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

Caroline Laverdiere, E. Anders Kolb, Jeffrey G. Supko, Richard Gorlick, Paul A. Meyers, Robert G. Maki, Leonard Wexler, George D. Demetri, John H. Healey, Andrew G. Huvos, Allen M. Goorin, Rochelle Bagatell, Ana Ruiz-Casado, Cecilia Guzman, Jose Jimeno, David Harmon

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)832-840
Number of pages9
JournalCancer
Volume98
Issue number4
DOIs
StatePublished - Aug 15 2003
Externally publishedYes

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Osteosarcoma
Pharmacokinetics

Keywords

  • Ecteinascidin-743 (ET-743)
  • Osteosarcoma
  • Phase II study
  • Sarcoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Laverdiere, C., Kolb, E. A., Supko, J. G., Gorlick, R., Meyers, P. A., Maki, R. G., ... Harmon, D. (2003). Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer, 98(4), 832-840. https://doi.org/10.1002/cncr.11563

Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. / Laverdiere, Caroline; Kolb, E. Anders; Supko, Jeffrey G.; Gorlick, Richard; Meyers, Paul A.; Maki, Robert G.; Wexler, Leonard; Demetri, George D.; Healey, John H.; Huvos, Andrew G.; Goorin, Allen M.; Bagatell, Rochelle; Ruiz-Casado, Ana; Guzman, Cecilia; Jimeno, Jose; Harmon, David.

In: Cancer, Vol. 98, No. 4, 15.08.2003, p. 832-840.

Research output: Contribution to journalArticle

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 2003, 'Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma', Cancer, vol. 98, no. 4, pp. 832-840. https://doi.org/10.1002/cncr.11563
Laverdiere C, Kolb EA, Supko JG, Gorlick R, Meyers PA, Maki RG et al. Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer. 2003 Aug 15;98(4):832-840. https://doi.org/10.1002/cncr.11563
Laverdiere, Caroline ; Kolb, E. Anders ; Supko, Jeffrey G. ; Gorlick, Richard ; Meyers, Paul A. ; Maki, Robert G. ; Wexler, Leonard ; Demetri, George D. ; Healey, John H. ; Huvos, Andrew G. ; Goorin, Allen M. ; Bagatell, Rochelle ; Ruiz-Casado, Ana ; Guzman, Cecilia ; Jimeno, Jose ; Harmon, David. / Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. In: Cancer. 2003 ; Vol. 98, No. 4. pp. 832-840.
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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.",
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author = "Caroline Laverdiere and Kolb, {E. Anders} and Supko, {Jeffrey G.} and Richard Gorlick and Meyers, {Paul A.} and Maki, {Robert G.} and Leonard Wexler and Demetri, {George D.} and Healey, {John H.} and Huvos, {Andrew G.} and Goorin, {Allen M.} and Rochelle Bagatell and Ana Ruiz-Casado and Cecilia Guzman and Jose Jimeno and David Harmon",
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T1 - Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma

AU - Laverdiere, Caroline

AU - Kolb, E. Anders

AU - Supko, Jeffrey G.

AU - Gorlick, Richard

AU - Meyers, Paul A.

AU - Maki, Robert G.

AU - Wexler, Leonard

AU - Demetri, George D.

AU - Healey, John H.

AU - Huvos, Andrew G.

AU - Goorin, Allen M.

AU - Bagatell, Rochelle

AU - Ruiz-Casado, Ana

AU - Guzman, Cecilia

AU - Jimeno, Jose

AU - Harmon, David

PY - 2003/8/15

Y1 - 2003/8/15

N2 - 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.

AB - 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.

KW - Ecteinascidin-743 (ET-743)

KW - Osteosarcoma

KW - Phase II study

KW - Sarcoma

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