Coproporphyrine Isomers and Methotrexate Elimination (COMETH)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT00822432
First received: January 13, 2009
Last updated: July 30, 2012
Last verified: January 2009
  Purpose

High dose methotrexate (MTX) is responsible of severe toxicity in patients in whom elimination from plasma is delayed. Factors responsible for MTX accumulation are partly known but some patients still experience toxicity despite adequate measures being taken. Our hypothesis is that renal tubular secretion may be impaired in these patients. This study aims at evaluating the performance of the UCP ratio (urinary ratio of coproporphyrins), a putative biomarker of tubular secretion, in predicting delayed MTX elimination.


Condition
Central Nervous System Neoplasms
Lymphoma, Large B-Cell, Diffuse
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Burkitt Lymphoma

Study Type: Observational
Study Design: Time Perspective: Cross-Sectional
Official Title: Urinary Ratio of the Coproporphyrins Isomers I and III and Its Relationships With Methotrexate Elimination in Patients With a Lymphoid Malignancy

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • MTX concentrations [ Time Frame: at the end of MTX infusion and every 24-hours until concentrations reach 0,2µM. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • The UCP I/(I+III) ratio [ Time Frame: before and at the end of MTX infusion and at the end of hospitalisation. ] [ Designated as safety issue: Yes ]
  • Five polymorphisms of the ABCC2 gene (-24C/T, 1249G/A, 3563T/A, 4544G/A) [ Time Frame: during the study ] [ Designated as safety issue: Yes ]
  • Blood cells count . [ Time Frame: before MTX infusion and at the end of hospitalisation ] [ Designated as safety issue: Yes ]
  • Renal function [ Time Frame: before MTX infusion and at the end of hospitalisation ] [ Designated as safety issue: Yes ]

Biospecimen Retention:   Samples With DNA

blood


Enrollment: 85
Study Start Date: October 2007
Study Completion Date: August 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)

Detailed Description:

MTX is a substrate of MRP2, a renal tubular transporter encoded by the ABCC2 gene. It has been shown that single nucleotide polymorphisms (SNPs) on the ABCC2 gene are associated with impairment of MTX elimination. Mutations on the ABCC2 gene are also responsible for the Dubin-Johnson syndrome, characterised by the absence of a functional MRP2 protein. Apart from hyperbilirubinaemia, the main biological perturbation observed in this disease is a typical increase of the urinary ratio of coproporphyrins I (I+ III) (UCP ratio). Our hypothesis is that the UCP ratio could be used as a biomarker of MRP2's activity, thus predicting MTX elimination. One hundred patients treated with high dose MTX will be recruited in this prospective study. Their UCP ratio will be measured before and after MTX administration and correlated with MTX clearance. A genetic analysis will be conducted to study the five more frequents SNPs of ABCC2 in each patient.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
  • Patients aged more than 18 y, hospitalized in the neurology or in the haematology department at PSP hospital of Paris or in the haematology department at CHU of Tours
  • Who should receive high-dose methotrexate (> 1 g/m2) for one of the following conditions : Central Nervous System Neoplasms; Lymphoma, Large B-Cell, Diffuse; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma or Burkitt lymphoma
Criteria

Inclusion criteria :

  • Patients receiving HDMTX (≥1g/m2) for a primitive cerebral lymphoma, a large cell lymphoma, a lymphoblastic lymphoma, a Burkitt's lymphoma or an acute lymphoblastic leukaemia,
  • over 18 years old,
  • Signed informed consent.
  • Affiliated to a medical assurance.
  • Able to respect the protocol.
  • Effective contraception for women.

Exclusion criteria :

  • renal failure,
  • liver failure,
  • hepatic cytolysis,
  • chronic respiratory deficiency,
  • pregnancy,
  • breast-feeding,
  • Concomitant medication: phenytoin, probenecid, trimethoprim, phenylbutazone, salicylates, non steroid anti-inflammatory, yellow fever vaccine.
  • Patient included in another study in the four weeks preceding his inclusion.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00822432

Locations
France
Pitié-Salpêtrière Hospital
Paris, France, 75013
University Hospital Centre of Tours
Tours, France, 37000
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Chantal Le Guellec, PharmD, PhD CHRU of Tours
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT00822432     History of Changes
Other Study ID Numbers: P061005
Study First Received: January 13, 2009
Last Updated: July 30, 2012
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
biomarkers
ABC transporters
MRP2
MTX pharmacokinetics

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Burkitt Lymphoma
Lymphoma
Nervous System Neoplasms
Lymphoma, Large B-Cell, Diffuse
Central Nervous System Neoplasms
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms, Experimental
Neoplasms by Site
Nervous System Diseases
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 01, 2014