Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin.
OBJECTIVE
To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin.


METHODS
Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion.


RESULTS
Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m(2)/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m(2). The MTD was 4.8 mg/m(2). At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non-small-cell lung cancer had a minor response. CONCLUSION YM155 can be administered safely at 4.8 mg/m(2)/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.
Tolcher
Anthony W
AW
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA. atolcher@start.stoh.com
Mita
Alain
A
Lewis
Lionel D
LD
Garrett
Christopher R
CR
Till
Elizabeth
E
Daud
Adil I
AI
Patnaik
Amita
A
Papadopoulos
Kyri
K
Takimoto
Chris
C
Bartels
Pamela
P
Keating
Anne
A
Antonia
Scott
S
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D020714:Maximum Tolerated Dose; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008875:Middle Aged; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010865:Pilot Projects; D000077022:Survivin; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009285:Naphthoquinones; D009363:Neoplasm Proteins; D000077022:Survivin; C523798:sepantronium