Background: PD-1 and PD-L1 inhibitors are standard of care therapies for relapsed/refractory cHL. A recent study of the anti–PD-1 antibody pembro followed by conventional chemotherapy has shown clinical benefit in the first-line setting for cHL (Allen PB et al. Blood 2020;137[10]:1318-1326). KEYNOTE-C11 (NCT05008224) is an open-label phase 2 study that is evaluating safety and efficacy of sequential pembro monotherapy and chemo followed by pembro consolidation in newly diagnosed early unfavorable or advanced-stage cHL. Methods: Eligible patients (pts) are adults with newly diagnosed and histologically confirmed early unfavorable (Ann Arbor stage I/II plus ≥1 NCCN unfavorable risk factor) or advanced-stage (Ann Arbor stage III/IV) cHL. Pts must have measurable disease per Lugano 2014 criteria and have not received prior radiation therapy, chemotherapy, immunotherapy, or other systemic therapy for cHL. All pts will receive pembro 200 mg IV Q3W for 3 cycles followed by PET to determine response. After pembro induction, all pts will receive 2 cycles of doxorubicin, vinblastine and dacarbazine (AVD day 1 and day 15 Q4W) and undergo another PET assessment (PET3). Pts with negative findings on PET3 (≤3 on the FDG-PET 5-point scale) will receive 2-4 additional cycles of AVD, depending on stage and bulk of disease; those with nonbulky early unfavorable disease will receive 2 cycles, and all others will receive 4 cycles. Pts with positive findings on PET 3 (≥4 on the FDG-PET 5-point scale) and aged < 60 years will transition to 2-4 cycles of escalated therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone, depending on bulk and stage of disease; those with nonbulky early unfavorable disease will receive 2 cycles, and all others will receive 4 cycles. Pts aged ≥60 years will continue to receive AVD for 4 cycles. All pts will then receive 4 cycles of pembro 400 mg Q6W as consolidation therapy. Treatment will continue until disease progression, unacceptable toxicity, investigator’s decision, or maximum duration of treatment is reached. Adverse events will be graded per CTCAE version 5.0. Primary end point is complete response (CR) by BICR per Lugano 2014 response criteria. Secondary end points include CR by investigator review per Lugano 2014 response criteria, rate of PET negativity by BICR according to the FDG-PET 5-point scale, duration of CR by BICR per Lugano 2014 response criteria, and safety and tolerability. Exploratory end points include 2-year modified PFS by BICR per Lugano 2014 response criteria and OS. Efficacy and safety will be evaluated in all pts who received ≥1 dose of pembrolizumab. CR rate with 95% CI will be reported per the Clopper-Pearson exact binomial method. Duration of CR, PFS, and OS will be estimated using the Kaplan-Meier method. Planned enrolment is 140 pts. Clinical trial information: NCT05008224.