Annals of Oncology Advance Access originally published online on April 17, 2007
Annals of Oncology 2007 18(6):1098-1103; doi:10.1093/annonc/mdm120
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© 2007 European Society for Medical Oncology
phase I and pharmacokinetics |
The use of pharmacokinetic and pharmacodynamic end points to determine the dose of AQ4N, a novel hypoxic cell cytotoxin, given with fractionated radiotherapy in a phase I study
1 Department of Oncology, Leicester Royal Infirmary, Leicester
2 Department of Oncology, Churchill Hospital, Oxford
3 University of Bradford, Bradford
4 Cancer Research UK, Drug Development Office, London
5 Cancer Research UK, Formulation Unit, Strathclyde University, Glasgow, UK
* Correspondence to: Prof. W. P. Steward, Department of Oncology, 2nd Floor, Osborne Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK. Tel: +44 0116-258-7597; Fax: +44 0116-258-7599; E-mail: wps1{at}le.ac.uk
Background: AQ4N (1,4-bis[[2-(dimethylamino)ethyl] amino]-5,8-dihydroxyanthracene-9, 10-dione bis-N-oxide dihydrochloride) is a prodrug which is selectively activated within hypoxic tissues to AQ4, a topoisomerase II inhibitor and DNA intercalator.
Patients and methods: In the phase I study, 22 patients with oesophageal carcinoma received an i.v. infusion of AQ4N (22.5–447 mg/m2) followed, 2 weeks later, by further infusion and radiotherapy. Pharmacokinetics and lymphocyte AQ4N and AQ4 levels were measured after the first dose. At 447 mg/m2, biopsies of tumour and normal tissue were taken after AQ4N administration.
Results: Drug-related adverse events were blue discolouration of skin and urine, grade 2–3 lymphopenia, grade 1–3 fatigue, grade 1–2 anaemia, leucopenia and nausea. There were no drug-related serious adverse events (SAEs). Three patients had reductions in tumour volume >50%, nine had stable disease. Pharmacokinetics indicated predictable clearance. Plasma area under the curve (AUC) at 447 mg/m2 exceeded AQ4N concentrations in mice at therapeutic doses and tumour biopsies contained concentrations of AQ4 greater than those in normal tissue. Tumour concentrations of AQ4 exceeded in vitro IC50 values for most cell lines investigated.
Conclusions: No dose-limiting toxic effects were observed and a maximum tolerated dose was not established. Tumour AQ4 concentrations and plasma AUC at 447 mg/m2 exceeded active levels in preclinical models. This dose was chosen for future studies with radiotherapy.
Key words: AQ4N, bioreductive, pharmacodynamics, pharmacokinetics, phase I study
Received for publication January 21, 2007. Revision received February 28, 2007. Accepted for publication March 1, 2007.
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