Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously.
Publication/Presentation Date
9-1-2003
Abstract
PURPOSE: To evaluate the safety, pharmacokinetics, and biological activity of suberoylanilide hydroxamic acid (SAHA) administered by 2-h i.v. infusion in patients with advanced cancer.
EXPERIMENTAL DESIGN: SAHA was administered for 3 days every 21 days in part A and 5 days for 1-3 weeks in part B. Dose escalation proceeded independently in patients with solid tumor and hematological malignancies (part B only). Pharmacokinetic studies were performed along with assessment of acetylated histones in peripheral blood mononuclear cells and tumor tissues.
RESULTS: No dose-limiting toxicities were observed in 8 patients enrolled in part A (75, 150, 300, 600, and 900 mg/m(2)/day). Among 12 hematological and 17 solid tumor patients enrolled in part B (300, 600, and 900 mg/m(2)/day), therapy was delayed > or = 1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m(2)/day x 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m(2)/day x 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m(2)/day x 5 days for 3 weeks developed acute respiratory distress and grade 3 hypotension. The cohort was expanded to 6 patients, and no additional dose-limiting toxicities were observed. Mean terminal half-life ranged from 21 to 58 min, and there was dose-proportional increase in area under the curve. An accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion was observed at higher dose levels. Posttherapy tumor biopsies showed an accumulation of acetylated histones by immunohistochemistry. Four (2 lymphoma and 2 bladder) patients had objective tumor regression with clinical improvement in tumor related symptoms.
CONCLUSIONS: Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo, and has antitumor activity in solid and hematological tumors.
Volume
9
Issue
10 Pt 1
First Page
3578
Last Page
3588
ISSN
1078-0432
Published In/Presented At
Kelly, W. K., Richon, V. M., O'Connor, O., Curley, T., MacGregor-Curtelli, B., Tong, W., Klang, M., Schwartz, L., Richardson, S., Rosa, E., Drobnjak, M., Cordon-Cordo, C., Chiao, J. H., Rifkind, R., Marks, P. A., & Scher, H. (2003). Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clinical cancer research : an official journal of the American Association for Cancer Research, 9(10 Pt 1), 3578–3588.
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
14506144
Department(s)
Administration and Leadership
Document Type
Article