Clinical trial NCT04300361: Identifying Novel Variants in the DPYD Gene in Patients of Non-Western Descent
Official title: A Prospective, Multicenter, Observational Study to Identify Novel Deleterious Variants in the DPYD Gene in Patients of Non-Western Descent: The DPYD-NOW Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Neoplasms
Keywords: Fluoropyrimidines
DPYD
Genotyping
Capecitabine
5-Fluorouracil
5-FU
Non-Western
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: The Netherlands Cancer Institute
name: Erasmus Medical Center
name: Haga Hospital
name: Medical Center Haaglanden
First posted: 2020-03-09
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Non-western patients with an indication for treatment with fluoropyrimidine-based chemotherapy. A patient is classified as non-Western if 1 of the parents or \> 2 of the grandparents are of non-Western descent.

Brief summary: This is a observational, multicenter study to identify novel variants of the DPYD gene which are possible deleterious in patients of non-Western descent.

Detailed description: Research has shown that DPYD-guided dose-individualization based on 4 DPYD variants (DPYD\*2A, c.1236G\>A, c.2846A\>T and c.1679T\>G) can significantly reduce severe fluoropyrimidine-related toxicity. However, these 4 variants are most likely not predictive for toxicity in patients of non-Western descent. In this study the DPYD gene of patients of non-Western descent will be sequenced to identify novel variants that could be associated with a reduced DPD enzyme activity and an increased risk of developing severe fluoropyrimdine-related toxicity. Additionally, the ability to predict if a DPYD variant is possibly deleterious by a recombinant model systen (DPYD-varifier) will be studied.

Eligibility criteria: Inclusion Criteria:

* Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient's best interest
* Patients need to be self-declared non-Western
* Age 18 years and older
* Able and willing to give written informed consent
* WHO performance status of 0, 1 or 2
* Life expectancy of at least 12 weeks
* Able and willing to undergo blood sampling for study related analysis
* Adequate baseline patient characteristics (complete blood count, hepatic function which involves serum bilirubin, ASAT, ALAT, and renal function)

Exclusion Criteria:

* Prior treatment with fluoropyrimidines
* Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient's safety

Primary outcomes:
measure: Presence of variants of the DPYD gene that are possibly associated with an increased risk of severe fluoropyrimidine-related toxicity in patients of non-Western descent
timeFrame: Patients will be followed for the first 2 cycles (each cycle is 28 days).
Secondary outcomes:
measure: DPD enzyme activity of patients carrying a novel DPYD variant compared to wildtype patients measured in peripheral blood mononuclear cells (PBMCs)
timeFrame: Through study completion, an average of 2 years
measure: Ability of the DPYD-varifier to predict if a novel DPYD variant is deleterious
timeFrame: Through study completion, an average of 2 years
measure: Frequency of DPYD variants per ethnic origin
timeFrame: Through study completion, an average of 2 years
measure: Correlation between genetic variants in genes other than DPYD and fluoropyrimidine-related toxicity
timeFrame: Through study completion, an average of 2 years
Other outcomes:
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