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

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

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

Study Overview

• Status: Unknown
• Conditions: Neoplasms
• Intervention / Treatment: Genetic: Sequencing of DPYD gene

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 Type: Observational
• Enrollment (Anticipated): 600

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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 Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Non-Western patients; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Erasmus Medical Center; The Netherlands Cancer Institute; Medical Center Haaglanden; Haga Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2020
• Primary Completion (Anticipated): March 1, 2022
• Study Completion (Anticipated): August 1, 2022

Study Registration Dates

• First Submitted: February 24, 2020
• First Submitted That Met QC Criteria: March 5, 2020
• First Posted (Actual): March 9, 2020

Study Record Updates

• Last Update Posted (Actual): March 9, 2020
• Last Update Submitted That Met QC Criteria: March 5, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Capecitabine; 5-Fluorouracil; 5-FU; Genotyping; Fluoropyrimidines; DPYD; Non-Western
• Other Study ID Numbers: DPNOW

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No