Background: Brentuximab vedotin, a CD30-targeted antibody-drug conjugate, has conditional approval in Europe for relapsed/refractory (RR) CD30-positive HL following autologous stem cell transplant (ASCT) or following ≥2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. ABVD, a common front-line regimen for advanced HL, achieves complete response (CR) rates of 70–80%. However, 10–20% of patients (pts) are refractory to front-line treatment and up to 35% relapse after front-line multi-modality therapy. In pts with relapsed HL post-ASCT, single-agent brentuximab vedotin yields an objective response rate of 75% (CR, 33%; Chen ASH 2012). In a phase 1 study in treatment-naïve HL pts, A+AVD was associated with manageable toxicity and a CR rate of 96%; brentuximab vedotin + ABVD was contraindicated due to pulmonary toxicity (Ansell ASH 2012). We hypothesized that substituting bleomycin with brentuximab vedotin would eliminate bleomycin-associated pulmonary toxicity and improve progression-free survival (PFS) compared to a standard ABVD regimen. Methods: This ongoing, open-label, randomized, multicenter study (NCT01712490) will compare A+AVD vs ABVD in 1040 pts with stage III/IV classical HL. Primary endpoint: modified (m) PFS (death, progression, and receipt of chemotherapy or radiotherapy by pts not in CR after completing A+AVD or ABVD will count as progression event). Key secondary endpoint: overall survival. Key inclusion criteria: histologically-confirmed previously untreated stage III/IV classical HL. Pts will be stratified by region and International Prognostic Score, and will be randomized 1:1 to receive A+AVD (brentuximab vedotin 1.2 mg/kg with each dose of AVD) or ABVD administered intravenously on Days 1 and 15 of 28-day cycles, for up to 6 cycles. Disease status and survival will be evaluated regularly until study closure. Safety assessments: incidence and severity of adverse events, changes to physical and laboratory tests. Clinical trial information: NCT01712490.