OXTOX: Can Oxaliplatin neurotoxicity be reduced with ibudilast in people with colorectal cancer – a phase II randomised study

Oxaliplatin chemotherapy improves survival but causes acute neuropathy (paraesthesias or dysesthesias) and chronic chemotherapy-induced peripheral neuropathy (CIPN) in almost all patients. The acute neurotoxicity is generally reversible, but severity is a predictor for chronic sensory neurotoxicity. CIPN is the most common dose-limiting factor for patients receiving oxaliplatin. It is sustained in ~25% and can have major impact on quality of life (QOL) and functional status. Prevention of neurotoxicity would lead to an increased ability to deliver recommended doses of chemotherapy, and greatly improve QOL and functional status for many patients. A potential mechanism of CIPN is via glial activation by inflammatory molecules in the spinal cord – cytokines, reactive oxygen species and nitrogen intermediates.

Animal models suggest ibudilast, a non-selective phosphodiesterase inhibitor with anti-inflammatory properties, given together with oxaliplatin, can prevent and treat neurotoxicity. It acts in the central and peripheral nervous system to reduce microglial activation. In vitro studies have shown ibudilast modulates glial activity and cytokine expression. We have demonstrated in a pilot study that ibudilast can stabilise or improve CIPN in people with metastatic colorectal or upper gastrointestinal cancer receiving oxaliplatin, and our pharmacokinetic study showed no impact of ibudilast on oxaliplatin or 5-flurouracil.

OXTOX aims to determine if administration of ibudilast concurrently with oxaliplatin can reduce neurotoxicity symptoms in cancer patients, without compromising the effectiveness of chemotherapy.