Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge. We hypothesized that using an immune checkpoint inhibitor to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 antibody-drug conjugate brentuximab vedotin (BV) could overcome resistance. E4412 is a Phase 1 ECOG-ACRIN sponsored study of the combinations of BV and ipilimumab (Ipi) and nivolumab (Nivo) in patients with R/R HL. Here we present the updated safety and response data on the full cohort of patients treated with BV + Nivo (Arms D-F). Methods: Patients with confirmed R/R HL were treated with Nivo 3 mg/kg and BV 1.2 mg/kg (Arm D) or 1.8 mg/kg (Arm E) with a 3 + 3 design, and an expansion cohort (Arm F) of 9 patients. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional year. Dose limiting toxicity (DLT) was defined within the first cycle of therapy. Results: As of 3/10/17 19 patients (1 ineligible) have been treated. Median age was 40, range (21-70); 9 patients were male. Patients were treated with a median of 3 prior therapies. Eight patients had prior SCT; 4 patients had prior BV. Safety: Nineteen of 19 patients are evaluable for safety. There were 2 significant treatment related adverse events (AEs): 1 patient in Arm E experienced a DLT (pneumonitis grade 3 with grade 3 dyspnea and hypoxia, and typhilits), and made a full recovery; 1 elderly patient in Arm F had grade 5 pneumonitis occurring in cycle 2. There were no other Grade 4 or 5 AEs; grade 3 AEs were one each: rash, puritis, and neutropenia. The most common grade 1-2 AEs were: transaminitis (9), peripheral sensory neuropathy (8), and rash (6); other grade 1-2 AEs included: diarrhea (4), blurry vision (3), and myalgias (2). One grade 1-2 infusion reaction was noted, this patient was able to receive subsequent therapy with pre-medication. Response: Response is shown below in Figure 1. Seventeen of 18 eligible patients are evaluable for response, one patient died after cycle 2 and response could not be assessed. The overall response rate (ORR) for the combination was 89%, with a CR rate of 50% (9/18) (95% CI: 26%-74%). There were 2 CRs and 1 PR in patients treated with prior BV. The 6 month PFS is 91% (95% CI: 75-100%), and median OS with a median follow-up of 6 months is not reached. Conclusion: In this study of the combination of Nivo and BV for R/R HL, therapy was generally well tolerated, however two patients experienced pneumonitis. In a heavily pretreated patient population, the ORR of 89% and CR rate of 50% suggests a deepening of response compared to either therapy alone. Optimization of this strategy is planned with ongoing accrual to cohorts receiving BV + Ipi + Nivo. Data will be updated to include longer term PFS and OS by the time of the meeting.