Phase IA/II Study of Oral Panobinostat (LBH589), a Novel Pan- Deacetylase Inhibitor (DACi) Demonstrating Efficacy in Patients with Advanced Hematologic Malignancies.

Abstract

Panobinostat (LBH589) is a novel and potent pan-deacetylase inhibitor (DACi) with broad preclinical activity in models of hematologic malignancies. This trial is evaluating panobinostat in patients (pts) with advanced hematologic malignancies with 2 schedules of oral administration: Monday/Wednesday/Friday (MWF) every week or MWF every other week. Each schedule is being assessed in 2 pt groups that differ by disease and the definition of hematologic dose-limiting toxicity (DLT): pts with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM); and pts with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic idiopathic myelofibrosis (CIMF), acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), or chronic lymphocytic leukemia (CLL). A 3-parameter Bayesian logistic regression model guides dose escalation, and a minimum of 6 evaluable pts at each dose level is required prior to dose escalation. To date, 128 pts have been enrolled: 79 pts with weekly dosing at 20, 30, 40, 60, and 80 mg/dose; and 49 pts dosed every other week with 30, 45, 60, and 80 mg/dose. The most common diseases have included AML (65 pts), HL (23 pts), and MM (12 pts). Panobinostat has rapid oral absorption (median Tmax 1 h, range 0.5–3 h), AUC and Cmax are dose-related, and mean effective t½ is 16.7 h. The adverse-event (AE) profile has been similar between the 2 schedules; the most common grade 3/4 AEs (≥10%) have been thrombocytopenia (43%), neutropenia (22%), febrile neutropenia (20%), fatigue (20%), and anemia (11%). In pts with lymphoma and myeloma, the principal DLT is thrombocytopenia, whereas in patients with AML, in whom grade 4 thrombocytopenia is not considered dose-limiting, the principal DLT is fatigue. With weekly dosing, the maximum tolerated dose (MTD) is 40 mg/dose in pts with lymphoma and myeloma, whereas the MTD is 60 mg/dose in pts with AML. The MTD has not been established for dosing every other week in either group of pts, but this regimen is not expected to provide greater dose intensity than weekly treatment. Anti-tumor activity has been observed in a group of 13 response-evaluable pts with relapsed/refractory HL, treated at doses ≥30 mg with both schedules: PR by computed tomography (CT), 5/13 pts (38%); metabolic PR by positron emission tomography (PET), 7/12 pts (58%) (PET assessment not performed in 1 pt); symptom improvement in 7 of the 9 pts with disease-related symptoms at baseline (78%); and disease control for up to 16+ cycles. Anti-tumor activity has also been observed in a group of 26 response-evaluable pts with AML, treated at doses ≥40 mg on the weekly schedule: 2 CRs, including 1 pt ongoing >1 yr; 1 pt aleukemic (marrow not assessable due to fibrosis) >10 months; 2 pts ongoing with decreased marrow blasts and disease control for 9 and 12 months. Activity has also been observed with panobinostat doses ≥30 mg in pts with other hematologic malignancies: CIMF (2 pts, both ongoing, 1 pt with decreased splenomegaly and transfusion independence >20 months, 1 pt with decreased splenomegaly >3 months); MDS (1 pt PR); MM (1 pt PR); and CD4+/56+ hematodermic neoplasm (1 pt PR). For future studies of single-agent panobinostat in HL, the recommended regimen is 40 mg p.o. MWF every week. A regimen of 60 mg p.o. MWF every week is recommended for further evaluation of panobinostat's single-agent activity in AML.