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Trial registered on ANZCTR


Registration number
ACTRN12619000192189
Ethics application status
Approved
Date submitted
18/01/2019
Date registered
11/02/2019
Date last updated
11/06/2019
Date data sharing statement initially provided
11/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Cimetidine for Reducing Oxaliplatin Neurotoxicity (CITRON)
Scientific title
Reducing Oxaliplatin Neurotoxicity: A Phase IB Randomized, Double-Blind, Placebo-Controlled, Crossover, Dose-Finding and Proof-of-Concept Trial of Cimetidine in Gastrointestinal Cancer Patients
Secondary ID [1] 296688 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Colorectal cancer 310880 0
Gastrointestinal cancer 310881 0
Condition category
Condition code
Cancer 309557 309557 0 0
Bladder
Cancer 310082 310082 0 0
Bowel - Anal
Cancer 310083 310083 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 310084 310084 0 0
Bowel - Small bowel (duodenum and ileum)
Cancer 310085 310085 0 0
Oesophageal (gullet)
Cancer 310086 310086 0 0
Pancreatic
Cancer 310093 310093 0 0
Liver
Cancer 310094 310094 0 0
Stomach
Cancer 310095 310095 0 0
Biliary tree (gall bladder and bile duct)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 313204 0
Treatment: Drugs
Comparator / control treatment
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.

The comparator study treatment will be matching placebo capsules containing no cimetidine. Placebo capsules will be given as a single oral dose 0.5 hours prior to the commencement of the oxaliplatin infusion.
Control group
Placebo

Outcomes
Primary outcome [1] 318507 0
Plasma pharmacokinetics of intact oxaliplatin defined by plasma concentration at steady-state (Css) and area under the plasma concentration-versus-time curve (AUC) of intact oxaliplatin
Timepoint [1] 318507 0
Single plasma sample will be collected and processed at the end of infusion on Day 1 of Cycles 1 and 2 for the main study.

For the optional sub-study, 16 plasma samples will be collected at pre-infusion, at 20, 40, 60 and 90 minutes after the start of the oxaliplatin infusion, at the end of the infusion and 5, 10, 20, 30, 60, 120, 180, 300 minutes, 24 and 72 hours, thereafter.
Secondary outcome [1] 365186 0
Motor nerve hyperexcitability as assessed by needle electromyography undertaken on day 3 (± one day) of cycle one and cycle two by a neurophysiologist
Timepoint [1] 365186 0
EMG will be undertaken on day 3 (± one day) of cycle one and cycle two.
Secondary outcome [2] 366560 0
Acute neurotoxicity symptoms after treatment with oxaliplatin, as compared to placebo assessed by study-specific questionnaire
Timepoint [2] 366560 0
At the end of cycle one and again at the end of cycle two.
Secondary outcome [3] 366561 0
Patient preference for cimetidine or placebo for reducing acute neurotoxicity symptoms from oxaliplatin assessed by study-specific questionnaire
Timepoint [3] 366561 0
At the end of cycle two.
Secondary outcome [4] 366562 0
To determine the safety of cimetidine given concurrently with oxaliplatin, adverse events will be recorded at the end of cycle one and cycle two based on medical history, vital signs measurement, physical examination findings and routine clinical laboratory assessments. Investigators will grade adverse events by CTCAE v4.0 and assign their causal relationships to the blinded study treatment. Adverse events causally related to study treatment and not expected from oxaliplatin-based chemotherapy alone will be considered in the evaluation of dose-limiting toxicities and for dose escalation decisions in the dose escalation phase of the trial
Timepoint [4] 366562 0
At the end of cycle one and cycle two

Eligibility
Key inclusion criteria
• Histologically proven advanced-stage gastrointestinal cancer
• Scheduled to undergo standard palliative-intent oxaliplatin-based chemotherapy
• Age>18 years
• Written informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 21164 0
New Zealand
State/province [1] 21164 0

Funding & Sponsors
Funding source category [1] 301265 0
Government body
Name [1] 301265 0
Health Research council
Address [1] 301265 0
PO Box 5541, Wellesley Street, Auckland 1141
Country [1] 301265 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
85 Park Road, Grafton, Auckland, 1023
Country
New Zealand
Secondary sponsor category [1] 300906 0
None
Name [1] 300906 0
Address [1] 300906 0
Country [1] 300906 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302009 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 302009 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 302009 0
New Zealand
Date submitted for ethics approval [1] 302009 0
Approval date [1] 302009 0
21/09/2018
Ethics approval number [1] 302009 0

Summary
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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88838 0
Prof Mark McKeage
Address 88838 0
University of Auckland, Faculty of Medical and Health Sciences
85 Park Road, Grafton, Auckland 1023
Country 88838 0
New Zealand
Phone 88838 0
+64 09 9237322
Fax 88838 0
Email 88838 0
m.mckeage@auckland.ac.nz
Contact person for public queries
Name 88839 0
Miss Prashannata Khwaounjoo
Address 88839 0
University of Auckland, Faculty of Medical and Health Sciences
85 Park Road, Grafton, Auckland 1023
Country 88839 0
New Zealand
Phone 88839 0
+64 09 923 1594
Fax 88839 0
Email 88839 0
p.khwaounjoo@auckland.ac.nz
Contact person for scientific queries
Name 88840 0
Prof Mark McKeage
Address 88840 0
University of Auckland, Faculty of Medical and Health Sciences
85 Park Road, Grafton, Auckland 1023
Country 88840 0
New Zealand
Phone 88840 0
+64 09 923 1594
Fax 88840 0
Email 88840 0
m.mckeage@auckland.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results