Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung usually caused by asbestos exposure. Median OS following frontline chemotherapy with pemetrexed/cisplatin (pem/cis) is ~12 months. There is no established second line therapy. 40-50% of MPM tumors exhibit disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Mesothelioma cell lines that lack merlin are more sensitive to focal adhesion kinase (FAK) inhibitors than those with wild type merlin. Furthermore, pem/cis enrich cancer stem cells (CSCs) in tumors, while FAK inhibitors have been found to decrease CSCs in mesothelioma models. Given the sensitivity of mesothelioma cells lacking merlin and the effect on CSCs, the use of a FAK inhibitor in a maintenance setting after first line chemotherapy may be an attractive strategy to extend survival of MPM patients. Defactinib (VS-6063) is an oral inhibitor of FAK. Methods: A multinational, randomized, double-blind, placebo controlled, clinical trial will determine if defactinib provides superior clinical benefit compared with placebo as a maintenance treatment in patients with MPM following frontline therapy with pem/platinum therapy. Approximately 370 eligible patients with PR or SD following at least 4 cycles of pem/cis or pem/carboplatin will be enrolled. Patients will receive defactinib 400mg BID or matched placebo (1:1). Patients will continue treatment until disease progression. Randomization will be stratified by merlin status (high vs low) as determined by immunohistochemistry on archival tumor tissue. Primary endpoints will include OS and PFS. An adaptive enrichment design at the interim analysis may restrict patients to those with low merlin protein expression if benefit is observed among the subpopulation. Secondary endpoints include patient-reported outcomes, objective response and safety and tolerability. Twenty-eight sites are actively recruiting patients across 8 countries. NCT01870609