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

• Conditions: Neoplasms
• Interventions: Genetic: Sequencing of DPYD gene

• Registration Number: NCT04300361
• Lead Sponsor: Leiden University Medical Center

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.

Study Timeline

• Study First Submitted: 2020-02-24
• Status Verified: 2020-03
• Study Start: 2020-03-01
• Study First Submitted QC: 2020-03-05
• Last Update Submitted: 2020-03-05
• Study First Posted: 2020-03-09
• Last Update Posted: 2020-03-09
• Primary Completion: 2022-03-01
• Study Completion: 2022-08-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 600

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

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Non-Western patients	Sequencing of DPYD gene	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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
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
Ability of the DPYD-varifier to predict if a novel DPYD variant is deleterious	Through study completion, an average of 2 years