ctDNA-Guided Therapy for Relapsed/Refractory Hodgkin Lymphoma

PRIMARY OBJECTIVE: I. To determine the ctDNA/MRD-negative, PET-negative complete response rate for cHL patients undergoing treatment with pembro + GVD. SECONDARY OBJECTIVES: I. To determine progression-free survival (PFS) overall survival (OS) at 2 years among patients receiving non-transplant consolidation. II. To determine PFS and OS at 2 years for the overall cohort. III. To determine the proportion of patients treated with pembro + GVD and non-transplant consolidation who ultimately undergo Autologous Stem Cell Transplant (ASCT) within 2 years. IV. To determine the rate of discordance between Positron Emission Tomography (PET)/Computerized tomography (CT) response and ctDNA/MRD response. V. To determine the incidence of adverse events, including immune-related adverse events, in patients receiving pembro + GVD and pembrolizumab consolidation. VI. To assess health-related quality of life (HRQOL) and patient-reported outcomes (PROs) as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) 29 and Functional Assessment of Cancer Therapy-COmprehensive Score for financial Toxicity (FACIT-COST). VII. To determine the proportion of patients with relapsed or refractory cHL for whom baseline Foresight CLARITY LDT genotyping from the peripheral blood is successful EXPLORATORY OBJECTIVES: I. To evaluate the kinetics of ctDNA/MRD clearance in the peripheral blood after pembro + GVD. II. To evaluate the ctDNA/MRD-negative complete response (CR) rate and 2-year PFS stratified by cHL molecular subgroup at diagnosis (H1 vs H2 genotype). III. To evaluate long term efficacy and toxicity outcomes for up to 5 years. IV. To compare the performance of identification of phased variants from plasma genotyping with identification of phased variants from archival tissue genotyping. OUTLINE: Participants will undergo response assessment and ctDNA/MRD assessment using phased variant enrichment and detection sequencing (PhasED-Seq) using Foresight CLARITY LDT. A composite response assessment will be used to determine eligibility for non-transplant consolidation. Participants who achieve a response after 2 cycles of pembro + GVD will be eligible for non-transplant consolidation with 8 cycles of pembrolizumab and/or 30 Gray (Gy) involved-site radiotherapy (ISRT). Participants not achieving a response will discontinue study therapy and proceed to study follow-up, during which time participants can receive standard of care salvage therapy and ASCT, if eligible. Participants will be followed for up to 5 years from trial entry for long term efficacy and toxicity outcomes.