Randomized, double-blind, placebo-controlled study of tremelimumab for second-and third-line treatment of unresectable pleural or peritoneal mesothelioma

Background: Mesothelioma is an uncommon cancer principally caused by asbestos exposure. After 1st-line pemetrexed/platinum, there are no approved or active agents. Novel approaches are clearly needed. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is expressed upon T-cell activation, modulating and eventually inhibiting the T-cell immune response. Tremelimumab is a fully human anti-CTLA-4 antibody that has been investigated in more than 1000 patients (pts) with various tumor types. A single-center, single-arm phase 2 trial of tremelimumab in 29 mesothelioma pts who progressed on 1 prior line of platinum-based therapy demonstrated encouraging activity, including durable partial responses lasting 6 and 18 mos, disease control in 31% of pts, median overall survival (OS) of 10.7 mos, and 1- and 2-y survival rates of 48% and 37%, respectively (Maio, Lancet Oncol 2013). Methods: This multicenter, international, phase 2b, randomized, double-blind, placebo-controlled study (NCT01843374 ) enrolls pts with unresectable pleural or peritoneal mesothelioma who progressed after 1-2 lines of treatment that must have included a prior anti-folate-platinum-based regimen. Pts, stratified by EORTC status (low vs. high risk), line of therapy (2nd vs. 3rd), and anatomical site (pleural vs. peritoneal) are randomized 2:1 to tremelimumab or placebo. The primary endpoint is OS; secondary efficacy end points include OS rate at 18 mos, patient-reported outcomes, disease control rate (DCR), progression-free survival (PFS), overall response rate (ORR), and duration of response, based on modified RECIST criteria for pleural mesothelioma and RECIST criteria v1.1 for peritoneal mesothelioma. Exploratory objectives include clinical outcomes (DCR, PFS, ORR, and duration of response) based on immune-related response criteria; health-related quality of life, disease-related symptoms, pain, and health status in pts with durable clinical activity; and biomarkers (cellular, protein, and nucleic acid) and their association with tremelimumab treatment and clinical outcome. Recruitment is ongoing to a total of 564 pts at approximately180 centers globally.