title: A phase I study of vorinostat combined with bortezomib in Japanese patients with relapsed or refractory multiple myeloma.
abstract: This study was undertaken to evaluate safety and pharmacokinetics and to determine treatment doses of vorinostat plus bortezomib in Japanese patients with relapsed or refractory multiple myeloma (MM). Of 9 originally enrolled patients, 2 were refractory to bortezomib, and both experienced dose-limiting toxicity (DLT), prompting a protocol amendment to exclude bortezomib-refractory individuals. Patients not considered bortezomib refractory (N = 7) received 21-day cycles of 1.3 mg/m(2) intravenous bortezomib (Days 1, 4, 8, and 11) and oral vorinostat 400 mg (Days 1 through 14) and were further evaluated. Vorinostat and bortezomib treatment doses were determined by DLT and safety, tolerability, and treatment response were assessed. Of 7 enrolled patients, 6 were evaluated, and one developed DLTs. The most common adverse events were leukopenia, neutropenia, thrombocytopenia, diarrhea, nausea, decreased appetite, and vomiting. Combination of vorinostat plus bortezomib did not increase vorinostat exposure at Day 11 [AUC0-24 h ratio (95% CI) = 1.08 (0.80, 1.45)]; geometric mean AUC0-24 h ratio for bortezomib (90% CI) was 1.96 (1.24-3.12). Objective therapeutic response occurred in 3 patients, including 1 complete response and 2 partial responses. Vorinostat 400 mg plus bortezomib 1.3 mg/m(2) was safe and well-tolerated in Japanese patients with relapsed or refractory MM not considered bortezomib refractory (NCT00858234).
authors.affiliation: Department of Hematology and Oncology, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa, 259-1193, Japan. yoshioga@is.icc.u-tokai.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Ogura
authors.affiliation: Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kensei
authors.initials: K
authors.lastname: Tobinai
authors.affiliation: Department of Hematology and Oncology, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa, 259-1193, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Hematology and Oncology, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa, 259-1193, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ohmachi
authors.affiliation: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Merck and Co., Inc., Kenilworth, NJ, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hanson
authors.affiliation: MSD K.K., Tokyo, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: MSD K.K., Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.affiliation: MSD K.K., Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimamoto
authors.affiliation: National Cancer Center, Tokyo, Japan.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hotta
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044466:Asian People; D000069286:Bortezomib / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D012008:Recurrence; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D000069286:Bortezomib
keywords: Bortezomib; HDAC inhibitor; Multiple myeloma; Phase I study; Vorinostat