Background: The activity of agents that target the vascular endothelial growth factor (VEGF) pathway in metastatic renal cell cancer (mRCC) may be enhanced in combination with agents that inhibit non-VEGF angiogenesis pathways and may lead to improved outcomes for pts. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the TGFβ superfamily that is expressed on endothelial cells and is involved in blood vessel maturation. Dalantercept (Dal) is an ALK1 receptor-fusion protein that inhibits signaling through ALK1 and has demonstrated additive efficacy with a VEGF receptor (VEGFR) TKI in RCC models. Methods: Part 1 of this randomized 2-part phase 2 study assessed the safety and tolerability of Dal plus axitinib, a VEGFR TKI in pts. with mRCC who had up to 3 prior lines of therapy and determined the recommended phase 2 dose (RP2D). Cohorts of 3-6 pts. each received Dal (0.6, 0.9, or 1.2 mg/kg) SC Q3W and axitinib 5 mg PO BID. An expansion cohort at the RP2D will enroll an additional 10-20 pts. Eligibility criteria include 1 prior VEGFR TKI, ≤ 3 prior tx., and ECOG ≤1. Results: 13 pts. were enrolled in the three cohorts (n= 4, 4, 5) and there were no DLTs within 28 days of the first dose. Of the 13 pts., 46% had ≥ 2 prior tx and 15% had 2 prior anti-VEGF tx. Common Dal-related AEs were grade 1-2 diarrhea, fatigue, anemia, arthralgia, creatinine rise, constipation, nausea, dysphonia, headache, muscle spasms. There have been no Dal associated SAEs. AEs associated with axitinib did not occur with higher than expected frequency or severity. 3 of 12 (25%) evaluable patients (2 at 0.6 mg/kg and 1 at 0.9 mg/kg) 2 of whom had three prior tx, achieved partial responses and were on study for ≥ 10 cycles (7.5 mo). 6 of 11 (55%) evaluable pts. completed ≥ 6 cycles (4.5 mo). Enrollment in the expansion cohort at 1.2mg/kg Dal is ongoing. Conclusions: In this pretreated mRCC population, the combination of Dal and axitinib is well tolerated and associated with clinical activity including disease control in the majority of pts.These data support 1.2 mg/kg as the RP2D of Dal in the randomized double-blind part 2 of this study in which pts. will be randomized to Dal + axitinib vs. placebo + axitinib. Clinical trial information: NCT01727336.