Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04269369
Recruitment Status : Not yet recruiting
First Posted : February 13, 2020
Last Update Posted : February 13, 2020
Sponsor:
Information provided by (Responsible Party):
Jessa Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Colon Cancer Stomach Tumor Anal Tumor Pancreas Cancer Esophageal Cancer Drug: 5-Fluorouracil Phase 4

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: In a subgroup of patients, a parallel study model will be used. In 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. After obtaining written informed consent, patients will be randomized in a 1:1 ratio to one of the two study groups.
Masking: None (Open Label)
Masking Description: The study is not blinded (not for the patients participating in the trial and not for the treating physicians).
Primary Purpose: Treatment
Official Title: Implementation of Pre-emptive Geno- and Phenotyping in 5-Fluorouracil- or Capecitabine-treated Patients With the Aim of Reducing Toxicity
Estimated Study Start Date : February 18, 2020
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2021


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.





Primary Outcome Measures :
  1. The frequency of severe fluoropyrimidine-related toxicity [ Time Frame: about 3 months ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04269369


Contacts
Layout table for location contacts
Contact: An Lambaerts +3211338461 an.lambaerts@jessazh.be
Contact: Liesbeth Decoutere +3211338411 liesbeth.decoutere@jessazh.be

Sponsors and Collaborators
Jessa Hospital
Investigators
Layout table for investigator information
Principal Investigator: An Lambaerts Jessa Hospital
Layout table for additonal information
Responsible Party: Jessa Hospital
ClinicalTrials.gov Identifier: NCT04269369    
Other Study ID Numbers: FluorouracilCapecitabine001
First Posted: February 13, 2020    Key Record Dates
Last Update Posted: February 13, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
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
Additional relevant MeSH terms:
Layout table for MeSH terms
Pancreatic Neoplasms
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Endocrine Gland Neoplasms
Pancreatic Diseases
Endocrine System Diseases
Fluorouracil
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs