3022 Background: LAQ824 is a novel cinnamic acid hydroxamate that inhibits HDAC activity and acetylates hsp90 thereby inducing proteosomal degradation of Bcr-Abl and her-2.
METHODS
LAQ824 was administered as a 3 hr IV infusion on days 1-3 of a 21 day cycle to adult pts with advanced solid tumors. A modified continuous reassessment method (MCRM) was used.
RESULTS
28 pts (median age: 54 yrs; 16M, 12F) were treated at 7 dose levels (mg/m2): 6 (3 pts); 12 (4 pts); 24 (4 pts); 36 (4 pts); 48 (4 pts); 72 (8 pts); 100 (1 pt.).
WHO PS
0 (7 pts.), 1 (19 pts.), 2 (2 pts.). Grade 3 (G3) or G4 toxicities included transient G3 transaminitis (2 pts), G3 fatigue (1 Pt), G3 atrial fibrillation, without changes in QTc (1 pt), G3 creatinine increase, in 1 pt with advanced prostate cancer, and grade 4 ↑ bilirubin in 1 pt with liver metastases. Other toxicities: transient (<1 wk) G2 transaminitis (3 pts); G2 hyperbilirubinemia (1 pt); transient (< 1 wk) G3 thrombocytopenia (3 pts); G2 fatigue (3 pts) and G2 nausea (5 pts). Six of 7 pts with LFT abnormalities had liver metastases. Monitoring with > 400 ECGs on study, demonstrated 1 ECG with a QTc > 500 msec. 3/28 pts had stable disease: 5 (SCLC), 6 (melanoma), and 10 (hepatoma) cycles. PD assessment for histone acetylation (HA) in peripheral blood lymphocytes demonstrated increases at ≥ 12 mg/m2, increases on days of dosing at ≥ 36 mg/m2, increases for at least 24 hours post dose at ≥ 48 mg/m2, and increases for at least 48 hours post dose at ≥ 72 mg/m2. PK was evaluated in 25 pts (over 6-72 mg/m2) by noncompartmental analysis. Plasma LAQ824 concentrations were determined by HPLC/MS/MS assay. Exposure (AUC) increased proportionally with increasing dose. Mean AUCs(0-24) were 240.6 and 2721.7 ng.h/mL, respectively, for 6 and 72 mg/m2 on Day 1. Mean terminal half-lives ranged from 8 to 14 hr. Comparison of AUC on Day 1 and 3 indicated a 1.5 fold drug accumulation. Cmax was observed at 1.5 h after the beginning of infusion in > 50% of patients, indicating non-linear PK.
CONCLUSIONS
LAQ824 is a novel HDAC inhibitor which is well tolerated and exhibits dose dependent PD effects. Evaluation of pts at 72 mg/m2dose level is in progress. [Table: see text].