Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines
NCT ID: NCT02324452
Last Updated: 2018-05-11
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
NA
1103 participants
INTERVENTIONAL
2015-03-31
2018-03-31
Brief Summary
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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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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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heterozygous carrier of DPYD variant
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
Fluoropyrimidine (capecitabine or 5-fluorouracil)
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.
wild type for DPYD
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
Fluoropyrimidine (capecitabine or 5-fluorouracil)
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.
Interventions
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Fluoropyrimidine (capecitabine or 5-fluorouracil)
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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)
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
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
18 Years
ALL
No
Sponsors
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The Netherlands Cancer Institute
OTHER
Responsible Party
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Principal Investigators
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JHM Schellens, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
The Netherlands Cancer Institute
Locations
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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
Countries
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References
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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.
Knikman 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.
Henricks 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.
Jacobs 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.
Other Identifiers
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2014-005064-15
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
M14DPD
Identifier Type: -
Identifier Source: org_study_id
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