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

被引:70
作者
Laverdiere, C
Kolb, EA
Supko, JG
Gorlick, R
Meyers, PA
Maki, RG
Wexler, L
Demetri, GD
Healey, JH
Huvos, AG
Goorin, AM
Bagatell, R
Ruiz-Casado, A
Guzman, C
Jimeno, J
Harmon, D
机构
[1] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA
[2] Harvard Med Sch, Div Hematol Oncol, Dana Farber Harvard Canc Ctr, Boston, MA USA
[3] Mem Sloan Kettering Canc Ctr, Dept Med, Div Med Oncol, New York, NY 10021 USA
[4] Mem Sloan Kettering Canc Ctr, Dept Surg, Div Orthoped Surg, New York, NY 10021 USA
[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA
[6] Univ Arizona, Hlth Sci Ctr, Dept Pediat, Tucson, AZ 85721 USA
[7] PharmaMar SA, Tres Cantos, Spain
关键词
ecteinascidin-743 (ET-743); osteosarcoma; sarcoma; Phase II study;
D O I
10.1002/cncr.11563
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 mug/m(2) 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 X 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 X hr/mL [n = 12]) or Grade 1-2 (52.6 +/- 15.6 ng X 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.
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收藏
页码:832 / 840
页数:9
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