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Completed

NCT Number: NCT02324452

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

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.

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Key information

Conditions

Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Additional inclusion criteria for patients in subgroup of study:

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

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
  • Women who are pregnant or breast feeding
  • 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)
  • Patients with a homozygous polymorphic genotype or compound heterozygous genotype for DPYD

Treatment and study plan

Fluoropyrimidine (capecitabine or 5-fluorouracil)

Drug

Patient that are a heterozygous carrier of a DPYD variant will receive a reduced dosage of capecitabine or 5-fluorouracil (25-50% reduction, depending on which SNP is identified). The dose will be titrated in subsequent cycles, to achieve maximal safe exposure. Patients that are wild type (not carrying any of the for DPYD variants) will receive a normal (full) dose.

Other names: Xeloda, Capecitabine, 5-fluorouracil, fluorouracil, 5-FU

Primary outcomes

  1. Safety: incidence of severe treatment-related toxicity (CTC grade 3 to 5)

    Time frame: patients will be followed during fluoropyrimidine treatment, expected average of 1 year

    The incidence of severe treatment-related toxicity (CTC grade 3 to 5) in patients carrying DPYD variants compared to wild type patients and compared to a historical cohort of DPYD heterozygous patients treated with a full dose of fluoropyrimidines

Secondary outcomes

  1. Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective

    Time frame: patients will be followed during fluoropyrimidine treatment, expected average of 1 year

    Costs in the group where dose individualization of fluoropyrimidines based on upfront genotyping is performed is compared to a historic cohort without dose individualization. Costs include costs for genotyping, fluoropyrimidine drug therapy and costs related to adverse events.

  2. DPD phenotype, defined as deficient or not deficient

    Time frame: Prior to start of fluoropyrimidine treatment of the patient (pre dose)

    Several phenotyping tests that assess DPD enzyme activity will be compared and clinical sensitivity, specificity, positive predictive value and negative predictive value of each test will be determined

  3. Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life

    Time frame: At first week of start of fluoropyrimidine treatment of the patient

    In patients with heterozygous DPYD mutations the plasma levels of capecitabine, 5-FU and metabolites will be determined to assess the pharmacokinetic (PK) profile in these patients given reduced doses of capecitabine and 5-FU

Sponsors and collaborators

Lead sponsor

The Netherlands Cancer Institute

Other

Registry information

Important dates

Study start
2015
Primary completion
2018
Study completion
2018
First posted
Dec 24, 2014
Registry last updated
May 11, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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