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| Name | Class |
|---|---|
| Leiden University Medical Center | OTHER |
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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 phenotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.
In this study a phenotypic approach will be studied to determine the additional value of pretreatment uracil level-guided dose individualization in wildtype patients. Patients with a pretreatment serum uracil concentration above 16 ng/ml will be treated with a 50% reduced fluoropyrimidine starting dose. The pretreatment serum uracil levels in DPYD variant carriers will be assessed retrospectively and non-interventional. Additionally, the effect of a higher dose reduction in c.1236G>A and c.2846A>T DPYD variants carriers (50% instead of 25%) will be studied.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 |
|
| heterozygous carrier of c.1236G>A or c.2846A>T 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 c.1236G>A or c.2846A>T of these SNPs |
|
| Homozygous or compound heterozygous carrier of DPYD variants | 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 homozygous or compound heterozygous for these SNPs |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fluoropyrimidine (capecitabine or 5-fluorouracil) | Drug | Patients that are found to be wild type and have a pre-treatment uracil concentration above 16 ng/mL will receive a reduced dosage of capecitabine or 5-fluorouracil (50% reduction). The dose will be titrated after 2 cycles , to achieve maximal safe exposure. Patients that are wildtype with a uracil concentration below 16 ng/mL will receive a normal (full) dose. |
| Measure | Description | Time Frame |
|---|---|---|
| Safety: incidence of severe fluoropyrimidine-related toxicity (CTCAE grade 3 to 5) in wild type patients | Patients with a pre-treatment uracil concentration above 16 ng/ml will be followed until end of treatment (expected average of 1 year). Otherwise, patients will be followed for the first 2 cycles (each cycle is 28 days). |
| Measure | Description | Time Frame |
|---|---|---|
| Safety: incidence of severe treatment-related toxicity (CTCAE grade 3 to 5) in heterozygous carriers of c.1236G>A or c.2846A>T DPYD variants | Patients will be followed during fluoropyrimidine treatment, expected average of 1 year | |
| Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jonathan Knikman, PharmD | Contact | +31 (0)20 512 9111 | j.knikman@nki.nl | |
| Annemieke Cats, MD, PhD | Contact | a.cats@nki.nl |
| Name | Affiliation | Role |
|---|---|---|
| Annemieke Cats, MD, PhD | Netherlands Cancer Institute - Antoni van Leeuwenhoek | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Netherlands Cancer Institute - Antoni van Leeuwenhoek | Recruiting | Amsterdam | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30348537 | Background | 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. | |
| 33020924 |
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| 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 |
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|
| Fluoropyrimidine (capecitabine or 5-fluorouracil) | Drug | Patients that are heterozygous carriers of c.1236G>A or c.2846A>T DPYD variant will receive a reduced dosage of capecitabine or 5-FU (50 % reduction). The dose will be titrated after 2 cycles, to achieve maximal safe exposure. |
|
| Fluoropyrimidine (capecitabine or 5-fluorouracil) | Drug | Patients with homozygous or compound heterozygous DPYD variants will be treated with a reduced dose of capecitabine or 5-FU based on the DPD enzyme activity measured in peripheral blood mononuclear cells. |
|
| During the first administration of fluoropyrimidine treatment |
| 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 |
| Assessment of feasibility of dose titration following an initial dose reduction | During fluoropyrimidine treatment, expected average of 1 year |
| Assessment of geriatric parameters for grade 3-5 toxicity and/or treatment discontinuation | During fluoropyrimidine treatment, expected average of 1 year |
| Derived |
| Knikman JE, Gelderblom H, Beijnen JH, Cats A, Guchelaar HJ, Henricks LM. Individualized Dosing of Fluoropyrimidine-Based Chemotherapy to Prevent Severe Fluoropyrimidine-Related Toxicity: What Are the Options? Clin Pharmacol Ther. 2021 Mar;109(3):591-604. doi: 10.1002/cpt.2069. Epub 2020 Nov 12. |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |