A phase I and pharmacokinetic study of ecteinascidin-743 on a daily x 5 schedule in patients with solid malignancies.
OBJECTIVE
The purpose of this study was to (a) assess the feasibility of administering ecteinascidin-743 (ET-743), a novel DNA minor-groove disrupting agent of marine origin, administered as a daily i.v. infusion for 5 days every 3 weeks; (b) recommend a dose for Phase II studies; (c) characterize its pharmacokinetic behavior; and (d) seek preliminary evidence of anticancer activity.


METHODS
Patients with advanced solid malignancies were treated with escalating doses of ET-743 as a daily 1-h i.v. infusion for 5 days every 3 weeks. Plasma and urine were sampled on both days 1 and 5 of the first course. Pharmacokinetic parameters were related to the principal toxicities.


RESULTS
Forty-two patients were treated with 118 courses of ET-743 at doses ranging from 6 to 380 microg/m(2)/day. Elevations in hepatic transaminases were common at ET-743 dose levels > or =216 microg/m(2)/day, resolved rapidly, and were never dose limiting nor cumulative. Instead, hematological toxicity was the principal toxicity that precluded dose escalation. The maximum tolerated dose of ET-743 that could be administered repetitively was 325 microg/m(2)/day. Antitumor activity was noted in three patients with leiomyosarcoma and primary peritoneal and ovarian carcinomas. The pharmacokinetics of ET-743 were dose independent, and drug accumulation over the 5 days of treatment was modest, with the ratio of the area under the plasma-versus-time curve on day 5 to that on day 1 averaging 2.05. The volume of distribution at steady state was large (mean, 1037 liters/m(2)), and the mean terminal half life on day 5 was 26.81 h.


CONCLUSIONS
The maximum tolerated dose of ET-743 that can be administered repetitively is 325 microg/m(2)/day daily x 5 every 3 weeks, which is recommended for disease-directed clinical trials. The acceptable toxicity profile of ET-743 on the divided-dose schedule evaluated in this trial, as well as the generally superior antitumor activity associated with divided-dose schedules in preclinical studies, provides a rationale for further evaluation of ET-743 on this administration schedule.
Villalona-Calero
Miguel A
MA
Institute for Drug Development, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 78229, USA. villalona-1@medctr.osu.edu
Eckhardt
S Gail
SG
Weiss
Geoffrey
G
Hidalgo
Manuel
M
Beijnen
Jos H
JH
van Kesteren
Charlotte
C
Rosing
Hilde
H
Campbell
Elizabeth
E
Kraynak
Maura
M
Lopez-Lazaro
Luis
L
Guzman
Cecilia
C
Von Hoff
Daniel D
DD
Jimeno
Jose
J
Rowinsky
Eric K
EK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004149:Dioxoles / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D044005:Tetrahydroisoquinolines; D013997:Time Factors; D014018:Tissue Distribution; D000077606:Trabectedin
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077606:Trabectedin