Clinical trial NCT01547923: Pre-therapeutic Identification of Dihydropyrimidine Dehydrogenase Gene (DPD) Deficiency for Predicting Toxicity to Fluoropyrimidines
Official title: The Medical-financial Evaluation of Pre-therapeutic Screening by a Joint Phenotypic-pharmacogenetic Approach for Metabolic Fluoropyrimidine Enzyme Deficiency in Terms of Serious Toxicity Risk Prevention : a Multicentric Case Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Colorectal Cancer
Intravenous 5 Fluorouracile
Keywords: Colorectal Cancer
DihydroPyrimidine Dehydrogenase
Lethal toxicity
Fluoropyrimidine
Lead sponsor: Institut Cancerologie de l'Ouest
Sponsor class: OTHER
First posted: 2012-03-08
Enrollment: 1142
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Number and nature of grade IV toxicity.
timeFrame: Up to 4 weeks.
Secondary outcomes:
measure: Number of grade III-IV toxic events.
timeFrame: Up to 6 months.
measure: Mortality rate.
timeFrame: up to 6 months.
measure: Medical-financial study of pre-therapeutic screening.
timeFrame: Up to 6 months.
Other outcomes:
Locations:
city: Angers
country: France
facility: ICO Paul Papin
city: Besançon
country: France
facility: CHU Jean Minjoz
city: Brest
country: France
facility: CHU Morvan
city: Caen
country: France
facility: CHU Côte de Nacre
city: Caen
country: France
facility: Centre François Baclesse
city: Chambray-les-Tours
country: France
facility: Pôle Santé Léonard de Vinci
city: Chateau-Gontier
country: France
facility: Centre Hospitalier du Haut Anjou
city: Cholet
country: France
facility: Centre Hospitalier
city: Cornebarrieu
country: France
facility: Clinique des Cèdres
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: La Flèche
country: France
facility: CH Sarthe et Loir
city: La Roche Sur Yon
country: France
facility: Centre Hospitalier Les oudairies
city: Laval
country: France
facility: Centre Hospitalier
city: Le Mans
country: France
facility: Centre Hospitalier
city: Lille
country: France
facility: Centre Oscar Lambret
city: Nancy
country: France
facility: Centre d'oncologie de Gentilly
city: Nantes
country: France
facility: CHU Hotel Dieu
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: HEGP
city: Pierre Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Saumur
country: France
facility: Centre Hospitalier
city: St Herblain
country: France
facility: ICO René Gauducheau
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Toulouse
country: France
facility: Hôpital Purpan
city: Tours
country: France
facility: CHU Trousseau
Study officials:
affiliation: Institut Cancerologie de l'Ouest
name: Olivier Capitain, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: