A Phase I/II Trial Evaluating the Use of a Histone Deacetylase Inhibitor LBH589 in Addition to Corticosteroids in Patients with Acute Graft Versus Host Disease

Graft versus host disease (GVHD) remains a principal barrier to successful outcomes in allogeneic hematopoietic stem cell transplant (HCT). Corticosteroids are the current standard initial therapy for acute GVHD with complete responses of 25- 41%. New immunosuppressive strategies are required to improve acute GVHD management and decrease toxicities of immunosuppressive agents. We conclude that more effective acute GVHD therapy may improve survival after allogeneic HCT. The histone deacetylase inhibitor (HDACi) Vorinostat has been shown to reduce serum levels of pro-inflammatory cytokines with moderate efficacy in acute GVHD in murine pre-clinical HCT. We designed a protocol to test the safety and potential efficacy of a novel HDACi, 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. LBH589 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 the most potent HDACi. We have enrolled n=9 subjects, median age 52 (39-62 yo), male n=6/female n=3, median onset of GVHD day +34 post HCT (17-108 days) with overall GVHD grade II (n=6) or III (n=3).  The first three patients were treated with 2.5 mg/m2 intravenously (IV) weekly x4 and a subsequent subject was treated with 5mg/m2 IV weekly x 4 achieving GVHD CR (n=2) and PR (n=2) on day +8 (after LBH589) and all achieved GVHD CR on day+15. Due to manufacturer discontinuation of the IV formulation, we amended the protocol to use PO LBH589. Using 10mg PO thrice weekly 48 hours apart for 4 weeks, we treated 2 subjects which both discontinued study drug due to GHVD progression within 7 days of LBH589. Due to safety concerns, the next group received a reduced dose of 5 mg PO thrice weekly x 4 (Level -1). Thus far we have accrued 4 subjects at this dose. By day +8, the GVHD response was PR=2 and CR=2 with all in GVHD CR on day+15. Toxicities include reversible thrombocytopenia and neutropenia grade 1-2 (CTCAE 4) possibly related to study drug. The overall GVHD CR rate of 80% by day +15 in our initial cohort is encouraging, suggesting a role for HDACi LBH589 as a tool to improve success of corticosteroids for GVHD treatment. Correlative studies are planned to address pharmacodynamics of LBH589 on inflammatory cytokines, to correlate DAC enzymatic activity inhibition with clinical response and to study LBH589 proteins/histones acetylation effect on T-cell subsets.