Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines
2 other identifiers
interventional
1,103
1 country
17
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for not_applicable
Started Mar 2015
Typical duration for not_applicable
17 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
December 9, 2014
CompletedFirst Posted
Study publicly available on registry
December 24, 2014
CompletedStudy Start
First participant enrolled
March 1, 2015
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 1, 2018
CompletedStudy Completion
Last participant's last visit for all outcomes
March 1, 2018
CompletedMay 11, 2018
May 1, 2018
2.8 years
December 9, 2014
May 7, 2018
Conditions
Outcome Measures
Primary Outcomes (1)
Safety: incidence of severe treatment-related toxicity (CTC grade 3 to 5)
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
patients will be followed during fluoropyrimidine treatment, expected average of 1 year
Secondary Outcomes (3)
Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective
patients will be followed during fluoropyrimidine treatment, expected average of 1 year
DPD phenotype, defined as deficient or not deficient
Prior to start of fluoropyrimidine treatment of the patient (pre dose)
Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life
At first week of start of fluoropyrimidine treatment of the patient
Study Arms (2)
heterozygous carrier of DPYD variant
EXPERIMENTALPatients 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
wild type for DPYD
EXPERIMENTALPatients 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
Interventions
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.
Eligibility Criteria
You may qualify if:
- 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)
- 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
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (17)
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Amsterdam, Netherlands
Wilhelmina Hospital Assen
Assen, Netherlands
Amphia Hospital
Breda, Netherlands
Reinier de Graaf Hospital
Delft, Netherlands
Deventer Hospital
Deventer, Netherlands
Hospital Gelderse Vallei
Ede, Netherlands
Catharina Hospital
Eindhoven, Netherlands
Leiden University Medical Center
Leiden, Netherlands
Maastricht University Medical Center
Maastricht, Netherlands
Canisius-Wilhelmina Hospital
Nijmegen, Netherlands
Laurentius Hospital
Roermond, Netherlands
Bravis Hospital
Roosendaal, Netherlands
Erasmus MC
Rotterdam, Netherlands
Franciscus Gasthuis & Vlietland
Rotterdam, Netherlands
Haga Hospital
The Hague, Netherlands
Medical Center Haaglanden
The Hague, Netherlands
University Medical Center Utrecht
Utrecht, Netherlands
Related Publications (4)
Knikman JE, Lopez-Yurda M, Meulendijks D, Deenen MJ, Schellens JHM, Beijnen J, Cats A, Guchelaar HJ. A Nomogram to Predict Severe Toxicity in DPYD Wild-Type Patients Treated With Capecitabine-Based Anticancer Regimens. Clin Pharmacol Ther. 2024 Feb;115(2):269-277. doi: 10.1002/cpt.3100. Epub 2023 Nov 29.
PMID: 37957132DERIVEDKnikman JE, Wilting TA, Lopez-Yurda M, Henricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Nieboer P, Droogendijk HJ, Creemers GJ, Mandigers CMPW, Imholz ALT, Mathijssen RHJ, Portielje JEA, Valkenburg-van Iersel L, Vulink A, van der Poel MHW, Baars A, Swen JJ, Gelderblom H, Schellens JHM, Beijnen JH, Guchelaar HJ, Cats A. Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis. J Clin Oncol. 2023 Dec 10;41(35):5411-5421. doi: 10.1200/JCO.22.02780. Epub 2023 Aug 28.
PMID: 37639651DERIVEDHenricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Frederix GWJ, Kienhuis E, Creemers GJ, Baars A, Dezentje VO, Imholz ALT, Jeurissen FJF, Portielje JEA, Jansen RLH, Hamberg P, Ten Tije AJ, Droogendijk HJ, Koopman M, Nieboer P, van de Poel MHW, Mandigers CMPW, Rosing H, Beijnen JH, Werkhoven EV, van Kuilenburg ABP, van Schaik RHN, Mathijssen RHJ, Swen JJ, Gelderblom H, Cats A, Guchelaar HJ, Schellens JHM. DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol. 2018 Nov;19(11):1459-1467. doi: 10.1016/S1470-2045(18)30686-7. Epub 2018 Oct 19.
PMID: 30348537DERIVEDJacobs BA, Deenen MJ, Pluim D, van Hasselt JG, Krahenbuhl MD, van Geel RM, de Vries N, Rosing H, Meulendijks D, Burylo AM, Cats A, Beijnen JH, Huitema AD, Schellens JH. Pronounced between-subject and circadian variability in thymidylate synthase and dihydropyrimidine dehydrogenase enzyme activity in human volunteers. Br J Clin Pharmacol. 2016 Sep;82(3):706-16. doi: 10.1111/bcp.13007. Epub 2016 Jun 3.
PMID: 27161955DERIVED
MeSH Terms
Conditions
Interventions
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
JHM Schellens, MD, PhD
The Netherlands Cancer Institute
Study Design
- Study Type
- interventional
- Phase
- not applicable
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
December 9, 2014
First Posted
December 24, 2014
Study Start
March 1, 2015
Primary Completion
January 1, 2018
Study Completion
March 1, 2018
Last Updated
May 11, 2018
Record last verified: 2018-05