Phase I trial of escalating doses of paclitaxel plus doxorubicin and dexrazoxane in patients with advanced breast cancer

Joseph A. Sparano, James Speyer, William J. Gradishar, Leonard Liebes, Rajeshwari Sridhara, Sandra Mendoza, David Fry, Merrill J. Egorin

Research output: Contribution to journalArticle

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Abstract

Purpose: To determine the maximum-tolerable dose (MTD) of paclitaxel given as a 3-hour intravenous (IV) infusion that could be used in conjunction with doxorubicin and dexrazoxane, and to determine the effect of dexrazoxane on the pharmacokinetics of paclitaxel and doxorubicin. Patients and Methods: Twenty-five patients with advanced breast cancer received dexrazoxane (600 mg/m2 by IV infusion over 15 minutes), followed 15 minutes later by doxorubicin (60 mg/m2 IV), followed 15 minutes later by paclitaxel (150 or 175 mg/m2 by IV infusion over 3 hours) in cohorts of three to six patients using a standard phase I design without (group A) and with (group B) granulocyte colony-stimulating factor (G-CSF). Treatment continued until there was a substantial decrease in the left ventricular ejection fraction (LVEF), congestive heart failure, progressive disease, or physician discretion to discontinue. Results: The MTD of paclitaxel was 150 mg/m2, and adjunctive therapy with G-CSF was required to prevent febrile neutropenia. Dexrazoxane had no significant effect on the pharmacokinetics of paclitaxel or doxorubicin. After a median cumulative doxorubicin dose of 360 mg/m2 (range, 60 to 870 mg/m2), no patient developed congestive heart failure or had a decrease in LVEF below normal. An objective response occurred in all five patients with locally advanced breast cancer and in eight of 20 patients (40%; 95% confidence interval, 19% to 61%) with metastatic breast cancer. Conclusion: When combined with doxorubicin (60 mg/m2) and dexrazoxane (600 mg/m2), paclitaxel given as a 3-hour infusion had an MTD of 150 mg/m2, and G-CSF was required to prevent febrile neutropenia. Dexrazoxane had no effect on the pharmacokinetics of paclitaxel or doxorubicin. No patient in this trial had a decrease in the LVEF below normal, compared with about 20% to 50% of patients treated with doxorubicin and paclitaxel without dexrazoxane in other trials.

Original languageEnglish (US)
Pages (from-to)880-886
Number of pages7
JournalJournal of Clinical Oncology
Volume17
Issue number3
StatePublished - Mar 1999

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Dexrazoxane
Paclitaxel
Doxorubicin
Breast Neoplasms
Granulocyte Colony-Stimulating Factor
Intravenous Infusions
Stroke Volume
Febrile Neutropenia
Pharmacokinetics
Heart Failure
Confidence Intervals
Physicians

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sparano, J. A., Speyer, J., Gradishar, W. J., Liebes, L., Sridhara, R., Mendoza, S., ... Egorin, M. J. (1999). Phase I trial of escalating doses of paclitaxel plus doxorubicin and dexrazoxane in patients with advanced breast cancer. Journal of Clinical Oncology, 17(3), 880-886.

Phase I trial of escalating doses of paclitaxel plus doxorubicin and dexrazoxane in patients with advanced breast cancer. / Sparano, Joseph A.; Speyer, James; Gradishar, William J.; Liebes, Leonard; Sridhara, Rajeshwari; Mendoza, Sandra; Fry, David; Egorin, Merrill J.

In: Journal of Clinical Oncology, Vol. 17, No. 3, 03.1999, p. 880-886.

Research output: Contribution to journalArticle

Sparano, JA, Speyer, J, Gradishar, WJ, Liebes, L, Sridhara, R, Mendoza, S, Fry, D & Egorin, MJ 1999, 'Phase I trial of escalating doses of paclitaxel plus doxorubicin and dexrazoxane in patients with advanced breast cancer', Journal of Clinical Oncology, vol. 17, no. 3, pp. 880-886.
Sparano, Joseph A. ; Speyer, James ; Gradishar, William J. ; Liebes, Leonard ; Sridhara, Rajeshwari ; Mendoza, Sandra ; Fry, David ; Egorin, Merrill J. / Phase I trial of escalating doses of paclitaxel plus doxorubicin and dexrazoxane in patients with advanced breast cancer. In: Journal of Clinical Oncology. 1999 ; Vol. 17, No. 3. pp. 880-886.
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abstract = "Purpose: To determine the maximum-tolerable dose (MTD) of paclitaxel given as a 3-hour intravenous (IV) infusion that could be used in conjunction with doxorubicin and dexrazoxane, and to determine the effect of dexrazoxane on the pharmacokinetics of paclitaxel and doxorubicin. Patients and Methods: Twenty-five patients with advanced breast cancer received dexrazoxane (600 mg/m2 by IV infusion over 15 minutes), followed 15 minutes later by doxorubicin (60 mg/m2 IV), followed 15 minutes later by paclitaxel (150 or 175 mg/m2 by IV infusion over 3 hours) in cohorts of three to six patients using a standard phase I design without (group A) and with (group B) granulocyte colony-stimulating factor (G-CSF). Treatment continued until there was a substantial decrease in the left ventricular ejection fraction (LVEF), congestive heart failure, progressive disease, or physician discretion to discontinue. Results: The MTD of paclitaxel was 150 mg/m2, and adjunctive therapy with G-CSF was required to prevent febrile neutropenia. Dexrazoxane had no significant effect on the pharmacokinetics of paclitaxel or doxorubicin. After a median cumulative doxorubicin dose of 360 mg/m2 (range, 60 to 870 mg/m2), no patient developed congestive heart failure or had a decrease in LVEF below normal. An objective response occurred in all five patients with locally advanced breast cancer and in eight of 20 patients (40{\%}; 95{\%} confidence interval, 19{\%} to 61{\%}) with metastatic breast cancer. Conclusion: When combined with doxorubicin (60 mg/m2) and dexrazoxane (600 mg/m2), paclitaxel given as a 3-hour infusion had an MTD of 150 mg/m2, and G-CSF was required to prevent febrile neutropenia. Dexrazoxane had no effect on the pharmacokinetics of paclitaxel or doxorubicin. No patient in this trial had a decrease in the LVEF below normal, compared with about 20{\%} to 50{\%} of patients treated with doxorubicin and paclitaxel without dexrazoxane in other trials.",
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AU - Liebes, Leonard

AU - Sridhara, Rajeshwari

AU - Mendoza, Sandra

AU - Fry, David

AU - Egorin, Merrill J.

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