A phase I pharmacokinetic and pharmacodynamic study of SU5416 and Adriamycin in inflammatory breast cancer

B. Overmoyer, K. Robertson, M. Persons, R. Shenk, J. Lewin, J. Jesberger, N. Ziats, K. Tserng, C. Hoppel, P. Hartman, J. Wasman, F. Abdul-Karim, E. Newton, B. Cooper, C. Connell, J. Pluda, K. McCrae, S. Remick

Research output: Contribution to journalArticlepeer-review

Abstract

SU5416 is an anti-angiogenic molecule that inhibits VEGF-mediated signaling through Flk-1. This Phase I trial of SU5416 and Adriamycin (ADR) in stage IIIB/IV inflammatory breast cancer examines the toxicity of SU5416 and its in vivo effects via correlative studies performed pre-treatment, after 2 and 5 cycles. 15 patients (pts) have received dose-escalated SU5416 IV/1hr twice weekly for 15 wk, with dose-escalated ADR IVP q21 days for 5 cycles. All pts then undergo modified radical mastectomy (MRM) followed by XRT and TAM for ER/PR+ disease. Preliminary Results: 13 pts had gr 1 headache with the first administration of SU5416; 13 pts had gr 1-2 phlebitis. ADR 75 mg/m2 had 2 DLTs (neutropenia) and none with 60 mg/m2 (MTD). No pts progressed on therapy. Ten pts have undergone MRM. All breast specimens contained diffuse angiolymphatic invasion. Median of 9 lymph nodes were positive (range: 0-25). MR perfusion estimation demonstrated decreased tumor blood flow (Kep=efflux rate constant pre- vs post-Rx F=3.30, P=0.065). VEGF levels increased with therapy (mean: pre- 24.9 pg/ml, post- 41.3 pg/ml, P<0.01); levels of basic fibroblast growth factor (bFGF) varied. Tumor microvessel density (MVD) did not change (mean: pre-32.2, post-19.8, P= 0.106). PK analysis of SU5416 alone, vs SU5416 with ADR yielded a shorter t1/2β: 27.8 vs 19.9 min (P<0.01). This is due to a smaller Vd when ADR is added (16 vs 12.8 L/m2; P=0.04). Conclusions: SU5416 combined with ADR has an acceptable toxicity profile. Treatment is associated with a reduction in MR tumor blood flow and an increase in VEGF levels, but no change in bFGF levels or MVD.

Original languageEnglish (US)
Number of pages1
JournalBreast Cancer Research and Treatment
Volume69
Issue number3
StatePublished - Jan 1 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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