Background: Nivo is a human IgG4 monoclonal antibody immune checkpoint inhibitor that targets programmed death receptor-1 (PD-1) on activated immune cells and disrupts engagement of the receptor by its ligands PD-L1 and PD-L2. cHL tumors very frequently harbor amplifications at 9p24.1, causing overexpression of PD-L1 and PD-L2, which suggests a unique dependence on the PD-1 pathway for survival. This tumor may therefore be particularly sensitive to PD-1 blockade. In a phase 1 study (NCT01592370) of 23 heavily pretreated pts with cHL, nivo showed an acceptable safety profile and promising anti-tumor activity, with an investigator-assessed ORR of 87% and median duration of response not reached after a median follow-up of 23 months. Moreover, 60% of responders had a response within 8 wks (Ansell SM et al, NEJM 2015;372:311–9; Ansell SM et al, ASH 2015 [583]). Immune-modulating therapy, which requires pts to mount an immune response, may be more effective before exposure to many prior chemotherapy regimens. We hypothesized that nivo could lead to deep responses in pts never exposed to chemotherapy, and could synergize with chemotherapy to provide curative treatment. We are therefore testing nivo in combination with chemotherapy in pts with newly diagnosed cHL, with a window period to assess response to single-agent immunotherapy. Methods: This study involves Cohort D of the broader phase 2 study of nivo in cHL (NCT02181738). To be eligible for Cohort D, pts must be ≥ 18 years with newly diagnosed cHL (stage III, IV, or IIB with B symptoms, extranodal or bulky disease) and ECOG performance status < 2. Nivo 240 mg IV is administered every 2 wks for 4 doses, then every 2 wks with AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) for 6 cycles (22 wks). Safety and tolerability of the regimen is being assessed. Primary endpoint is the proportion of pts with ≥ 1 treatment-related grade 3–5 AEs ≤ 30 days after the last study dose. Other selected endpoints include treatment discontinuation rate and incidence of treatment-related grade 3–5 AEs during nivo monotherapy and nivo-AVD combination, objective response rates, and biomarker studies. Planned enrollment in Cohort D is 50 pts. Clinical trial information: NCT02181738