Trabectedin (ET-743, Yondelis®; J&J PRD, LLC, Titusville NJ) is a potent synthetic alkylating agent originally isolated from the marine tunicate Ecteinascidia turbinata
]. It binds to the minor groove of DNA in a sequence specific manner and its cytotoxicity is mediated through interfering with transcription coupled nucleotide excision repair and homologous recombination DNA repair pathways as well as inhibition of transcriptional activation [2
]. Trabectedin is cytotoxic at nanomolar concentrations in in vitro
and in vivo
preclinical tumor models [7
]. Several doses and schedules have been studied in adults, and the recommended dose and schedule for sarcomas in adults is 1.5 mg/m2
infused over 24 h every 21 days [8
]. Frequently reported adverse events included serum transaminase elevations, myelosuppression, nausea, emesis and fatigue. Dose-limiting toxicities (DLTs) were myelosuppression (neutropenia and thrombocytopenia), fatigue and rhabdomyolysis.
In clinical trials in adults, the definition of hepatic DLT was grade 3 or 4 hepatic dysfunction that did not recover by day 28 of the treatment cycle. Although serum transaminase elevations were common, they did not fulfill this DLT definition. Data from more than 5000 adults treated with multiple cycles of trabectedin indicate that these transient elevations in serum transaminases are not indicative of cumulative hepatotoxicity. Liver biopsies from patients treated with trabectedin in combination with liposomal doxorubicin did not demonstrate permanent hepatic damage [10
]. In addition, dexamethasone mitigates trabectedin-related, transient hepatic toxicity [11
The anti-tumor activity of trabectedin appears to be dose and schedule dependent. Objective responses on the initial adult phase I study were achieved in patients with liposarcoma, breast cancer and osteosarcoma treated at doses of 1.5 mg/m2
and above, however, doses higher than 1.5 mg/m2
were not tolerable [9
]. In a study in patients with lipo and leiomyosarcoma randomized to receive either the weekly 3-hour or every 3 week 24-hour infusion schedule, the 24-hour infusion was associated with an increased time to progression [15
]. Based on modest response rates and duration of stable disease in adults with sarcomas, particularly liposarcoma and leiomyosarcoma [16
], trabectedin 1.5 mg/m2
IV over 24 h has been approved for refractory sarcomas by the European Medicines Agency (EMA).
A prior pediatric phase I trial utilizing a 3-hour infusion schedule defined a maximum tolerated dose (MTD) of 1.1 mg/m2
every 21 days [22
]. Dexamethasone was administered to patients receiving doses ≥ 1.3 mg/m2
, but prophylactic growth factor support was not allowed during cycle 1. The definition of hepatic DLT was any grade 4 elevation in serum ALT/AST. Toxicities included dose-limiting serum ALT/AST elevations and neutropenia. Non-dose limiting toxicities were nausea, emesis, fatigue and anemia. A complete response was observed in a patient with Ewing sarcoma.
We conducted a limited dose escalation phase I trial of trabectedin in children age 4–16 years with refractory or recurrent solid tumors to establish the safety, toxicity profile, and pharmacokinetics of a 24-hour infusion schedule of trabectedin in children.