TY - JOUR
T1 - Phase I clinical trial of histone deacetylase inhibitor
T2 - Suberoylanilide hydroxamic acid administered intravenously
AU - Kelly, Wm Kevin
AU - Richon, Victoria M.
AU - O'Connor, Owen
AU - Curley, Tracy
AU - MacGregor-Curtelli, Barbara
AU - Tong, William
AU - Klang, Mark
AU - Schwartz, Lawrence
AU - Richardson, Stacie
AU - Rosa, Eddie
AU - Drobnjak, Marija
AU - Cordon-Cordo, Carlos
AU - Chiao, Judy H.
AU - Rifkind, Richard
AU - Marks, Paul A.
AU - Scher, Howard
PY - 2003/10/1
Y1 - 2003/10/1
N2 - 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.
AB - 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.
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M3 - Article
C2 - 14506144
AN - SCOPUS:12444321545
SN - 1078-0432
VL - 9
SP - 3578
EP - 3588
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10 I
ER -