Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients With Advanced Cancer

Cornell University, Итак, New York, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 07/2005; 23(17):3923-31. DOI: 10.1200/JCO.2005.14.167
Source: PubMed

ABSTRACT 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 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.
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.
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.

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Available from: Owen A O'Connor, Dec 25, 2013
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    • "Treatment with HDAC inhibitors resulted in growth arrest, terminal differentiation, apoptosis, or autophagic cell death. Thus, development of HDAC inhibitors as therapeutic agents for cancer treatment has been attempted (Kelly et al., 2005; Bolden et al., 2006). "
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    • "Vorinostat (VRS), a histone deacetylase inhibitor, has been approved by the FDA for treatment of cutaneous T-cell lymphoma (CTCL) (Cai et al., 2010; Choo, Ho & Lin, 2008). In clinical trials, it was used for a variety of hematopoietic and solid tumor indications (Bolden, Peart & Johnstone, 2006; Kelly et al., 2005). It can effectively induce cell cycle arrest, cell differentiation, and apoptosis (Marks & Breslow, 2007). "
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