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Trial registered on ANZCTR


Registration number
ACTRN12621001117808
Ethics application status
Approved
Date submitted
12/07/2021
Date registered
23/08/2021
Date last updated
23/08/2021
Date data sharing statement initially provided
23/08/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Pre-treatment dihydropyrimidine dehydrogenase (DPYD) genotyping in patients receiving fluoropyrimidine (5-Fluorouracil or Capecitabine) chemotherapy: A clinical implementation study of the effect of individualised dosing on treatment related toxicity
Scientific title
Pre-treatment dihydropyrimidine dehydrogenase (DPYD) genotyping to individualise fluoropyrimidine-based chemotherapy: An evaluation of clinical implementation and treatment-related toxicity.
Secondary ID [1] 303458 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cancer 320766 0
Condition category
Condition code
Cancer 320386 320386 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Pre-treatment dihydropyrimidine dehydrogenase (DPYD) genotyping to individualise fluoropyrimidine-based chemotherapy dosing

All patients receiving fluoropyrimidine chemotherapy for the first time will be offered pre-treatment Sanger DNA sequencing to identify the four DPYD variant genotypes most associated with increased toxicity - single nucleotide polymorphisms c.1905+1G>A (*2A, rs3918290), c.1679T>G (*13, rs55886062), c.2846A>T (rs67376798), and c.1236G>A (rs56038477, E412E, in haplotype B3). Participants will be required to provide a blood sample only.

Those patients with no DPYD variants will proceed receive a 100% dose as planned.

Those patients identified with a single heterozygote DPYD variant will receive a 50% dose reduction for the first two cycles.

For safety reasons, any patients identified as a homozygous genotype or compound heterozygote should not receive fluoropyrimidines and alternative treatment will be recommended. The alternative type of treatment will be at the discretion of the treating Medical Oncologist but may include a different type of chemotherapy such as Raltitrexed.

Results will be checked by the clinician as well as pharmacy and trial coordinators to ensure adherence to the intervention.
Intervention code [1] 321132 0
Treatment: Drugs
Intervention code [2] 321238 0
Early detection / Screening
Comparator / control treatment
Treatment toxicity compared between those who have a variant and those who don't
For further comparison, a retrospective review will also be undertaken of toxicity rates for all patients who received fluoropyrimidine treatment at the Royal Brisbane and Womens Hospital in 2019.
Control group
Historical

Outcomes
Primary outcome [1] 328219 0
Incidence of severe treatment related toxicity (CTC grade 3 or higher) within 60 days of a patient beginning fluoropyrimidine treatment.
Timepoint [1] 328219 0
Within 60 days of beginning treatment
Secondary outcome [1] 398119 0
Unplanned hospital admissions related to treatment within 60 days of a patient beginning fluoropyrimidine treatment will be reviewed from the patients electronic medical record.
Timepoint [1] 398119 0
Within 60 days of a patient beginning fluoropyrimidine treatment
Secondary outcome [2] 398121 0
Rates of fluoropyrimidine dose intensity during the first 60 days of beginning fluoropyrimidine treatment will be reviewed from the patients electronic medical record
Timepoint [2] 398121 0
At the conclusion of the study
Secondary outcome [3] 398122 0
Documented practical clinical implementation issues including testing timeframes. This will be assessed via an audit of study records and liaison with Pathology completing the testing.
Timepoint [3] 398122 0
At the conclusion of the study
Secondary outcome [4] 398684 0
Rates of fluoropyrimidine dose delays during the first 60 days of beginning fluoropyrimidine treatment will be reviewed from the patients electronic medical record
Timepoint [4] 398684 0
At the conclusion of the study

Eligibility
Key inclusion criteria
a. Pathologically confirmed malignancy for which treatment with a fluoropyrimidine at full dose (with or without other chemotherapy agents or radiation) is deemed clinically appropriate
b. Adult patient (> 18 years)
c. Receiving their first dose of fluoropyrimidine (either as a single agent or in combination) between 1 July, 2021 and 30 June, 2022.
d. Willing to provide blood sample for pharmacogenetic testing
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a. Inability to provide informed consent
b. Prior use of fluoropyrimidines
c. Women who are pregnant or breast-feeding
d. Patients with a previously known homozygous polymorphic genotype or compound heterozygous genotype for DPYD.

