e-Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2021

Can Oxaliplatin neurotoxicity be reduced with ibudilast in people with metastatic colorectal cancer – a phase II randomised study (#406)

Janette L Vardy 1 2 , Christina Teng 2 , Corrinne Renton 3 , Prunella Blinman 1 2 , Deme Karikios 4 , Peter Fox 5 , Connie Diakos 6 , Lorraine Chantrill 7 , Robin Mitchell 8 , Susanna Park 9 , Martin Stockler 9 , Haryana Dhillon 3
  1. Concord Cancer Centre, Concord, NSW, Australia
  2. Sydney Medical School, Concord Clinical School, University of Sydney, Sydney, NSW, Australia
  3. CeMPED, University of Sydney, Sydney, NSW, Australia
  4. Nepean Cancer Care Centre, Nepean Hospital , Nepean
  5. Orange Health Service, Orange
  6. Royal North Shore Hospital, St Leonards, NSW, Australia
  7. Illawarra Shoalhaven Local Health District, Wollongong
  8. AGITG Consumer Advisory Panel, Sydney
  9. Faculty of Medicine and Health, The University of Sydney , Sydney

Background:
Chemotherapy-induced peripheral neuropathy (CIPN) is the most common reason for early cessation of oxaliplatin.  Ibudilast is an oral selective phosphodiesterase inhibitor that regulates glial cells.  A pre-clinical rodent model showed ibudilast prior to oxaliplatin prevented tactile allodynia.1 Our pilot study in patients with metastatic colorectal (CRC) or upper gastrointestinal cancer found ibudilast may improve or stabilise symptoms of acute neurotoxicity and CIPN.  Our pharmacokinetic sub-study found no change in platinum or fluorouracil levels with ibudilast.2 

 

Aim: We aim to determine whether ibudilast can decrease acute neurotoxicity severity and CIPN in patients with metastatic CRC receiving oxaliplatin with either FOLFOX or CAPOX (+/- targeted therapy), and to determine whether ibudilast will decrease dose reductions of oxaliplatin due to neurotoxicity.

 

Study design:

A randomised phase II trial evaluating ibudilast (30mg PO bd) compared with placebo.  Participants are randomised 1:1, stratified by: chemotherapy regimen (FOLFOX vs CAPOX), previous oxaliplatin adjuvant chemotherapy (Yes/No), diagnosis of diabetes (Yes/No), sex, body mass index (>30 vs <30), and age (>70 vs <70 years). Major exclusion criteria: Existing peripheral neuropathy, adjuvant oxaliplatin within 12-months, oxaliplatin for metastatic disease, inadequate organ function, ECOG PS > 3, insufficient English for questionnaires.

Ibudilast/placebo commences 2 days prior to first cycle of chemotherapy and continues for duration of oxaliplatin.  Participants complete assessments for CIPN at baseline, day 1 and 3 of chemotherapy, and 1, 3, 6, 9, and 12 months after finishing chemotherapy. Primary endpoint: acute neurotoxicity (Oxaliplatin Acute Symptom Questionnaire).  Key secondary endpoints: CIPN, treatment adherence, Quality-of-life, toxicity and safety, progression-free survival. Analysis will be according to intention-to-treat. Planned sample size 100 patients.

Status:

Study opened December 2020, five sites are recruiting, additional sites under review, four participants have been randomised to date. The study is funded by an AGITG Innovation Grant.

 

  1. Johnston IN, Tan M, Cao J, et al: Ibudilast reduces oxaliplatin-induced tactile allodynia and cognitive impairments in rats. Behav Brain Res 334:109-118, 2017
  2. Teng C, Reuter SE, Blinman PL, et al: Ibudilast for prevention of oxaliplatin-induced acute neurotoxicity: a pilot study assessing preliminary efficacy, tolerability and pharmacokinetic interactions in patients with metastatic gastrointestinal cancer. Cancer Chemother Pharmacol 86:547-558, 2020