Phase I and pharmacokinetic study of trabectedin, a DNA minor groove binder, administered as a 24-h continuous infusion in Japanese patients with soft tissue sarcoma.
BACKGROUND
Trabectedin is a novel anticancer agent used to treat soft tissue sarcoma (STS). This phase I study of trabectedin was performed to determine the recommended dose for phase II studies in Japanese patients with STS.


METHODS
Patients who had STS refractory to, or who could not tolerate, anthracycline-based chemotherapy were enrolled. The starting dose of trabectedin was 0.9 mg/m(2), given as a 24-h continuous infusion every 21 days. The dose was escalated to 1.2 mg/m(2) and then to 1.5 mg/m(2), using a "3 + 3" cohort expansion design. Plasma samples were collected for pharmacokinetic analysis.


RESULTS
Fifteen patients received 1 of 3 dose levels of trabectedin. Dose-limiting toxicity occurred in two of three patients at 1.5 mg/m(2): 1 had a grade 3 increase in creatine phosphokinase and grade 3 anorexia, and the other had grade 4 platelet count decreased. Frequent grade 3 or 4 adverse events (AEs) included elevations of alanine aminotransferase and aspartate aminotransferase and decrease in neutrophil count. The frequency and severity of AEs were clearly greater at 1.5 mg/m(2) than at the lower doses. Pharmacokinetic analysis showed that the area under the concentration-time curve at a dose of 1.2 mg/m(2) was adequate to produce antitumor activity. A partial response was obtained in three patients with translocation-related sarcomas (1 each with myxoid liposarcoma, synovial sarcoma, and extraskeletal Ewing sarcoma).


CONCLUSIONS
The recommended dose of trabectedin for phase II studies is 1.2 mg/m(2) in Japanese patients with STS. Trabectedin may be especially effective against translocation-related sarcomas.
Department of Orthopaedic Surgery, Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan, uedat@onh.go.jp.
Takafumi
T
Ueda
Shigeki
S
Kakunaga
Masashi
M
Ando
Kan
K
Yonemori
Hideshi
H
Sugiura
Kenji
K
Yamada
Akira
A
Kawai
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004247:DNA / Q000187:drug effects*; D004149:Dioxoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077606:Trabectedin; D055815:Young Adult
D000970:Antineoplastic Agents; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D004247:DNA; D000077606:Trabectedin