Open AccessPhase I and pharmacokinetic study of vorinostat (suberoylanilide hydroxamic acid) in Japanese patients with solid tumors
Author(s) -
Fujiwara Yutaka,
Yamamoto Noboru,
Yamada Yasuhide,
Yamada Kazuhiko,
Otsuki Tetsuya,
Kanazu Shinichi,
Iwasa Takashi,
Hardwick James S.,
Tamura Tomohide
Publication year - 2009
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01237.x
Subject(s) - vorinostat , pharmacokinetics , dosing , medicine , maximum tolerated dose , pharmacology , anorexia , gastroenterology , histone deacetylase inhibitor , toxicity , histone deacetylase , chemistry , biochemistry , gene , histone
Vorinostat (suberoylanilide hydroxamic acid), a potent, oral histone deacetylase inhibitor, has demonstrated clinical activity in non‐Japanese patients with various hematological and solid tumors. We sought to determine the maximum tolerated dose and a recommended phase II dose for 18 Japanese patients with solid tumors (median age, 58 years; range, 25–72 years) who failed standard therapy. Patients received vorinostat for 14 days followed by a 7‐day rest. The initial dose was 100 mg twice daily escalating by 100 mg twice daily. Once‐daily dosing was tested at 400 and 500 mg. A maximum tolerated dose could not be identified. Dose‐limiting toxicities (thrombocytopenia, anorexia, and fatigue) were observed in two of six patients receiving 200 mg twice daily and in one of six patients receiving 500 mg once daily. In the 100–500 mg dose range, vorinostat area under the concentration–time curve increased in proportion to dose with a pharmacokinetic profile similar to that established in non‐Japanese patients. Vorinostat doses of 200 mg twice daily or 500 mg once daily for 14 days followed by a 7‐day rest were well tolerated and are candidate doses for phase II trials, although a maximum tolerated dose for vorinostat was not reached. ( Cancer Sci 2009; 100: 1728–1734)