A phase I and pharmacokinetic study of ecteinascidin-743 (Yondelis) in children with refractory solid tumors. A Children's Oncology Group study.
OBJECTIVE
To determine the dose-limiting toxicity (DLT) and the maximum tolerated dose of ecteinascidin-743 (ET-743, Yondelis) in children with refractory solid tumors, to establish the recommended dose for pediatric phase II trials, and to characterize the pharmacokinetics of ET-743 in children.


METHODS
ET-743 was administered as a 3-hour i.v. infusion every 21 days. The starting dose was 1,100 microg/m(2) with planned dose escalation of 200 microg/m(2) increments. Pharmacokinetic sampling was done during the first treatment course.


RESULTS
Twelve evaluable patients received a total of 29 courses. One grade 4 DLT (prolonged grade 4 neutropenia) was noted at the first dose level. At the second dose level (1,300 microg/m(2)), there were two DLTs (reversible grade 4 elevations of hepatic transaminase); hence the maximum tolerated dose was defined as 1,100 microg/m(2). Overall, reversible hepatic toxicity, manifested as grade 3 or 4 elevations in hepatic transaminase, occurred in more than 50% of the patients. No grade 3 or 4 thrombocytopenia was reported at either dose level and only one episode of isolated creatine phosphokinase grade 4 elevation was observed. One complete response was documented after six courses in a patient with metastatic Ewing sarcoma. The pharmacokinetics of ET-743 in 8 children was characterized by a terminal disposition phase with a mean half-life of 43.8 +/- 18.4 hours, a total body clearance of 28.2 +/- 10.5 L/h/m(2), and a 959 +/- 807 L/m(2) steady-state apparent volume of distribution.


CONCLUSIONS
ET-743 is safe. The phase II recommended dose of ET-743 administered as a 3-hour i.v. infusion following premedication with dexamethasone is 1,100 microg/m(2).
Lau
Loretta
L
New Agent and Innovative Therapy Program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Supko
Jeffery G
JG
Blaney
Susan
S
Hershon
Linda
L
Seibel
Nita
N
Krailo
Mark
M
Qu
Wenchun
W
Malkin
David
D
Jimeno
Jose
J
Bernstein
Mark
M
Baruchel
Sylvain
S
D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004149:Dioxoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D016879:Salvage Therapy; D044005:Tetrahydroisoquinolines; D013997:Time Factors; D000077606:Trabectedin
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin