A Phase I/II Trial Evaluating The Use Of a Histone Deacetylase Inhibitor Panobinostat (LBH589) In Addition To Glucocorticoids In Patients With Acute Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) remains the principal obstacle to achieve successful outcomes in allogeneic hematopoietic stem cell transplant (HCT). Glucocorticoids are the current standard initial treatment for acute GVHD with complete responses of 25% to 41%. New immunosuppressive strategies are required to improve management of acute GVHD and decrease toxicities of immunosuppressive agents. We conclude that more effective acute GVHD therapy might improve remission rates that will result in better survival after allogeneic HCT. Vorinostast, a histone deacetylase inhibitor (HDACi) have shown efficacy for acute GVHD prevention. This protocol was design to test the safety and potential efficacy of a novel HDACi, panobinostat (LBH589), administered to patients with acute GVHD within 72 hours of initiation of glucocorticoid therapy (methylprednisolone 0.8 mg/Kg/day IV or equivalent for at least 14 days) as first line therapy. Panobinostat is a potent inhibitor of deacetylases and HSP90 belonging to a structurally novel class of the cinnamic hydroxamic acid class of compounds and is one of most potent HDAC inhibitors. We have enrolled n=13 subjects, median age 52 (range, 39-63) years, male n=8/female n=5, median day of GVHD development day + 37 post HCT (26 -528 days) with overall grade GVHD II (n=8) or III (n=5). The first three patients were treated with 2.5MG/M2 intravenously (IV) weekly x 4 and subsequent subject was treated with 5MG/M2 IV weekly x 4 achieving all GVHD CR by day +15. Patients were treated with azole for fungal prophylaxis. Due to manufacturer discontinuation of IV formulation production we were obliged to amend the protocol to use PO Panobinostat. Using 10MG PO TIW 3 doses q week x 4 weeks, we treated 2 subjects which were both discontinued from study drug as evidence of GHVD progression within 7 days of Panobinostat. Due to safety concerns, the next group was treated with a reduce dose of 5 MG PO TIW q week x 4 (Level -1). So far we have accrued 7 subjects whom by day 15 achieved GVHD CR (n:4) and PR (n:3) majority being in CR (n:6/7) on day +28 and PR (n:1). Toxicities by CTCAE 4.0 criteria included reversible thrombocytopenia and neutropenia grade 1-2 possible related to study drug. We are encouraged with a GVHD CR rate of 57% on day +15 and 86% CR at study drug completion on day+36. These results suggest a role HDACi Panobinostat as a tool to improve success of glucocorticoids for GVHD treatment. Correlative studies are planned to address pharmacodynamics of Panobinostat on inflammatory cytokines, to correlate DAC enzymatic activity inhibition and clinical response and to proteins/histones acetylation in T-cell subsets.