Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of LBH589A: A novel histone deacetylase inhibitor

Abstract

3025 Background: LBH589A is a novel histone deacetylase inhibitor which inhibits HDAC enzyme activity, activates p21 and inhibits proliferation of tumor cell lines at nanomolar concentrations. Methods: In this phase I trial, LBH589A was administered IV as a 30-minute infusion either on days 1–3 and 8–10 of a 21 day cycle (arm 1) or on days 1–3 and 15–17 of a 28 day cycle (arm 2). Results: Thirteen pts. (median age: 64.3 years; 10M, 3F) have been treated. Tumor types: renal cell (4 pts), NSCLC (2 pts), sarcoma (2 pts), hepatocellular (1 pt), colon (1 pt), others (3 pts). In arm 1, 11 pts. have been treated at dose levels (mg/m2): 1.2 (2 pts), 2.4 (3 pts), 4.8 (3 pts), 7.2 (3 pts). In arm 2, two pts. have been treated at dose levels: 2.4 (1 pt), 4.8 (1 pt). Performance status: 0 (3 pts), 1 (10 pts). One DLT (prolonged G2 thrombocytopenia) has been observed at the 7.2 mg/m2 dose level in arm 1. Other toxicities (all cycles): G3 neutropenia (1 pt), G3 hypoglycemia (1 pt), G2 thrombocytopenia (2 pts), and G2 anemia (2 pts). No abnormalities observed in >100 ECGs. Six of 13 pts. have exhibited stable disease (range 2–8 cycles, tumors: renal (3 pts), sarcoma (1 pt), NSCLC (1 pt), hepatocellular (1 pt)). To determine if LBH589A increases histone acetylation, Western blots were performed on total cell lysates from peripheral blood lymphocytes. Increased acetylation was observed in 1 of 2 pts. at 2.4 mg/m2 and in 2 of 3 pts. at 4.8 mg/m2 up to 24 hrs after the third dose. Onset of acetylation was rapid (1h) and, in 1 patient at 4.8 mg/m2 dose, lasted up to 7 days after the first dose. PK samples were collected on days 1 and 3 of cycle 1 and analyzed using a noncompartmental analysis. Plasma LBH589A concentrations were determined using HPLC/MS/MS assay. AUC increased proportionally with dose and mean AUCs (0–24h) were 37.7, 85.8 and 151.1 ng.h/mL, respectively, for 1.2, 2.4 and 4.8 mg/M2 dose levels on Day 3. Terminal half-life was approximately 15–20 hrs. Conclusions: In this phase I study, LBH589A given IV appears to be well tolerated with consistent PD effects. Additional evaluation is continuing at the 7.2 mg/m2 dose level for arm 1 and at the 9.6 mg/m2 dose level a for arm 2. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis; Novartis Germany Novartis Novartis Novartis