Background: The VEGF/VEGFR and PDGF/PDGFR pathways are potential therapeutic targets in mesothelioma. Cediranib, a VEGFR/PDGFR inhibitor, showed anti-tumor activity in a salvage monotherapy study S0509. Methods: S0905 combined cediranib (2 dose cohorts 30 mg and 20 mg daily) with cisplatin and pemetrexed for 6 cycles followed by maintenance cediranib in unresectable chemo-naïve MPM patients. Results: A total of 20 patients (7 to cohort 1 - 30 mg, 13 to cohort 2 - 20 mg) were enrolled. In first cohort, 2 patients reported grade 3 DLTs of diarrhea and fatigue. Cohort 2 DLTs included 2 patients with grade 3 hyponatremia/dehydration and mucositis. For all cycles, 12 patients reported Grade 3 AEs, the most common being diarrhea (4), dehydration (3), fatigue (3) and neutropenia (3). Two grade 4 thrombocytopenia were reported with 1 treatment-related death (cohort 2) due to pneumonia/sepsis. Based on the toxicity profile, a decision was made to proceed with cediranib 20 mg daily for the remaining phase I/II trial. Two radiographic response measurements were utilized (RECIST 1.1, modified RECIST). 18/20 patients were evaluable for response by RECIST 1.1 (7 - 30 mg cohort, 11 - 20 mg cohort). The RECIST 1.1 RR was 22% (95% CI: 6% - 48%) and median PFS was 14 months (95% CI: 8 – 17). Two patients had inadequate assessments and are classified as non-responders. There were 19 patients measurable by modified RECIST with RR 53% (95% CI: 29%-76%) and median PFS 10 months (7-13). For all patients, the median OS was 16 months (95% CI: 11-19). One patient in the 30 mg cohort remains on trial after 25 cycles of therapy; 2 patients at the 20 mg cohort remain on trial on cycles 19 and 15 of therapy. Conclusions: Cisplatin-pemetrexed-cediranib shows significant clinical activity and acceptable toxicity with cediranib 20 mg/day. The randomized phase II portion of the trial is ongoing. Clinical trial information: NCT01064648.