Neoplasms
Conditions
Keywords
Fluoropyrimidines, Phenotyping, Genotyping, Dose-individualization, Capecitabine, 5-Fluorouracil, 5-FU
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.
Interventions
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.
Sponsors
Leiden University Medical Center
The Netherlands Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | 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). |
Secondary
| Measure | Time frame |
|---|---|
| Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life | 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 |
| 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 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 |
Countries
Netherlands
Contacts
Primary ContactJonathan Knikman, PharmD
Backup ContactAnnemieke Cats, MD, PhD
Outcome results
None listed