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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01547923
Recruitment Status : Unknown
Verified March 2012 by ICO Paul Papin.
Recruitment status was:  Recruiting
First Posted : March 8, 2012
Last Update Posted : March 8, 2012
Information provided by (Responsible Party):
ICO Paul Papin

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.

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

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2296 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : June 2008
Estimated Primary Completion Date : December 2012
Estimated Study Completion Date : December 2012

Arm Intervention/treatment
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.

Primary Outcome Measures :
  1. 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 :
  1. 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.

  2. 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.

  3. 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01547923

Contact: Virginie Berger, MD, PhD 33 2 41 35 27 34
Contact: Jessy Delaye, M Sc 33 2 41 35 29 31

ICO Paul Papin Recruiting
Angers, France, 49933
Contact: Olivier Capitain, MD, PhD   
Principal Investigator: Olivier Capitain, MD, PhD         
CHU Jean Minjoz Recruiting
Besançon, France, 25000
Contact: Christophe Borg, MD   
Principal Investigator: Christophe Borg, MD         
CHU Morvan Not yet recruiting
Brest, France, 29609
Contact: Hélène Simon, MD   
Principal Investigator: Hélène Simon, MD         
CHU Côte de Nacre Recruiting
Caen, France, 14033
Contact: Karine Bouhier Leporrier, MD   
Principal Investigator: Karine Bouhier Leporrier, MD         
Centre François Baclesse Recruiting
Caen, France, 14076
Contact: Marie-Pierre Galais, MD   
Principal Investigator: Marie-Pierre Galais, MD         
Pôle Santé Léonard de Vinci Recruiting
Chambray-les-Tours, France, 37175
Contact: Pierre-Etienne Cailleux, MD   
Principal Investigator: Pierre-Etienne Cailleux, MD         
Centre Hospitalier du Haut Anjou Recruiting
Chateau-Gontier, France, 53204
Contact: Valérie Rossi, MD   
Principal Investigator: Valérie Rossi, MD         
Centre Hospitalier Recruiting
Cholet, France, 49325
Contact: Medhi Kaassis, MD   
Principal Investigator: Medhi Kaassis, MD         
Clinique des Cèdres Not yet recruiting
Cornebarrieu, France, 31700
Contact: Isabelle Roque, MD   
Principal Investigator: Isabelle Roque, MD         
Hôpital Henri Mondor Recruiting
Créteil, France, 94010
Contact: Isabelle Baumgaertner, MD   
Principal Investigator: Isabelle Baumgaertner, MD         
CH Sarthe et Loir Recruiting
La Flèche, France, 72205
Contact: Ludovic Rosenfeld, MD   
Principal Investigator: Ludovic Rosenfeld, MD         
Centre Hospitalier Les oudairies Recruiting
La Roche Sur Yon, France, 85929
Contact: Roger Faroux, MD   
Principal Investigator: Roger Faroux, MD         
Centre Hospitalier Recruiting
Laval, France, 53015
Contact: Claire Stampfli, MD   
Principal Investigator: Claire Stampfli, MD         
Centre Hospitalier Recruiting
Le Mans, France, 72037
Contact: Oana Cojocarasu, MD   
Principal Investigator: Oana Cojocarasu, MD         
Centre Oscar Lambret Recruiting
Lille, France, 53020
Contact: Eric Amela, MD   
Principal Investigator: Eric Amela, MD         
Centre d'oncologie de Gentilly Recruiting
Nancy, France, 54100
Contact: Célia Roemer-Becuwe, MD   
Principal Investigator: Celia Roemer Becuwe, MD         
CHU Hotel Dieu Recruiting
Nantes, France, 44093
Contact: Tamara Matysiak, MD   
Principal Investigator: Tamara Matysiak Budnik, MD         
Centre Antoine Lacassagne Recruiting
Nice, France, 06189
Contact: Eric François, MD   
Principal Investigator: Eric François, MD         
HEGP Not yet recruiting
Paris, France, 75015
Contact: Julien Taieb, MD   
Principal Investigator: Julien Taieb, MD         
Centre Hospitalier Lyon Sud Recruiting
Pierre Bénite, France, 69495
Contact: Cécile Fournel-Federico, MD   
Principal Investigator: Cécile Fournel Federico, MD         
Centre Hospitalier Recruiting
Saumur, France, 49403
Contact: Véronique Guérin-Meyer, MD   
Principal Investigator: Véronique Guérin-Meyer, MD         
ICO René Gauducheau Recruiting
St Herblain, France, 44805
Contact: Jaafar Bennouna, MD   
Principal Investigator: Jaafar Bennouna, MD         
Institut Claudius Regaud Recruiting
Toulouse, France, 31052
Contact: Jean-Pierre Delord, MD   
Principal Investigator: Jean-Pierre Delord, MD         
Hôpital Purpan Recruiting
Toulouse, France, 31059
Contact: Corinne Couteau, MD   
Principal Investigator: Corinne Couteau, MD         
CHU Trousseau Recruiting
Tours, France, 37044
Contact: Thierry Lecomte, MD   
Principal Investigator: Thierry Lecomte, MD         
Sponsors and Collaborators
ICO Paul Papin
Principal Investigator: Olivier Capitain, MD, PhD ICO Paul Papin

Responsible Party: ICO Paul Papin Identifier: NCT01547923     History of Changes
Other Study ID Numbers: CPP-380
2008-000026-39 ( EudraCT Number )
First Posted: March 8, 2012    Key Record Dates
Last Update Posted: March 8, 2012
Last Verified: March 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