title: Phase I dose-escalating study of panobinostat (LBH589) administered intravenously to Japanese patients with advanced solid tumors.
abstract: Panobinostat (LBH589) is a potent pan-histone deacetylase inhibitor. As a result of promising preclinical data, Phase I and II clinical trials of intravenous and oral panobinostat have been conducted in patients with a wide variety of hematologic and solid tumors. This is the first report of a phase I study to evaluate intravenous panobinostat given on days 1 and 8 of a 21-day cycle in patients with solid tumors. The primary objective was to characterize the safety and tolerability of panobinostat by evaluating the occurrence of dose-limiting toxicity (DLT) and determining the maximum tolerated dose (MTD) in Japanese patients with advanced solid tumors. Secondary objectives included characterizing the pharmacokinetics and assessing antitumor activity. Fourteen patients were assigned to three dose levels (Cohort 1: 10 mg/m(2) [three patients], Cohort 2: 15 mg/m(2) [three patients], Cohort 3: 20 mg/m(2) [eight patients]), according to a standard "3 + 3" design. One patient who received 20 mg/m(2) had a DLT (grade 3 elevation of γ-glutamyl transpeptidase for >7 days). Thrombocytopenia was observed in all patients (grade 3 or 4 in 8), the severity of which was dependent on the dose and platelet count at baseline. The thrombocytopenia rapidly resolved within 8 days. Plasma panobinostat levels increased dose dependently, without clinically significant drug accumulation. Stable disease for ≥4 months was observed in six patients; however, there were no complete or partial responses. It is feasible to conclude that 20 mg/m(2) was the MTD and recommend as the starting dose for phase II clinical trials.
authors.affiliation: Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.
authors.forename: Sachi
authors.initials: S
authors.lastname: Morita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Oizumi
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.forename: Koichi
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Megumi
authors.initials: M
authors.lastname: Inada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yuki
authors.forename: Naomi
authors.initials: N
authors.lastname: Kiyota
authors.forename: Ayako
authors.initials: A
authors.lastname: Mitsuma
authors.forename: Masataka
authors.initials: M
authors.lastname: Sawaki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanii
authors.forename: Junko
authors.initials: J
authors.lastname: Kimura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ando
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D007564:Japan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077767:Panobinostat; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat