is not yet known if combination chemotherapy works better with or without bevacizumab in treating malignant mesothelioma.

Detailed Description
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OBJECTIVES: I. Compare the time to progression of patients with malignant mesothelioma treated with gemcitabine and cisplatin with or without bevacizumab. II. Compare the objective response rate in patients treated with these regimens. III. Compare the toxicity of these regimens when administered to these patients. IV. Compare the median and overall survival of patients treated with these regimens. V. Assess plasma vascular endothelial growth factor and serum vascular cell adhesion molecule-1 levels before, during, and after study therapy as predictors of outcome in these patients. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to histology (epithelial vs other) and ECOG performance status (0 vs 1). Patients are randomized to one of two treatment arms. ARM I: Patients receive gemcitabine IV over 30 minutes on days 1 and 8 and cisplatin IV over 30-60 minutes (beginning after gemcitabine infusion) and bevacizumab IV over 30-90 minutes (beginning after cisplatin infusion) on day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve stable disease (SD), complete response (CR), or partial response (PR) after the sixth course may receive bevacizumab as a single agent once every 3 weeks in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive gemcitabine and cisplatin as in arm I and placebo IV over 30-90 minutes (beginning after cisplatin infusion) on day 1. Treatment repeats as in arm I. Patients who achieve SD, CR, or PR after the sixth course may receive placebo as a single agent once every 3 weeks in the absence of disease progression.

Official Title
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A Double Blind, Placebo Controlled Randomized Phase II Trial Of Gemcitabine And Cisplatin With Or Without The VEGF Inhibitor Bevacizumab (NSC #704865) In Patients With Malignant Mesotheloma

Conditions
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Advanced Malignant Mesothelioma, Epithelial Mesothelioma, Localized Malignant Mesothelioma, Recurrent Malignant Mesothelioma, Sarcomatous Mesothelioma

Intervention / Treatment
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* Drug: gemcitabine hydrochloride
* Drug: cisplatin
* Biological: bevacizumab
* Other: placebo
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed malignant pleural or peritoneal mesothelioma that is not amenable to curative surgery Epithelial, sarcomatoid, or mixed subtype Evidence of gross unresectability, including, but not limited to, the following conditions: Direct extension into the chest wall Mediastinal or hilar lymphadenopathy Pulmonary or cardiac function that is inadequate to tolerate resection Sarcomatoid or mixed histology Pleural mesothelioma must be stage II or greater using the International Mesothelioma Interest Group staging system Measurable disease outside prior irradiation port At least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan Pleural effusions and ascites are not considered measurable lesions Site in pleura, lung, liver, or retroperitoneum that can be assessed by MRI for evaluation of blood flow No obvious tumor involvement of major vessels by CT scan No known brain metastases Performance status - ECOG 0-1 More than 3 months WBC at least 3,000/mm^3 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 No history of bleeding diathesis Bilirubin normal AST/ALT no greater than 2.5 times upper limit of normal INR no greater than 1.5 Creatinine no greater than 1.5 mg/dL Creatinine clearance at least 60 mL/min If 1+ or greater proteinuria on dipstick, then must have less than 500 mg of protein/24-hour urine collection No significant renal impairment See Disease Characteristics No history deep vein thrombosis No myocardial ischemia or infarction within the past 6 months No uncompensated coronary artery disease within the past 6 months No uncontrolled hypertension No symptomatic congestive heart failure No unstable angina pectoris within the past 6 months No cardiac arrhythmia No transient ischemic attack within the past 6 months No cerebrovascular accident within the past 6 months No other arterial thromboembolic event within the past 6 months No clinically significant peripheral artery disease See Disease Characteristics No history of pulmonary embolism No prior allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab or other study agents No other active malignancy within the past 5 years except nonmelanoma skin cancer or carcinoma in situ of the cervix No ongoing or active infection No other concurrent uncontrolled illness that would preclude study participation No psychiatric illness or social situations that would preclude compliance Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No growth factors for 24 hours before, during, or for 24 hours after cytotoxic chemotherapy See Biologic therapy Prior intrapleural cytotoxic agents (including bleomycin) allowed No prior systemic cytotoxic chemotherapy See Disease Characteristics At least 4 weeks since prior radiotherapy and recovered See Disease Characteristics At least 6 weeks since prior major surgery At least 30 days since prior investigational drug No other concurrent investigational or commercial agents or therapies No concurrent combination antiretroviral therapy for HIV-positive patients

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 gemcitabine IV over 30 minutes on days 1 and 8 and cisplatin IV over 30-60 minutes (beginning after gemcitabine infusion) and bevacizumab IV over 30-90 minutes (beginning after cisplatin infusion) on day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve stable disease (SD), complete response (CR), or partial response (PR) after the sixth course may receive bevacizumab as a single agent once every 3 weeks in the absence of disease progression or unacceptable toxicity. | Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm II<br>Patients receive gemcitabine and cisplatin as in arm I and placebo IV over 30-90 minutes (beginning after cisplatin infusion) on day 1. Treatment repeats as in arm I. Patients who achieve SD, CR, or PR after the sixth course may receive placebo as a single agent once every 3 weeks in the absence of disease progression. | Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Other: placebo<br>* Given IV<br>* Other names: PLCB;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 |
| --- | --- | --- |
| Time to disease progression | The two treatment groups will be compared using a stratified logrank test. Kaplan-Meier time-to-event curves will be constructed for each treatment group. Median time-to-progression in each group and corresponding 95% confidence intervals will be derived using the method described in Brookmeyer and Crowley. | Time from randomization until the first evidence of progression, up to 9 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate | Will be compared between groups using chi-square or Fisher exact tests, as appropriate. | Up to 6 months | 
| Objective response rate (complete and partial response) | Will be compared between groups using chi-square or Fisher exact tests, as appropriate. | Up to 6 months | 
| Rate of disease stabilization | Will be compared between groups using chi-square or Fisher exact tests, as appropriate. | Up to 6 months | 
| Overall survival | Kaplan-Meier estimates of overall survival rates will be derived and compared between the two groups using a stratified log-rank test. | Up to 9 years | 
| Incidence of adverse events graded according to NCI CTCAE version 3.0 | Toxicity rates will be compared between the two groups via chi-square or Fisher exact tests. | Up to 9 years |