BRENTUXIMAB VEDOTIN AND BENDAMUSTINE (BvB) IN PATIENTS WITH RELAPSED OR REFRACTORY HODGKIN LYMPHOMA: AN INTERNATIONAL, MULTICENTER, SINGLE-ARM, PHASE 1–2 TRIAL

BACKGROUND: The major objective of this study was to explore the safety and clinical activity of Brentuximab vedotin (Bv) and bendamustine in combination in patients with relapsed or refractory Hodgkin Lymphoma. Bv produces high response rates and durable progression-free survival (PFS) in CD30-expressing lymphomas and is approved for the treatment of relapsed Hodgkin lymphoma (HL) and relapsed ALCL. Bendamustine (B) is active agent across the lymphoproliferative malignancies, though the PFS among patients with HL and PTCL is modest. METHODS: This was an international, multicenter, single-arm, Phase 1–2 study of BvB in patients with relapsed or refractory HL and ALCL. Eligible patients were required to have relapsed/refractory CD30+ biopsy proven HL or ALCL and an ECOG Performance Status ≤2. In the Phase 1, HL patients were deemed eligible if they developed progressive disease following or after declining ASCT, or had at least 2 prior multi-agent chemotherapy regimens. In the Phase 2, patients with HL were eligible if they had relapsed or refractory disease after one line of therapy. Eligible ALCL patients were required to have relapsed after at least one prior multi-agent chemotherapy regimen and if they were not eligible for or have declined ASCT. The primary objective of the Phase I portion of this study was to identify the maximum tolerated dose (MTD) and dose limiting toxicity (DLT). The primary endpoint of the Phase 2 portion was to determine the overall response rate (ORR; complete response [CR] plus partial response [PR])) based on an intention to treat analysis (ITT). Secondary objectives of Phase 1–2 included assessing for duration of response, progression free survival and overall survival. Response was evaluated using International Harmonization Project Group 2007 Revised Response Criteria. Bv was escalated from 1.2mg/kg Day 1, and B from 70mg/m2 Days 1 and 2 every 21 days until the MTD or recommended phase 2 dose (RP2D) was reached. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov number NCT01657331. FINDINGS: 65 patients (only 1 ALCL) were treated, 28 on the Phase 1 and 37 on the phase 2. While the MTD of the combination was not reached, the single agent MTD of Bv (1.8mg/kg Day 1) and RP2D of B (90mg/m2 Days 1 and 2) were identified as the RP2D of the combination. Patients were heavily treated, 65% (42 of 65) had an autologous or allogeneic stem cell transplant or both. The Phase 1 revealed modest toxicity. The major Grade 3/4 toxicities included Grade 3 lung infection in 5 (14%) patients in the Phase 2, and Grade 3/4 neutropenia in 13 (24%) patients across the Phase 1 and 2. The Phase 1 and 2 overall response rates (ORR) were 61% and 78% respectively, with 43% (16 of 27) patients treated in the Phase 2 attaining a complete remission (CR). In the Phase 2, the median PFS has not been reached and duration of response (DOR) was 3.4 months. There was a total of 23 deaths with 21 due to progression of disease, 2 occurring after being transplanted, and none of which were treatment related. INTERPRETATION: This demonstrates that BvB might be an effective salvage regimen for patients with HL, with a favorable safety profile. FUNDING: Seattle Genetics, The Lymphoma Research Fund of Columbia University and National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873 provided support for this investigator initiated sponsored trial. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.