Reduction of MTX Levels After Glucarpidase Treatment in DLBCL Patients at Risk of CNS

  • STATUS
    Recruiting
  • End date
    Dec 15, 2023
  • participants needed
    18
  • sponsor
    Fundacion CRIS de Investigación para Vencer el Cáncer
Updated on 15 September 2021

Summary

Diffuse large B-cell lymphoma (DLBCL) is an aggressive subset of non-Hodgkin's lymphoma (NHL). Central nervous system (CNS) involvement in patients with NHL is a serious complication. The outcome of patients with CNS relapse is extremely poor, with a median survival of 4-6 months.

One approach to reduce CNS relapse in high-risk patients is the use of systemic high-dose intravenous (iv) methotrexate (HMTX) chemotherapy. Currently available methods of MTX clearance, including dialysis-based methods, have shown limited efficacy.

Glucarpidase hydrolyses MTX to inactive metabolites that are partially metabolised by the liver, thus providing an alternative route of limiting renal excretion.

The administration of Glucarpidase could prevent MTX toxicity as a whole as well as the following consequences. The aim of this study is to analyse the prophylactic effect of 2,000 units of glucarpidase administered after 12 hours of HDMTX on MTX clearance and on the incidence and severity of MTX-related toxicity.

Description

Glucarpidase hydrolyzes the terminal glutamate residue from MTX to inactive metabolites [4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamic acid] which are partially metabolized by the liver, thus providing an alternative route of limitation to renal excretion.

Administration of Glucarpidase cause a clinically important 99% or greater sustained MTX reduction being immediate in most patients, 87% of them experiencing a 95% reduction in serum MTX concentration at a median of 15 min post-Glucarpidase Early administration of Glucarpidase could avoid MTX toxicity as whole as well as the following consequences. The aim of this study is to analyze the prophylactic effect of 2,000 unit Glucarpidase administered after 12 hour of HDMTX on the MTX clearance and on the incidence and severity of MTX related-toxicity.

According to normal clinical practice, patients will receive for curative intent rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) by standard protocol on a 21-day cycle (a total of 6 cycles), plus 3 infusion of systemic intravenous MTX at a dose of 3 g/m2 for CNS prophylaxis (HDMTX) at cycles 1, 3 and 5.

Glucarpidase will be capped at 2,000 units per dose (in two vials of 1,000 units/vial) given as a single intravenous (IV) bolus injection over 5 minutes. Glucarpidase will be administered 12 hours following each HDMTX at cycles 1, 3 and 5.

Clinical laboratory evaluation of Hematology and Biochemistry will be conducted at each step of this study, according to the local laboratory method, to determine occurrences of adverse events (AE) or serious adverse events (SAE) following the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0).

According to standard practice, the blood MTX levels will be monitored according to the local laboratory method, already in place for this purpose. In addition, blood samples for analysis of MTX levels by LC-MS/MS should be drawn at the different time-point.

Therefore, the pharmacokinetic study of MTX clearance includes a quantification of MTX plasma level before and after Glucarpidase administration, assessed by Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis performed by Eurofins|ADME Bioanalyses. Collection times are defined as described:

T0 is the time 12 hours after the MTX infusion starts, with reference to T0. As previously mentioned, plasma MTX levels will be measured at:

  • T0 (pre-Glucarpidase i.v. injection) It will be considered maximum plasma MTX level
  • T0+15 minutes (15 minutes after the end of Glucarpidase administration)
  • T0+6hrs (6 hours after Glucarpidase is given)
  • T0+ 12 hrs (12 hours after Glucarpidase is given)
  • T0+ 24hrs (24 hours after Glucarpidase is given Antibodies anti-Glucarpidase (ADA) will be assessed 12 hours after the MTX infusions starts before Glucarpidase administration (reference to T0) and at the follow-up visit month 3 (after the end of RCHOP treatment). In case of positively response for antibodies at any time-point, the evaluation of immune response to Glucarpidase includes a quantification of the Glucarpidase immunogenicity assessed by a neutralization assay performed by Eurofins|ADMEBioanalyses.

Statistical analyses will be conducted based on the available data, without using techniques for inputting missing values, but describing the number of missing values for each analysis. All statistical tests will be performed at a significance level of = 0.05, unless specifically stated otherwise.

The primary outcome will be assessed by a descriptive analysis of MTX levels: - As a categorical variable: >95% reduction of MTX (yes/no) after 6 hours after administration of 2,000 units of Glucarpidase. In addition, co-primary outcomes will be assessed by a descriptive analysis of MTX levels: - As a numerical variable: MTX in mol/L before and after 15 minutes, 6 hours, 12 hours and 24 hours after administration of 2,000 units of Glucarpidase. - As a numerical variable: MTX change from baseline in mol/L after 15 minutes, 6 hours, 12 hours and 24 hours after administration of 2,000 units of Glucarpidase. - As a categorical variable: >95% reduction of MTX (yes/no) after 15 minutes, 12 hours and 24 hours after administration of 2,000 units of Glucarpidase.

Details
Condition Diffuse Large B-Cell Lymphoma, overdose of drug with toxic effect, diffuse large b cell lymphoma, drug toxicity, diffuse large cell lymphoma
Treatment Glucarpidase 1000 UNT [Voraxaze]
Clinical Study IdentifierNCT05022797
SponsorFundacion CRIS de Investigación para Vencer el Cáncer
Last Modified on15 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Subjects aged 18-70 years
Patients with diagnosis of diffuse large B-cell lymphoma
Patients at high risk of CNS involvement (>2 extranodal sites plus an elevated LDH or /and involvement of high-risk extranodal sites including testes, paranasal sinuses, breast, liver, adrenal and renal)
Patients who will receive HDMTX (three cycles) into R-CHOP regimen (6 cycles) prescribed according to normal clinical practice
Absence of focal neurological signs
Absence of CNS involvement determined by cerebrospinal fluid (CSF) cytometry flow test prior to start treatment
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Absolute neutrophil count 1800-7500/L, platelet count 130.000- 450.000/ L, hemoglobin 13,5-18 g/dL
Serum creatinine 1.5 x the upper limit of normal (ULN) or glomerular filtration rate (GFR) 60ml/min/1.73m^2
Total serum bilirubin 2 x ULN. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) 2.5 x ULN
Ability to understand and the willingness to sign a written informed consent document
In women of childbearing potential (from menarche and until becoming post-menopausal [i.e., no menses for 12 months with an alternative medical cause], unless permanently sterile) and men, use of highly effective measure of contraception (abstinence, hormonal contraception, intra-uterine device [IUD], intrauterine hormone-releasing system, [IUS], or anatomical sterility in self or partner) committed during 3 months after the last IMP administration

Exclusion Criteria

Malignant disease, other than those being treated in this study. Exceptions to this exclusion include malignancies that were treated curatively and have not recurred within 2 years after completion of treatment
Patients suffered from cardiovascular diseases (arrhythmias, previous heart failure, thromboembolic disease)
Previous treatment with Glucarpidase
Pregnant or breastfeeding women
Concomitant treatment with agents which interact with methotrexate metabolism or excretion
Known intolerance/hypersensitivity to Glucarpidase or any of its excipients
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