Cediranib (C) in patients (pts) with malignant mesothelioma (MM): A phase II trial of The University of Chicago Phase II Consortium.

Abstract

7027 Background: Vascular endothelial growth factor (VEGF) signaling plays a key role in MM biology. In preclinical models, agents that target VEGF inhibit MM growth. In phase II trials, several VEGF inhibitors have demonstrated modest activity in MM pts. We performed a multi-center phase II trial of C, an oral tyrosine kinase inhibitor of VEGFR 1, 2, 3 and PDGFR-α, in MM pts. Methods: Eligible pts had unresectable, histologically-confirmed MM, measurable disease, and PS 0-1. No more than 1 prior regimen of chemotherapy was permitted. C was initially dosed at 45 mg orally daily. Due to toxicity, an amendment in 6/07 decreased the dose to 30 mg daily. CT scans were obtained Q2 28-day cycles. Primary endpoint: objective response rate. A Simon, optimal, 2-stage design required 3 responses in 21 pts to proceed to a 2nd stage, and 8 responses in 50 MM pts for further investigation. Results: 50 pts enrolled 3/06-9/10 at 9 centers. Pt characteristics: male 84%; median age 64 (range 44-81); PS 0/1: 30%/70%; disease site pleural/peritoneal: 94%/6%; epithelial/sarcomatoid/biphasic/unknown: 72%/4%/12%/12%; prior chemotherapy: 88%; thrombocytosis: 26%. Median cycles delivered: 2 (range 1-14); 48% pts required dose reduction. Discontinued C for toxicity: 26% of all pts, 47% of pts at 45 mg dose. Partial responses (PR): 10% (3/15 pts at 45 mg, 2/35 pts at 30 mg), stable disease (SD): 34% (7/15 pts at 45 mg, 10/35 pts at 30 mg). Disease control rate (PR + SD): 44%. Median response duration: 8.3 mo (range 7.3-12.9). Survival: median progression-free: 1.9 mo (95% CI: 0.1, 14.2); median overall: 4.4 mo (95% CI: 0.9, 41.7); 1-year: 15%. Grade 3/4 toxicity: fatigue 24%, hypertension 22%, diarrhea 8%, hyponatremia 6%, thrombosis 6%, acute renal failure 4%, mucositis 4%, angioedema 2%, arrhythmia 2%, headache 2%, obstruction 2%, posterior leukoencephalopathy 2%, seizure 2%. Conclusions: This trial did not meet its prespecified response endpoint. The 45 mg dose of C was poorly tolerated. Supported by NCI grant N01-CM-62201.