Phase IA/II Study of Oral LBH589, a Novel Deacetylase Inhibitor (DACi), Administered on 2 Schedules, in Patients with Advanced Hematologic Malignancies.

LBH589 is a novel cinnamic acid hydroxamate DACi which induces apoptosis in multiple hematologic tumor cell lines in vitro at nanomolar levels. LBH589 has been administered orally, once-a-day, on Monday/Wednesday/Friday, every week (Arm 1) or every other week (Arm 2), in cycles of 28 days, to adult pts with advanced hematologic malignancies. A 3-parameter Bayesian logistic regression model guided dose escalation. To date, 61 pts, median age 67 yrs (range 16–87), 40 male, 21 female, have been enrolled: 33 pts in Arm 1 at dose levels (mg/dose) of 20 (9 pts), 30 (12 pts), 40 (10 pts), and 60 (2 pts); 28 pts in Arm 2 at dose levels (mg/dose) of 30 (7 pts), 45 (12 pts), and 60 (9 pts). Diseases treated have included AML (36 pts), MDS (7 pts), MM (3 pts), NHL (3 pts), HL (3 pts), CML-BP (2 pts), CML-CP (1 pt), CMML (2 pts), Ph⁺ ALL (2 pts), CLL (1 pt), and chronic idiopathic myelofibrosis (CIMF) (1 pt). The MTD has not yet been determined for either schedule. In Arm 1, at the 40 mg dose level, 2 pts experienced G3 (dose-limiting) fatigue. No DLTs have been reported in Arm 2. The adverse event (AE) profile has been similar in both arms. The most common AEs (≥20%) include nausea (51%), diarrhea (43%), fatigue (39%), thrombocytopenia (31%), vomiting (30%), febrile neutropenia (28%), anorexia (26%), pyrexia (26%), dyspnea (23%), asthenia (21%), and peripheral edema (21%). The most common G3/4 AEs (≥10%) include thrombocytopenia (30%), febrile neutropenia (25%), fatigue (16%), and neutropenia (15%). Based on >2400 ECGs, no QTcF >500 msec has been recorded. In each arm, at the highest dose level explored to date, average QTcF change from baseline was <10 msec. PK has been evaluated on day 1 and at steady state by noncompartmental analysis. Mean terminal t_1/2 ranged from 13–20 hrs. In Arm 1, C_max and AUC_0-inf increased linearly with dose after single and multiple doses. In Arm 2, C_max did not increase with dose, whereas AUC_0-inf increased linearly with dose only at steady state. However, the apparent differences between arms may be due to interpatient variability. Increased histone acetylation in peripheral blood leucocytes and bone marrow biopsies was observed at doses ≥20 mg. At higher dose levels, LBH589 has shown evidence of clinical activity in multiple indications, including HL (metabolic PR - Arm 1: 30mg [2 pts], Arm 2: 45mg [1 pt]); CD4+/56+ hematodermic neoplasm (PR - Arm 2: 45mg [1 pt]); CIMF (clinical improvement, transfusion independence - Arm 1: 30mg [1 pt]); and AML (CR [1 pt], significant decrease in blood and/or bone marrow blasts [3 pts] - all Arm 1: 40mg [total of 6 pts with AML in this cohort]). In both arms, the median number of cycles was 2 (range 1–11). LBH589 appears to be well tolerated and has shown evidence of clinical activity in multiple indications. Dose escalation is ongoing at 60mg (Arm 1) and 80mg (Arm 2).