A Pilot Trial of Adriamycin, Pembrolizumab, Vinblastine and Dacarbazine (APVD) for Patients with Untreated Classical Hodgkin Lymphoma

Background: ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) forms the backbone of frontline management of classical Hodgkin lymphoma (CHL) in North America regardless of stage. Expected cure rates with upfront therapy approach 75% in advanced stage, and 85-90% in early stage. A novel regimen incorporating brentuximab vedotin sought to improve upon ABVD in untreated advanced stage CHL patients (brentuximab vedotin + AVD). While it demonstrated a modest modified PFS benefit, it was associated with notable toxicities including higher rates of neuropathy and infection. PD-1 inhibition is highly effective in relapsed/refractory CHL, leading to the FDA approval of nivolumab and pembrolizumab in this setting. The first-line setting may represent the ideal time for a PD-1 inhibitor, with relatively intact host immunity and coexistence of malignant cells and T-cells in the microenvironment. Using a proven chemotherapy backbone, we designed a trial adding pembrolizumab to AVD chemotherapy (APVD) without a PD-1 inhibitor lead-in for untreated CHL (NCT03331341).

Methods: This is a single arm pilot study combining pembrolizumab with AVD in untreated CHL of any stage. Eligibility requires ECOG 0-1, adequate organ function, and measurable disease. The trial intends to enroll 30 patients. AVD is given at standard doses on days 1 and 15 of a 28-day cycle. Pembrolizumab (200 mg IV) is given starting cycle 1 day 1 and every 21 days thereafter (cycle 1 day 22, cycle 2 day 15 etc.). The primary objective is to estimate the safety of delivering 2 cycles of APVD. The study will be determined a success if > 85% of subjects are able to complete 2 cycles of therapy without a dose delay > 3 weeks. Operationally, the stopping rule will be activated if the lower limit of the 95% confidence interval of toxicity crosses 15%. Thus, the trial would stop if 4/10, 7/20, 8/25, or 9/30 had a dose delay of >3 weeks due to toxicity. The secondary objective is to estimate the FDG-PET2 negative (Deauville score 1-3) after 2 cycles of APVD. Exploratory objectives include overall and progression free survival, predictive capacity of PET2 after APVD, peripheral blood flow cytometry of T-cell subsets, and analysis of ctDNA. After PET2 response assessment, subjects may continue APVD for up to 6 total cycles, or pursue treatment deemed appropriate for their stage/risk factors (including alternate systemic therapy or radiotherapy) at investigator discretion.

Results: Six subjects have enrolled and received 2 cycles of therapy. Median age of these subjects was 28 years (range 18-69). Most subjects have advanced stage (stage II n=1 (17%), stage III n=3 (50%), stage IV n=2, (33%)). 3/6 (50%) of subjects had B symptoms at diagnosis, while 1/6 (17%) had bulky disease. Among the 6 subjects enrolled thus far, all have completed the first 2 cycles of therapy without any treatment delays. 3/6 subjects achieved a complete metabolic response (Deauville 1-3) on PET2, and 3/6 had a partial response (PR) with Deauville 4. The only subject who has completed all 6 cycle of therapy had a PET2 with Deauville 4 which converted to Deauville 2 upon completion of all therapy. There were no grade 2+ AEs attributable to pembrolizumab. No serious AEs have been reported. Non-hematologic grade 1 AEs of note include fatigue (50%), AST/ALT increase (33%), nausea (33%), arthralgia (17%), diarrhea (17%), maculopapular rash (17%), fever (17%), and alkaline phosphatase increased (17%).

Conclusion: The concurrent combination of pembrolizumab with AVD chemotherapy for untreated CHL has been safe to date without any dose delays, serious adverse events, or immune-related adverse events of grade 2 or higher. All patients treated thus far achieved an objective response by PET2, with 3/6 achieving a complete metabolic response by interim scan. One subject has completed all therapy with a complete metabolic response (Deauville 2) after PET2 showed Deauville 4. Trial enrollment is ongoing.