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

Sponsor

Institut Cancerologie de l'Ouest (Other)

Overall Status

Terminated

CT.gov ID

NCT01547923

Collaborator

(none)

1,142

Enrollment

Locations

Arms

56.6

Actual Duration (Months)

45.7

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

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. Genetic: Blood sample for phenotypic and pharmacogenetic analysis.	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

1142 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

Actual Study Start Date :

Jun 16, 2008

Actual Primary Completion Date :

Mar 1, 2013

Actual Study Completion Date :

Mar 4, 2013

Arms and Interventions

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).
Other: 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.

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).

Other: 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.

Outcome Measures

Primary Outcome Measures

Number and nature of grade IV toxicity. [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. [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. [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. [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	ICO Paul Papin	Angers	France	49933
2	CHU Jean Minjoz	Besançon	France	25000
3	CHU Morvan	Brest	France	29609
4	CHU Côte de Nacre	Caen	France	14033
5	Centre François Baclesse	Caen	France	14076
6	Pôle Santé Léonard de Vinci	Chambray-les-Tours	France	37175
7	Centre Hospitalier du Haut Anjou	Chateau-Gontier	France	53204
8	Centre Hospitalier	Cholet	France	49325
9	Clinique des Cèdres	Cornebarrieu	France	31700
10	Hôpital Henri Mondor	Créteil	France	94010
11	CH Sarthe et Loir	La Flèche	France	72205
12	Centre Hospitalier Les oudairies	La Roche Sur Yon	France	85929
13	Centre Hospitalier	Laval	France	53015
14	Centre Hospitalier	Le Mans	France	72037
15	Centre Oscar Lambret	Lille	France	53020
16	Centre d'oncologie de Gentilly	Nancy	France	54100
17	CHU Hotel Dieu	Nantes	France	44093
18	Centre Antoine Lacassagne	Nice	France	06189
19	HEGP	Paris	France	75015
20	Centre Hospitalier Lyon Sud	Pierre Bénite	France	69495
21	Centre Hospitalier	Saumur	France	49403
22	ICO René Gauducheau	St Herblain	France	44805
23	Institut Claudius Regaud	Toulouse	France	31052
24	Hôpital Purpan	Toulouse	France	31059
25	CHU Trousseau	Tours	France	37044