Background: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis involved in blood vessel maturation and stabilization. Concurrent targeting of ALK1 and vascular endothelial growth factor (VEGF) signaling results in dual angiogenic blockade and augmented inhibition of tumor growth in RCC xenograft models. Dalantercept (Dal) is an ALK1 receptor-fusion protein that acts as a ligand trap and has demonstrated monotherapy activity with an acceptable safety profile in a completed Phase 1 study. Methods: Part 1 of this study evaluated the safety, tolerability, and preliminary activity of escalating dose levels of Dal plus standard dose axitinib in pts with advanced RCC. 3-6 pts each received 0.6, 0.9, or 1.2 mg/kg Dal SC Q3W and axitinib 5 mg PO BID. Key eligibility: predominantly clear cell RCC, 1 prior VEGFR TKI, ≤ 3 prior tx. Results: As of January 16, 2015, a total of 29 pts were enrolled. During dose escalation, 15 pts were enrolled in 3 cohorts (n = 6, 4, 5) at dose levels of 0.6, 0.9 and 1.2 mg/kg, respectively. There were no DLTs. The 1.2 mg/kg dose level was expanded to include 9 more pts and edema events including peripheral edema (n = 8), fluid overload (n = 1), and ascites (n = 1) were reported. The 0.9 mg/kg dose level was then expanded to include 5 more pts. This dose level was well tolerated (4 pts with grade 1 edema, 1 pt with pleural effusion and no ascites), and selected for Part 2. AEs ( > 30%) regardless of attribution included: fatigue, diarrhea, dysphonia, peripheral edema, nausea, decreased appetite, epistaxis, hypertension, arthralgia, creatinine rise, cough, and hand-foot rash. There were no grade 4/5 related adverse events. 28 pts were evaluable by RECIST v1.1. The ORR was 25% (n = 7). Disease control (PR+SD) at 6 months was 57% (n = 16). The preliminary median PFS is 8.3 months for all dose levels combined. The mPFS at the 0.9 mg/kg dose level has not been reached. Conclusions: The combination of dalantercept and axitinib is well tolerated and has shown encouraging activity in pts who have received prior VEGF, mTOR, and immune therapies. Part 2 of this study will randomize 130 pts to dalantercept + axitinib vs. placebo + axitinib and is actively accruing patients. Clinical trial information: NCT01727336