Background: Brentuximab vedotin (ADCETRIS), a CD30-targeted antibody-drug conjugate, has been approved for adults with relapsed or refractory CD30+ HL in 39 countries including the US and Europe. Front-line ABVD achieves complete response (CR) rates of 70–80% in patients (pts) with advanced HL. However, 10–20% of pts are refractory to front-line treatment and an additional ≤25% relapse. Further, bleomycin-induced pulmonary toxicity occurs in 10–25% of pts (Horning, J Clin Oncol 1994). In pts with relapsed HL post-autologous stem cell transplantation, objective response rate to single-agent brentuximab vedotin is 75% (CR, 33%; Chen, ASH 2012). In a ph 1 dose-escalation study (NCT01060904), 51 pts with treatment-naïve HL stage IIA bulky or stage IIB–IV disease were enrolled to evaluate safety, maximum tolerated dose and antitumor activity of brentuximab vedotin combined with ABVD (A+ABVD) or AVD (A+AVD) (Younes, Lancet Oncol 2013). 80% pts had stage III–IV, 25% had International Prognostic Score ≥4. Brentuximab vedotin was given on days 1 and 15 of 28-day cycles (≤6 cycles), 25 pts received ABVD plus brentuximab vedotin at 0.6, 0.9, or 1.2 mg/kg; 26 received AVD plus brentuximab vedotin 1.2 mg/kg. A+AVD was associated with a PET2 negative rate of 92%, CR rate of 96% and manageable toxicity. Although A+ABVD induced an unacceptably high rate of pulmonary toxicity compared to known rates with ABVD alone, pulmonary toxicity was not observed in the A+AVD cohort. We hypothesized that substituting bleomycin with brentuximab vedotin may improve progression-free survival (PFS) compared to ABVD and, eliminate bleomycin-related pulmonary toxicity. Methods: ECHELON-1 (NCT01712490), an ongoing, open-label, randomized, ph 3 study, will compare A+AVD vs ABVD in 1,040 pts with untreated stage III/IV classical HL. Pts will receive A+AVD (brentuximab vedotin 1.2 mg/kg with each dose of AVD) or ABVD on Days 1 and 15 of 28-day cycles (≤6 cycles). Primary endpoint: modified PFS (death, progression, receipt of chemotherapy or radiotherapy by pts not in CR after completing front-line therapy). Clinical trial information: NCT01712490.