Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer

Abstract

Purpose: To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer.

Patients and methods: Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition.

Results: Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months.

Conclusions: Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.

Fig 1

Mean plasma concentrations of suberoylanilide hydroxamic acid on cycle 1/day 9 after oral administration of 200 mg every day (qd) or twice a day (bid), 300 mg bid, 400 mg qd or bid, or 600 mg qd under fed conditions.

Fig 2

Relationship between area under the curve to infinity (AUC_N) and maximum concentration (C_max) and dose on cycle 1/day 8 after administration of suberoylanilide hydroxamic acid under fasting conditions. qd, every day; bid, twice a day.

Fig 3

Average histone H3 acetylation by dose group. Histones were isolated at the times indicated following ingestion of suberoylanilide hydroxamic acid and enzyme-linked immunosorbent assays performed as described in Patients and Methods. The number of patients analyzed in the 200-, 300-, 400-, and 600-mg groups was five, three, seven, and three, respectively. Each determination was performed in triplicate and the error bars represent the standard error of the mean.

Fig 4

Long-term evaluation of peripheral-blood mononuclear cells for histone H3 acetylation in patients.