Methotrexate Early Toxicity Monitoring
Trial statusNot yet recruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18+
SponsorAssistance Publique Hopitaux De Marseille
About this trial
High-dose methotrexate (MTX) is the main componement of first line treatment in primary central nervous system lymphoma. Renal toxicity is the main dose limiting toxicity because of major MTX elimination by the kidneys. MTX crystallizes in renal tubules, leading to a renal failure (RF) and further delaying its elimination. When RF occurs, MTX accumulates, prolonging the duration of treatment exposure. MTX prolonging exposure can cause life-threatening complications and delay further treatments in the patient. Preventive measures have been developped, such as alkaline fluid hyperhydration and folic acid administration, to try to reduce the risk of these adverse events.
In suspected severe RF in link to MTX is suspected, glucarpidase can be administared. However, this is an expensive treatment and not all patients recover normal renal function despite its use.
MTX is an essential treatment for the management of PCNSL which is currently a curable disease especially in patients who are able to receive a consolidation treatment as thiotepa-based intensive consolidation followed by autologous stem cell transplantation (IC-ASCT). IC-ASCT requires a normal renal function, which could be impaired by severe RF secondary to MTX.
The purpose of the study is to investigate how early dosing MTX could be used to simulate late concentrations. Early monitoring of MTX elimination could be implemented to identify patients at risk of delayed elimination and thus introduce rapid mesures as early administration of glucarpidase.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Adult patient aged 18 years or older,
Patient with a primary lymphoma of the central nervous system, histologically or cytologically proven,
Patient eligible for high-dose methotrexate treatment (> at 500 mg/m 2), in the first line of treatment,
Patient who has received information regarding the study and signed an informed consent,
Disqualifiers
Patient treated with a therapy complementary to the standard 1st-line treatment based on high-dose MTX as part of a clinical research protocol,
Patient in a period of exclusion from another research protocol at the time of signing consent,
Subjects covered by articles L1121-5 to 1121-8 of the Public Health Code (minor patient, adult patient under guardianship or curatorship, patient deprived of liberty, pregnant or breastfeeding woman).
Trial design
Design model
Single group
Treatments tested in this trial
methotrexate plasmatic dosing
Other interventionMethotrexate (MTX) dosage at 2,4,6,8,24 and 48 hours
Treatment groups
50 Participants
are divided into 1 treatment groupGroup A: Patients suffering from primary central nervous system lymphomas PCNSLExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Accuracy measurement of Bayesian model
Determine, in patients with Primary Central Nervous System Lymphoma (PCNL), the most efficient Bayesian model for predicting the delay in MTX elimination using a pharmacometry approach (in silico modeling based on a population approach) based on the early dosage of methotrexate in plasma.
Time frame
48 hours post MTXSecondary outcomes
1
Determine the Bayesian model for predicting renal toxicity of MTX T48H using a pharmacometric approach (in silico modeling) based on early dosing of methotrexate in plasma
Renal toxicity shall be defined as acute renal failure graded according to CTCAE V5 in relation to the value of serum creatinine before administration of MTX.
Time frame
48 hours post MTX2
Determine the bayesian model for predicting MTX clearance 72 hours after MTX using a pharmacometric approach (in silico modeling) based on early dosing of methotrexate in plasma
Delay in elimination will be defined by a methotrexate dosage 72 hours after administration (T72H) beyond 0.2 μmol/L.
Time frame
72 hours post MTX3
Estimate in an exploratory approach the performance of the Bayesian model for predicting the delay in MTX elimination at 48 hours using a pharmacometric approach (in silico modeling)
Correlation between, early dosage of methotrexate in plasma and other parameters of interest measured at baseline (before MTX administration) such as patient age, albumin and creatinine clearance.
Time frame
48 hours post4
Estimate in an exploratory approach the performance of the Bayesian model for predicting overexposure to MTX at 48 hours using a pharmacometric approach (in silico modeling)
Correlation between, early dosage of methotrexate in plasma and other parameters of interest measured at baseline (before MTX administration) such as patient age, albumin and creatinine clearance. Overexposure to MTX is defined by a measured T48H \> 10 μmol/L.
Time frame
48 hours post MTXSponsors and contacts
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Source ClinicalTrials.gov
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