Improving the Safety of Fluoropyrimidine-based Chemotherapy

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 phenotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.

Detailed Description
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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.

Official Title
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Improving the Safety of Fluoropyrimidine-based Chemotherapy by Combined DPYD Genotype-guided and DPD Phenotype-guided Dose Individualization: The ALPE2U Study

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)
* Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)
* 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 Patient need to be of Western descent Age ≥ 18 Able and willing to give written informed consent WHO performance status of 0, 1 or 2 Able and willing to undergo extra blood sampling for study related analysis 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: 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 in the opinion of the treating physician Patients treated with the combination of a fluoropyrimidine and irinotecan

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: 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>* 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.<br>|
| Experimental: heterozygous carrier of c.1236G>A or c.2846A>T 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 c.1236G>A or c.2846A>T of these SNPs | Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)<br>* 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.<br>|
| Experimental: Homozygous or compound heterozygous carrier of DPYD variants<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 homozygous or compound heterozygous for these SNPs | Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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). | 

Secondary Outcome Measures

| Outcome Measure | 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 |  | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fluoropyrimidines, Phenotyping, Genotyping, Dose-individualization, Capecitabine, 5-Fluorouracil, 5-FU