Background: Up to 30% of pts. with RCC present with metastatic disease and 5-year survival among these pts. is less than 10%. VEGF-targeted and mTOR inhibiting drugs constitute SOC in this setting but anti-tumor effects are generally short-lived and there exists a pressing need for new therapeutic strategies. Among pts. with tumors progressing through multiple prior lines of therapy, the GOLD trial (Motzer et al., Lancet Oncology 2014) reported that sorafenib and the comparator agent dovitinib achieved PFS of approx. 4 mos. CRLX101 is a novel camptothecin (CPT)-containing nanoparticle drug conjugate that delivers sustained levels of active CPT into cancer cells while reducing systemic exposure and toxicity. In addition to its topo-1 effect, CRLX101 durably inhibits HIF-1α, a hypoxia-induced transcription factor implicated in tumor angiogenesis, metastasis, and resistance to VEGF inhibitors. Clear cell RCC (ccRCC) accounts for approx. 80% of RCC and is characterized by high levels of HIF-1α, providing an ideal clinical setting in which to evaluate potential synergy between CRLX101 and the VEGF inhibitor bevacizumab (BEV). Phase 2 data presented separately at this conference highlight notable signals of RCC activity for this combination with objective response rate (ORR) and median progression free survival (mPFS) exceeding 20% and 9 mos., respectively. Methods: This randomized clinical trial is being conducted at approx. 40 U.S. cancer centers and will enroll 110 pts. with advanced, unresectable metastatic RCC who have completed 2 or 3 prior regimens of therapy. The primary endpoint will compare PFS among 90 ccRCC pts. treated with concurrently administered CRLX101 + BEV vs. SOC (any approved agent per investigator choice not previously used in the same patient). Statistical power is set at 80% to detect an increase in mPFS from 3.5 mos. to 5.8 mos. (HR~0.6). Secondary/exploratory endpoints incl. OS, ORR, safety, PK, and plasma biomarkers of efficacy. Additionally, 20 pts. with non-ccRCC histology will be evaluated independently. Enrollment is ongoing and is expected to be complete by the end of 2015. Clinical trial information: NCT02187302