Clinical trial NCT04194957: Improving the Safety of Fluoropyrimidine-based Chemotherapy
Official title: Improving the Safety of Fluoropyrimidine-based Chemotherapy by Combined DPYD Genotype-guided and DPD Phenotype-guided Dose Individualization: The ALPE2U Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Neoplasms
Keywords: Fluoropyrimidines
Phenotyping
Genotyping
Dose-individualization
Capecitabine
5-Fluorouracil
5-FU
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Leiden University Medical Center
First posted: 2019-12-11
Enrollment: 1440
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 phenotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient's best interest
2. Patient need to be of Western descent
3. Age ≥ 18
4. Able and willing to give written informed consent
5. WHO performance status of 0, 1 or 2
6. Able and willing to undergo extra blood sampling for study related analysis
7. Adequate baseline patient characteristics, in the opinion of the treating physician (complete blood count, hepatic function which involves serum bilirubin, AST, ALT, and renal function)

Exclusion Criteria:

1. Prior treatment with fluoropyrimidines
2. Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient's safety in the opinion of the treating physician
3. Patients treated with the combination of a fluoropyrimidine and irinotecan

Primary outcomes:
measure: Safety: incidence of severe fluoropyrimidine-related toxicity (CTCAE grade 3 to 5) in wild type patients
timeFrame: 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).
Secondary outcomes:
measure: 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
timeFrame: Patients will be followed during fluoropyrimidine treatment, expected average of 1 year
measure: Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life
timeFrame: During the first administration of fluoropyrimidine treatment
measure: Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective
timeFrame: Patients will be followed during fluoropyrimidine treatment, expected average of 1 year
measure: Assessment of feasibility of dose titration following an initial dose reduction
timeFrame: During fluoropyrimidine treatment, expected average of 1 year
measure: Assessment of geriatric parameters for grade 3-5 toxicity and/or treatment discontinuation
timeFrame: During fluoropyrimidine treatment, expected average of 1 year
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute - Antoni van Leeuwenhoek
Study officials:
affiliation: Netherlands Cancer Institute - Antoni van Leeuwenhoek
name: Annemieke Cats, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.