Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines

Study Overview
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Brief Summary
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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.

Official Title
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Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient's best interest Age ≥ 18 years Able and willing to give written informed consent WHO performance status of 0, 1 or 2 Life expectancy of at least 12 weeks Able to swallow and retain oral medication Able and willing to undergo blood sampling for pharmacogenetic and phenotyping analysis Minimal acceptable safety laboratory values (ANC, platelet count, hepatic function, renal function) Additional inclusion criteria for patients in subgroup of study: Able and willing to undergo blood sampling and breath sampling at several time points Able and willing to receive uracil for the test dose assay Able and willing to receive [2-13C] -labeled uracil for the breath test Exclusion Criteria: Prior treatment with fluoropyrimidines Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient's safety Women who are pregnant or breast feeding 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) Patients with a homozygous polymorphic genotype or compound heterozygous genotype for DPYD

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: heterozygous carrier of DPYD variant<br>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 | Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)<br>* 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.<br>* Other names: 5-FU;|
| Experimental: wild type for DPYD<br>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 | Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)<br>* 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.<br>* Other names: 5-FU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 
| 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 |