Final Analysis: Phase II Study of Oral Panobinostat In Relapsed/Refractory Hodgkin Lymphoma Patients Following Autologous Hematopoietic Stem Cell Transplant

Abstract Abstract 419 Background: Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of proteins involved in multiple oncogenic pathways. Historically, patients with post-transplant relapsed or refractory Hodgkin lymphoma (HL) have a poor prognosis with no standard of care. Preclinical evaluation of panobinostat has demonstrated potent anti-tumor activity against HL cell lines. Evaluation of panobinostat in the phase I setting demonstrated promising activity in patients with relapsed/refractory HL. In this Phase II study, the efficacy of panobinostat in post-transplant relapsed/refractory HL was evaluated. Methods: Oral panobinostat was administered at a dose of 40 mg three times per week (e.g. MWF), every week, in 21-day cycles. Dose modification was allowed for management of adverse events (AEs). Response was assessed every 2 cycles by CT/MRI scan. The primary endpoint is objective response rate (ORR). Secondary objectives include time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival, and safety and tolerability. Results: As of June 11, 2010, 129 patients have been enrolled and treated. The median age was 32 years (18–75). Patients received a median number of 4 (2–7) prior systemic regimens, 69% of patients received prior radiotherapy, and 10% received prior allogeneic stem cell transplant. Most patients (78%) received ≥ 1 additional therapies following transplant prior to receiving study drug while 41% were refractory to their last prior systemic therapy or transplant. The median time to relapse after first AHSCT was 8 months. A total of 19 patients are ongoing. In the efficacy analysis, 129 patients were evaluable for response or discontinued early. A reduction in measurable tumor size was observed in 99 (77%) patients; responses were observed in 35 patients (5 complete responses + 30 partial responses; ORR 27%). Preliminary median DOR was 6.9+ months, median TTR was 7.4 weeks (4.1–51.3), and median PFS was 5.7+ months. Baseline characteristics among the responders were similar to the overall population treated. Among the responders, 66% had primary refractory disease. The median number of prior systemic regimens, the median time to relapse post-AHSCT and those refractory to their most recent prior therapy were also similar to the overall population treated. Twelve (34%) responders are ongoing, and 7 responders have been on study long term (> 12 months). Common related AEs (mostly grade 1/2) included diarrhea, nausea, fatigue, vomiting, anorexia, dysgeusia, asthenia, constipation, leukopenia, and muscle spasms. Common related grade 3/4 AEs included thrombocytopenia, anemia, and neutropenia. Thrombocytopenia was reversible with dose hold or modification and was manageable long term. Conclusion: This pivotal study represents the largest, prospective, multicenter international trial conducted in this patient population. Single-agent panobinostat demonstrates sustained anti-tumor activity, resulting in durable responses in heavily pretreated classical HL patients who relapse or are refractory post-transplant. Patients treated in this study represent a population with a poor prognosis in which most patients had relapsed <1 year following transplant. A disease control rate (CR + PR + SD) of 82% and an estimated DOR of 6.9+ months was observed. The safety profile of panobinostat remains stable and the most notable AE was manageable, reversible thrombocytopenia. Data from patients receiving panobinostat long-term (> 12 months) are available. This is a positive trial and the data continue to mature. The final analysis of the efficacy and safety data will be presented at the meeting. Disclosures: Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. Younes:Novartis: Clinical Support, Honoraria; Seattle Genetics: Clinical Support, Honoraria; Syndax: Clinical Support, Honoraria; Roche: Honoraria; Biogen Idec: Honoraria; Sanofi Aventis: Clinical Support, Honoraria; SBIO: Clinical Support, Honoraria. Kaufman:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Research Support; Merck: Research Support. Le Corre:Novartis: Employment. Gallagher:Novartis: Employment. Shen:Novartis: Employment.