Coproporphyrine Isomers and Methotrexate Elimination

Lymphoma, Large B-Cell, Diffuse Clinical Trial

— COMETH  

Official title:

Urinary Ratio of the Coproporphyrins Isomers I and III and Its Relationships With Methotrexate Elimination in Patients With a Lymphoid Malignancy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00822432
• Other study ID #: P061005
• Status: Completed
• Phase: N/A
• First received: January 13, 2009
• Last updated: July 30, 2012
• Start date: October 2007
• Est. completion date: August 2011

Study information

• Verified date: January 2009
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 85
• Est. completion date: August 2011
• Est. primary completion date: August 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Time Perspective: Cross-Sectional

Related Conditions & MeSH terms

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

Locations

Country	Name	City	State
France	Pitié-Salpêtrière Hospital	Paris
France	University Hospital Centre of Tours	Tours

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTX concentrations		at the end of MTX infusion and every 24-hours until concentrations reach 0,2µM.	Yes
Secondary	The UCP I/(I+III) ratio		before and at the end of MTX infusion and at the end of hospitalisation.	Yes
Secondary	Five polymorphisms of the ABCC2 gene (-24C/T, 1249G/A, 3563T/A, 4544G/A)		during the study	Yes
Secondary	Blood cells count .		before MTX infusion and at the end of hospitalisation	Yes
Secondary	Renal function		before MTX infusion and at the end of hospitalisation	Yes