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.

Modulation of cellular radiation responses by histone deacetylase inhibitors

“…Similarly, TSA which is associated with excessive toxicity and is unstable in vivo has limited clinical applicability (Jung, 2001;Hess-Stumpp, 2005). However, other hydroxamic acid derivatives including SAHA and pyroxamide have completed phase I trials and are progressing further in clinical trials (Kelly et al, 2002(Kelly et al, , 2003Kelly and Marks, 2005). Results from phase I trials have shown that intravenous SAHA formulations are safe and can inhibit HDAC activity in malignant and normal cells (Kelly et al, 2002(Kelly et al, , 2003Kelly and Marks, 2005).…”

“…However, other hydroxamic acid derivatives including SAHA and pyroxamide have completed phase I trials and are progressing further in clinical trials (Kelly et al, 2002(Kelly et al, , 2003Kelly and Marks, 2005). Results from phase I trials have shown that intravenous SAHA formulations are safe and can inhibit HDAC activity in malignant and normal cells (Kelly et al, 2002(Kelly et al, , 2003Kelly and Marks, 2005). Importantly, SAHA was shown to possess anticancer activity in a broad range of hematologic and solid cancers.…”

Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

“…Indeed, chemical inhibitors of HDACs have been shown to inhibit tumor cell growth and induce differentiation and cell death. [5] Several such inhibitory agents, including suberoyanilide hydroxamic acid (SAHA, aka virinostat) and depsipeptide (FR901228) have reached clinical trials, [6][7][8] and SAHA has been approved by the FDA for use in cutaneous T-cell lymphoma (CTCL). The HDAC inhibitors (HDACIs) also enhance the cytotoxic effects of both radiation and chemotherapeutic drugs.…”

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

“…The reversible nature of epigenetic changes in cancer cells by inhibitory agents has been explored as a new avenue for cancer treatment. Histone deacetylase (HDAC) inhibitors were recently found to be well-tolerated in patients with hematologic and solid malignancies [17]. Several classes of HDAC inhibitors exist, and they display diverse effects on cellular functions.…”