ADHO2131: A Randomized Phase 3 Interim Response Adapted Trial Comparing Standard Therapy with Immuno-Oncology Therapy for Children and Adults with Newly Diagnosed Stage I and II Classic Hodgkin Lymphoma

ABSTRACT Chemotherapy in combination with consolidative radiotherapy (RT) has long-been the standard of care for early-stage classic Hodgkin lymphoma (cHL). We hypothesize that incorporation of immunotherapy (IO) will improve progression-free survival (PFS) and maintain overall survival (OS) while simultaneously minimizing long-term morbidity and treatment-related mortality by reducing exposure to radiotherapy and high cumulative chemotherapy doses. We have addressed this hypothesis in the consensus development of AHOD2131, which is a phase 3 study developed as a collaboration between COG and the adult NCTN groups. The study will enroll patients ages 5 to 60 years with newly diagnosed early-stage cHL and will investigate the targeted CD30-antibody drug conjugate, Brentuximab Vedotin (Bv), with PD-1 blockade (nivolumab) compared with a standard chemotherapy regimen, with or without RT. The primary objective is to compare the PFS of patients with early-stage cHL treated through a response-adapted design with either standard therapy or with an IO approach (brentuximab vedotin and nivolumab). Patients will be randomized to standard chemotherapy versus IO therapy following initial response assessment by PET/CT after two courses of ABVD. All will be stratified as favorable or unfavorable based on initial disease risk features, and those who are PET2 positive (defined as 5 Point Score, 5PS 4 or 5) will receive involved site radiotherapy (ISRT). Overall, RT exposure will be reduced compared to prior COG HL trials but within the standard of care per National Comprehensive Cancer Network (NCCN) pediatric lymphoma guidelines. In addition to the primary outcome of PFS, the study will examine the impact of the incorporation of an IO approach, and will measure the effect of therapy on acute and long-term adverse effects including health-related quality of life (HRQoL) and overall survival for up to 12 years. We expect to enroll 1875 patients over 5 years of accrual, for an estimated 1782 evaluable patients (PET2 negative/rapid early responder [RER] n = 1514; PET2 positive/slow-early responder [SER] n = 268). By examining both shorter-term PFS and longer-term OS (12-year), and by prospectively collecting detailed data on toxicity outcomes, this protocol will be practice changing for both pediatric and adult patients with cHL and will ultimately define the role of an IO approach in the management of early-stage HL. Importantly, AHOD2131 further strengthens the collaboration between adult and pediatric consortia as we continue to develop and conduct collaborative clinical trials, and will thus establish the standard of care treatment for early-stage HL across the age continuum.