Randomized, Double-Blind, Placebo-Controlled Study of Tremelimumab for Second-Line and Third-Line Treatment of Unresectable Pleural or Peritoneal Mesothelioma

Abstract

ABSTRACT Background: Mesothelioma (MM) is a malignant tumor originating from the cells lining the coelomic cavities of the body, principally caused by asbestos exposure. Asbestos causes immunosuppression/dysfunction in the coelomic cavities micro-environment. First-line treatment for advanced MM is pemetrexed/platinum chemotherapy, but effective second-line treatments are lacking, highlighting a need for new treatment approaches. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a co-inhibitory receptor expressed on activated T cells. Tremelimumab is a human anti-CTLA-4 antibody that has been investigated in ∼1000 patients (pts) with various tumor types. A single institution, investigator-initiated phase 2 trial (NCT01649024) in advanced MM showed encouraging activity with tremelimumab, including disease control in 31% of 29 pts, two durable partial responses lasting 6 and 18 months (mos), median overall survival (OS) of 10.7 mos, and 1- and 2-year (y) survival rates of 48% and 37%, respectively (Calabro, Lancet Oncol 2013). Trial design: This is an ongoing global, multicenter, phase 2b, randomized, double-blind study (NCT01843374) in pts with unresectable pleural or peritoneal MM who progressed after 1–2 lines of treatment, including an anti-folate-platinum-based regimen for advanced disease. 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 endpoints include OS rate at 18 mos, 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 modified RECIST criteria v1.1 for peritoneal mesothelioma), and patient-reported outcomes. Exploratory objectives include clinical outcomes based on immune-related response criteria; health-related quality of life, pain, disease-related symptoms, and health status in pts with durable clinical activity; and biomarkers. Recruitment is ongoing at ∼180 centers globally to a target of ∼564 randomized pts.This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting Chicago, June 2014 (TPS7609). Disclosure: A. Scherpereel: PI for the trial MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; R. Cornelissen: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Di Pietro: Employee of Medimmune and owns stock/stock options in AstraZeneca; H.L. Kindler: Research funding and ad hoc consultant MedImmune. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; K. Nackaerts: Research funding for conduct of MedImmune-sponsored ph IIb randomized placebo-controlled tremelimumab study for malignant mesothelioma patients(D48803).MedImmune considers research funding received for the conduct of a MedImmune-sponsored study a COI; S.J. Antonia: Received honoraria from BMS & MedImmune/AZ for work related to designing, implementing, and analyzing various clinical trials. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; L. Calabro: I have research funding to disclose from MedImmune. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; D. Fu: I am an employee of MedImmune, LLC, Gaithersburg. And I have stock of AstraZeneca; P.B. Robbins: I am an employee of MedImmune, LLC, Gaithersburg. I have stock of AstraZeneca; R. Ibrahim: I am an employee of MedImmune, LLC, Gaithersburg. And I have stock of AstraZeneca; M. Maio: Advisory Boards for BMS, GSK, Roche, MedImmune. He has received clinical research grants from BMS and MedImmune. MedImmune considers research funding received for the conduct of a MedImmune-sponsored study as COI.