A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer

Kathy Miller, Jose Manuel Trigo, Catherine Wheeler, Alan Barge, Jacqui Rowbottom, George Sledge, Jose Baselga

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Abstract

Purpose: To determine the efficacy and safety of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase with additional activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously treated metastatic breast cancer, Patients and Methods: Eligible patients had histologicatly confirmed metastatic breast cancer and had received prior treatment with an anthracycline and taxane; measurable disease was required. Patients were enrolled sequentially into one of two dose cohorts, 100 or 300 mg orally once daily; 28 days defined one cycle. The primary end point was objective response rate; pharmacokinetics and serial pharmacodynamic studies were obtained. Results: Forty-six patients were enrolled between May 2002 and April 2003, and 44 were evaluable for response. Diarrhea was the most commonly reported toxicity and seemed dose related (grade ≥2: 4.5% and 37.5% in the 100 and 300 mg cohorts, respectively). Rash was reported by 26% of patients but was never worse than grade 2. Seven patients in the 300 mg cohort had asymptomatic grade 1 prolongation of the QTc interval. Hypertension requiring treatment was not reported. There were no objective responses; one patient in the 300 mg cohort had stable disease ≥24 weeks. All patients in the 300 mg cohort and 90% of patients in the 100 mg cohort achieved steady-state concentrations exceeding the IC50 for VEGF inhibition in preclinical models. Conclusion: ZD6474 monotherapy was generally well tolerated but had limited monotherapy activity in patients with refractory metastatic breast cancer.

Original languageEnglish
Pages (from-to)3369-3376
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number9
DOIs
StatePublished - May 1 2005

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Vascular Endothelial Growth Factor Receptor-2
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Breast Neoplasms
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
Anthracyclines
Exanthema
Vascular Endothelial Growth Factor A
Inhibitory Concentration 50
Diarrhea
Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. / Miller, Kathy; Trigo, Jose Manuel; Wheeler, Catherine; Barge, Alan; Rowbottom, Jacqui; Sledge, George; Baselga, Jose.

In: Clinical Cancer Research, Vol. 11, No. 9, 01.05.2005, p. 3369-3376.

Research output: Contribution to journalArticle

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abstract = "Purpose: To determine the efficacy and safety of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase with additional activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously treated metastatic breast cancer, Patients and Methods: Eligible patients had histologicatly confirmed metastatic breast cancer and had received prior treatment with an anthracycline and taxane; measurable disease was required. Patients were enrolled sequentially into one of two dose cohorts, 100 or 300 mg orally once daily; 28 days defined one cycle. The primary end point was objective response rate; pharmacokinetics and serial pharmacodynamic studies were obtained. Results: Forty-six patients were enrolled between May 2002 and April 2003, and 44 were evaluable for response. Diarrhea was the most commonly reported toxicity and seemed dose related (grade ≥2: 4.5{\%} and 37.5{\%} in the 100 and 300 mg cohorts, respectively). Rash was reported by 26{\%} of patients but was never worse than grade 2. Seven patients in the 300 mg cohort had asymptomatic grade 1 prolongation of the QTc interval. Hypertension requiring treatment was not reported. There were no objective responses; one patient in the 300 mg cohort had stable disease ≥24 weeks. All patients in the 300 mg cohort and 90{\%} of patients in the 100 mg cohort achieved steady-state concentrations exceeding the IC50 for VEGF inhibition in preclinical models. Conclusion: ZD6474 monotherapy was generally well tolerated but had limited monotherapy activity in patients with refractory metastatic breast cancer.",
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