Phase I and Pharmacology study of Ropidoxuridine (IPdR) as prodrug for iododeoxyuridine-mediated tumor radiosensitization in advanced GI cancer undergoing radiation

Purpose: Iododeoxyuridine (IUdR) is a potent radiosensitizer, however, its clinical utility is limited by dose limiting systemic toxicities and the need for prolonged continuous infusion. 5-iodo-2-pyrimidinone-29-deoxyribose (IPdR) is an oral (PO) prodrug of IUdR that, compared to IUdR, is easier to administer and less toxic with a more favorable therapeutic index in preclinical studies. Here, we report the clinical and pharmacologic results of a first-in-human phase I dose escalation study of IPdR + concurrent radiation therapy (RT) in patients with advanced metastatic gastrointestinal (GI) cancers. Experimental Design: Adult patients with metastatic GI cancers referred for palliative RT to the chest, abdomen or pelvis were eligible for study. Patients received IPdR PO once daily (QD) x 28 days beginning seven days prior to the initiation of RT (37.5 Gy in 2.5Gy x 15 fractions). A two-part dose escalation scheme was used, pharmacokinetic studies were performed at multiple time points, and all patients were assessed for toxicity and response to Day 56. Results: Nineteen patients were entered on study. Dose limiting toxicity was encountered at 1800mg QD, and the recommended Phase II dose is 1200mg QD. Pharmacokinetic analyses demonstrated achievable and sustainable levels of plasma IUdR >1µM/L (levels previously shown to mediate radiosensitization). Two complete, three partial and 9 stable responses were achieved in target lesions. Conclusions: Administration of IPdR PO QD x 28 days with RT is feasible and tolerable at doses that produce plasma IUdR levels >1µM/L. These results support the investigation of IPdR + RT in phase II studies.