BACKGROUND This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide plus sunitinib in metastatic renal cell carcinoma (RCC) patients. METHODS Patients with histologically confirmed, metastatic RCC were treated with 10 mg/day lenalidomide plus 37.5 mg/day sunitinib, orally in 21-day cycles. Doses were escalated to determine the MTD in phase I, with additional patients planned at this dose in phase II. Primary end points were MTD and response rate. RESULTS Sixteen patients received a median of 2, 3, and 5 cycles in cohort 1 [lenalidomide 10 mg (days 1-21) and sunitinib 37.5 mg (days 1-21)], cohort 2 [lenalidomide 10 mg (days 1-21) and sunitinib 37.5 mg (days 1-14)], and cohort 3 [lenalidomide 15 mg (days 1-21) and sunitinib 37.5 mg (days 1-14)], respectively. Median treatment durations were 41, 63, and 97 days for lenalidomide; and 41, 57, and 97.5 days for sunitinib. The MTD was found to be continuous dosing of lenalidomide 10 mg/day plus sunitinib 37.5 mg/day for 14 of 21 days. Dose-limiting toxicities included neutropenia, leukopenia, thrombocytopenia, asthenia, atrial fibrillation, and increased transaminases. The most frequent grade 3-4 treatment-emergent adverse events were hematologic, including neutropenia and leukopenia. One patient achieved partial response, and seven had stable disease of which three were confirmed at subsequent tumor assessments. B cells and several T-cell subsets were modulated versus baseline. CONCLUSIONS The dose schedules of lenalidomide and sunitinib evaluated in this study were not well tolerated; cumulative toxicity precluded enrollment at the MTD.