Background: Higher sunitinib drug exposure is associated with better response (RR), progression free (PFS) and overall survival (OS). Retrospective data show poorer PFS and OS in patients (pts) with minimum toxicity on the 28 day (d)/14 d schedule vs pts needing dose/schedule changes. We hypothesized that toxicity-driven dose/schedule changes would optimize drug exposure. Methods: In a prospective phase II study (eligibility identical to EFFECT trial, JCO 30(12):1371) with the primary endpoint of improving PFS from 8.5 (EFFECT 4/2) to 14 months (mo), pts start on 50 mg/d for 28 d with treatment (Rx) breaks reduced to 7 d. Pts with grade-2 toxicity before d 28 stay on 50 mg with the d on Rx individually reduced aiming for ≤ grade-2 toxicity. Dose is reduced to 37.5 mg in pts that do not tolerate 50 mg for at least 7 d and to 25 mg in pts that do not tolerate 37.5 mg for 7 d with individualized duration of Rx. Pts with minimum toxicity on d 28 are dose escalated to 62.5 mg and then 75 mg on a 14/7 d schedule. Pts that develop grade-2 toxicity by d 28, stay on a 28/7d schedule. Results: With accrual completed and 116 pts entered at 12 centers, 83 pts are evaluable for RR (at least two CTs 2 mo apart) with median followup of 11.6 mo (Heng favorable 25%, intermediate 63%, poor 12%). Nine pts came off study early due to toxicity (5), non-compliance (2) or global deterioration (2). Of 61 pts still on therapy, 24 are too early for RR. Of 83 evaluable pts (37 still on Rx), 18 (21.7%) were dose escalated to 62.5 mg (11) and 75 mg (7). For 39 pts (47%), who would have been dose reduced by standard criteria, a 50 mg dose was continued for 7 - 24 d, while 7 pts (8.4%) stayed on a 28d schedule. Dose was reduced to 37.5 mg in 13 pts (15.7% vs 36 - 63% in 4 trials) and to 25 mg in 6 pts (7.2 % vs 15 - 19% in 4 trials). Rx was stopped due to toxicity in 7/116 pts (6% vs 15-19% in 4 trials). Best response was complete (CR) in 4 pts, partial (PR) in 38 pts, stable (SD, median 6.4 mo on Rx) in 32 pts and progression in 9 pts (10.8% vs 24.6% in EFFECT) for a CR+PR (median 14.3 mo on Rx) rate of 50.6% (vs 32% in EFFECT) and CR+PR+SD rate of 89.2% (vs 75% in EFFECT). Conclusions: Individualized dosing is safe and feasible in a multicenter setting and associated with improved dose intensity and one of the highest RR reported for mRCC. Clinical trial information: NCT01499121