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

Colorectal Cancer Clinical Trial

— DPD côlon  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01547923
• Other study ID #: CPP-380
• Secondary ID: 2008-000026-39
• Status: Terminated
• Phase: N/A
• Start date: June 16, 2008
• Est. completion date: March 4, 2013

Study information

• Verified date: March 2020
• Source: Institut Cancerologie de l'Ouest
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1142
• Est. completion date: March 4, 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Intravenous 5 Fluorouracile

Intervention

Genetic:
• 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).
• Blood sample for phenotypic and pharmacogenetic analysis.
Blood sample (lithium heparinate) will be taken prior to treatment but not analysed.

Locations

Country	Name	City	State
France	ICO Paul Papin	Angers
France	CHU Jean Minjoz	Besançon
France	CHU Morvan	Brest
France	Centre François Baclesse	Caen
France	CHU Côte de Nacre	Caen
France	Pôle Santé Léonard de Vinci	Chambray-les-Tours
France	Centre Hospitalier du Haut Anjou	Chateau-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	Centre Hospitalier	Saumur
France	ICO René Gauducheau	St Herblain
France	Hôpital Purpan	Toulouse
France	Institut Claudius Regaud	Toulouse
France	CHU Trousseau	Tours

Sponsors (1)

Lead Sponsor	Collaborator
Institut Cancerologie de l'Ouest

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number and nature of grade IV toxicity.	The percentage of severe toxicity (grade IV) will be analyzed in each arm. We expect a reduction of the early, severe, grade IV acute side-effects from 3% to 0.6% in the detected group with adapted doses.	Up to 4 weeks.
Secondary	Number of grade III-IV toxic events.	We expect a reduction of the number of grade III-IV toxic events, whenever they occur, from 25% to 5% in the detected group with adapted doses.	Up to 6 months.
Secondary	Mortality rate.	The current mortality rate of 3 per thousand patients will be cut to 0 in the detected group with adapted doses.	up to 6 months.
Secondary	Medical-financial study of pre-therapeutic screening.	We will carry out a comparison of the prevention costs and the costs related to treating patients with toxicity. Direct costs and indirect costs will be taken into account.	Up to 6 months.