Inflammatory breast cancer as a model disease to study tumor angiogenesis: Results of a phase IB trial of combination SU54 16 and doxorubicin

Beth Overmoyer, Pingfu Fu, Charles Hoppel, Tomas Radivoyevitch, Robert Shenk, Marjie Persons, Paula Silverman, Kelly Robertson, Nicholas P. Ziats, Jay K. Wasman, Fadi W. Abdul-Karim, John A. Jesberger, Jeffrey Duerk, Paul Hartman, Shelli Hanks, Jonathan Lewin, Afshin Dowlati, Keith McCrae, Percy Ivy, Scot C. Remick

Research output: Contribution to journalArticle

Abstract

Purpose: We used inflammatory breast cancer (IBC) as amodel disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin. Experimental Design: Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 andd oxorubicin for induction therapy. The dose of SU5416 (administered on days 1and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalatedin cohorts of three patients starting at 110 and 60 mg/m2, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy. Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached( 50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher Cmax of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival. Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.

Original languageEnglish (US)
Pages (from-to)5862-5868
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number19
DOIs
StatePublished - Oct 1 2007

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Inflammatory Breast Neoplasms
Doxorubicin
Mastectomy
Neoplasms
Angiogenesis Inhibitors
Microvessels
Plasma Cells
Neutropenia
Disease-Free Survival
Research Design
Therapeutics
Endothelial Cells
Heart Failure
Pharmacokinetics
Magnetic Resonance Imaging
Semaxinib
Breast Neoplasms
Biopsy
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Inflammatory breast cancer as a model disease to study tumor angiogenesis : Results of a phase IB trial of combination SU54 16 and doxorubicin. / Overmoyer, Beth; Fu, Pingfu; Hoppel, Charles; Radivoyevitch, Tomas; Shenk, Robert; Persons, Marjie; Silverman, Paula; Robertson, Kelly; Ziats, Nicholas P.; Wasman, Jay K.; Abdul-Karim, Fadi W.; Jesberger, John A.; Duerk, Jeffrey; Hartman, Paul; Hanks, Shelli; Lewin, Jonathan; Dowlati, Afshin; McCrae, Keith; Ivy, Percy; Remick, Scot C.

In: Clinical Cancer Research, Vol. 13, No. 19, 01.10.2007, p. 5862-5868.

Research output: Contribution to journalArticle

Overmoyer, B, Fu, P, Hoppel, C, Radivoyevitch, T, Shenk, R, Persons, M, Silverman, P, Robertson, K, Ziats, NP, Wasman, JK, Abdul-Karim, FW, Jesberger, JA, Duerk, J, Hartman, P, Hanks, S, Lewin, J, Dowlati, A, McCrae, K, Ivy, P & Remick, SC 2007, 'Inflammatory breast cancer as a model disease to study tumor angiogenesis: Results of a phase IB trial of combination SU54 16 and doxorubicin', Clinical Cancer Research, vol. 13, no. 19, pp. 5862-5868. https://doi.org/10.1158/1078-0432.CCR-07-0688
Overmoyer, Beth ; Fu, Pingfu ; Hoppel, Charles ; Radivoyevitch, Tomas ; Shenk, Robert ; Persons, Marjie ; Silverman, Paula ; Robertson, Kelly ; Ziats, Nicholas P. ; Wasman, Jay K. ; Abdul-Karim, Fadi W. ; Jesberger, John A. ; Duerk, Jeffrey ; Hartman, Paul ; Hanks, Shelli ; Lewin, Jonathan ; Dowlati, Afshin ; McCrae, Keith ; Ivy, Percy ; Remick, Scot C. / Inflammatory breast cancer as a model disease to study tumor angiogenesis : Results of a phase IB trial of combination SU54 16 and doxorubicin. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 19. pp. 5862-5868.
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abstract = "Purpose: We used inflammatory breast cancer (IBC) as amodel disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin. Experimental Design: Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 andd oxorubicin for induction therapy. The dose of SU5416 (administered on days 1and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalatedin cohorts of three patients starting at 110 and 60 mg/m2, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy. Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached( 50 months of study follow-up). Four patients (22{\%}) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher Cmax of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival. Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.",
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T1 - Inflammatory breast cancer as a model disease to study tumor angiogenesis

T2 - Results of a phase IB trial of combination SU54 16 and doxorubicin

AU - Overmoyer, Beth

AU - Fu, Pingfu

AU - Hoppel, Charles

AU - Radivoyevitch, Tomas

AU - Shenk, Robert

AU - Persons, Marjie

AU - Silverman, Paula

AU - Robertson, Kelly

AU - Ziats, Nicholas P.

AU - Wasman, Jay K.

AU - Abdul-Karim, Fadi W.

AU - Jesberger, John A.

AU - Duerk, Jeffrey

AU - Hartman, Paul

AU - Hanks, Shelli

AU - Lewin, Jonathan

AU - Dowlati, Afshin

AU - McCrae, Keith

AU - Ivy, Percy

AU - Remick, Scot C.

PY - 2007/10/1

Y1 - 2007/10/1

N2 - Purpose: We used inflammatory breast cancer (IBC) as amodel disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin. Experimental Design: Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 andd oxorubicin for induction therapy. The dose of SU5416 (administered on days 1and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalatedin cohorts of three patients starting at 110 and 60 mg/m2, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy. Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached( 50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher Cmax of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival. Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.

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