Implementation and Quality Assurance of DPYD-genotyping in Patients Treated With Fluoropyrimidines.

Implementation and Quality Assurance of DPYD-genotyping in Patients Treated With Fluoropyrimidines

The purpose of this study is to examine the benefits of a clinical implementation of a DPYD-genotype test to patients starting treatment with fluoropyrimidines (Fluorouracil (5-FU), capecitabine, tegafur).

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Gastric Cancer; Rectal Cancer; Bile Duct Cancer; Colon Cancer; Pancreas Cancer; Oesophageal Cancer; Adverse Drug Event
• Intervention / Treatment: Genetic: DPYD genotype

Detailed Description

Patients with specific genetic mutations in the DPYD-gene have lower activity of the dihydropyrimidine dehydrogenase (DPD) enzyme, which is the rate-limiting enzyme in the metabolism of fluoropyrimidines. Fluoropyrimidines are commonly used as chemotherapeutic drugs and include 5-Fluorouracil, capecitabine, and tegafur. Patients with decreased DPD activity are at higher risk of serious adverse events when treated with standard doses of fluoropyrimidines

This study will examine the clinical implementation of the pre-emptive DPYD-genotype test. The test will analyze four of the most common genetic mutations(SNPs) in the DPYD-gene that leads to significant decreased DPD-activity

In patients with DPYD-variant mutations, the recommended starting dose is 50%. This dose reduction will possibly reduce the rate of serious adverse events. Patients who are homozygous or compound heterozygous for a DPYD-mutation will not be treated with fluoropyrimidines due to the high risk of fatal adverse effects.

Aim To reduce the overall incidence of severe adverse reactions(grade >= 3) to chemotherapy regimens containing 5-FU, capecitabine, or S1 in an unselected population of colorectal, non-colorectal GI cancer, or breast cancer patients through pre-emptive DPYD-genotyping.

Design The investigators will conduct an open clinical trial using historical controls. The investigators will implement pre-emptive genotype testing of about 1000 consecutive patients subject to 5-FU, capecitabine, or S1 treatment for colorectal, non-colorectal GI, or breast cancer. The investigators will use a historical control group of about 500 consecutive similar patients.

Genotype and Phenotype Patients included in the study who are genotyped for DPYD will have blood collected for a post hoc phenotype test. The blood samples will be used to measure levels of uracil.

Some patients in the historic cohort have donated blood to an independent biobank at the time of their cancer treatment. These samples will be used for post hoc DPYD-genotype analysis after the necessary ethical approvals.

Cost-effectiveness An economic analysis will be undertaken to examine if implementing the DPYD-genotype is cost-effective.

• Study Type: Observational
• Enrollment (Actual): 722

Contacts and Locations

Study Locations

• Denmark
  • Syddanmark
    • Odense, Syddanmark, Denmark, 5000
      • The Department of Oncology at University of southern denmark

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

Cancer patients treated at The Department of Oncology at Odense University Hospital (OUH)

Description

Inclusion Criteria:

• Patients with cancer that are eligible for systemic treatment with 5-FU, capecitabine, or tegafur.

Exclusion Criteria:

• Patients that earlier have been treated with 5-FU, capecitabine, or tegafur

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Retrospective; Historic group. Patients treated in the historic control group did not receive DPYD-genotype before treatment with fluorouracil, capecitabine, tegafur. They received standard start doses of 5-FU, capecitabine, tegafur.
Prospective; Participants enrolled in the prospective group will give a blood sample for immediate DPYD genotyping. Once the results from these tests are in, the treating oncologist have immediate access to the participant's genetic test results and can make dosing decisions/changes to the participant's chemotherapy prescription. The recommended starting doses for 5-FU, capecitabine, tegafur are. No DPYD-gene variant = normal starting dose (100%) 1 DPYD-gene variant (heterozygous) = Reduced starting dose (50%) Homozygous for 1 DPYD variant or compound heterozygous (>1 variants) = Treatment with 5-FU, capecitabine, tegafur is not recommended .	Genetic: DPYD genotype; The SNPs included in this study are the following (dbSNP Reference SNP) rs3918290(c.1905+1G>A) rs67376798(c.2846A>T) rs55886062(c.1679T>G) rs56038477(75017182)/(c.1236G>A); Other Names: Dihydropyrimidine dehydrogenase (DPD) enzyme activity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Rate of grade 3-5 adverse events (CTCAE) Version 5.0	Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-FU or capecitabine or S1-related mortality, all patients	Rate of mortality related to adverse drug reaction	Up to 6 months
5-FU or capecitabine or S1-related mortality, DPYD variant carriers	Rate of mortality related to adverse drug reactions in patients with a DPYD gene variant.	Up to 6 months
Overall mortality, all patients	Rate of mortality in all patients	Up to 6 months
Overall mortality, DPYD variant carriers	Rate of mortality in patients with DPYD-variants.	Up to 6 months
Length of hospital stay	Number of days participants is admitted to the hospital.	Up to 6 months
Rate of discontinuation of fluoropyrimidines due to adverse events		Up to 6 months

Collaborators and Investigators

• Sponsor: University of Southern Denmark
• Collaborators: Odense University Hospital
• Investigators: Principal Investigator: Per Damkier, MD, PhD, University of Southern Denmark

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Actual): June 1, 2022
• Study Completion (Actual): October 1, 2022

Study Registration Dates

• First Submitted: December 16, 2021
• First Submitted That Met QC Criteria: March 3, 2022
• First Posted (Actual): March 4, 2022

Study Record Updates

• Last Update Posted (Actual): November 1, 2022
• Last Update Submitted That Met QC Criteria: October 31, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Biliary Tract Diseases; Pancreatic Diseases; Bile Duct Diseases; Biliary Tract Neoplasms; Pancreatic Neoplasms; Cholangiocarcinoma; Drug-Related Side Effects and Adverse Reactions; Bile Duct Neoplasms
• Other Study ID Numbers: R231-A14057

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