Precise-HL trial: Personalized reduction of chemotherapy intensity through ctdna evaluation in advanced Hodgkin lymphoma

Abstract

Abstract Introduction Nivolumab-AVD has become a new standard for untreated advanced stage Hodgkin lymphoma in North America. However, future directions to improve outcomes in these patients are not defined at this time and may be challenging based on the excellent outcomes for patients treated with this regimen. While most patients achieve a cure, the data over the past decade has confirmed dose dependent risks of anthracycline exposure independent of mediastinal radiation, particularly in younger patients (van Wimnegen et al Blood 2017). Efforts to maintain high cure rates while limiting toxicity are warranted. Data using phased variant enrichment and detection sequencing (PhasED-Seq) for measurable residual disease (MRD) assessment in classic Hodgkin lymphoma (CHL) suggests that the majority of patients receiving first line therapy clear circulating tumor DNA early with PD1-inhibitor-based combination approaches (Lynch et al ASH 2024, Alig et al Nature 2023, Herrera et al. ICML 2025). The PRECISE-HL trial will assess a response-adaptive CHL treatment approach utilizing PhasED-Seq to reduce the overall chemotherapy burden for patients with early MRD-negativity when treated with nivolumab-AVD (NCT06745076). Methods This is a multi-center phase 2, open label pilot study of six cycles of response-adapted therapy based on MRD testing by PhasED-Seq for untreated stage III or IV CHL. First patient was enrolled in February 2025. Patients will receive the combination of nivolumab (240 mg IV), doxorubicin (25 mg/m2 IV), vinblastine (6 mg/m2 IV) dacarbazine (375 mg/m2 IV) on days 1 and 15 of 28-day cycles. Blood samples for PhasED-Seq testing at baseline and post cycle 2 will be sent to Foresight Diagnostics for rapid processing (estimated turn-around time 10-14 days). For patients with undetectable MRD at cycle 3 day 1, the doxorubicin, vinblastine, and dacarbazine will be removed from Cycle 5 and Cycle 6 while continuing nivolumab. For patients with detectable or inconclusive MRD, treatment after interim assessment will continue with all 4 agents for 6 total cycles. Planned enrollment is 125 patients. The primary endpoint is 1-year PFS in patients with undetectable MRD after 2 cycles of treatment. The secondary endpoints include 1-year PFS in MRD positive patients after 2 cycles of treatment, 2-year PFS in the overall cohort and stratified by MRD status, as well as best overall response as complete response (CR) or partial response (PR). Exploratory endpoints include MRD assessments at other timepoints and in long term follow up, patient reported outcomes, and cardiac biomarkers. The primary efficacy benchmark for this trial is a 1-year progression-free survival (PFS) rate of ≥94% among interim ctDNA negative patients, based on historical data from the S1826 study. We anticipate approximately 80% (n=100) are expected to be ctDNA-negative at C3D1 following frontline therapy. In this ctDNA-negative subgroup, we estimated the probability of observing ≥94 progression-free survivors at 1 year under various true PFS rates. If the true 1-year PFS is 95% or 96%, the probability of achieving this benchmark is 0.77 and 0.89, respectively. In contrast, if the true 1-year PFS is 90%, the probability drops to 0.12. These thresholds were used to define a signal of sufficient efficacy to justify further evaluation of this approach. Key eligibility criteria include untreated stage 3 or 4 classic Hodgkin lymphoma, age 18+, measurable disease per Lugano criteria, and adequate marrow, renal, and hepatic function. Key exclusion criteria include current or prior autoimmune disease except vitiligo or thyroid disease on stable replacement doses, active cardiac disease or ejection fraction < 50%, prior malignancies within 2 years, and pregnant or nursing women.