Background: Vascular endothelial growth factor (VEGF) inhibitors have produced demonstrable but limited clinical benefit for various cancers. One mechanism of resistance includes revascularization secondary to up-regulation of alternative pro-angiogenic signals such as platelet derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) pathway. Nintedanib (Nin) is an oral triple kinase inhibitor that blocks the VEGFR, PDGFR and FGFR pathways and may improve antitumor activity by overcoming resistance to anti-VEGF therapies. This study evaluated the safety & tolerability (primary objective) of Nin in combination with bevacizumab (Bev). Methods: Patients (pts) were treated with escalating doses of Nin (150mg or 200mg oral twice daily) and Bev (15 mg/kg once intravenously every 3 weeks) until disease progression or unacceptable toxicity using standard 3 + 3 phase1 design. The plasma levels of angiogenic biomarkers were correlated with clinical outcomes. Results: Eighteen pts with advanced tumors [lung (9), colon (8) and cervical (1)] pretreated with at least two lines of chemo were enrolled. Fifty percent (9 patients) were pretreated with bev. The final dose of Nin is 200mg twice a day with no observed dose limiting toxicities (DLT). The common adverse events were fatigue (grade 1-3); nausea & diarrhea (grade 1-2). Two pts came off study due to grade 3 fatigue. The disease control rate (DCR) was 72% (1 CR,1 PR & 11 SD).The median progression free survival (PFS) was 4 months (m), and median overall survival (OS) was 14m. The PFS rate at 6, 12, and 18m was 22%, 11%, and 11% and the OS rate at 6, 12, and 18 m was 83%, 70% and 28% respectively. Durable clinical response was observed in pre-Bev treated pts (1CR, 4 SD). The median OS for colon (n = 8) not reachable with 57% alive at 18m; median OS for lung (n = 9) was 13m with 13% alive at 18m. Better DCR was correlated with lower baseline PIGF levels as well as increased level from baseline. Longer PFS was associated with higher than the median baseline values for VEFGR2, E-selectin and lower SDF-1α. Conclusions: Nin was well tolerated with Bev with no DLT’s. Significant clinical activity was observed in Bev pretreated patients suggesting Nin can overcome Bev resistance. Clinical trial information: NCT02835833