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 microg/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.
Laverdiere
Caroline
C
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Kolb
E Anders
EA
Supko
Jeffrey G
JG
Gorlick
Richard
R
Meyers
Paul A
PA
Maki
Robert G
RG
Wexler
Leonard
L
Demetri
George D
GD
Healey
John H
JH
Huvos
Andrew G
AG
Goorin
Allen M
AM
Bagatell
Rochelle
R
Ruiz-Casado
Ana
A
Guzman
Cecilia
C
Jimeno
Jose
J
Harmon
David
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002648:Child; D004149:Dioxoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012516:Osteosarcoma / Q000188:drug therapy* / Q000556:secondary*; D016879:Salvage Therapy; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin