Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma

BACKGROUND Recurrent osteosarcoma is a drug‐resistant disease with a dismal prognosis. The objective of this Phase II study was to evaluate the activity of ecteinascidin 743 (ET‐743) as a salvage therapy in these patients. METHODS Patients with recurrent osteosarcoma who had received standard chemotherapeutic agents were eligible. ET‐743 was administered at a dose of 1500 μg/m2 as a 24‐hour infusion every 3 weeks. Pharmacokinetic studies were performed during the first cycle. RESULTS Twenty‐five patients were enrolled, 23 of whom were assessable for response (median age of 18 years; range, 12–67 years). The median number of previous chemotherapeutic agents was five (range, three to eight previous agents). Sixty‐one cycles were administered (median number of cycles per patient was 2; range, 1–9 cycles per patient). Three patients (12%) achieved minor responses (49% 36% and 25%, respectively). Fifteen patients (60%) developed a transient elevation of hepatic transaminases (Grade 3 or 4 [according to the National Cancer Institute Common Toxicity Criteria]), which was not cumulative. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 12 patients (48%) and 6 patients (24%), respectively. The mean area under the curve (AUC) in 4 patients experiencing Grade 4 toxicity (76.4 ± 29.3 ng × hr/mL) was significantly greater (P = 0.034) than that in those for whom the most severe toxicity was Grade 3 (39.5 ± 17.2 ng × hr/mL [n = 12]) or Grade 1‐2 (52.6 ± 15.6 ng × hr/mL [n = 5]). There were no other significant correlations found between pharmacokinetic variables and patient characteristics, toxicity, or therapeutic response. CONCLUSIONS ET‐743 was found to be well tolerated in heavily pretreated osteosarcoma patients but had limited antitumor activity as a single agent. The combination of ET‐743 with cisplatin or doxorubicin should be considered. Cancer 2003;98:832–40. © 2003 American Cancer Society. DOI 10.1002/cncr.11563 Ecteinascidin 743 (ET‐743) is a new agent that appeared to be well tolerated but was found to have limited activity as a single agent in the current Phase II study in heavily pretreated patients with recurrent osteosarcoma.