Background: GBM, the most common primary brain tumor in adults, has an aggressive clinical course and a median survival of 12–15 months post first-line therapy with maximal surgical resection, radiation, and temozolomide. Bevacizumab is approved in the US for pts with progressive disease following therapy; no data has shown durable improvement of disease-related symptoms or overall survival (OS). With limited efficacy of current therapy, more effective treatments to extend survival and preserve quality of life are needed. Ipilimumab, a cytotoxic T-lymphocyte antigen-4 receptor blocking antibody, has shown clinical activity in advanced melanoma pts with brain metastases; preclinical studies demonstrate a benefit from combining a programmed death-1 (PD-1) pathway inhibitor with radiation in a mouse glioma model. We present a phase IIb, randomized, open-label study to evaluate the efficacy and safety of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, alone or with ipilimumab, vs bevacizumab in pts with recurrent GBM. Methods: Pts with Karnofsky performance status ≥70, grade IV malignant glioma treated with radiotherapy and temozolomide, and documented first GBM recurrence within 28 days of randomization are eligible. Pts with >1 recurrence of GBM, extracranial disease, autoimmune conditions, or previous VEGF inhibitor or anti-angiogenic treatment are ineligible. Safety cohort 1; nivolumab 3 mg/kg [n=10; Q2W x 4] and nivolumab 1 mg/kg + ipilimumab 3 mg/kg [n=10; Q3W x 4 followed by nivolumab 3 mg/kg Q2W]) will establish safety and tolerability in GBM pts. Upon successful completion of cohort 1, efficacy cohort 2 will enroll up to 240 pts with recurrent GBM, randomized 1:1:1 to receive nivolumab, nivolumab + ipilimumab (dosed as cohort 1), or bevacizumab (10 mg/kg Q2W). The primary objectives are to evaluate safety in cohort 1 and OS in cohort 2, vs bevacizumab, with secondary objectives of PFS and ORR. Responses will be assessed (Response Assessment Neuro-Oncology criteria) at the end of wks 6 and 12, and Q8W until progression or treatment discontinuation. Clinical trial information: NCT02017717.