Phase I trial of high-dose mitoxantrone plus cyclophosphamide and filgrastim in patients with advanced breast carcinoma

Joseph A. Sparano, N. Robert, P. Silverman, H. Lazarus, U. Malik, U. Venkatraj, C. Sarta

Research output: Contribution to journalArticle

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Abstract

Purpose: To determine the maximum-tolerated dose (MTD) of mitoxantrone that could be safely used in combination with cyclophosphamide and filgrastim in patients with advanced breast carcinoma. Patients and Methods: Twenty- seven patients with metastatic (n = 24) or locally advanced (n = 3) breast carcinoma received escalating doses of mitoxantrane (16, 20, 24, 28, or 32 mg/m2) plus cyclaphasphamide at one of three dose levels: group 1, 1,200 mg/m2; group 2, 2,400 mg/m2; and group 3, 600 mg/m2. All patients also received filgrastim 5 μg/kg administered subcutaneously beginning on day 2 and continuing until the postnadir absolute neutrophil count (ANC) was ≤ 10,000/μL. Treatment was repeated every 3 weeks if the ANC was ≤ 2,000/μL and platelet count ≤ 90,000/μL for a maximum of six cycles. Dose escalation occurred within each group if zero of three or one of four patients had dose- limiting toxicity during the first cycle. Results: The MTD of mitoxantrone was 24 mg/m2 in group 1, less than 16 mg/m2 in group 2, and 28 mg/m2 in group 3. Neutropenia was dose-limiting, and cumulative neutropenia and thrombocytopenia occurred with continued therapy. Nonhematalogic toxicity consisted predominantly of nausea, vomiting, alopecia, and fatigue. Three patients (11%) had a ≤ 10% decrease in the left ventricular ejection fraction (LVEF), one patient (4%) had a decrease in the LVEF below normal, and none developed clinical congestive heart failure. Of patients with stage IV breast carcinoma who had nat received prior chemotherapy for advanced disease, objective responses occurred in nine of 20 (45%), and the median response duration was 5 months. Conclusion: Incombination with 600 mg/m2 of cyclophosphamide and filgrastim, the MTD of mitoxantrone is 28 mg/m2, a dose that is approximately twofold to 2.8-fold higher than the conventional dose used without a hematopoietic growth factor.

Original languageEnglish (US)
Pages (from-to)2576-2583
Number of pages8
JournalJournal of Clinical Oncology
Volume14
Issue number9
StatePublished - 1996

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Mitoxantrone
Cyclophosphamide
Breast Neoplasms
Maximum Tolerated Dose
Neutropenia
Stroke Volume
Neutrophils
Filgrastim
Alopecia
Platelet Count
Thrombocytopenia
Nausea
Vomiting
Fatigue
Intercellular Signaling Peptides and Proteins
Heart Failure
Drug Therapy
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sparano, J. A., Robert, N., Silverman, P., Lazarus, H., Malik, U., Venkatraj, U., & Sarta, C. (1996). Phase I trial of high-dose mitoxantrone plus cyclophosphamide and filgrastim in patients with advanced breast carcinoma. Journal of Clinical Oncology, 14(9), 2576-2583.

Phase I trial of high-dose mitoxantrone plus cyclophosphamide and filgrastim in patients with advanced breast carcinoma. / Sparano, Joseph A.; Robert, N.; Silverman, P.; Lazarus, H.; Malik, U.; Venkatraj, U.; Sarta, C.

In: Journal of Clinical Oncology, Vol. 14, No. 9, 1996, p. 2576-2583.

Research output: Contribution to journalArticle

Sparano, JA, Robert, N, Silverman, P, Lazarus, H, Malik, U, Venkatraj, U & Sarta, C 1996, 'Phase I trial of high-dose mitoxantrone plus cyclophosphamide and filgrastim in patients with advanced breast carcinoma', Journal of Clinical Oncology, vol. 14, no. 9, pp. 2576-2583.
Sparano, Joseph A. ; Robert, N. ; Silverman, P. ; Lazarus, H. ; Malik, U. ; Venkatraj, U. ; Sarta, C. / Phase I trial of high-dose mitoxantrone plus cyclophosphamide and filgrastim in patients with advanced breast carcinoma. In: Journal of Clinical Oncology. 1996 ; Vol. 14, No. 9. pp. 2576-2583.
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abstract = "Purpose: To determine the maximum-tolerated dose (MTD) of mitoxantrone that could be safely used in combination with cyclophosphamide and filgrastim in patients with advanced breast carcinoma. Patients and Methods: Twenty- seven patients with metastatic (n = 24) or locally advanced (n = 3) breast carcinoma received escalating doses of mitoxantrane (16, 20, 24, 28, or 32 mg/m2) plus cyclaphasphamide at one of three dose levels: group 1, 1,200 mg/m2; group 2, 2,400 mg/m2; and group 3, 600 mg/m2. All patients also received filgrastim 5 μg/kg administered subcutaneously beginning on day 2 and continuing until the postnadir absolute neutrophil count (ANC) was ≤ 10,000/μL. Treatment was repeated every 3 weeks if the ANC was ≤ 2,000/μL and platelet count ≤ 90,000/μL for a maximum of six cycles. Dose escalation occurred within each group if zero of three or one of four patients had dose- limiting toxicity during the first cycle. Results: The MTD of mitoxantrone was 24 mg/m2 in group 1, less than 16 mg/m2 in group 2, and 28 mg/m2 in group 3. Neutropenia was dose-limiting, and cumulative neutropenia and thrombocytopenia occurred with continued therapy. Nonhematalogic toxicity consisted predominantly of nausea, vomiting, alopecia, and fatigue. Three patients (11{\%}) had a ≤ 10{\%} decrease in the left ventricular ejection fraction (LVEF), one patient (4{\%}) had a decrease in the LVEF below normal, and none developed clinical congestive heart failure. Of patients with stage IV breast carcinoma who had nat received prior chemotherapy for advanced disease, objective responses occurred in nine of 20 (45{\%}), and the median response duration was 5 months. Conclusion: Incombination with 600 mg/m2 of cyclophosphamide and filgrastim, the MTD of mitoxantrone is 28 mg/m2, a dose that is approximately twofold to 2.8-fold higher than the conventional dose used without a hematopoietic growth factor.",
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T1 - Phase I trial of high-dose mitoxantrone plus cyclophosphamide and filgrastim in patients with advanced breast carcinoma

