A PHASE 1/2 Clinical Trial of Brentuximab-Vedotin and Bendamustin in Elderly Patients with Previously Untreated Advanced Hodgkin Lymphoma (HALO STUDY. NCT identifier : 02467946): Preliminary Report

Background Treatment of elderly patients with HL remains a difficult challenge as the efficacy and safety of standard ABVD treatment proved unsatisfactory compared to adults. Bendamustin (Be), and Brentuximab Vedotin (BV), are active drugs, with a good tolerance and a high level of response in relapsing/refractory HL. However, when doses of 1.8 mcg/Kg. are used every 21 days in association with Be 70 mg. day 1 and 2 in the frontline therapy of the elderly, as in the part C of the phase II SGN35-015 study (NCT identifier NCT01716806) overwhelming toxicity does occur. Therefore, we chose to test a slightly attenuated combination schedule for first-line HL treatment in the aged. Patients and methods: In 2015 we launched a prospective multicenter open-label study aimed at assessing the safety and efficacy of Be-BV combination in advanced-stage (IIB-IVB) elderly HL patients, with the following schedule: BV: 1.2 mg/kg D1 and Be 90 mg/m2/day, D1 and D2, every 3 weeks up to 6 cycles, in advanced-stage (IIB-IVB) patients aged 60-80 years (NCT identifier…) . The study is split in 2 phases: the phase 1 (safety: 12 patients) with the main objective to evaluate the tolerability and toxicity and the phase 2 (efficacy: 48 patients), with the primary objective of Be-BV overall response rate. Secondary endpoints of the phase 2 are the efficacy of Be-BV combination in terms of 3-Y PFS and OS and the prediction of treatment outcome by early interim PET. Ten centers, 5 from Italy and 5 from France, participate to the study. An early (after the 2^nd cycle: PET-2) and final (after the 6^th cycle PET-6) response assessment by FDG-PET is planned. A central review of all PET images is planned and the response assessed according to Lugano criteria. Patients with progressive disease at any time or not in CR after 4 cycles receive salvage therapy according to local investigator choice. Results Demographics were as follows: histology breakdown: HL, classic NOS, 5; classic, nodular sclerosis 4, classic mixed cellularity 4, and lymphocyte rich 1. Mean Hb value was 13,2gr/dl, WBC 9.9 x 10³/μl, Albumin 36.9 gr/l, LDH 494 U/l; 1 had stage II, 6 stage III and 7 stage IV. B-symptoms were present in in 7. IPS was 0-2 in 7, ≥ 3 in 7. The median Medical Outcome Study (MOS) physical function score was 52.5% (20-90) and 70% had a time to "up and go" score of > 13.5 seconds. Mean age was 77,3 (62-80). Fourteen received study treatment and one has just been registered. Ninety-four adverse effects were recorded, 66 of them (69%) for whom the relationship with the investigational drugs was considered highly probable, probable, possible and dubious. None of them was unexpected. Thirty-nine WHO grade 3-4 toxicities have been recorded most of them hematologic: neutropenia (7), Lymphopenia (25), thrombocytopenia (2), pulmonary embolism (1), CMV reactivation (1), fever (1), allergic reaction (1) and rash (1). No treatment related deaths have been so far recorded, and the non-relapse mortality is 0. Upon inclusion of the first 12 patients the Data and Safety Monitoring Board decided on study continuation as only 2 stopping rules were met. Nine patients underwent PET-2: 7 were in complete metabolic response; 2 patients in partial metabolic responses according to local evaluation entered CR at the evaluation by PET-Scan after 4 cycles. Five patients are on treatment and no data are available on their PET-2 result and one patient has just been registered. Conclusion: These preliminary results suggest that (1) the Be-BV combination has a largely expected and manageable hematological toxicity; (2) the drug combination is highly effective in elderly HL patients.