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

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified March 2012 by ICO Paul Papin.
Recruitment status was:  Recruiting
Information provided by (Responsible Party):
ICO Paul Papin Identifier:
First received: February 28, 2012
Last updated: March 5, 2012
Last verified: March 2012
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.

Condition Intervention Phase
Colorectal Cancer
Intravenous 5 Fluorouracile
Genetic: Blood sample for phenotypic and pharmacogenetic analysis.
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
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

Further study details as provided by ICO Paul Papin:

Primary Outcome Measures:
  • Number and nature of grade IV toxicity. [ Time Frame: Up to 4 weeks. ]
    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.

Secondary Outcome Measures:
  • Number of grade III-IV toxic events. [ Time Frame: Up to 6 months. ]
    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.

  • Mortality rate. [ Time Frame: up to 6 months. ]
    The current mortality rate of 3 per thousand patients will be cut to 0 in the detected group with adapted doses.

  • Medical-financial study of pre-therapeutic screening. [ Time Frame: Up to 6 months. ]
    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.

Estimated Enrollment: 2296
Study Start Date: June 2008
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A : pre-therapeutic screening for DPD deficiency
Prior to treatment by fluoropyrimidines,a DPD deficiency is identified by a joint phenotypic-pharmacogenetic approach.
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).
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.
Genetic: Blood sample for phenotypic and pharmacogenetic analysis.
Blood sample (lithium heparinate) will be taken prior to treatment but not analysed.

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.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
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Please refer to this study by its identifier: NCT01547923

ICO Paul Papin
Angers, France, 49933
CHU Jean Minjoz
Besançon, France, 25000
CHU Morvan
Brest, France, 29609
CHU Côte de Nacre
Caen, France, 14033
Centre François Baclesse
Caen, France, 14076
Pôle Santé Léonard de Vinci
Chambray-les-Tours, France, 37175
Centre Hospitalier du Haut Anjou
Chateau-Gontier, France, 53204
Centre Hospitalier
Cholet, France, 49325
Clinique des Cèdres
Cornebarrieu, France, 31700
Hôpital Henri Mondor
Créteil, France, 94010
CH Sarthe et Loir
La Flèche, France, 72205
Centre Hospitalier Les oudairies
La Roche Sur Yon, France, 85929
Centre Hospitalier
Laval, France, 53015
Centre Hospitalier
Le Mans, France, 72037
Centre Oscar Lambret
Lille, France, 53020
Centre d'oncologie de Gentilly
Nancy, France, 54100
CHU Hotel Dieu
Nantes, France, 44093
Centre Antoine Lacassagne
Nice, France, 06189
Paris, France, 75015
Centre Hospitalier Lyon Sud
Pierre Bénite, France, 69495
Centre Hospitalier
Saumur, France, 49403
ICO René Gauducheau
St Herblain, France, 44805
Institut Claudius Regaud
Toulouse, France, 31052
Hôpital Purpan
Toulouse, France, 31059
CHU Trousseau
Tours, France, 37044
Sponsors and Collaborators
ICO Paul Papin
Principal Investigator: Olivier Capitain, MD, PhD ICO Paul Papin
  More Information

Responsible Party: ICO Paul Papin Identifier: NCT01547923     History of Changes
Other Study ID Numbers: CPP-380  2008-000026-39 
Study First Received: February 28, 2012
Last Updated: March 5, 2012

Keywords provided by ICO Paul Papin:
Colorectal Cancer
DihydroPyrimidine Dehydrogenase
Lethal toxicity

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases processed this record on February 20, 2017