A Phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of a novel histone deacetylase inhibitor LAQ824 in patients with hematologic malignancies

Abstract

3024 Background: LAQ824 is a novel cinnamic acid hydroxamate that inhibits HDAC activity, IC50 of 0.03 μM, and acetylates hsp90 thereby inducing proteosomal degradation of Bcr-Abl and her-2. Methods: LAQ824 is administered by a 3 hr IV infusion on days 1–3 of a 21 day cycle to pts with ALL, AML, CLL, CML in blast crisis or advanced MDS. Modified continuous reassessment method (MCRM) was utilized for dose escalation. Results: 21 pts (median age: 68 yrs; 14 M, 7 F) with AML (15 pts), MDS (4 pts) and CLL (2 pts) have been treated at dose levels (mg/m2): 6 (2 pts); 12 (3 pts); 24 (3 pts); 36 (4 pts); 54 (4 pts); 80 (5 pts). One patient experienced DLT, at the 54 mg/m2 dose level, (cerebral bleed secondary to thrombocytopenia in a CLL patient with rapid disease progression). Grade 2 hyperbilirubinemia was seen in 6 pts. but was rapidly reversible (generally in < 1 week). Monitoring with > 400 ECGs, demonstrates no QTc prolongation. One patient with de novo M1 AML achieved a CR after 2 cycles, and remains in CR after 6 cycles. Six patients had stable disease (5 pts, 4 AML, 1 MDS) or hematologic improvement (1 pt, MDS). PD study for increased histone acetylation (HA) in peripheral lymphocytes was seen on days of dosing ≥ 12 mg/m2, and at ≥ 36 mg/m2 was present for 24 hours after the last dose. PK in 15 pts receiving LAQ824 over a dose range of 6–54 mg/m2 were evaluated by noncompartmental analysis. Plasma LAQ824 concentrations were determined using HPLC/MS/MS assay. Exposure (AUC) increased proportionally with increasing dose. The mean AUCs(0–24) were 165.4 and 1816.8 ng.h/mL, respectively, for 6 and 54 mg/m2 on Day 1. The mean terminal half-lives ranged from 9 to 18 hr. Comparison of AUC between Day 3 and Day 1 indicated a 1.5 fold drug accumulation. Maximum plasma concentrations (Cmax) were observed at 1.5 h after the beginning of infusion, not at the end of infusion, in more than 50% of patients, indicating a non-linear PK. Conclusions: LAQ824 is a novel HDAC inhibitor which is well tolerated, exhibits dose dependent PD effects, and has shown evidence of clinical activity in hematologic malignancies. Further dose escalation is in progress. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceutics Novartis Novartis Novartis