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

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.

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.

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.

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.

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.