OXTOX

Aim

To determine whether ibudilast has the potential to decrease the severity of acute neurotoxicity and CIPN in patients with metastatic CRC receiving oxaliplatin.

Background

Oxaliplatin is commonly used to treat colorectal cancer (CRC) and upper gastrointestinal cancers (UGI). It improves survival but causes acute neuropathy (paraesthesias or dysesthesias) and chronic chemotherapy-induced peripheral neuropathy (CIPN) in almost all patients. The prevalence of moderate to severe acute neurotoxicity in patients receiving oxaliplatin is 85-95% (sensitivity touching cold items 79%, discomfort with cold drinks 72%, throat discomfort 59%, muscle cramps 40%, laryngo-pharyngeal dysesthesia 1-2%). Acute toxicity peaks on day 3 following infusion but may not fully resolve between cycles, and is worse in cycle 2 than cycle 1. The mechanism is believed to be slowed sodium channel inactivation. Severity of acute neurotoxicity predicts chronic sensory neuropathy.

Chronic CIPN from oxaliplatin results in sensory ataxia and dysesthesia. It is believed to be caused by accumulation of oxaliplatin in the dorsal root ganglion, potentially leading to axonal degeneration, mitochondrial disruption, and/or glial activation. CIPN is dose dependent and is the most common dose-limiting factor for patients receiving oxaliplatin. Knowing the optimal time to stop treatment early is problematic as CIPN can continue to worsen for a few months after stopping treatment (“coasting”). Recovery is often not complete, with residual deficits in most patients, minimal improvement on axonal excitability parameters, and 25% having sustained moderate severity CIPN. 1 Of the 136 CRC patients attending our Survivorship Clinic received oxaliplatin and 75% of them required dose reduction, and 37 stopped early, 24 (65%) due to CIPN. Of the 56 evaluable responses, 46% (26) of patients who received oxaliplatin reported at least moderate neuropathy, compared with 18% who did not receive oxaliplatin, a mean of 9 months after chemotherapy.16 CIPN has a major impact on quality of life (QOL), functional status, and return to daily life.

There are no preventative agents for CIPN and few treatment options. Prevention of neurotoxicity would lead to increased ability to deliver recommended doses of chemotherapy, and improve quality of life and functional status for many patients.

Ibudilast is a non-selective phosphodiesterase inhibitor with anti-inflammatory properties, approved for treatment of asthma and post stroke dizziness in Japan. 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.

Clinical Trial Design

A randomised, non-comparative, calibrated phase II trial evaluating ibudilast (30mg PO bd) and placebo to determine whether ibudilast can decrease acute neurotoxicity severity and CIPN in patients with metastatic CRC receiving oxaliplatin with either FOLFOX or CAPOX, and to determine whether ibudilast will reduce dose modifications of oxaliplatin due to neurotoxicity.

Key Eligibility Criteria

Inclusion Criteria:
1. Adults >18 years old with histologically confirmed metastatic adenocarcinoma CRC who are to commence chemotherapy with oxaliplatin (i.e. FOLFOX or CAPOX).
2. Sufficient written English to complete questionnaires.
3. Adequate organ function, defined as renal function with glomerular filtration rate >50mL/min, adequate bone marrow (platelets>100 X 109 L-1, neutrophil count >1.5 X 109 L-1), and hepatic (<1.5 X the upper limit of normal (ULN), with the exception that GGT may be elevated <3 X ULN as long as bilirubin is within normal range).
4. ECOG performance status of 0-2.

Exclusion Criteria:
1. Existing peripheral neuropathy of any grade (e.g. due to diabetes mellitus, B12 deficiency, alcohol abuse, or use of nucleoside reverse transcriptase inhibitors).
2. Prior treatment with oxaliplatin within the past 6 months.
3. Any contraindication to taking ibudilast, including uncontrolled nausea or vomiting with chemotherapy.

Principal Investigator

Prof Janette Vardy

Detailed Information Available on

More detailed information available online at the Australian New Zealand Clinical Trial Registry (ANZCTR)