A Phase III Randomized, Double Blind, Placebo Controlled Multi-Center Study Of Panobinostat For Maintenance Of Response In Patients With Hodgkin Lymphoma Who Are At Risk For Relapse After High Dose Chemotherapy and Autologous Stem Cell Transplant: Final Results After Early Trial Discontinuation (2013)

Introduction High dose chemotherapy with autologous stem cell transplant (ASCT) is the treatment of choice for Hodgkin Lymphoma (HL) patients suffering from relapse or progression after first line therapy. However, patients with recurrence after ASCT have a very poor prognosis. Thus, the oral deacetylase inhibitor panobinostat was evaluated as maintenance therapy for patients at risk for relapse after ASCT to prevent recurrences. Methods HL patients after ASCT with at least one of the risk factors: primary refractory disease, early relapse (&lt;12 months), multiple relapses, stage III/IV disease or hemoglobin &lt;10,5 g/dl at relapse prior to transplant were randomized to receive oral panobinostat (45mg three times a week, every other week, QOW) or placebo (2:1 randomization) in this phase III randomized, double blind, placebo controlled multi-center trial. As per the original protocol, disease-free survival (DFS) was the primary endpoint. However, the trial was terminated prematurely due to slow recruitment and the new primary objective was the provision of drug to ongoing patients randomized to panobinostat in an open label phase and to the evaluation of safety in the whole patient population. Results The study was closed to enrollment and data were unblinded with only a total of 41 patients out of the planned 367 patients enrolled; 27 patients in the panobinostat arm and 14 patients in the placebo arm. Three patients (1 from the panobinostat arm and 2 from the placebo arm) never received treatment. Data are reported for patients treated during the randomized phase and no formal statistical analyses were conducted. The median duration of treatment was longer in the placebo arm (217 days) than in the panobinostat arm (176 days, randomized phase). The majority of patients in both treatment arms had an exposure of ≥ 24 weeks (53.8% in the panobinostat arm, 75% in the placebo arm). In the panobinostat arm, the most common reasons that patients discontinued were due to withdrawal of consent (29.8%) and adverse events (22.2%), whereas in the placebo arm, patients most commonly discontinued due to disease progression (28.6%). Most adverse events (AEs) occurred more frequently in the panobinostat arm (randomized phase). The most frequently reported AEs as compared to the placebo arm included: diarrhea (88.5%/25%), nausea (57.7%/8.3%), vomiting (46.2%/25%), fatigue (34.6%/25%), neutropenia (26.9%/33.3%), thrombocytopenia (26.9%/8.3%), oropharyngeal pain (26.9%/0%), headache (23.1%/0%), nasopharyngitis (19.2%/0%), upper respiratory infection (19.2%/8.3%), decreased appetite (15.4%/16.7%), pyrexia (15.4%/8.3%), influenza like illness (15.4%/0%) and sinusitis (15.4%/8.3%). Overall, the incidence of grade 3/4 AEs was 65.4% in the panobinostat arm during the randomized phase and 41.7% in the placebo arm. In the panobinostat arm, the most frequently reported grade 3/4 AEs were neutropenia (26.9%), thrombocytopenia (15.4%), and diarrhea, vomiting and fatigue (all 11.5%). In the placebo arm, the most frequently reported grade 3/4 AEs were neutropenia (33.3%), leukopenia (16.7%) and herpes zoster (16.7%). Although efficacy could not be formally evaluated due to the small number of patients in this trial, it is interesting to note that more patients from the placebo arm discontinued from the study due to disease progression (28.6% vs. 14.8% panobinostat patients). Conclusion The safety observations from this study were consistent with the general safety profile known for panobinostat. The use of panobinostat in a maintenance setting in a QOW schedule appeared to have acceptable tolerability in a population of patients with HL who are at risk for relapse after high dose chemotherapy and ASCT. Disclosures: von Tresckow: Takeda: Honoraria, Reimbursement of congress, travel, and accommodation costs , Reimbursement of congress, travel, and accommodation costs Other; Novartis: Consultancy, Honoraria. Szer:Novartis: Membership on an entity’s Board of Directors or advisory committees. Sureda:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria.