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

Propper, D. et al. (2003) 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, 21(2), pp. 203-210. (doi:10.1200/JCO.2003.02.008)

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Abstract

Purpose: 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. Patients and Methods: Twenty-four patients with advanced solid cancer were treated at seven dose levels (700 to 4,060 mg/m(2)/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 ([C-11]XR5000) pharmacokinetics. Results: 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/m(2)/120 hours, and the MTD was 3,010 mg/m(2)/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. [C-11]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 m(2)/mL/sec) increased when [C-11]XR5000 was administered during an infusion of XR5000 (0.403 +/- 0.1), compared with [C-11]XR5000 given alone (0.292 +/- 0.1; P < .05), indicating that tumor drug exposure was not saturated. Conclusion: The recommended dose for XR5000 in phase 11 studies is 3,010 mg/m(2)/120 hours. PET studies with 1 1 C-labeled drug were feasible and demonstrated in vivo distribution into tumors. Saturation of tumor exposure was not reached at the MTD.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Paul, Mr James
Authors: Propper, D., de Bono, J., Saleem, A., Ellard, S., Flanagan, E., Paul, J., Ganesan, T., Talbot, D., Aboagye, E., Price, P., Harris, A., and Twelves, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Clinical Oncology
ISSN:0732-183X

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