Phase I/II Study of the Novel Combination of Panobinostat (LBH589) and Everolimus (RAD001) In Relapsed/Refractory Hodgkin and Non-Hodgkin Lymphoma
Authors: Younes Anas , Copeland Amanda , Fanale Michelle A. , Hagemeister Fredrick , Fayad Luis , Pro Barbara , Faria Silvana C. , Ji Yuan , Medeiros L. Jeffrey , Berry Donald A , Buglio Daniela 
Published: October 2019

Abstract
Abstract 3964
mTOR and deacetylase (DAC) inhibitors have demonstrated single agent activity in patients with relapsed and refractory lymphoma. Synergy between DAC inhibitors and mTOR inhibitors has been observed in lymphoma cell lines in vitro. Thus we combined the pan-DACi panobinostat (LBH589) with mTOR inhibitor everolimus (RAD001) in a phase I/II study in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The purpose of this study is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) in addition to examining the clinical efficacy of this novel regimen. Patients were eligible if they had relapsed or refractory Hodgkin or non-Hodgkin lymphoma regardless of the number of prior regimens, including autologous and allogeneic transplantation. Everolimus was self administered orally daily and panobinostat three times weekly. To date, a total of 12 patients have been enrolled [Table 1]. The histologic subtypes include small lymphocytic (n=1), follicular (n=2), mantle cell (n=2), hodgkin (n=5), diffuse large B-cell (n=1) and one discordant Hodgkin/marginal zone lymphoma. The median number of prior therapies is 4 with 6 patients receiving prior autologous transplantation. 11 patients are evaluable for safety and response. The DLT was thrombocytopenia observed in the 4th cohort with a dose of 30mg panbobinostat and 10mg of everolimus. Therefore an additional 6 patients are being dosed at the 20mg panobinostat and 10mg everolimus cohort to confirm the safety of this combined dose. Treatment side effects were manageable with the following grade 3/4 adverse events most commonly observed: thrombocytopenia 45% (n=5), neutropenia 45% (n=5) and fatigue 18% (n=2). One death occurred on study, possibly related to pulmonary embolus. 10 out of 11 evaluable patients had tumor reduction ranging from -31% to -63% with 5 of these patients continuing on therapy. Changes in several cytokines and growth factors were observed at day 8 including VGEF, IL-10 and IL-13. This data demonstrates promising activity of this novel combination in a variety of lymphomas even at the lower dose levels. Once the MTD is identified, the phase II portion will enroll patients to confirm the efficacy of this novel regimen.
Dose Level Everolimus Panobinostat N 1 5mg 10mg 3 2 5mg 20mg 3 3 10mg 20mg 4 4 10mg 30mg 2

Disclosures:
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. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. Fanale:Seattle Genetics: Research Funding; Novartis: Honoraria, Research Funding; Millenium: Research Funding; Genentech: Research Funding. Fayad:Genentech: Research Funding. Pro:Allos Therapeutics, Inc.: Research Funding.