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 is an ALK1 receptor-fusion protein that acts as a ligand trap by binding to ligands, bone morphogenetic proteins (BMP) 9 and 10. Part 1 of this study evaluated the safety, tolerability, and preliminary activity of escalating dose levels of dalantercept (0.6, 0.9, and 1.2 mg/kg) plus standard doses of axitinib (5 mg PO BID) every 3 weeks in patients with advanced RCC who received at least one prior VEGFR TKI and no more than 3 prior tx. 29 pts were enrolled in Part 1 and the combination was associated with an acceptable safety profile and preliminary activity (25% RR, preliminary median PFS of 8.3 months for all dose levels combined). The mPFS for the 0.9mg/kg dose level has not been reached. AEs ( > 30%) regardless of attribution: 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. The 0.9 mg/kg dose level was selected for Part 2. Methods: Part 2 is a multi-center Phase 2 study and is actively accruing patients across approximately 50 sites in the US. In Part 2, 130 patients will be randomized 1:1 to dalantercept plus axitinib or placebo plus axitinib in a double-blinded fashion. Key eligibility: predominantly clear cell RCC; ECOG 0-1; 1 prior VEGFR TKI. 1 prior mTOR inhibitor and any number of prior immune therapies are also permitted. An independent DMC will evaluate safety data during the study. The primary endpoint is PFS. Secondary endpoints include: ORR by RECIST v1.1, OS, pharmacokinetic assessments, and pharmacodynamic evaluations of ALK1 pathway and other angiogenesis markers in serum and archived tumor specimens. Clinical trial information: NCT01727336