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

Leiden University Medical Center600 enrolled

Overview

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

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 Type

OBSERVATIONAL

Enrollment

600

Conditions

Neoplasms

Interventions

Sequencing of DPYD geneGENETIC

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

Time frame: Patients will be followed for the first 2 cycles (each cycle is 28 days).

Secondary Outcomes

DPD enzyme activity of patients carrying a novel DPYD variant compared to wildtype patients measured in peripheral blood mononuclear cells (PBMCs)

Time frame: Through study completion, an average of 2 years

Ability of the DPYD-varifier to predict if a novel DPYD variant is deleterious

Time frame: Through study completion, an average of 2 years

Frequency of DPYD variants per ethnic origin

Time frame: Through study completion, an average of 2 years

Correlation between genetic variants in genes other than DPYD and fluoropyrimidine-related toxicity

Time frame: Through study completion, an average of 2 years

Central Contacts

Hans Gelderblom, Prof.

CONTACT

+31 (0)71 - 526 9111 a.j.gelderblom@lumc.nl

Jesse Swen, PhD

CONTACT

+31 (0)71 - 5262790 j.j.swen@lumc.nl

Data from ClinicalTrials.gov

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