None listed
Conditions
Brief summary
A randomized, double-blind, placebo-controlled, cross-over, phase IB clinical trial. In combination with oxaliplatin, patients will be randomized to receive either a Cimetidine capsule(s) (200, 400 or 800 mg) (active study treatment) 30 minutes prior to the oxaliplatin infusion at Cycle 1 of the chemotherapy or a matching blank capsule(s) (placebo study treatment). On the second treatment cycle (Cycle 2), the patient will cross-over to the other study treatment (active or placebo) that they did not receive in the first treatment cycle. Endpoints to be measured after cycle 1 and 2 for comparison within each subject will include: 1) oxaliplatin pharmacokinetics; 2) EMG motor nerve hyperexcitability score; 3) adverse events attributable to study treatment; 4) tolerability of study treatment; 5) presence or absence of acute neurotoxicity symptoms, and 6) which study treatment was preferred by patients for reducing neurotoxicity. The study will consist of a dose-escalation phase to be followed by a cohort-expansion phase. In the dose escalation phase, the dose of cimetidine will be escalated using a traditional 3+3+3 rule based design in sequential cohorts of three or more patients. After completion of the dose-escalation phase, a cohort-expansion phase will recruit 30 patients for the evaluation of treatment with the recommended fixed dose of cimetidine.
Interventions
Subjects will be randomly allocated to blinded treatment with cimetidine during cycle one of oxaliplatin treatment then crossover to placebo treatment in cycle two, or will receive the same blinded treatments in the opposite sequence. Cimetidine or placebo capsules will be given as a single oral dose 0.5 hours prior to commencement of the oxaliplatin infusion.
In the dose-escalation phase of the trial, the dose of cimetidine will be increased sequentially in cohorts of three patients using a tr
Subjects will be randomly allocated to blinded treatment with cimetidine during cycle one of oxaliplatin treatment then crossover to placebo treatment in cycle two, or will receive the same blinded treatments in the opposite sequence. Cimetidine or placebo capsules will be given as a single oral dose 0.5 hours prior to commencement of the oxaliplatin infusion. In the dose-escalation phase of the trial, the dose of cimetidine will be increased sequentially in cohorts of three patients using a traditional 3+3+3 rule-based oncology phase I clinical trial design. The dose escalation phase of the trial will explore cimetidine treatment given concurrently with oxaliplatin at six dose-levels (200, 400, 800, 1200, 1600 and 2000 mg). Following treatment of the first cohort of three patients at a given dose-level, three main possibilities exist: 1) if all three patients have DLT, then that dose-level will be declared the MTD and the next cohort of three patients will be treated at the next lowest dose-level; 2) if none of three patients have DLT, then the next cohort of three patients will be treated with the next highest dose level, and; 3) if one or two of three patients had DLT, then the next cohort of three patients will be treated at the same dose-level to expand that dose level. Dose escalation may stop when one or more of the following has occurred: 1) the maximally tolerated dose of cimetidine is reached; 2) cimetidine was found to significantly alter the pharmacokinetics of oxaliplatin, or; 3) the recommended dose for cohort expansion of cimetidine has been reached. After identifying a cimetidine dose recommended for cohort expansion, 30 patients will be recruited to receive a fixed dose of cimetidine using the crossover design to generate clinical proof-of-concept in the cohort expansion phase of the trial. Oxaliplatin chemotherapy (dose of either (= or > 100 mg/m2 ) will be given as per institutional protocols for standard care as an intravenous infusion over 2 hours using an infusion pump to achieve a constant rate of infusion during the period of oxaliplatin administration. Frequency of administration will be dependent on the chemo regimen prescribed the doctor which may be administration of the chemotherapy on Day 1 of a 2 or 3 weekly cycle. Similarly, a washout period of two to three weeks (depending on the chemo regimen) will occur between the first and second treatments. Intervention adherence or fidelity is not NA to the chemotherapy given as it will be as per standard care. The cimetidine/placebo will be given to the patient to take orally by a research nurse 1/2 hr before chemotherapy begins.
Sponsors
University of Auckland
Study design
Allocation
Randomised controlled trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
• Histologically proven advanced-stage gastrointestinal cancer • Scheduled to undergo standard palliative-intent oxaliplatin-based chemotherapy • Age>18 years • Written informed consent
Exclusion criteria
• Early- or locally advanced-stage gastrointestinal cancer for curative-intent oxaliplatin-based therapy in the adjuvant, neoadjuvant, chemoradiation or other settings • Prior exposure to oxaliplatin or other neurotoxic chemotherapies including by not limited cisplatin, vincristine, vinorelbine, docetaxel or paclitaxel. • Pregnant or nursing women • Any concomitant medications recommended to avoid with cimetidine or oxaliplatin • Creatinine clearance less than or equal to 50ml/min • Total bilirubin greater than 1.5*ULN • AST or ALT greater than 3.0*ULN or greater than 5.0*ULN if due to liver metastases • Pre-existing peripheral neuropathy greater than Grade 1 • Contraindications to EMG • Contraindications to repeated pharmacokinetic blood sampling
Outcome results
None listed