COMETH: Coproporphyrine Isomers and Methotrexate Elimination

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Completed

CT.gov ID

NCT00822432

Collaborator

(none)

Enrollment

Locations

Duration (Months)

42.5

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

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	Intervention/Treatment	Phase
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 Design

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 :

Oct 1, 2007

Actual Primary Completion Date :

Aug 1, 2011

Actual Study Completion Date :

Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
1

Outcome Measures

Primary Outcome Measures

MTX concentrations [at the end of MTX infusion and every 24-hours until concentrations reach 0,2µM.]

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.