Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines

Netherlands Cancer Institute (NKI)

Status: Completed

Conditions: Neoplasms

Treatments: Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Study type: Interventional

Funder types: Other

Identifiers

NCT02324452

M14DPD

2014-005064-15 (EudraCT Number)

Details and patient eligibility

About

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 genotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.

In addition to the genotyping, the DPD phenotype of all patients will be determined by measuring the baseline dihydrouracil/uracil (DHU/U) ratio, in order to investigate whether phenotype-guided treatment can further improve patient safety. In a subgroup of patients, other phenotyping methods will be tested: measuring the plasma levels of uracil after a uracil test dose and a uracil breath test after a dose of [2-13C] -labeled uracil. To validate these tests, these phenotyping results will be compared with the results of a DPD activity assay (which measures DPD enzyme activity in peripheral blood mononuclear cells), which is considered the gold standard in measuring DPD phenotype.

Enrollment: 1,103 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient's best interest
2. Age ≥ 18 years
3. Able and willing to give written informed consent
4. WHO performance status of 0, 1 or 2
5. Life expectancy of at least 12 weeks
6. Able to swallow and retain oral medication
7. Able and willing to undergo blood sampling for pharmacogenetic and phenotyping analysis
8. Minimal acceptable safety laboratory values (ANC, platelet count, hepatic function, renal function)

Additional inclusion criteria for patients in subgroup of study:

1. Able and willing to undergo blood sampling and breath sampling at several time points
2. Able and willing to receive uracil for the test dose assay
3. Able and willing to receive [2-13C] -labeled uracil for the breath test

Exclusion criteria

1. Prior treatment with fluoropyrimidines
2. Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient's safety
3. Women who are pregnant or breast feeding
4. Both men and women who refuse to use reliable contraceptive methods throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms)
5. Patients with a homozygous polymorphic genotype or compound heterozygous genotype for DPYD

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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1,103 participants in 2 patient groups

heterozygous carrier of DPYD variant

Experimental group

Description:

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 one of these SNPs

Treatment:

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

wild type for DPYD

Experimental group

Description:

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

Treatment:

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)