Phase I clinical trial of histone deacetylase inhibitor: Suberoylanilide hydroxamic acid administered intravenously Journal Article

Authors: Kelly, Wm K.; Richon, V. M.; O'connor, O.; Curley, T.; Macgregor-Cortelli, B.; Tong, W.; Klang, M.; Schwartz, L.; Richardson, S.; Rosa, E.; Drobnjak, M.; Cordon-Cardo, C.; Chiao, J. H.; Rifkind, R.; Marks, P. A.; Scher, H.
Article Title: Phase I clinical trial of histone deacetylase inhibitor: Suberoylanilide hydroxamic acid administered intravenously
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/m2/day), therapy was delayed ≥1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m2/day × 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m2/day × 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m2/day × 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.
Keywords: immunohistochemistry; adolescent; adult; clinical article; controlled study; treatment outcome; aged; aged, 80 and over; middle aged; histone deacetylase inhibitor; clinical trial; constipation; drug activity; fatigue; neutropenia; advanced cancer; area under the curve; diarrhea; dose response; drug safety; solid tumor; antineoplastic agents; anorexia; controlled clinical trial; liver toxicity; gastrointestinal symptom; heart disease; leukopenia; thrombocytopenia; vomiting; cancer pain; kidney failure; tumor biopsy; antineoplastic activity; tumor regression; dose-response relationship, drug; bladder tumor; biopsy; time factors; abdominal pain; dyspnea; hyperglycemia; skin; hypotension; hematologic malignancy; hematologic neoplasms; histone; thromboembolism; acute heart infarction; thrombosis; lymphoma; vorinostat; hydroxamic acids; area under curve; drug blood level; phase 1 clinical trial; drug half life; heart arrhythmia; infusions, intravenous; abdominal cramp; drug tolerance; histones; histone deacetylases; heart muscle ischemia; hematologic disease; bone marrow toxicity; acetylation; adult respiratory distress syndrome; respiratory distress; humans; human; male; female; priority journal; article
Journal Title: Clinical Cancer Research
Volume: 9
Issue: 10
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2003-09-01
Start Page: 3578
End Page: 3588
Language: English
PUBMED: 14506144
PROVIDER: scopus
Notes: Export Date: 12 September 2014 -- Source: Scopus