Phase II trial of anti-transforming growth factor-beta (TGFß) monoclonal antibody GC1008 in relapsed malignant pleural mesothelioma (MPM).

Abstract

7077 Background: TGFβ is a pleiotropic cytokine overexpressed by MPM. Based on preclinical data documenting a key role for TGFβ in promoting growth and progression of MPM, we are conducting a phase II trial of GC1008 in patients (pts) with progressive MPM. Methods: Pts with progressive MPM by modified RECIST criteria and PS 0-1 with 1-2 prior systemic therapies (at least 1 pemetrexed-based) are eligible. Treatment plan: GC1008 3mg/kg IV over 90 minutes every 21 days. Responses are assessed by modified RECIST every 6 weeks. The primary endpoint is progression-free survival (PFS) rate at 3 months; secondary objectives include safety with GC1008, response rate by modified RECIST, time to progression (TTP), and overall survival (OS). Results: The modified Gehan stage 1 stopping criterion of 1/13 pts with 3 month PFS has been exceeded. To date, 13 pts (10 PS 0; 3 PS 1) with MPM (median age 69; 2F, 11M; 11 epithelial, 1 sarcomatoid, 1 biphasic) enrolled. Treatment-related toxicities include G1/2 fatigue (3 pts), nausea (1 pt) and xerosis (1 pt). Other adverse events possibly related to GC1008 were rapid disease progression in 1 pt after 2 cycles, and G2 skin keratoacanthoma in 1 pt after 5 cycles. Three pts met the primary objective of 3 month PFS at 4.1, 4.2 and 9 months each. Stable disease (SD) was seen in 3 pts (23%). Median TTP is 1.4 months (95% CI 1.2-∞); median OS is 13 months (95% CI 6-∞). Increased serum mesothelin levels have closely tracked disease progression. Serum from 6/13 pts showed new antibodies against MPM tumor lysates as measured by immunoblotting. Two of 3 pts with SD had anti-tumor antibody responses. Mean baseline plasma level of TGFβ was 2447 pg/ml but did not correlate with baseline plasma TGFβ or TTP. Conclusions: GC1008 was well tolerated in pretreated MPM patients. SD occurred in 3 pts, all with prior disease progression. Evidence for humoral anti-tumor immunity was seen in nearly half of enrollees and in 2 of 3 pts with SD. OS compares favorably to prior single-agent studies in pretreated MPM.