PHASE I/II STUDY OF BRENTUXIMAB VEDOTIN IN REFRACTORY/RELAPSED HODGKIN LYMPHOMA PATIENTS TREATED BY CHEMOTHERAPY (ICE) IN SECOND LINE BEFORE AUTOLOGOUS TRANSPLANTATION.

Abstract

Introduction: About 10–15% of patients with localized and 25–30% with disseminated classical HL failed to respond or relapse after primary conventional treatment. Autologous stem cell transplantation (ASCT) is a standard of care after salvage chemotherapy leading to an increased disease free survival (DFS). With this strategy approximately 60% to 80% of patients proved to be chemo sensitive become eligible for ASCT. As the disease status before ASCT appears to be the most important factor predicting outcome, second line chemotherapy has to be more efficient. Brentuximab-Vedotin (BV), a CD30-directed antibody conjugated to the highly potent anti-microtubule agent monomethyl auristatin E (MMAE), has shown significant activity in a phase II single arm, open label, multicenter pivotal study (SG035-0003) in patients with relapsed or refractory HL, of whom 71% had primarily refractory disease. Given the above, it seems to be logical and feasible to use BV in patients treated with ICE before auto SCT to induce a significantly higher (metabolic) CR rate, as judged by FDG-PET negativity. Otherwise, Moskowitz et al. have reported that negativity of FDG-PET improves EFS (>80% compared with 28.9% for those patients with improvement of CT but with persistent PET positivity). Methods: In order to increase the complete response (CR) rate judged by FDG-PET in patients with primary refractory or first relapse cHL, we added Brentuximab Vedotin to ICE (Ifosfamide, carboplatine, and etoposide) chemotherapy (ICE-BV). In the first dose-finding part of the study (phase I), the optimal dose of BV with ICE (3 cycles) will be established. In the second part the efficacy of BV with ICE will be assessed at the fixed optimal dose level of both BV and ICE. Results: Phase I study was activated in 5 centers of the LYSA group and 10 patients have already been enrolled. Patients received 3 cycles of ICE-BV and one cycle of BV before ASCT. Three patients were enrolled in the first cohort, BV: 1.2 mg/kg and 7 patients in cohort two (BV: 1.8 mg/kg). Clinical characteristics at inclusion were median age: 29.5 years (range: 22–55), sex ratio (M/F): 6/4, and status of the disease: refractory: 3 patients and relapse: 7 patients. Efficacy and toxicity are currently analyzed. Conclusion: The first part of ICE-BV before ASCT in R/R HL patients has been completed. Phase II will start after the validation of BV dose by the Independent Data Monitoring Committee (IDMC). Keywords: brentuximab vedotin; classical Hodgkin lymphoma (cHL); ICE.