AU - Sparano, Joseph A.

AU - Robert, N.

AU - Silverman, P.

AU - Lazarus, H.

AU - Malik, U.

AU - Venkatraj, U.

AU - Sarta, C.

PY - 1996

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N2 - Purpose: To determine the maximum-tolerated dose (MTD) of mitoxantrone that could be safely used in combination with cyclophosphamide and filgrastim in patients with advanced breast carcinoma. Patients and Methods: Twenty- seven patients with metastatic (n = 24) or locally advanced (n = 3) breast carcinoma received escalating doses of mitoxantrane (16, 20, 24, 28, or 32 mg/m2) plus cyclaphasphamide at one of three dose levels: group 1, 1,200 mg/m2; group 2, 2,400 mg/m2; and group 3, 600 mg/m2. All patients also received filgrastim 5 μg/kg administered subcutaneously beginning on day 2 and continuing until the postnadir absolute neutrophil count (ANC) was ≤ 10,000/μL. Treatment was repeated every 3 weeks if the ANC was ≤ 2,000/μL and platelet count ≤ 90,000/μL for a maximum of six cycles. Dose escalation occurred within each group if zero of three or one of four patients had dose- limiting toxicity during the first cycle. Results: The MTD of mitoxantrone was 24 mg/m2 in group 1, less than 16 mg/m2 in group 2, and 28 mg/m2 in group 3. Neutropenia was dose-limiting, and cumulative neutropenia and thrombocytopenia occurred with continued therapy. Nonhematalogic toxicity consisted predominantly of nausea, vomiting, alopecia, and fatigue. Three patients (11%) had a ≤ 10% decrease in the left ventricular ejection fraction (LVEF), one patient (4%) had a decrease in the LVEF below normal, and none developed clinical congestive heart failure. Of patients with stage IV breast carcinoma who had nat received prior chemotherapy for advanced disease, objective responses occurred in nine of 20 (45%), and the median response duration was 5 months. Conclusion: Incombination with 600 mg/m2 of cyclophosphamide and filgrastim, the MTD of mitoxantrone is 28 mg/m2, a dose that is approximately twofold to 2.8-fold higher than the conventional dose used without a hematopoietic growth factor.

AB - Purpose: To determine the maximum-tolerated dose (MTD) of mitoxantrone that could be safely used in combination with cyclophosphamide and filgrastim in patients with advanced breast carcinoma. Patients and Methods: Twenty- seven patients with metastatic (n = 24) or locally advanced (n = 3) breast carcinoma received escalating doses of mitoxantrane (16, 20, 24, 28, or 32 mg/m2) plus cyclaphasphamide at one of three dose levels: group 1, 1,200 mg/m2; group 2, 2,400 mg/m2; and group 3, 600 mg/m2. All patients also received filgrastim 5 μg/kg administered subcutaneously beginning on day 2 and continuing until the postnadir absolute neutrophil count (ANC) was ≤ 10,000/μL. Treatment was repeated every 3 weeks if the ANC was ≤ 2,000/μL and platelet count ≤ 90,000/μL for a maximum of six cycles. Dose escalation occurred within each group if zero of three or one of four patients had dose- limiting toxicity during the first cycle. Results: The MTD of mitoxantrone was 24 mg/m2 in group 1, less than 16 mg/m2 in group 2, and 28 mg/m2 in group 3. Neutropenia was dose-limiting, and cumulative neutropenia and thrombocytopenia occurred with continued therapy. Nonhematalogic toxicity consisted predominantly of nausea, vomiting, alopecia, and fatigue. Three patients (11%) had a ≤ 10% decrease in the left ventricular ejection fraction (LVEF), one patient (4%) had a decrease in the LVEF below normal, and none developed clinical congestive heart failure. Of patients with stage IV breast carcinoma who had nat received prior chemotherapy for advanced disease, objective responses occurred in nine of 20 (45%), and the median response duration was 5 months. Conclusion: Incombination with 600 mg/m2 of cyclophosphamide and filgrastim, the MTD of mitoxantrone is 28 mg/m2, a dose that is approximately twofold to 2.8-fold higher than the conventional dose used without a hematopoietic growth factor.

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