Background: Despite advances in chemotherapy, relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains an unmet medical need. HL has a unique biology in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment. We hypothesized that using immune checkpoint inhibitor therapy to activate the immune microenvironment, and concurrently targeting HRS cells with the CD30 antibody-drug conjugate brentuximab vedotin (BV), could overcome tumor cell resistance. E4412 is a phase 1 ECOG-ACRIN sponsored study of the combination 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 + IPI. Methods: Patients were treated with BV 1.8mg/kg and IPI: 1 mg/kg or 3mg/kg, followed by an expanded cohort of BV + IPI 3mg/kg. BV was administered every 21 days for 16 cycles; IPI every 21 days x 4 and then every 3 months for one year. Results: As of 5/26/16: 23 planned patients have been treated; 21 patients were eligible for response assessment. The median age was 32 years (range: 20-49). Patients were heavily pretreated with a median of 4 prior therapies (1-13). Four patients had prior treatment with BV; 10 had prior SCT. BV + IPI was well tolerated, with no DLTs noted. The most common treatment-related adverse events (AEs) were: rash, diarrhea, and peripheral sensory neuropathy. Grade 3 and 4 AEs included: grade 3 infusion reaction, rash, vomiting, peripheral sensory neuropathy, and 1 grade 4 thrombocytopenia. For 21 evaluable patients, the overall response rate (ORR) for BV + IPI was 71% with a complete response (CR) rate of 48%. An additional 2 patients had stable disease (SD). The median progression free survival (PFS) is 1.02 years with a median follow-up of 0.48 years; the median overall survival (OS) has not been reached with a median follow-up of 1.16 years. Conclusion: Our data confirms the tolerability and activity of BV+IPI in a heavily pretreated R/R HL patient population. Optimization of this combination strategy is ongoing with accrual to cohorts receiving BV + NIVO, and BV + IPI + NIVO.