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A Phase I and Pharmacokinetic Study of Ecteinascidin-743 (Yondelis) in Children with Refractory Solid Tumors. A Children's Oncology Group Study

¹ The Hospital for Sick Children, Toronto, Ontario, Canada; ² Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; ³ Texas Children's Cancer Center, Houston, Texas; ⁴ Ste. Justine Hospital, Montreal, Canada; ⁵ University of Washington, Seattle, Washington; ⁶ Keck School of Medicine, University of Southern California, Los Angeles, California; and ⁷ PharmaMar, S.A., Madrid, Spain

Requests for reprints: Sylvain Baruchel, New Agent and Innovative Therapy Program Hospital for Sick Children Toronto, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.

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 µg/m² with planned dose escalation of 200 µg/m² 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 µg/m²), there were two DLTs (reversible grade 4 elevations of hepatic transaminase); hence the maximum tolerated dose was defined as 1,100 µg/m². 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/m², and a 959 ± 807 L/m² 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 µg/m².

Key Words: Phase I trial • pediatric • ET-743 • pharmacokinetics • cancer

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