Perlmutter Cancer Center

Site for 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. The study expects 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. This is a randomized trial comparing an IO approach with or without radiation therapy to a standard chemotherapy approach with or without radiation therapy in early stage cHL. All patients will be stratified by favorable vs. unfavorable features at study enrollment. Patients are considered unfavorable if they have one or more of the following factors: (1) large mediastinal mass (> 10 cm by CT or 1/3 max chest diameter by CXR), (2) > 3 nodal sites, (3) B symptoms with ESR > 30, (4) ESR > 50 without B symptoms, and (5) age > 50 years. All patients will receive 2 cycles of ABVD chemotherapy. Subsequently, a rapid central review will be performed to determine early response assessment (PET2), which will be utilized to randomize patients to receive either conventional chemotherapy or an IO approach with nivolumab and brentuximab vedotin. If a patient is deemed to not meet study eligibility staging criteria at the time of PET2 central review, the patient will be removed from protocol therapy. All SER patients (5PS 4, 5) will receive involved site radiation therapy (ISRT). Following randomization, the patient may be assigned to one of the following treatment arms: • Arm A (Favorable RER, Standard Therapy): ABVD x 2 • Arm B (Favorable RER, IO Therapy): Brentuximab vedotin + Nivolumab x 4 Arm C (Favorable SER, Standard Therapy): eBEACOPP x 2, ISRT • Arm D (Favorable SER, IO Therapy): Brentuximab vedotin + Nivolumab x 4, ISRT • Arm E (Unfavorable RER, Standard Therapy): AVD x 4 • Arm F (Unfavorable RER, IO Therapy): Brentuximab vedotin + Nivolumab x 4 • Arm G (Unfavorable SER, Standard Therapy): eBEACOPP x 2, ISRT • Arm H (Unfavorable SER, IO Therapy): Brentuximab vedotin + Nivolumab x 4, ISRT