A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of CHR-3996, a class 1 selective histone deacetylase inhibitor (HDACi), in patients with advanced solid tumors.

Abstract

2552 Background: CHR-3996, a class 1 selective HDACi inhibiting HDAC 1, 2, and 3 at low nanomolar concentrations, demonstrated antitumor activity in several xenograft tumor models. Objectives of this study were to explore (1) tolerability and safety profile, (2) PK, (3) PD effects in PBMC and hair follicles, and (4) antitumor activity of once-daily continuous oral administration of 28-day cycles. Methods: 3 patients were enrolled at each dose level and the cohort was expanded in the event of a DLT. Results: 21 subjects, 5F:16M, median age 61 yrs (23–77) have been enrolled at 5 (n=3), 10 (n=4), 20 (n=3), 40 (n=7), and 80 mg (n=4). Median number of cycles administered is 2 (1–10). Dose-limiting toxicity (DLT) was observed in one patient at 40 mg (grade 3 atrial fibrillation). This cohort was expanded, but no further DLTs were observed. Most frequent drug-related AEs were fatigue (11), nausea (9), and vomiting (5). PK analysis revealed rapid absorption (Tmax 1-3 h) and mean elimination plasma half-life of 3 hrs. Cmax and AUC (0- t) increased dose proportionally. Mean AUC values at doses ≥ 40 mg exceeded levels effective in xenograft studies. No accumulation of CHR-3996 was seen on Day 28. 5 subjects demonstrated stable disease at or after cycle 2 (SD lasting 2, 10, 2.5, 3, 4 cycles, respectively). Preliminary PD analysis in PBMCs shows increases in histone acetylation with increasing dose. Confocal analysis of protein acetylation in hair follicles will be reported on. Conclusions: CHR-3996 is well tolerated and accrual is ongoing to establish the recommended dose for phase II studies. Plasma levels of CHR-3996 achieved exceed those required for antitumor efficacy in preclinical models, without significant toxicity. Dose escalation is ongoing, and updated results will be presented at the meeting, along with an assessment of histone acetylation as a pharmacodynamic biomarker in PBMCs and hair follicles. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chroma Therapeutics, The Institute of Cancer Research Chroma Therapeutics