Abstract B80: A Phase II randomized, double-blind, placebo-controlled study of tremelimumab for second- and third-line treatment in patients with unresectable pleural or peritoneal mesothelioma.
Authors: Calabro Luana , Krug Lee M. , DiPietro Alessandra , Antonia Scott , Hassan Raffit , Narwal Rajesh , Robbins Paul , Fu Dongyue , Shalabi Aiman , Abdullah Hesham , Ibrahim Ramy , Kindler Hedy , Maio Michele 
Published: August 2014

Abstract
Malignant mesothelioma (MM) is an uncommon cancer, caused principally by asbestos exposure. No treatments after first-line platinum-pemetrexed (1) have shown survival benefit (2), thus novel approaches are needed. Asbestos exposure induces immunosuppression and immune dysfunction in the mesothelium environment mainly by hyperactivation of regulatory T lymphocytes and over-production of cytokines that inhibit cytotoxic T lymphocytes and natural killer cells (3). Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) modulates and eventually switches off T cell activation. Tremelimumab binds to the CTLA-4 antigen, preventing its negative regulatory signaling to cytotoxic T cells (4). Results from a single arm phase 2 study of tremelimumab in 29 patients with MM who progressed on a platinum-based regimen showed promising 1- and 2- year survival rates (48.3% and 36.7%) and a safety profile consistent with previous tremelimumab studies. Two patients had durable partial response (6 and 15+ mo.): 1 after initial progressive disease. The disease control rate (DCR) was 31.0%: 5 patients had prolonged stable disease (9 to 27+ mo.). In addition, absolute levels of CD4+ICOS+ T cells significantly correlated (P = .007) with favorable overall survival (ClinicalTrials.gov # NCT01649024)(5). This study has been expanded to include an additional 29 patients who receive tremelimumab every 4 weeks for 6 doses, then every 12 weeks until confirmed disease progression. The expansion study completed enrollment in July 2013 (ClinicalTrials.gov # NCT01655888). Here we describe the design of a phase 2, randomized, double-blind, placebo-controlled study that is enrolling patients with unresectable pleural or peritoneal MM who progressed following 1 or 2 prior treatments, including a first-line platinum-pemetrexed regimen. Patients are randomized in a 2:1 ratio to receive either tremelimumab or placebo with stratification by EORTC status (low- vs high-risk), line of therapy (second vs third), and anatomical site (pleural vs peritoneal). Enrollment will include 180 patients at approximately 150 centers in multiple countries. The primary endpoint is overall survival. Secondary endpoints are durable DCR; progression-free survival (PFS); patient-reported outcomes (pain, disease-related symptoms, and time to deterioration of disease-related symptoms); duration of response and overall response rate (ORR); tremelimumab safety profile, immunogenicity, and pharmacokinetics. Exploratory endpoints are DCR, PFS, duration of response and ORR based on immune-related response criteria. Health-related quality of life, disease-related symptoms, pain, and health status in patients with durable clinical activity, as well as the association of biomarkers with tremelimumab and clinical outcomes will also be explored (ClinicalTrials.gov #NCT01843374).
This study is sponsored by MedImmune.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B80.
Citation Format: Luana Calabro, Lee M. Krug, Alessandra DiPietro, Scott Antonia, Raffit Hassan, Rajesh Narwal, Paul Robbins, Dongyue Fu, Aiman Shalabi, Hesham Abdullah, Ramy Ibrahim, Hedy Kindler, Michele Maio. A Phase II randomized, double-blind, placebo-controlled study of tremelimumab for second- and third-line treatment in patients with unresectable pleural or peritoneal mesothelioma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B80.