Background: MPM is a rare cancer originating from multipotent mesothelial cells capable of differentiating into epithelial, sarcomatoid, or biphasic (mixed) neoplasms. The only approved 1^st-line chemotherapeutic regimen for unresectable MPM, combination pemetrexed/cisplatin extends OS to only approximately one year, illustrating a need for improved treatment strategies. In the present trial, we are investigating the efficacy and safety of nintedanib (BIBF 1120) combined with pemetrexed/cisplatin for the treatment of unresectable MPM. Nintedanib is an oral, twice-daily, angiokinase inhibitor targeting most prominently vascular endothelial growth factor receptors 1–3, platelet-derived growth factor receptors α/β, and fibroblast growth factor receptors 1–3, as well as Src and Abl kinase signaling, which are involved in regulating tumor angiogenesis, growth, and metastasis of MPM. These signaling pathways are also implicated in the pathogenesis and maintenance of MPM. In previous studies, we demonstrated that nintedanib can be co-administered with various anti-cancer drugs to safely and significantly increase survival in patients (pts) with non-small cell lung cancer. Methods: A total of 86 pts—at least 18 years of age and with ECOG score of 0 or 1 and histologically confirmed epithelioid or biphasic MPM—will be randomized in a 1:1 ratio to receive either up to 6 cycles of 1^st-line combination pemetrexed (500 mg/m²)/cisplatin (75 mg/m²) on day one administered along with nintedanib (200 mg bid) or placebo from days two to 21. Pts who do not develop progressive disease (PD) will continue to receive maintenance treatment with either nintedanib or placebo until PD. The primary endpoint is PFS. Secondary endpoints are OS and baseline change in forced vital capacity as a measure of pulmonary function. Frequency and severity of adverse events will also be evaluated as a measure of safety. All pts will attend an end-of-trial visit when they discontinue study treatment permanently, and return for follow-up visits until the end of trial, death, or loss to follow-up. Clinical trial information: NCT01907100.