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.
OBJECTIVE
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.


METHODS
Eligible patients had histologically 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 IC(50) for VEGF inhibition in preclinical models.


CONCLUSIONS
ZD6474 monotherapy was generally well tolerated but had limited monotherapy activity in patients with refractory metastatic breast cancer.
Miller
Kathy D
KD
Indiana University, Indianapolis, Indiana 46202, USA. kathmill@iupui.edu
Trigo
Jose Manuel
JM
Wheeler
Catherine
C
Barge
Alan
A
Rowbottom
Jacqui
J
Sledge
George
G
Baselga
Jose
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009362:Neoplasm Metastasis; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D018943:Anthracyclines; D001952:Bridged-Ring Compounds; D010880:Piperidines; D011799:Quinazolines; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; C080625:taxane; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib