Background: Mesothelin is highly expressed in epithelioid mesothelioma. Amatuximab is a chimeric monoclonal antibody that binds to mesothelin. Amatuximab was studied in a Phase II trial in MPM, demonstrating a safety profile of amatuximab in combination with P/C consistent with that seen previously for the P/C regimen alone. Although PFS was not significantly different from historical results of P/C alone, the median OS was 14.8 months (as compared to 13.3 months for P/C). The post-hoc PK/PD analysis demonstrated that amatuximab trough concentrations were a significant predictor of both OS and PFS with higher amatuximab concentrations associated with longer OS (583 days; p = 0.02) and PFS (238 days; p < 0.001). Methods: This Phase II, double-blind, placebo-controlled study (NCT02357147) is ongoing in 6 countries. Eligible patients (pts) have a confirmed diagnosis of unresectable, epithelioid MPM with measurable disease at screening, and an ECOG Performance Status 0 or 1. Prior chemotherapy, radiation, or surgery with curative intent is not allowed. 560 subjects will be randomized 1:1 to receive weekly amatuximab, 5 mg/kg or saline placebo IV in combination with P, 500 mg/m², and C, 75 mg/m², on Day 1 of each 21-day cycle for 6 cycles. Pts with objective tumor response or stable disease (RECIST modified for MPM) continue amatuximab monotherapy or placebo weekly until disease progression or study termination. The primary endpoint is a comparison of OS between amatuximab and placebo groups in the intent-to-treat population using the unstratified log-rank test. Secondary endpoints include PFS, overall response rate, and duration of response. Safety assessments will consist of monitoring and recording all adverse events (graded by NCI CTCAE v4.03) and human anti-drug antibody measurements. An interim analysis for futility will be performed by an Independent Assessment Group after 86 OS events are accrued. An Independent Data Monitoring Committee will review the results of the interim analysis for futility and provide final recommendations. As of 31 Jan 2016, 9 of the planned 560 pts are enrolled. Clinical trial information: NCT02357147