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

   

Authors:	Kelly, W. K.; O'Connor, O. A.; Krug, L. M.; Chiao, J. H.; Heaney, M.; Curley, T.; MacGregore-Cortelli, B.; Tong, W.; Secrist, J. P.; Schwartz, L.; Richardson, S.; Chu, E.; Olgac, S.; Marks, P. A.; Scher, H.; Richon, V. M.
Article Title:	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. © 2005 by American Society of Clinical Oncology.
Keywords:	adult; cancer chemotherapy; controlled study; treatment response; aged; major clinical study; clinical trial; drug activity; fatigue; neutropenia; advanced cancer; diarrhea; drug safety; side effect; cancer patient; anorexia; controlled clinical trial; infection; anemia; nausea; thrombocytopenia; vomiting; dehydration; antineoplastic activity; continuous infusion; enzyme linked immunosorbent assay; hyperglycemia; hyponatremia; nonhodgkin lymphoma; drug mechanism; cardiotoxicity; western blotting; mesothelioma; vorinostat; drug bioavailability; drug blood level; phase 1 clinical trial; drug half life; heart arrhythmia; drug dose regimen; histone deacetylase; hypocalcemia; angina pectoris
Journal Title:	Journal of Clinical Oncology
Volume:	23
Issue:	17
ISSN:	0732-183X
Publisher:	American Society of Clinical Oncology
Date Published:	2005-06-10
Start Page:	3923
End Page:	3931
Language:	English
DOI:	10.1200/jco.2005.14.167
PROVIDER:	scopus
PMCID:	PMC1855284
PUBMED:	15897550
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-21244464349&partnerID=40&md5=260d82b50e499775e70afaf70204e0a9
Notes:	--- - "Cited By (since 1996): 474" - "Export Date: 24 October 2012" - "CODEN: JCOND" - "Source: Scopus"

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