Phase I study of YM155, a novel survivin suppressant, in patients with advanced solid tumors.
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.
Satoh
Taroh
T
Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan. taroh@med.kindai.ac.jp
Okamoto
Isamu
I
Miyazaki
Masaki
M
Morinaga
Ryotaroh
R
Tsuya
Asuka
A
Hasegawa
Yoshikazu
Y
Terashima
Masaaki
M
Ueda
Shinya
S
Fukuoka
Masahiro
M
Ariyoshi
Yutaka
Y
Saito
Toshikazu
T
Masuda
Noriyuki
N
Watanabe
Hirokazu
H
Taguchi
Tetsuo
T
Kakihara
Toru
T
Aoyama
Yumiko
Y
Hashimoto
Yohko
Y
Nakagawa
Kazuhiko
K
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
C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium