Background: Median overall survival (OS) is ~1 year with P/C, the standard front-line treatment for patients (pts) with unresectable MPM; additional improvement is needed. Nintedanib (N) is an oral, twice-daily, triple angiokinase inhibitor of VEGF, PDGF and FGF as well as Src and Abl kinase signalling, all of which are involved in regulating tumor angiogenesis, growth, and metastasis of MPM. Inhibition of the VEGF pathway has been validated as a treatment approach for MPM (J Clin Oncol 2015;33:A7500). Nintedanib (VARGATEF) in combination with docetaxel is approved in the European Union and other countries for locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after first-line chemotherapy and has shown clinical benefit in trials in several tumor types. The current study was extended from a Phase II to a confirmatory Phase II/III trial after all Phase II pts had enrolled. Methods: Chemo-naive pts from 25 countries ( ≥ 18 years of age, ECOG PS 0–1, and histologically confirmed epithelioid/biphasic MPM; 87 pts in Phase II/310‒450 pts in Phase III) will be randomized (1:1) to receive up to 6 cycles of P (500 mg/m²)/C (75 mg/m²) on Day 1 plus N (200 mg bid) or placebo from Days 2–21. Pts without disease progression (PD) will continue to receive maintenance treatment with N or placebo until PD. The primary endpoint is progression-free survival (PFS); OS is the key secondary endpoint. The study will use an adaptive design strategy, with sample size reassessment by an external DMC based on interim analysis to ensure sufficient power for PFS/OS. Additional secondary endpoints include objective tumor response and disease control according to modified RECIST. Other assessments include frequency/severity of adverse events, laboratory parameters, change in forced vital capacity, health-related quality-of-life and exploratory predictive biomarker analyses in tumor/blood specimens. The study is currently enrolling pts into Phase III. Clinical trial information: NCT01907100