Implementation of Pre-emptive Geno- and Phenotyping in 5-Fluorouracil- or Capecitabine-treated Patients

Implementation of Pre-emptive Geno- and Phenotyping in 5-Fluorouracil- or Capecitabine-treated Patients With the Aim of Reducing Toxicity

The aim of this study is to investigate if the systematic implementation of pre-emptive geno- and phenotyping, and therefore a dose reduction based on the French guidelines and the literature during the first month of treatment, reduces grade 3 or greater toxicity in patients treated with 5-FU (5-fluorouracil) or capecitabine.

Therefore, a monocentric, partial prospective and partial retrospective trail was designed.

Study Overview

• Status: Unknown
• Conditions: Esophageal Cancer; Colon Cancer; Pancreas Cancer; Stomach Tumor; Anal Tumor
• Intervention / Treatment: Drug: 5-Fluorouracil

Detailed Description

5-FU (5-fluorouracil) and its oral prodrug capecitabine are commonly used drugs in various chemotherapy regimens. According to the literature, approximately 30% of the patients experience at least a grade three toxicity during treatment, mainly characterized by diarrhea, mucositis, hematological toxicity or hand-foot syndrome. This toxicity can lead to discontinuation or interruption of the therapy, hospitalization and in 1% of the cases even to mortality. This leads to an increase in health care costs, mainly driven by the cost of hospitalization.

The metabolism of 5-FU and its prodrug is primarily determined by the dehydropyrimidine dehydrogenase (DPD) enzyme. The gene encoding for this enzyme, the DPYD, is known for his genetic polymorphism. Five percent of the population has a partial DPYD deficiency and 0.01 to 0.1 percent has a full DPYP deficiency. Partial deficiency leads to a reduced activity of DPD and therefore to a reduced degradation of 5-FU or capecitabine to its inactive metabolites. This leads to an increased toxicity. The four DPYD variants considered most clinically relevant are DPYD * 2A, DPYD * 13, c.1236G> A and c.2846A> T. Patients with polymorphisms DPYD * 2A and DPYD * 13 have no residual enzyme activity, while in patients with polymorphisms 1236G> A and c.2846A> T, there is still partial enzyme activity present. In addition to genotyping, partial DPYD deficiency can also be detected by phenotyping. In the case of reduced enzyme activity of DPYD, the degradation of uracil is disturbed, causing an increase in uracil and a decrease in UH2 in plasma. There is a strong correlation between the UH2 / U ratio in plasma and the halflife, clearance and plasma levels of 5-FU.

French guidelines, HAS (La Haute Autorité de santé), recommend to adjust the dose of these drugs at the start of treatment based on the results of both the genetic and phenotypic studies.

The aim of this study is to investigate if the systematic implementation of pre-emptive geno- and phenotyping, and therefore a dose reduction based on the French guidelines and the literature during the first month of treatment, reduces grade 3 or greater toxicity in patients treated with 5-FU or capecitabine.

Therefore, a monocentric, partial prospective and partial retrospective trail was designed.

• Study Type: Interventional
• Enrollment (Anticipated): 250
• Phase: Phase 4

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients aged 18 years or older
• WHO (world health organization) classification 0,1 or 2
• A suspected start with 5-FU or capecitabine in mono or combination therapy
• The knowledge of the result of the geno and phenotyping before the start of the treatment

Exclusion Criteria:

• Not meeting inclusion criteria
• Homozygote genotype or uracil 100 ng/ml or greater
• The lacking of the result of the geno and / or phenotyping before the start of treatment
• Patients who received 5-FU or capecitabine in the past

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group A; Dosage according to French guidelines	Drug: 5-Fluorouracil; The aim of this study is to investigate if the systematic implementation of pre-emptive geno- and phenotyping, and therefore a dose reduction based on the French guidelines and the literature during the first month of treatment, reduces grade 3 or greater toxicity in patients treated with 5-FU or capecitabine. Therefore a dosing table was obtained by combining the results of the study by Henricks et al., Launay et al. and Yang et al. and the recommendations from the French HAS guideline. The treatment schedule then will be discussed by the team of doctors and paramedics at the weekly MOC (multidisciplinary cancer consultation). Complementary, the pharmacist provides dose advice with regard to the start of 5-FU or capecitabine treatment. In a subgroup, the group of patients with genotype "wild type" and phenotype "intermediate metabolizer", a comparison will be made between group A with dosage according to French guidelines and group B with dosage according to literature.
EXPERIMENTAL: Group B; Dosage according to literature	Drug: 5-Fluorouracil; The aim of this study is to investigate if the systematic implementation of pre-emptive geno- and phenotyping, and therefore a dose reduction based on the French guidelines and the literature during the first month of treatment, reduces grade 3 or greater toxicity in patients treated with 5-FU or capecitabine. Therefore a dosing table was obtained by combining the results of the study by Henricks et al., Launay et al. and Yang et al. and the recommendations from the French HAS guideline. The treatment schedule then will be discussed by the team of doctors and paramedics at the weekly MOC (multidisciplinary cancer consultation). Complementary, the pharmacist provides dose advice with regard to the start of 5-FU or capecitabine treatment. In a subgroup, the group of patients with genotype "wild type" and phenotype "intermediate metabolizer", a comparison will be made between group A with dosage according to French guidelines and group B with dosage according to literature.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The frequency of severe fluoropyrimidine-related toxicity	The primary endpoint of the study is the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 5 grade ≥3) fluoropyrimidine-related toxicity across the entire treatment duration. Toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients and poor or intermediate metabolizers and extensive metabolizers will be compared.	about 3 months

Collaborators and Investigators

• Sponsor: Jessa Hospital
• Investigators: Principal Investigator: An Lambaerts, Jessa Hospital

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): February 18, 2020
• Primary Completion (ANTICIPATED): September 30, 2021
• Study Completion (ANTICIPATED): September 30, 2021

Study Registration Dates

• First Submitted: February 11, 2020
• First Submitted That Met QC Criteria: February 12, 2020
• First Posted (ACTUAL): February 13, 2020

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2020
• Last Update Submitted That Met QC Criteria: February 12, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fluorouracil
• Other Study ID Numbers: FluorouracilCapecitabine001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No