Pre-therapeutic Identification of Dihydropyrimidine Dehydrogenase Gene (DPD) Deficiency for Predicting Toxicity to Fluoropyrimidines

NCT ID: NCT01547923

Last Updated: 2020-03-25

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: NA
• Total Enrollment: 1142 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-06-16
• Study Completion Date: 2013-03-04

Brief Summary

The aim of this study is to demonstrate the medical and financial benefit of pre-therapeutic screening of DPD deficiency for predicting toxicity to fluoropyrimidines.

Detailed Description

The fluoropyrimidines, of which 5-Fluorouracil is the most important, represent a family of medication that is used in particular in cancerology. They are molecules widely used in cancerology since they can be found in nearly 45% of chemotherapy protocols and in the treatment of about 50% of cancers (colorectum, oesophagus, stomach, breast, upper digestive and respiratory tracts). They are not only used in metastatic situations but also more and more in adjuvant situations, in other words for patients treated for a localised tumour, presenting a risk of relapse. A severe toxic risk cannot be tolerated in these conditions, and the doctor should assure the maximum level of safety for his patients. These medicines are the cause of 3% of grade IV toxicity from the first or second administration, and for 0.3% of deaths. To this one can add on a total of 20 to 25% grade III-IV toxic events.

Anticancer treatment is mostly administered by body size and in the best of cases after a few basic biological examinations such as a haemogram and renal status, without taking into consideration any individual particularities, whether genetic or epigenetic. Among potential toxicity risk factors one can find individual metabolic differences linked to genetic modifications of metabolism enzymes as well as differences in the chemical receptors and transporters.

For fluoropyrimidines, a polymorphism was found for the dihydropyrimidine dehydrogenase gene (DPD), a major catabolism enzyme. A deficit of this enzyme is a major counter-indication for the use of these medicines.

Early determination of DPD status would allow identification of patients at risk and would thus help in subsequent dose adjustment or selection of other treatment modalities.

Conditions

Colorectal Cancer; Intravenous 5 Fluorouracile

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

A : pre-therapeutic screening for DPD deficiency

Prior to treatment by fluoropyrimidines,a DPD deficiency is identified by a joint phenotypic-pharmacogenetic approach.

Group Type: EXPERIMENTAL

Blood sample for phenotypic and pharmacogenetic analysis.

Intervention Type: GENETIC

Prior to treatment by 5-FU, a DPD deficiency is identified thanks to just one blood sample (lithium heparinate).

B : no pretherapeutic research of DPD deficiency

For patients included in this arm, a blood sample will be taken prior to treatment by fluoropyrimidines but not analysed. If grade 3 or 4 toxicity levels are encountered during treatment, DPD deficiency will be detected.

Group Type: OTHER

Blood sample for phenotypic and pharmacogenetic analysis.

Intervention Type: GENETIC

Blood sample (lithium heparinate) will be taken prior to treatment but not analysed.

Interventions

Blood sample for phenotypic and pharmacogenetic analysis.

Prior to treatment by 5-FU, a DPD deficiency is identified thanks to just one blood sample (lithium heparinate).

Intervention Type: GENETIC

Blood sample for phenotypic and pharmacogenetic analysis.

Blood sample (lithium heparinate) will be taken prior to treatment but not analysed.

Intervention Type: GENETIC

Eligibility Criteria

Inclusion Criteria

• colorectal cancer, histologically confirmed, with all types included (including adjuvant cases), requiring treatment with intravenous 5-fluorouracil.
• anterior chemotherapy authorised, with the exception of chemotherapy containing a derivate of 5-Fluorouracil
• Age > or = 18 years
• WHO Performance status < or = 2
• Haematologic and hepatic parameters : neutrophils > or = 1000 /mm3, platelets > or = 100000/mm3, Total bilirubin < or = 2 x ULN, AST and ALT < or = 3 x ULN, APL < or = 5 x ULN
• Complete initial assessment before first treatment administration for imaging and pharmacogenetic, within 15 days for biology, and within 7 days for clinical examination.
• Signed written informed consent

Exclusion Criteria

• Prior chemotherapy with fluoropyrimidines
• Symptomatic or uncontrolled ventral nervous system metastases
• Psychiatric Disease disrupting the trial understanding and the enlightened and voluntary consent character
• Patient who is pregnant or breast feeding
• Woman not consenting to use adequate contraceptive precautions during the study
• Patient who can not submit itself to the formal follow-up for psychological, social, family or geographical reasons
• Significant serious pathology or any instable medical condition (cardiac pathology uncontrolled, myocardial infarction within 6 months before enrollment, systemic active uncontrolled infection)
• any investigational agent within 4 weeks before enrollment

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Institut Cancerologie de l'Ouest

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Olivier Capitain, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Institut Cancerologie de l'Ouest

Locations

ICO Paul Papin

Angers, , France

CHU Jean Minjoz

Besançon, , France

CHU Morvan

Brest, , France

CHU Côte de Nacre

Caen, , France

Centre François Baclesse

Caen, , France

Pôle Santé Léonard de Vinci

Chambray-lès-Tours, , France

Centre Hospitalier du Haut Anjou

Château-Gontier, , France

Centre Hospitalier

Cholet, , France

Clinique des Cèdres

Cornebarrieu, , France

Hôpital Henri Mondor

Créteil, , France

CH Sarthe et Loir

La Flèche, , France

Centre Hospitalier Les oudairies

La Roche-sur-Yon, , France

Centre Hospitalier

Laval, , France

Centre Hospitalier

Le Mans, , France

Centre Oscar Lambret

Lille, , France

Centre d'oncologie de Gentilly

Nancy, , France

CHU Hotel Dieu

Nantes, , France

Centre Antoine Lacassagne

Nice, , France

HEGP

Paris, , France

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

ICO René Gauducheau

Saint-Herblain, , France

Centre Hospitalier

Saumur, , France

Institut Claudius Regaud

Toulouse, , France

Hôpital Purpan

Toulouse, , France

CHU Trousseau

Tours, , France

Countries

France

Other Identifiers

2008-000026-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CPP-380

Identifier Type: -

Identifier Source: org_study_id