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

ABSTRACT

Introduction: 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
• chemotherapy neurotoxicity
• nerve hyperexcitability
• pharmacokinetics
• phase I clinical trial design
• chemoprotection
• crossover trial

Article highlights

• Oxaliplatin neurotoxicity is a major treatment-limiting toxicity that often leads to long-term neurological deficits reducing quality of life and limiting treatment delivery.

• Currently oxaliplatin-induced neurotoxicity is unavoidable and difficult to treat, therefore neuroprotective therapeutics against this toxicity are urgently required.

• Previous negative phase III trials of treatments for preventing oxaliplatin-induced neurotoxicity were often done without any prior dose-finding, pharmacological or pilot clinical evaluations.

• A phase Ib randomised, double-blind, placebo-controlled, cross-over study design may provide a robust and efficient approach to decision-making about which investigational therapeutics and doses should be evaluated in phase II/III trials, and which treatments should be abandoned before extensive late-phase clinical evaluation.

• The study design and rationale, specific study endpoints, including pharmacokinetics, safety and tolerability, electromyographic score for motor nerve hyperexcitability, patient-reported treatment preference and acute neurotoxicity symptoms, will be discussed in this article.

• The proposed phase Ib trial design does not allow assessments of the effects of the study treatments on chronic neurotoxicity of oxaliplatin. However, it represents an efficient approach for initial clinical evaluation and optimal dose-finding of these investigational treatments for preventing oxaliplatin-induced neurotoxicity. Therefore, it will be complementary to later confirmatory phase II/III parallel-group design studies, in which the effects on chronic neurotoxicity and anti-tumor efficacy of oxaliplatin are assessed.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This incluzdes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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This paper was not funded