Coproporphyrine Isomers and Methotrexate Elimination (COMETH)

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: NCT00822432
Recruitment Status : Completed
First Posted : January 14, 2009
Last Update Posted : July 31, 2012
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:
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 or disease
Central Nervous System Neoplasms Lymphoma, Large B-Cell, Diffuse Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Burkitt Lymphoma

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.

Study Type : Observational
Actual Enrollment : 85 participants
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
Study Start Date : October 2007
Actual Primary Completion Date : August 2011
Actual Study Completion Date : August 2011


Primary Outcome Measures :
  1. MTX concentrations [ Time Frame: at the end of MTX infusion and every 24-hours until concentrations reach 0,2µM. ]

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

Biospecimen Retention:   Samples With DNA

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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
  • 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

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.

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): NCT00822432

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

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Assistance Publique - Hôpitaux de Paris Identifier: NCT00822432     History of Changes
Other Study ID Numbers: P061005
First Posted: January 14, 2009    Key Record Dates
Last Update Posted: July 31, 2012
Last Verified: January 2009

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

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