The current standard of care for relapsed/refractory classic Hodgkin lymphoma (R/R cHL) is salvage chemotherapy followed by autologous stem cell transplantation (ASCT), but treatment paradigms are evolving in the era of highly active novel agents and with more sensitive tools to assess measurable residual disease (MRD). Novel salvage regimens combining immune checkpoint inhibitors with chemotherapy, such as pembrolizumab + GVD (pembro-GVD), have unprecedented complete response (CR) rates up to 95% in the second line setting. As high-dose chemotherapy and ASCT can cause significant short- and long-term toxicities, ensuring appropriate patient selection and avoiding over-treatment are important priorities. This multicenter, phase 2 trial will use PET imaging and real-time circulating tumor DNA (ctDNA) sequencing to 1) guide the choice of consolidation for patients with R/R cHL receiving pembro-GVD and 2) omit ASCT for those achieving metabolic CR and undetectable ctDNA (MRD-negative CR).

This single arm study will enroll 38 adult patients with R/R cHL at six sites across California (UCSF, UCSF Fresno, UC Davis, UC Irvine, UCLA, UCSD) through the University of California Hematologic Malignancies Consortium. Eligible patients will have ECOG performance status ≤2, biopsy-confirmed R/R cHL after first-line anthracycline-based chemotherapy, measurable plasma ctDNA at baseline, and PET-avid measurable disease.

Patients treated with a checkpoint inhibitor-based regimen in the first line setting (e.g. nivolumab + AVD) who have primary refractory disease or early relapse (<6 months after end of treatment) are excluded. Patients will have baseline PET imaging and plasma ctDNA measured by PhasED-Seq (Foresight CLARITY), performed by Foresight Diagnostics. Patients will receive 2 cycles of pembro-GVD followed by repeat PET scan (PET2) and ctDNA-MRD assessment. Patients achieving metabolic CR on PET2 (Deauville 1-3) and undetectable MRD will receive 2 more cycles of pembro-GVD, followed by non-transplant consolidation with 8 cycles of pembrolizumab and/or 30 Gy involved site radiotherapy for localized disease. Patients with a partial or indeterminate response on PET2 and undetectable MRD will receive 2 more cycles of pembro-GVD, followed by PET4, and those achieving CR on PET4 will also receive non-transplant consolidation. Patients not achieving metabolic CR or with detectable MRD will receive standard of care salvage therapy and ASCT, if eligible.

The primary endpoint is the MRD-negative CR rate after completing pembro-GVD. The key secondary endpoint is 2-year progression-free survival (PFS) for patients receiving non-transplant consolidation. Other secondary endpoints include overall survival, the rate of discordance between PET and ctDNA-MRD responses, and patient-reported outcomes assessing health-related quality of life and financial toxicity. We hypothesize that over 60% of patients (at least 23 of 38) will achieve MRD-negative CR and eligibility for non-transplant consolidation. If 23 responders are observed among 38 patients, the 95% exact binomial confidence interval for the response rate will be (0.434, 0.760) with a width of 0.326. We hypothesize that patients receiving non-transplant consolidation will have 2-year PFS over 80%. If 19 out of 23 patients (82.6%) remain progression-free at 2 years, the 95% exact binomial confidence interval for PFS will be (0.612, 0.950).

To our knowledge, this is the first trial using real-time ctDNA sequencing to guide therapy for patients with R/R cHL. This study will assess whether high-dose chemotherapy and ASCT can be omitted for select patients with R/R cHL and may advance the use of ctDNA as a tool for lymphoma response assessment. This study is supported by a grant from the Gateway for Cancer Research and UCSF Society of Hellman Fellows. Clinical trial information: NCT07021989.

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2025
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