A multicenter, double-blind, placebo-controlled randomized phase II trial of gemcitabine/cisplatin (GC) plus bevacizumab (B) or placebo in patients (pts) with malignant mesothelioma (MM)

Abstract

7019 Background: MM pts have the highest VEGF levels of any solid tumor, and high VEGF is a poor prognostic factor. Anti-VEGF antibodies decrease MM growth in pre-clinical models. Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody to VEGF. GC is an active regimen in MM. Methods: We are conducting a multi-center, double-blind, placebo-controlled randomized phase II trial of GCB vs. GCP in MM pts. Primary endpoint: time to progression. Eligible pts have unresectable, histologically confirmed MM; no prior chemotherapy; PS 0–1; measurable disease; no tumor involvement of major vessels; no bleeding or thrombosis. Pts are stratified by PS (0/1) and histology (epithelial/other). Pts receive G 1250 mg/m2 days (D) 1, 8, Q 21D, C 75 mg/m2 D1 Q 21D, and B or P 15 mg/kg D1 Q 21D, for 6 cycles, then single-agent B or P Q21D. CT scans are obtained Q2 cycles. Plasma VEGF levels are obtained pretreatment. 102 pts enrolled 12/01–11/04 at 10 centers, 95 (47 GCB, 48 GCP) are evaluable. Pt characteristics (GCB/GCP): male 74%/83%; median age 62/63.5 (range 20–83); PS: 0 32%/29%, 1 68%/71%; epithelial 74%/77% sarcomatoid/biphasic 26%/23%; site of origin: pleura 91%/90%, peritoneum 9%/8%, tunica vaginalis 0%/2%; thrombocytosis 36%/40%. Results: Cycles administered: 588 (range 1–39, median 5). Grade ¾ hematologic toxicity (%pts, GCB/GCP): neutropenia 23%/21%; anemia 0%/6%; thrombocytopenia 15%/15%; other toxicity (all grades, grade ¾): epistaxis 34%/6%, 4%/0%; proteinuria 36%/23%, 2%/0%; hypertension 28%/6%, 11%/2%; thrombosis 7%/6%, 7%/6%; visceral perforation 0%/0%. Median baseline plasma VEGF 114.5/179 pg/ml. Conclusion: The study arms are well-balanced. Grade ¾ toxicities were not statistically greater for GCB except for hypertension (all grades p=0.006) and epistaxis (all grades p=0.001). Individualized treatment assignments and efficacy outcomes remain blinded until 106 evaluable pts enroll. Supported by grants from NCI (N01-CM-17102) and the Mesothelioma Applied Research Foundation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Lilly Oncology Genentech, Lilly Oncology Genentech, Lilly Oncology