Abstract Background: Combination therapy of nivolumab plus full-dose ipi (3 mg/kg) provided greater efficacy than either inhibitor alone but with increased toxicity (55% treatment-related adverse events [TRAEs]). Results from part 1B of the phase I/II KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) showed preliminary efficacy in pts with melanoma treated with standard-dose pembro (2 mg/kg every 3 weeks [Q3W]) + reduced-dose ipi (1 mg/kg Q3W for 4 doses). This combination appeared superior to historical studies with single-agent anti-PD-1, but 42% of pts had TRAEs. Part 1C of KEYNOTE-029 will explore 2 additional dosing regimens of this combination to further investigate efficacy and minimize the occurrence of the toxicity observed in part 1B. Methods: Eligibility criteria include age ≥18 yr; histologically confirmed unresectable stage III/IV melanoma not amenable to local therapy; no prior treatment ([neo]adjuvant treatment, excluding PD-1/PD-L1 or BRAF/MEK inhibitors is allowed, provided pts did not discontinue for TRAEs, all related AEs returned to baseline or stabilized, and relapse did not occur during or within 6 mo of treatment discontinuation for anti-CTLA-4 therapy); measurable disease per RECIST v1.1; ECOG performance status 0 or 1; no active brain metastases (baseline brain MRI required); and no active autoimmune disease requiring systemic therapy within the past 2 yr or history of pneumonitis requiring steroids. In part 1C, ~100 pts are to be randomly assigned 1:1 to receive pembro 200 mg Q3W + ipi 50 mg Q6W (arm 1) or ipi 100 mg Q12W (arm 2). Combination treatment will continue for ≤24 wk in arm 1 and ≤48 wk in arm 2, followed by pembro monotherapy for ≤24 mo or until progressive disease (PD), intolerable toxicity, patient withdrawal, or physician decision to discontinue. Tumor imaging will be performed every 6 wk until wk 24, then every 12 wk thereafter. Response will be assessed per RECIST v1.1 by independent central review (for efficacy) and modified RECIST v1.1 by investigator review (for treatment decisions). Survival follow-up will occur every 12 wk. AEs will be graded throughout the study and for 30 d thereafter per NCI CTCAE v4.0. Pts with investigator-determined, confirmed complete response (CR) who received ≥24 wk of pembro and ≥2 doses of pembro after initial CR may discontinue pembro; pts with investigator-determined, confirmed CR or very good partial response (percentage change from baseline in tumor size >60%) who received ≥1 ipi dose may discontinue ipi. Pts experiencing stable disease or better who subsequently experience PD may be eligible for a second treatment course with pembro + ipi or pembro monotherapy (maximum 17 doses of pembro and 4 doses of ipi). Eligible pts with PD may remain on treatment until a confirmatory scan ≥4 wk later. Primary end points are safety and ORR; secondary end points include PFS, OS, and duration of response. Citation Format: Michael B. Atkins, Matteo S. Carlino, Andrew G. Hill, Catriona M. McNeil, Georgina V. Long, Victoria Atkinson, Jonathan S. Cebon, Michael B. Jameson, Wen-Jen Hwu, John A. Thompson, James Anderson, Blanca Homet Moreno, Nageatte Ibrahim, Antoni Ribas. KEYNOTE 029: A phase I/II randomized trial of pembrolizumab (pembro) plus 2 dose regimens of ipilimumab (ipi) for advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT065. doi:10.1158/1538-7445.AM2017-CT065