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The Enzymatic Activity of Lymphocyte Dihydropyrimidine Dehydrogenase DPD in the Blood as a Predictive and Prognostic Factor in Patients With Digestive Cancer in the First or Second Metastatic Line (DPD DIG)

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ClinicalTrials.gov Identifier: NCT03205735
Recruitment Status : Recruiting
First Posted : July 2, 2017
Last Update Posted : July 23, 2019
Sponsor:
Information provided by (Responsible Party):
Centre Antoine Lacassagne

Brief Summary:
An observational study of a prospective, analytical, monocentric cohort which does not modify the patient care because the phenotyping of the dihydropyrimidine déshydrogénase DPD (lymphocyte activity) is already carried out in routine hospital. The analysis will be based on clinical, radiological and biological criteria.

Condition or disease Intervention/treatment
Metastatic or Locally-advanced Digestive Cancer Diagnostic Test: lymphocyte DPD dosage

Detailed Description:

Used for nearly sixty years, 5-fluorouracil (5-FU) is the oldest drug prescribed in the treatment of digestive cancers and, still today, the most prescribed drug in digestive cancer. 5-FU belongs to the class of anti-metabolites. There is an oral precursor of 5-FU which is currently available and used in digestive cancer: Xeloda® (capecitabine).

The problem is that fluoropyrimidines are 80% metabolised to 5-fluoro-5,6-dihydrouracil (5-FUH2) by a key enzyme: dihydropyrimidine dehydrogenase (DPD). There is inter-individual variability in the activity of this enzyme, partly related to genetic factors [1]. An abundant literature has already shown that a decrease in the activity of this enzyme results in an increase in the half-life of 5-FU. Thus, patients with a deficit in DPD activity have a risk of overexposure to chemotherapy in this class, and consequently an increased risk of acute, early and severe toxicity.

Since the 1990th years, many authors have shown that there is considerable inter-individual variability in the plasma concentration of 5 FU after bolus [5] or continuous infusion [6]. These variations in plasma concentrations of 5FU are probably related to a 5-FU catabolism variability related to the activity of DPD.

It has also been shown that there is a correlation between 5FU plasma level, tumor response and toxicity [7, 8]. A Phase III study showed that there was a significant impact on the response rate (33.7% VS 18.3%) p = 0.004 if doses of 5-FU were adjusted to plasma levels of 5-FU versus body surface [9]. Median survival was 16 months in the control arm versus 22 months in the experimental arm (P = 0.08), with severe grade 3-4 toxicities statistically increased in the control arm (p = 0.03). An adaptation of doses of 5-FU to the body surface, as it is done today, is in conclusion insufficient to obtain reproducible plasma concentrations due to an interindividual variability of the metabolism, linked to the activity of the DPD .

These data suggest that DPD activity, by modulating plasma concentration, may be a predictive factor of fluoropyrimidine response and also a prognostic factor. To our knowledge, there are no studies that have demonstrated a direct link between DPD activity, tumor response, and survival impact. Recently, Chamorey and al. [10] showed that the high level of DPD enzyme activity (> 0.30 nmol / min / mg protein) was significantly correlated with lower overall survival and progression-free survival. This was a retrospective analysis of 130 patients treated with fluoropyrimidines regardless of the tumor primitive (digestive, breast, ENT).

These results, presented in spite of their significance, are the result of a retrospective study that is subject, as a minimum, to selection bias. It therefore seemed important to make a prospective study, centered on digestive cancers. The prospective nature will limit selection bias and restriction to digestive cancers in which fluoropyrimidines have a main function and limit confunding biases. The selection of the first and second lines of palliative chemotherapy will increase the population studied and thus the power of the statistical analysis.

If the initial results were confirmed, this will allow DPD to be approached from a new angle and will encourage multicenter controlled prospective studies with the Antoine-Lacassagne center as the national promotor.

In our study, we decided to evaluate DPD activity using an enzymatic radio technique that directly evaluates the activity of the enzyme in blood lymphocytes, which is the original technique and the oldest.


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Study Type : Observational [Patient Registry]
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 24 Months
Official Title: The Enzymatic Activity of Lymphocyte Dihydropyrimidine Dehydrogenase DPD in the Blood as a Predictive and Prognostic Factor in Patients With Digestive Cancer in the First or Second Metastatic Line
Actual Study Start Date : June 29, 2017
Estimated Primary Completion Date : September 29, 2019
Estimated Study Completion Date : December 29, 2019

Group/Cohort Intervention/treatment
normal DPD result group
patients group with a normal DPD result
Diagnostic Test: lymphocyte DPD dosage
lymphocyte DPD dosage in peripheral blood

elevated DPD result group
patients group with an elevated DPD result
Diagnostic Test: lymphocyte DPD dosage
lymphocyte DPD dosage in peripheral blood




Primary Outcome Measures :
  1. progression free survival [ Time Frame: june 2019 ]
    progression free survival calculated between diagnosis date and progression date or death date


Secondary Outcome Measures :
  1. overall survival [ Time Frame: june 2019 ]
    overall survival calculated between diagnosis date and lastest news date or death

  2. treatment response [ Time Frame: june 2019 ]
    treatment response defined according to RECIST 1.1 criteria

  3. toxicities evaluation [ Time Frame: june 2019 ]
    toxicities evaluated according to NCI-CTCAE version 4.0



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Metastatic or locally-advanced digestive cancer
Criteria

Inclusion Criteria:

  • Be > or = to 18 of age on day of signing informed consent
  • ECOG 0 to 2,
  • Patient with digestive cancer, all histologic type,
  • Patient who will receive a metastatic or locally-advanced first or second line treatment by 5-FU or capecitabine,
  • Patient with measurable lesions based on RECIST 1.1 criteria,
  • Be willing and able to provide written informed consent/assent for the trial,
  • Health care insurance available

Exclusion Criteria:

  • Be < to 18 of age on day of signing informed consent,
  • Patient without measurable lesion based on RECIST 1.1 criteria,
  • ECOG > 2,
  • Patients refusing to participate in the study or unable to give an oral consent,
  • Contraindication of 5-FU or capecitabine treatment,
  • People particularly vulnerable as defined in Articles L.1121-5 to -8 of the French Healthcare Code, including: person deprived of freedom by an administrative or judicial decision, adult being the object of a legal protection measure or outside state to express their consent, pregnant or breastfeeding women.

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 ClinicalTrials.gov identifier (NCT number): NCT03205735


Contacts
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Contact: Eric FRANCOIS, Dr +33 4 92031163 eric.francois@nice.unicancer.fr

Locations
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France
Centre Antoine Lacassagne Recruiting
Nice, France, 06000
Contact: Eric FRANCOIS, Md    +33492031663    eric.francois@nice.unicancer.fr   
Principal Investigator: Eric FRANCOIS, md         
Sponsors and Collaborators
Centre Antoine Lacassagne

Additional Information:

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Responsible Party: Centre Antoine Lacassagne
ClinicalTrials.gov Identifier: NCT03205735     History of Changes
Other Study ID Numbers: 2017/25
First Posted: July 2, 2017    Key Record Dates
Last Update Posted: July 23, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases