Although most patients (pts) with newly diagnosed stage III or IV Hodgkin lymphoma (HL) will be cured with initial therapy (tx), about 20-25% of pts will have relapsed or refractory (R/R) HL. The standard initial tx for adults with advanced stage HL, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), is associated with pulmonary toxicity due to bleomycin. Recent studies have demonstrated that in pts with a negative interim PET scan, the omission of bleomycin after 2 cycles is non-inferior with regards to survival. However, a significant proportion of pts have a positive interim PET scan and require escalation to BEACOPP - an effective but toxic regimen associated with secondary malignancies and infertility. Recently, the addition of brentuximab vedotin (BV) to AVD chemotherapy (BV-AVD) demonstrated improved modified and traditionally-defined progression-free survival (PFS) compared to ABVD. However, the BV-AVD regimen was associated with higher rates of neutropenia, sepsis, and peripheral neuropathy compared to ABVD, and there still was a ~20% failure rate. In adolescent and young adult pts with advanced stage HL, there is a similar ~20% failure rate using ABVE-PC (AB, vincristine, etoposide, prednisone, cyclophosphamide) and response-adapted radiation therapy (RT) - with RT use in a majority of pts. There remains room to improve outcomes in pediatric and adult pts with newly diagnosed advanced stage HL. The PD-1 pathway plays a critical role in the pathogenesis of HL and the disease is exquisitely sensitive to PD-1 blockade, as demonstrated in clinical trials of nivolumab and pembrolizumab in pts with heavily treated R/R HL. A phase II trial evaluating nivolumab combined with AVD (N-AVD) demonstrated promising safety and efficacy in pts with newly diagnosed HL. The incorporation of PD-1 blockade into front-line tx represents a clear opportunity to potentially improve the outcomes and tolerability of initial tx for pts with newly diagnosed advanced stage HL. A meeting was convened between the North American cooperative group Lymphoma Committee chairs, expert HL researchers and physicians, representatives from the Cancer Therapy Evaluation Program (CTEP), and patient advocates with the goals of harmonizing treatment approaches in advanced stage HL across pediatric and adult pts and reaching consensus regarding the optimal study design for a randomized trial incorporating PD-1 blockade into frontline tx for pts with advanced stage HL. Study champions were identified from each of the North American cooperative groups (SWOG, ECOG-ACRIN, Alliance, Canadian Cancer Trials Group, and Children's Oncology Group) and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes were included in the study team. The resulting clinical trial - S1826, led by SWOG Cancer Research Network - represents the largest advanced stage HL study in the history of the North American cooperative groups and the first prospective collaboration between COG and the adult cooperative groups in HL. S1826 (NCT03907488) is a randomized, phase III study of N-AVD versus BV-AVD in pts with newly diagnosed advanced stage HL. Eligible pts must be 12 years or older and have stage III or IV HL. Pts are randomized 1:1 to receive 6 cycles of treatment with either N-AVD or BV-AVD. Pts randomized to BV-AVD are required to receive G-CSF prophylaxis for neutropenia. Pts are eligible to receive RT to residually metabolically active areas on the end of treatment (EOT) PET scan at the discretion of the treating investigator. Pts are stratified during randomization based on age, international prognostic score, and intention to use EOT RT. The primary endpoint is to compare the PFS in pts randomized to N-AVD versus BV-AVD. Secondary endpoints include overall survival, event-free survival, the EOT complete metabolic response rate, and the safety and tolerability of N-AVD compared to BV-AVD. Another key secondary endpoint will be a comparison of patient-reported symptoms and health-related quality of life (overall, fatigue, neuropathy) between the study arms. 940 eligible pts are expected to be accrued over 4 years with a total of 987 pts assuming an expected ineligible rate of 5%. The S1826 study represents an unprecedented effort across the North American clinical trial cooperative groups to improve the cure rate in advanced stage HL and harmonize treatment approaches across pediatric and adult pts. Figure Disclosures Herrera: Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Research Funding; Karyopharm: Consultancy; Immune Design: Research Funding; Pharmacyclics: Research Funding. Rutherford:Heron: Consultancy; Regeneron: Research Funding; Juno: Consultancy; Dova: Consultancy; Genentech/Roche: Research Funding; AstraZeneca: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy, Research Funding; Kite: Consultancy; LAM Therapeutics: Research Funding; Seattle Genetics: Consultancy. Parsons:Seattle Genetics: Consultancy. Prica:astra zeneca: Honoraria; seattle genetics: Honoraria; Gilead: Honoraria. Shipp:Ono Pharmaceutical: Honoraria; Celgene: Honoraria; Merck: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Bayer: Honoraria. Crump:Kite/Gilead: Consultancy; Roche: Consultancy; Servier: Consultancy. Kahl:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Research Funding. Leonard:Miltenyi: Consultancy; Roche/Genentech: Consultancy; BMS/Celgene: Consultancy; MEI Pharma: Consultancy; Gilead/Kite: Consultancy; Bayer: Consultancy; ADC Therapeutics: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; GenMab: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy. Smith:Karyopharm: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Seattle Genetics: Research Funding; Roche: Other: Travel expenses; Astellas: Consultancy; Portola Pharmaceuticals: Consultancy; Kite Pharmaceuticals: Research Funding; Bayer: Consultancy.

Milatuzumab (hLL1), a humanized anti-CD74 monoclonal antibody, has activity in preclinical NHL models. We conducted a phase 1 trial in previously treated B-cell malignancies. Dose escalation included 4 planned dose levels (1.5, 4, 6, and 8 mg/kg) with milatuzumab given twice weekly for 6 weeks. After dose level 1, the schedule was changed to daily (Monday-Friday) for 10 days. Twenty-two patients were treated. The most common possibly-related toxicities were infusion reaction, anemia, lymphopenia, neutropenia, and thrombocytopenia. Three patients experienced dose-limiting toxicity (neutropenia, neutropenia, rash) at dose levels 1, 2, and 4 respectively. Eight patients had stable disease, with no objective responses. The serum half-life of milatuzumab was ~2 hours. In 7 patients, In-111-imaging showed no clear evidence of tumor targeting. The short half-life may reflect CD74 rapid internalization and presence on extratumoral tissues; this antigen sink must be overcome to capitalize on the promising preclinical activity of the drug.