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.

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/m(2)) 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/m(2), 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/m(2) 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 IC(50) 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/m(2) exceeded active levels in preclinical models. This dose was chosen for future studies with radiotherapy.