title: Phase I study of YM155, a novel survivin suppressant, in patients with advanced solid tumors.
abstract: OBJECTIVE
  YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors.
  
  
  METHODS
  Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles.
  
  
  RESULTS
  Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m(2)/d. The MTD was determined to be 8.0 mg/m(2)/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m(2)/d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients.
  
  
  CONCLUSIONS
  YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m(2)/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan. taroh@med.kindai.ac.jp
authors.forename: Taroh
authors.initials: T
authors.lastname: Satoh
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Ryotaroh
authors.initials: R
authors.lastname: Morinaga
authors.forename: Asuka
authors.initials: A
authors.lastname: Tsuya
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Terashima
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ariyoshi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Saito
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Masuda
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Watanabe
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Taguchi
authors.forename: Toru
authors.initials: T
authors.lastname: Kakihara
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Aoyama
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008657:Metabolic Clearance Rate; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D009285:Naphthoquinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010352:Patient Dropouts / Q000706:statistics & numerical data; D000077022:Survivin; D016896:Treatment Outcome
chemical_list: C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium