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

  1. Caroline Laverdiere M.D.1,
  2. E. Anders Kolb M.D.1,
  3. Jeffrey G. Supko Ph.D.2,
  4. Richard Gorlick M.D.1,†,*,
  5. Paul A. Meyers M.D.1,
  6. Robert G. Maki M.D.3,‡,
  7. Leonard Wexler M.D.1,
  8. George D. Demetri M.D.2,§,
  9. John H. Healey M.D.4,
  10. Andrew G. Huvos M.D.5,
  11. Allen M. Goorin M.D.2,
  12. Rochelle Bagatell M.D.6,
  13. Ana Ruiz-Casado M.D.7,¶,
  14. Cecilia Guzman M.D.7,‖,
  15. Jose Jimeno M.D.7,††,
  16. David Harmon M.D.2

Article first published online: 12 JUN 2003

DOI: 10.1002/cncr.11563

Issue

Cancer

Cancer

Volume 98, Issue 4, pages 832–840, 15 August 2003

Additional Information

How to Cite

Laverdiere, C., Kolb, E. A., Supko, J. G., Gorlick, R., Meyers, P. A., Maki, R. G., Wexler, L., Demetri, G. D., Healey, J. H., Huvos, A. G., Goorin, A. M., Bagatell, R., Ruiz-Casado, A., Guzman, C., Jimeno, J. and Harmon, D. (2003), Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer, 98: 832–840. doi: 10.1002/cncr.11563

Author Information

  1. 1

    Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York

  2. 2

    Division of Hematology Oncology, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts

  3. 3

    Division of Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

  4. 4

    Division of Orthopedic Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

  5. 5

    Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York

  6. 6

    Department of Pediatrics, University of Arizona Health Sciences Center, Tucson, Arizona

  7. 7

    PharmaMar S. A., Tres Cantos, Spain

  1. †

    Fax: (212) 717-3239

  2. ‡

    Robert G. Maki, M.D., received funding to research studies from PharmaMar, Inc. and the National Cancer Institute (NCI Program Project Grant P01-CA47179).

  3. §

    George D. Demetri, M.D., received support for research and consulting (within acceptable Harvard conflict of interest rules) from corporate entities that currently are developing ET-743 (PharmaMar and Johnson & Johnson).

  4. Ana Ruiz-Casado, M.D., is employed as a medical oncologist for PharmaMar S. A.

  5. ‖

    Cecilia Guzman, M.D., was a full-time employee of PharmaMar S. A. during the course of the current study.

  6. ††

    Jose Jimeno, M.D., is Vice President of Scientific Development for PharmaMar S. A. and is a stockholder in the company.

*Department of Pediatrics, Howard Building 11th Floor, Room 1110, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

Publication History

  1. Issue published online: 1 AUG 2003
  2. Article first published online: 12 JUN 2003
  3. Manuscript Accepted: 5 MAY 2003
  4. Manuscript Revised: 29 APR 2003
  5. Manuscript Received: 25 FEB 2003

Funded by

  • PharmaMar S. A., Tres Cantos, Spain

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Keywords:

  • ecteinascidin-743 (ET-743);
  • osteosarcoma;
  • sarcoma;
  • Phase II study

Abstract

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

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