Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response

Nan Soon Wong, Robert A. Buckman, Mark Clemons, Shailendra Verma, Susan Dent, Maureen E. Trudeau, Kathie Roche, John Ebos, Robert Kerbel, Gerrit E. DeBoer, Donald J A Sutherland, Urban Emmenegger, Joyce M Slingerland, Sandra Gardner, Kathleen I. Pritchard

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Abstract

Purpose: Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). Patients and Methods: Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for ≥ 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results: Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. Conclusion: Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.

Original languageEnglish
Pages (from-to)723-730
Number of pages8
JournalJournal of Clinical Oncology
Volume28
Issue number5
DOIs
StatePublished - Feb 10 2010
Externally publishedYes

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Dalteparin
Vascular Endothelial Growth Factor Receptor
Prednisone
Methotrexate
Cyclophosphamide
Vascular Endothelial Growth Factor A
Breast Neoplasms
Drug Therapy
Therapeutics
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
Angiogenesis Inhibitors
Survival
Transaminases
Vomiting
Biomarkers
Safety
Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response. / Wong, Nan Soon; Buckman, Robert A.; Clemons, Mark; Verma, Shailendra; Dent, Susan; Trudeau, Maureen E.; Roche, Kathie; Ebos, John; Kerbel, Robert; DeBoer, Gerrit E.; Sutherland, Donald J A; Emmenegger, Urban; Slingerland, Joyce M; Gardner, Sandra; Pritchard, Kathleen I.

In: Journal of Clinical Oncology, Vol. 28, No. 5, 10.02.2010, p. 723-730.

Research output: Contribution to journalArticle

Wong, Nan Soon ; Buckman, Robert A. ; Clemons, Mark ; Verma, Shailendra ; Dent, Susan ; Trudeau, Maureen E. ; Roche, Kathie ; Ebos, John ; Kerbel, Robert ; DeBoer, Gerrit E. ; Sutherland, Donald J A ; Emmenegger, Urban ; Slingerland, Joyce M ; Gardner, Sandra ; Pritchard, Kathleen I. / Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 5. pp. 723-730.
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abstract = "Purpose: Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). Patients and Methods: Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for ≥ 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results: Forty-one eligible patients were accrued. Sixteen (39{\%}) had no prior chemotherapy for MBC; 15 (37{\%}) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27{\%}) and grade 3 vomiting in one patient (2{\%}). One patient (2{\%}) had CR, six (15{\%}) had PR, and three (7{\%}) had pSD, for a CBR of 10 (24{\%}) of 41 patients. Median TTP was 10 weeks (95{\%} CI, 8 to 17 weeks), and median OS was 48 weeks (95{\%} CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. Conclusion: Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.",
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T1 - Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response

AU - Wong, Nan Soon

AU - Buckman, Robert A.

AU - Clemons, Mark

AU - Verma, Shailendra

AU - Dent, Susan

AU - Trudeau, Maureen E.

AU - Roche, Kathie

AU - Ebos, John

AU - Kerbel, Robert

AU - DeBoer, Gerrit E.

AU - Sutherland, Donald J A

AU - Emmenegger, Urban

AU - Slingerland, Joyce M

AU - Gardner, Sandra

AU - Pritchard, Kathleen I.

PY - 2010/2/10

Y1 - 2010/2/10

N2 - Purpose: Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). Patients and Methods: Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for ≥ 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results: Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. Conclusion: Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.

AB - Purpose: Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). Patients and Methods: Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for ≥ 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results: Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. Conclusion: Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.

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