Identifying Novel Variants in the DPYD Gene in Patients of Non-Western Descent

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Prospective, Multicenter, Observational Study to Identify Novel Deleterious Variants in the DPYD Gene in Patients of Non-Western Descent: The DPYD-NOW Study

Conditions
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Neoplasms

Intervention / Treatment
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* Genetic: Sequencing of DPYD gene


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Non-Western patients<br>Patients of non-Western descent with an indication for treatment with fluoropyrimidine-based chemotherapy. A patient is classified as non-Western if a one (1) of the parents or more than two (>2) of the grand parents are of non-Western descent. | Genetic: Sequencing of DPYD gene<br>* The DPYD gene of non-Western patients will be sequenced to identify DPYD variants that are possibly associated with an increased risk of developing severe fluoropyrimidine-related toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | Patients will be followed for the first 2 cycles (each cycle is 28 days). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DPD enzyme activity of patients carrying a novel DPYD variant compared to wildtype patients measured in peripheral blood mononuclear cells (PBMCs) |  | Through study completion, an average of 2 years | 
| Ability of the DPYD-varifier to predict if a novel DPYD variant is deleterious |  | Through study completion, an average of 2 years | 
| Frequency of DPYD variants per ethnic origin |  | Through study completion, an average of 2 years | 
| Correlation between genetic variants in genes other than DPYD and fluoropyrimidine-related toxicity |  | Through study completion, an average of 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fluoropyrimidines, DPYD, Genotyping, Capecitabine, 5-Fluorouracil, 5-FU, Non-Western