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| ID | Type | Description | Link |
|---|---|---|---|
| 2014-005064-15 | EudraCT Number |
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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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| heterozygous carrier of DPYD variant | Experimental | 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 |
|
| wild type for DPYD | Experimental | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective | 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. | patients will be followed during fluoropyrimidine treatment, expected average of 1 year |
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Inclusion Criteria:
Additional inclusion criteria for patients in subgroup of study:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| JHM Schellens, MD, PhD | The Netherlands Cancer Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital | Amsterdam | Netherlands | ||||
| Wilhelmina Hospital Assen |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37957132 | Derived | 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. | |
| 37639651 | Derived |
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| DPD phenotype, defined as deficient or not deficient | 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 | 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 | 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 | At first week of start of fluoropyrimidine treatment of the patient |
| 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 |
| 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. |
| 30348537 | Derived | 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. |
| 27161955 | Derived | 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. |
| ID | Term |
|---|---|
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D000069287 | Capecitabine |
| D005472 | Fluorouracil |
| ID | Term |
|---|---|
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
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