Background: VEGF agents are a mainstay of therapy in advanced RCC. Bev has activity in RCC but was licensed with interferon-α, which can produce side effects and reduced QoL. Based on non-overlapping side effect profiles, we studied bortezomib (Bmib), a proteasome inhibitor, with the VEGF ligand monoclonal antibody, bevacizumab (Bmab). Primary objective was to examine safety/toxicity of 2 dose schedules of Bmib with Bmab with secondary aims of efficacy (benchmarked to NCI data) and correlatives. Methods: From 2005 and 2014, 62 RCC patients with clear cell or papillary predominant histology treated with 0-4 prior therapies were screened: 10 screen failed, 4 were ineligible (2 treated, 2 not) leaving 48 eligible patients, of whom 46 were evaluable for safety and efficacy endpoints with 20 in each of the phase II dose schedules. Regimens were randomly allocated, stratified by MSKCC group. Results: Best tolerated doses of Bmib with Bmab 10mg/kg IV q3wks on each regimen were A: 1.3 mg/m² on D 1, 4, 8 and 11 q3wks & B: 1.8 mg/m²on days 1 and 8 q3wks. MSKCC strata: low, intermediate, high risk in 43, 42%; 48, 49%; 9, 9% for schedules A and B, respectively; other baseline factors were not significantly different between A & B. Overall: nephrectomy 90%; ECOG 0 73%; male 71%; median age 57 years; Caucasian 48%, Hispanic 33%, Black 8%, Asian 10%;. Median cycles both arms: 5. Best RECIST 1.0 response PR: 13%, 13%; SD 52%, 48%; PD 26%, 35%; Reason off therapy: PD 58, 67%; toxicity 25, 17% in arms A, B. Median OS: 33.4, 14.7 months (p=0.69), TTP 11.2, 9.4 months, PFS 7.3, 6.6 months (p=0.61) in arms A, B. Grade 3+ tox: A 14/24 vs. B 13/24, p=1.0. Arm A had numerically more skin toxicities and grade 2/3 hematological tox (Plats and WBCs) compared to arm B but this was not statistically significant. Conclusions: Randomized comparisons of novel agents are feasible in renal cell cancer using risk factor algorithms. This VEGFrTKI contemporaneous series of Bmab based therapy with 2 schedules of Bmib suggests potential better outcomes for schedule A with more frequent dosing of Bmib – further sensitivity analysis is ongoing to determine whether this is explained by histology or therapeutic sequencing or likely to suggest proteasome as a target in RCC. Clinical trial information: NCT00184015