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      Use of positron emission tomography in pharmacokinetic studies to investigate therapeutic advantage in a phase I study of 120-hour intravenous infusion XR5000.

      Journal of clinical oncology : official journal of the American Society of Clinical Oncology

      Dose-Response Relationship, Drug, Acridines, administration & dosage, adverse effects, pharmacokinetics, Adult, Aged, Area Under Curve, Carbon Radioisotopes, diagnostic use, Female, Humans, Infusions, Intravenous, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms, drug therapy, metabolism, radionuclide imaging, Tissue Distribution, Tomography, Emission-Computed

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          XR5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) is a topoisomerase I and II inhibitor. Because the cytotoxicity of XR5000 increases markedly with prolonged exposure, we performed a phase I study of weekly XR5000 by 120-hour continuous infusion over 3 weeks. Twenty-four patients with advanced solid cancer were treated at seven dose levels (700 to 4,060 mg/m2/120 hrs) for a total of 67 cycles. Three patients underwent positron emission tomography (PET) studies at the maximum-tolerated dose (MTD) to evaluate normal tissue and tumor carbon-11 radiolabeled XR5000 ([11C]XR5000) pharmacokinetics. The dose-limiting toxicity was National Cancer Institute Common Toxicity Criteria (version 1) grade 4 chest and abdominal pain affecting the single patient receiving 4,060 mg/m2/120 hours, and the MTD was 3,010 mg/m2/120 hours. Other grade 3-4 toxicities, affecting single patients at the MTD, were myelosuppression (grade 4), raised bilirubin, vomiting, and somnolence (all grade 3). There was one partial response (adenocarcinoma of unknown primary); the remainder had progressive disease. [11C]XR5000 distributed well into the three tumors studied by PET. Tumor uptake (maximum concentration or area under the concentration versus time curve [AUC]) was less than in normal tissue in which the tumors were located. Tumor exposure (AUC; mean +/- SD in m2/mL/sec) increased when [(11)C]XR5000 was administered during an infusion of XR5000 (0.242 +/- 0.4), compared with [11C]XR5000 given alone (0.209 +/- 0.04; P <.05), indicating that tumor drug exposure was not saturated [corrected]. The recommended dose for XR5000 in phase II studies is 3,010 mg/m2/120 hours. PET studies with 11C-labeled drug were feasible and demonstrated in vivo distribution into tumors. Saturation of tumor exposure was not reached at the MTD.

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