Coproporphyrine Isomers and Methotrexate Elimination (COMETH)
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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 |
- MTX concentrations [ Time Frame: at the end of MTX infusion and every 24-hours until concentrations reach 0,2µM. ] [ Designated as safety issue: Yes ]
- 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 |
- 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.
Contacts and Locations| France | |
| Pitié-Salpêtrière Hospital | |
| Paris, France, 75013 | |
| University Hospital Centre of Tours | |
| Tours, France, 37000 | |
| 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:
|
Burkitt Lymphoma Neoplasms Leukemia Leukemia, Lymphoid Precursor Cell Lymphoblastic Leukemia-Lymphoma Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Lymphoma Nervous System Neoplasms Lymphoma, Large B-Cell, Diffuse Central Nervous System Neoplasms Epstein-Barr Virus Infections Herpesviridae Infections DNA Virus Infections Virus Diseases Tumor Virus Infections |
Lymphoma, Non-Hodgkin Neoplasms by Histologic Type Lymphoma, B-Cell Neoplasms, Experimental Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases 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 May 19, 2013