Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials

Linda Spiegelberg, Ruud Houben, Raymon Niemans, Dirk de Ruysscher, Ala Yaromina, Jan Theys, Christopher P. Guise, Jeffrey B. Smaill, Adam V. Patterson, Philippe Lambin, Ludwig J. Dubois*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

53 Citations (Web of Science)

Abstract

Hypoxia-activated prodrugs (HAPs) are designed to specifically target the hypoxic cells of tumors, which are an important cause of treatment resistance to conventional therapies. Despite promising preclinical and clinical phase I and II results, the most important of which are described in this review, the implementation of hypoxia-activated prodrugs in the clinic has, so far, not been successful. The lack of stratification of patients based on tumor hypoxia status, which can vary widely, is sufficient to account for the failure of phase III trials. To fully exploit the potential of hypoxia-activated prodrugs, hypoxia stratification of patients is needed. Here, we propose a biomarker-stratified enriched Phase III study design in which only biomarker-positive (i.e. hypoxia-positive) patients are randomized between standard treatment and the combination of standard treatment with a hypoxia-activated prodrug. This implies the necessity of a Phase II study in which the biomarker or a combination of biomarkers will be evaluated. The total number of patients needed for both clinical studies will be far lower than in currently used randomize-all designs. In addition, we elaborate on the improvements in HAP design that are feasible to increase the treatment success rates. (C) 2019 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.

Original languageEnglish
Pages (from-to)62-69
Number of pages8
JournalClinical and Translational Radiation Oncology
Volume15
DOIs
Publication statusPublished - Feb 2019

Keywords

  • Hypoxia-activated prodrugs
  • Phase III clinical trial
  • Biomarker
  • Hypoxia
  • C P450 REDUCTASE
  • POSITRON-EMISSION-TOMOGRAPHY
  • SQUAMOUS-CELL CARCINOMAS
  • OXYGEN-ENHANCED MRI
  • TUMOR HYPOXIA
  • ANTITUMOR-ACTIVITY
  • NECK-CANCER
  • LUNG-CANCER
  • EXTRAVASCULAR TRANSPORT
  • EVOFOSFAMIDE TH-302

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