Phase I and Pharmacology Study of Ropidoxuridine (IPdR) as Prodrug for Iododeoxyuridine-Mediated Tumor Radiosensitization in Advanced GI Cancer Undergoing Radiation

  • Clin Cancer Res. 2019 Oct 15;25(20):6035-6043. doi: 10.1158/1078-0432.CCR-19-0862.
Timothy Kinsella  1  2 ,  Howard Safran  3 ,  Susan Wiersma  2 ,  Thomas DiPetrillo  3 ,  Andrew Schumacher  4 ,  Kayla Rosati  3 ,  John Vatkevich  4 ,  Lawrence W Anderson  5 ,  Kimberly D Hill  6 ,  Charles Kunos  7 ,  Jerry M Collins  5
Affiliations
  • 1. Brown University Oncology Group (BrUOG), Providence, Rhode Island. [email protected].
  • 2. EMEK, Inc., Warwick, Rhode Island.
  • 3. Brown University Oncology Group (BrUOG), Providence, Rhode Island.
  • 4. Lifespan Cancer Institute, Providence, Rhode Island.
  • 5. Developmental Therapeutics Program (DTP), NCI, Bethesda, Maryland.
  • 6. Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
  • 7. Cancer Therapy Evaluation Program (CTEP), NCI, Bethesda, Maryland.
PMID: 31337643 DOI: 10.1158/1078-0432.CCR-19-0862
Abstract

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-2'-deoxyribose (IPdR) is an oral prodrug of IUdR that, compared with 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.

Patients and methods: Adult patients with metastatic GI cancers referred for palliative RT to the chest, abdomen, or pelvis were eligible for study. Patients received IPdR orally once every day × 28 days beginning 7 days before the initiation of RT (37.5 Gy in 2.5 Gy × 15 fractions). A 2-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 1,800 mg every day, and the recommended phase II dose is 1,200 mg every day. Pharmacokinetic analyses demonstrated achievable and sustainable levels of plasma IUdR ≥1 μmol/L (levels previously shown to mediate radiosensitization). Two complete, 3 partial, and 9 stable responses were achieved in target lesions.

Conclusions: Administration of IPdR orally every day × 28 days with RT is feasible and tolerable at doses that produce plasma IUdR levels ≥1 μmol/L. These results support the investigation of IPdR + RT in phase II studies.

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