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

Institut Cancerologie de l'Ouest

Status: Terminated

Conditions: Intravenous 5 Fluorouracile; Colorectal Cancer

Treatments: Genetic: Blood sample for phenotypic and pharmacogenetic analysis.

Study type: Interventional

Funder types: Other

Identifiers

NCT01547923

CPP-380

2008-000026-39 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1,142 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Prevention

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,142 participants in 2 patient groups

A : pre-therapeutic screening for DPD deficiency

Experimental group

Description:

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

Treatment:

Genetic: Blood sample for phenotypic and pharmacogenetic analysis.

Genetic: Blood sample for phenotypic and pharmacogenetic analysis.

B : no pretherapeutic research of DPD deficiency

Other group

Description:

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.

Treatment:

Genetic: Blood sample for phenotypic and pharmacogenetic analysis.

Genetic: Blood sample for phenotypic and pharmacogenetic analysis.