Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of LBH589, a novel deacetylase (DAC) inhibitor given intravenously on a new once weekly schedule

Abstract

14019 Background: LBH589 is a novel deacetylase inhibitor that inhibits proliferation of tumor cells at nanomolar levels. This phase I study tested the safety and tolerability of IV LBH589 once each week for 3 of 4 wks in pts with advanced solid tumors or lymphoma. Methods: LBH589 was administered IV over 30 min. on days 1, 8 and 15 of a 28-day cycle. Western blots on peripheral blood lymphocytes were used to study histone acetylation (HA). Plasma PK profiles were analyzed on Days 1 and 8. Results: Thirty five pts (median age: 70 yrs; 23M, 12F) have been treated on 3 dose levels [10 mg/m2 (8pts), 15 mg/m2 (8 pts), 20 mg/m2 (19 pts)] with the following tumor types: Cutaneous and peripheral T cell lymphoma (7 pts), prostate (6 pts), mesothelioma (4 pts), colon (3 pts) and other (15 pts). There was one dose-limiting toxicity (transient grade 4 thrombocytopenia) at 20 mg/m2, none at the lower doses. Other G3/G4 toxicities (all cycles) include: transient thrombocytopenia (G4–5 pts, G3–5 pts), neutropenia (G3–2 pts), anemia (G3–5 pts), G3 hypophosphatemia (1 pt), G3 hypokalemia (1 pt), G3 nausea (1 pt) and G3 pruritus (1 pt). Thrombocytopenia was transient. Of 2,042 ECGs, 1 pt had an increase in QTcF from baseline of > 60 msec another with a QTcF >500 msec, both at 20 mg/m2. There was a dose-dependent increase in HA 7 days after one dose with 43% (10 mg/m2), 50% (15 mg/m2) and 60% (20 mg/m2) of pts with increased acetylation. The LBH589 plasma conc. peaked at the end of the 0.5 hr infusion with a mean terminal half-life of 16 hr. Median Cmax achieved with 20 mg/m2 was 1,000 ng/mL (2.86 μM). The AUC0-inf increased linearly with IV doses of 10–20 mg/m2. One pt with CTCL achieved a complete response (CR) on cycle 3, Day 1; this pt had previously received oral LBH589 at 20 mg MWF, achieving a CR on cycle 6, Day 28 that lasted for 7 months. One peripheral T-Cell lymphoma pt achieved a partial response that has persisted for >7 months. One pt with prostate cancer has had a 26% reduction in nodal disease and > 50% drop in PSA in the first 2 cycles. Conclusions: The maximum tolerated dose of LBH589 given IV wkly on a 3 of 4 wk schedule is 20 mg/m2. This dose produced sustained PD effects and higher systemic exposure compared to oral LBH589. Preliminary evidence of antitumor activity has been observed. No significant financial relationships to disclose.