Preventing oxaliplatin-induced neurotoxicity: rationale and design of phase Ib randomized, double-blind, placebo-controlled, cross-over trials for early clinical evaluation of investigational therapeutics

Expert Opin Drug Metab Toxicol. 2016 Dec;12(12):1479-1490. doi: 10.1080/17425255.2016.1223625. Epub 2016 Aug 23.

Abstract

Oxaliplatin-based chemotherapy has become the standard treatment for colorectal cancer and other gastrointestinal tumor types. Oxaliplatin-induced neurotoxicity is a major treatment-limiting side effect that compromizes the delivery of cancer treatment and causes long-standing neurological deficits that negatively impact upon patient quality of life Areas covered: The prevention of oxaliplatin-induced neurotoxicity represents an important opportunity for new therapeutic product development to address this major unmet medical need. In this article, we describe a phase Ib clinical trial design, and study procedures and protocols, that we have developed and now propose for the early clinical evaluation of investigational therapeutics for preventing oxaliplatin-induced neurotoxicity. Expert opinion: Recently, several advances have been made in the development of research methodologies applicable to the clinical evaluation of investigational drugs for preventing oxaliplatin-induced neurotoxicity. As we gain better understanding of the mechanisms of oxaliplatin-induced neurotoxicity, we will be able to use these methods to develop and test more effective and targeted neuroprotective agents that may not only improve patients' quality of life but also improve treatment delivery and survival outcomes.

Keywords: Oxaliplatin; chemoprotection; chemotherapy neurotoxicity; crossover trial; nerve hyperexcitability; pharmacokinetics; phase I clinical trial design.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Clinical Trials, Phase I as Topic / methods
  • Cross-Over Studies
  • Double-Blind Method
  • Gastrointestinal Neoplasms / drug therapy
  • Humans
  • Neurotoxicity Syndromes / etiology
  • Neurotoxicity Syndromes / prevention & control*
  • Organoplatinum Compounds / administration & dosage
  • Organoplatinum Compounds / adverse effects*
  • Oxaliplatin
  • Quality of Life
  • Randomized Controlled Trials as Topic / methods
  • Research Design*

Substances

  • Antineoplastic Agents
  • Organoplatinum Compounds
  • Oxaliplatin