Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT05022797 |
| Other study ID # |
MDA-BTG-2020-01 |
| Secondary ID |
2020-004450-30 |
| Status |
Terminated |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
July 19, 2021 |
| Est. completion date |
November 22, 2022 |
Study information
| Verified date |
May 2024 |
| Source |
Fundacion CRIS de Investigación para Vencer el Cáncer |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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 α = 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 µmol/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 µmol/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.