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Nil
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Nil
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
• Prevalence rates of DYPD variants will be summarized as frequency (percent)
• Fluoropyrimidine dose/intensity will be summarized as a mean (percentage) for each different population group.
• Patient and treatment characteristics will be compared between pre and post DYPD testing implementation groups, as well as between those with and without a variant in the post DYPD testing implementation group, using chi-square or Fisher’s exact tests for categorical characteristics and t-tests or Mann-Whitney U tests for continuous characteristics as appropriate.
• For the primary outcome of toxicity experienced within 60 days of beginning fluoropyrimidine and the secondary outcome of having a readmission within 60 days of beginning fluoropyrimidine, univariable binary logistic regression analyses will be performed to observe the effect on these outcomes of pre and post DYPD testing implementation, and potential covariates.
• Covariates with a p-value < 0.2 will be considered further in multivariable logistic regression analyses alongside pre and post DYPD testing implementation groups.
• Covariates will be removed via a variable selection process to obtain a final adjusted model. Cohort will be forced to remain in the model.
• Statistical significance will be indicated at p < 0.05. A similar process will be performed for the comparison between having a variant and no variant in the post DYPD testing implementation group.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
12/07/2021
Date of last participant enrolment
Anticipated
30/06/2022
Actual
Date of last data collection
Anticipated
30/09/2022
Actual
Sample size
Target
280
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 19951 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 19952 0
The Prince Charles Hospital - Chermside
Recruitment hospital [3] 19953 0
North Lakes Health Precinct - North Lakes
Recruitment postcode(s) [1] 34657 0
4029 - Herston
Recruitment postcode(s) [2] 34658 0
4032 - Chermside
Recruitment postcode(s) [3] 34659 0
4509 - North Lakes

Funding & Sponsors
Funding source category [1] 307876 0
Hospital
Name [1] 307876 0
Queensland Health - Metro North Health
Country [1] 307876 0
Australia
Primary sponsor type
Hospital
Name
Queensland Health - Metro North Health
Address
Butterfield St, Herston QLD 4019
Country
Australia
Secondary sponsor category [1] 310074 0
None
Name [1] 310074 0
Address [1] 310074 0
Country [1] 310074 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307877 0
Royal Brisbane & Women's Hospital Human Research Ethics
Ethics committee address [1] 307877 0
Level 2, Building 34
Royal Brisbane & Women’s Hospital
Butterfield Street, Herston Qld 4029
Ethics committee country [1] 307877 0
Australia
Date submitted for ethics approval [1] 307877 0
09/04/2021
Approval date [1] 307877 0
01/06/2021
Ethics approval number [1] 307877 0
HREC/2021/QRBW/73708

Summary
Brief summary
This study aims to evaluate the feasibility of pre-treatment DPYD genotyping (a gene that codes for an enzyme that metabolises fluoropyrimidine chemotherapy). For those individuals who have a certain DPYD variant, the study will also aim to assess the safety of reducing their dose of fluoropyrimidine chemotherapy.

Who is it for?
You may be eligible for this study if you are aged 18 years or over and have a confirmed malignancy for which fluoropyrimidine chemotherapy is deemed clinically appropriate.

Study details
Participants will be asked to provide a blood sample for genetic testing. Based on results, individuals may have alterations to their treatment plan such as a 50% dose reduction for the first two cycles of chemotherapy or changes in the drug administered. Data on treatment-related toxicity will be collected.

It is hoped that data from this study will establish the clinical relevance of regular DPYD genotype testing for cancer treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108786 0
Dr Mark Nalder
Address 108786 0
Department of Medical Oncology
Cancer Care Services
Royal Brisbane & Women’s Hospital
Herston Qld 4029
Country 108786 0
Australia
Phone 108786 0
+61 07 3646 7983
Fax 108786 0
Email 108786 0
[email protected]
Contact person for public queries
Name 108787 0
Mark Nalder
Address 108787 0
Department of Medical Oncology
Cancer Care Services
Royal Brisbane & Women’s Hospital
Herston Qld 4029
Country 108787 0
Australia
Phone 108787 0
+61 07 3646 7983
Fax 108787 0
Email 108787 0
[email protected]
Contact person for scientific queries
Name 108788 0
Mark Nalder
Address 108788 0
Department of Medical Oncology
Cancer Care Services
Royal Brisbane & Women’s Hospital
Herston Qld 4029
Country 108788 0
Australia
Phone 108788 0
+61 07 3646 7983
Fax 108788 0
Email 108788 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Ethical approval.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
12509Study protocol    381432-(Uploaded-12-07-2021-09-31-20)-Study-related document.pdf



Results publications and other study-related documents

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