Phase II and Pharmacological Study of Oral Docetaxel Plus Cyclosporin A in Anthracycline Pre-Treated Metastatic Breast Cancer
Helgi H. Helgason, Stijn L.W. Koolen, Erik van Werkhoven, Mirte M. Malingre, C. Marielle F. Kruijtzer, Alwin D.R. Huitema, Margaret E. Schot, Wim M. Smit, Jos H. Beijnen and Jan H.M. Schellens
Affiliation: Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Introduction: Previously, we demonstrated that oral docetaxel plus the P-glycoprotein (Pgp; ABCB1) inhibitor
cyclosporin A (CsA) is safe and results in adequate exposure to docetaxel. This phase II study evaluates the anti-tumor
activity, safety and pharmacokinetics of oral docetaxel in combination with CsA in women with advanced breast cancer.
Materials and Methods: Patients with measurable advanced breast cancer were given one flat dose of 100 mg oral
docetaxel, preceded by one single dose of 15 mg/kg CsA, weekly for 6 weeks in a cycle of 8 weeks. Pharmacokinetic
monitoring of docetaxel and CsA was performed in week 1 and 9.
Results: Thirty-three patients with a median age of 50 years were recruited. Thirty patients were evaluable for toxicity and
twenty-six for response. All had received prior anthracycline treatment. The treatment was generally well tolerated with
manageable toxicity although many patients needed a dose reduction, most commonly because of fatigue and
uncomplicated neutropenia. The median treatment duration was 16 weeks (range 6 – 32). The overall response rate in
evaluable patients was 42% (95% CI: 23 – 63) and the median overall survival was 12.2 months (8.4 – 23.1). The interpatient
variability in the area under the curve of 100 mg orally administered docetaxel was moderate, respectively 49 and
30% in week 1 and 9.
Conclusion: Weekly oral docetaxel, combined with the booster drug CsA, is an active and safe treatment in anthracycline
pre-treated patients with advanced breast cancer.
Keywords: Anti-tumor activity, cyclosporin A, oral docetaxel, P-glycoprotein, phase II, safety.
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