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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Malignant Mesothelioma; Advanced Malignant Mesothelioma; Epithelial Mesothelioma; Sarcomatous Mesothelioma; Localized Malignant Mesothelioma
• Intervention / Treatment: Other: laboratory biomarker analysis; Biological: bevacizumab; Drug: gemcitabine hydrochloride; Drug: cisplatin; Other: placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Other: laboratory biomarker analysis; Correlative studies; Biological: bevacizumab; Given IV; Other Names: Avastin; anti-VEGF humanized monoclonal antibody; anti-VEGF monoclonal antibody; rhuMAb VEGF; Drug: gemcitabine hydrochloride; Given IV; Other Names: Gemzar; gemcitabine; dFdC; difluorodeoxycytidine hydrochloride; Drug: cisplatin; Given IV; Other Names: CDDP; DDP; CACP; CPDD
EXPERIMENTAL: 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.	Other: laboratory biomarker analysis; Correlative studies; Drug: gemcitabine hydrochloride; Given IV; Other Names: Gemzar; gemcitabine; dFdC; difluorodeoxycytidine hydrochloride; Drug: cisplatin; Given IV; Other Names: CDDP; DDP; CACP; CPDD; Other: placebo; Given IV; Other Names: PLCB

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: October 1, 2001
• Primary Completion (ACTUAL): May 1, 2006

Study Registration Dates

• First Submitted: December 7, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (ESTIMATE): January 27, 2003

Study Record Updates

• Last Update Posted (ESTIMATE): February 11, 2014
• Last Update Submitted That Met QC Criteria: February 10, 2014
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Gemcitabine; Antibodies; Cisplatin; Immunoglobulins; Bevacizumab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological
• Other Study ID Numbers: NCI-2012-02430 (REGISTRY: CTRP (Clinical Trial Reporting Program)); P30CA014599 (U.S. NIH Grant/Contract); N01CM17102 (U.S. NIH Grant/Contract); CDR0000069058; NCI-2710; UCCRC-11046A; 11046A (OTHER: University of Chicago); 2710 (CTEP)