http://clincancerres.aacrjournals.org/cgi/content/abstract/11/2/672
Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):672-7.
A Phase I and Pharmacokinetic Study of Ecteinascidin-743 (Yondelis)
in Children with Refractory Solid Tumors. A Children's Oncology Group
Study.
Lau L, Supko JG, Blaney S, Hershon L, Seibel N, Krailo M, Qu W,
Malkin D, Jimeno J, Bernstein M, Baruchel S.
The Hospital for Sick Children, Toronto, Ontario, Canada.
PURPOSE: 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.EXPERIMENTAL DESIGN: ET-743 was
administered as a 3-hour i.v. infusion every 21 days. The starting dose
was 1,100 mug/m(2) with planned dose escalation of 200 mug/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 mug/m(2)),
there were two DLTs (reversible grade 4 elevations of hepatic
transaminase); hence the maximum tolerated dose was defined as 1,100
mug/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.CONCLUSION:
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 mug/m(2).
PMID: 15701855 [PubMed – in process]