Interim PET-Adapted De-Escalation Chemotherapy Regimen for Advanced Stage Classical Hodgkin Lymphoma Using Brentuximab Vedotin, Pembrolizumab, Doxorubicin, and Dacarbazine: Phase 2 Safety and Efficacy Study

Background:

Brentuximab vedotin (Bv), Nivolumab (N) and Pembrolizumab (P) have revolutionized the management of advanced stage classical Hodgkin Lymphoma (AS cHL). Significant improvements in both safety and efficacy have been observed with the Echelon-1 (E1) and SWOG S1826 studies. In GHSG HD18 & HD21, PET adapted strategy showed that the numbers of cycles could be reduced without affecting impact on the efficacy. Pembrolizumab followed by AVD in frontline AS cHL with minimal immune mediated adverse events (IMAE)(Allen et al Blood Advances 2023). This study incorporates pembrolizumab into the Bv+AD regimen based on the lower incidence of IMAE observed with pembrolizumab and utilizes a PET-adapted strategy to reduce chemotherapy exposure for patients with a negative interim PET scan. NCT05922904

Objectives:

This study aims to assess the safety and efficacy of PET-Adapted de-escalation of chemotherapy regimen after achieving interim PET negative.

Methods:

Study is enrolling patients with newly diagnosed stage I/II bulky mediastinal disease (≥10 cm), stage III, or stage IV cHL. Subjects will receive three cycles of BvP+AD (Bv 1.2 mg/kg capped at 100kg), pembrolizumab 400 mg [P], doxorubicin 25 mg/m2 [A], and dacarbazine 375 mg/m2 [D]). Pembrolizumab was administered in Q6 week dosing intervals (C1D1, C2D15, C4D1 and C5D15), whereas the rest of the regimen were administered Q2 weeks. Interim PET scan was performed after cycle 3. Subjects achieving PET negativity defined as Deauville scores (DS) of 1 or 2 or 3 with > 90% reduction in total metabolic tumor volume (TMTV) will continue in the de-escalation arm. Subjects on the de-escalation arm will complete three additional cycles of only BvP. Subjects with positive interim PET defined as DS of 4, 5 or 3 < 90% reduction of TMTV would proceed with the standard arm to complete three additional cycles of BvP+AD, for a total of six cycles.

The primary efficacy endpoint is CR rate at the end of therapy (EOT). Key secondary endpoints include safety and tolerability, ORR, duration of response (DOR), duration of complete response (DOCR), and progression-free survival (PFS). Disease response and progression are assessed using Lugano Classification Revised Staging System for malignant lymphoma, incorporating Lymphoma Response to Immunomodulatory Therapy Criteria for nodal non-Hodgkin and Hodgkin lymphomas. TMTV was calculated using Lesion cut off SUV of 4.0, by MIM software Version 7.4.