Antineoplastic Agents

All Drugs and Chemicals

Fluorouracil

Capecitabine

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.

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.

Sequencing of DPYD gene

Hans Gelderblom, Prof.

Jesse Swen, PhD

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.

1. blood sample (whole blood) of 4 ml (EDTA-tube) for sequencing of the DPYD gene
2. blood samples (whole blood) of 6 ml (EDTA-tubes) each for determination of the DPD enzyme activity

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

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

The Netherlands Cancer Institute

Erasmus Medical Center

Haga Hospital

Medical Center Haaglanden

Leiden University Medical Center

Prof. dr.

Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Neoplasm Metastasis

Breast Neoplasms

Breast Diseases

Skin Diseases

Antimetabolites

capecitabine

eric levy, md

kahina rideller, CRA

ERIC LEVY, MD

jacques medioni, MD

eric levy, MD

joseph Gligorov, MD

Michèle TUBIANA HULIN, MD

VERONIQUE DIERAS, MD

Rémi LARGILLIER, MD

Standard administration of capecitabine use a 14 days administration. Routine practice in several intitution leads to use a 5 out of 7 days regimen, with less toxicity.

Purpose : to compare the pharmacokinetics of capecitabine, administered 5 days out of 7, as compared to the standard administration (14 days out of 21). The second end point is to compare toxicity with either regimen.

Method : Randomized study with two groups : one with standard administration , the second with 5/7 days regimen

Tolerance and Pharmacokinetics With Capecitabine 5 Out of 7 Days Regimen

Phase I/II Study of Tolerance and Pharmacokinetics With Capecitabine Given 5 Days Out of 7 in Metastatic Breast Cancer

Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie

Immunosuppressive Agents

Immunologic Factors

Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD\*2A, c.2846A\>T, c.1236G\>A/HapB3 and DPYD\*13) that are found to be wild type for these SNPs

Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD\*2A, c.2846A\>T, c.1236G\>A/HapB3 and DPYD\*13) that are found to be heterozygous for c.1236G\>A or c.2846A\>T of these SNPs

Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD\*2A, c.2846A\>T, c.1236G\>A/HapB3 and DPYD\*13) that are found to be homozygous or compound heterozygous for these SNPs

Patients that are found to be wild type and have a pre-treatment uracil concentration above 16 ng/mL will receive a reduced dosage of capecitabine or 5-fluorouracil (50% reduction). The dose will be titrated after 2 cycles , to achieve maximal safe exposure. Patients that are wildtype with a uracil concentration below 16 ng/mL will receive a normal (full) dose.

Fluoropyrimidine (capecitabine or 5-fluorouracil)

Patients that are heterozygous carriers of c.1236G\>A or c.2846A\>T DPYD variant will receive a reduced dosage of capecitabine or 5-FU (50 % reduction). The dose will be titrated after 2 cycles, to achieve maximal safe exposure.

Patients with homozygous or compound heterozygous DPYD variants will be treated with a reduced dose of capecitabine or 5-FU based on the DPD enzyme activity measured in peripheral blood mononuclear cells.

Jonathan Knikman, PharmD

Annemieke Cats, MD, PhD

In this study it will be determined whether the rate of severe toxicity associated with fluoropyrimidine treatment (capecitabine or 5-fluorouracil) can be significantly diminished by individualized dosing of fluoropyrimidines based on upfront phenotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.

In this study a phenotypic approach will be studied to determine the additional value of pretreatment uracil level-guided dose individualization in wildtype patients. Patients with a pretreatment serum uracil concentration above 16 ng/ml will be treated with a 50% reduced fluoropyrimidine starting dose. The pretreatment serum uracil levels in DPYD variant carriers will be assessed retrospectively and non-interventional. Additionally, the effect of a higher dose reduction in c.1236G\>A and c.2846A\>T DPYD variants carriers (50% instead of 25%) will be studied.

Improving the Safety of Fluoropyrimidine-based Chemotherapy

Improving the Safety of Fluoropyrimidine-based Chemotherapy by Combined DPYD Genotype-guided and DPD Phenotype-guided Dose Individualization: The ALPE2U Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Identifying Novel Variants in the DPYD Gene in Patients of Non-Western Descent	NCT04300361	Neoplasms	Sequencing of D...	18 Years -	Leiden University Medical Center
Tolerance and Pharmacokinetics With Capecitabine 5 Out of 7 Days Regimen	NCT00324610	Breast Neoplasm... Chemotherapy	capecitabine	18 Years -	Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
Improving the Safety of Fluoropyrimidine-based Chemotherapy	NCT04194957	Neoplasms	Fluoropyrimidin... Fluoropyrimidin... Fluoropyrimidin...	18 Years -	The Netherlands Cancer Institute
Improving the Safety of Fluoropyrimidine-based Chemotherapy	NCT04194957	Neoplasms	Fluoropyrimidin... Fluoropyrimidin... Fluoropyrimidin...	18 Years -	The Netherlands Cancer Institute

Spots Global Cancer Trial Database for fluoropyrimidines