A Phase 1 interventional study of Glucarpidase and Methotrexate (MTX) in Primary Central Nervous System Lymphoma, sponsored by Assistance Publique - Hôpitaux de Paris. Recruiting at 1 site in France. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-10-25.
Sponsored by Assistance Publique - Hôpitaux de Paris · Phase 1, Interventional, and Treatment
High dose intravenous Methotrexate (HD-MTX) is the key drug in the treatment of primary central nervous system lymphoma (PCNSL). HD-MTX is usually delivered with time interval ranging from 10 to 21 days. Reduction of injection time interval is limited by MTX renal excretion and systemic toxicity.
Glucarpidase (CPG2) is a recombinant bacterial rescue enzyme that cleaves circulating MTX into inactive metabolites, reducing plasma MTX concentrations within few minutes.
The research hypothesis is that CPG2 used after HD-MTX injection allows to reduce time interval between MTX injections, increase dose intensity of the chemotherapy, reduce systemic toxicity and duration of hospitalization.
Open-label multicenter Phase I dose finding trial based on 3+3 escalation design. The phase I will follow a standard "3+3" dose level escalation design with reduced time interval of HD-MTX injections at fixed dose of HD-MTX to establish the minimum tolerated time interval.
HD-MTX (methotrexate) is administered intravenously at the dose 3.5 g/m² (body surface area capped at 2 m2) over 2 to 3 hours, followed at H24 by glucarpidase with a 3 different MTX administration intervals: 8 days, 6 days, and 5 days.
Treatments will be continued for a maximum of 6 injections until disease progression, unacceptable toxicity, or investigator's/patient's decision.
Three dose levels could be explored under toxicity restrictions, where the dose combination for each cohort of three subjects will be determined by 3+3 escalation rule. Three schedule dose levels will be : every 8 days, every 6 days and every 5 days.
The starting schedule dose of HD-MTX will be one administration of HD-MTX every 8 days for 6 injections.
Dose of MTX will be fixed and will not be modified. No skipping of the dose level will be allowed. No intra-patient dose escalation is allowed.
The DLT evaluation period begins with the first dose of methotrexate and ends at the beginning of the 25th day after the first MTX infusion.
5,578 studies on the registry are indexed under Lymphoma; 825 are open to participants now.
This study's planned enrollment of 18 is below the median of 40 across 4,508 interventional studies indexed under Lymphoma.
Browse Lymphoma studies →Assistance Publique - Hôpitaux de Paris is the lead sponsor of 3,505 studies on the registry; 1,006 are open to participants now.
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Adequate haematological, renal and hepatic function (adequate Laboratory Parameters within 21 days):
Exclusion Criteria:
6 infusions of glucarpidase
Drug: Glucarpidase · Drug: Methotrexate (MTX)
Glucarpidase (CPG2) Dose: 2000 U (2 vials of 1000 U per dose) 5 minutes-intravenous administration 24 hours after each Methotrexate infusion (i.e. 6 times in the whole protocol)
MTX will be administred 6 times during the protocol, at a variable interval of 8, 6 or 5 days. It will be administrated in a 2 to 3-hour IV infusion, at the dose of 3.5 g/m2 (body surface area capped at 2 m2). Each MTX administration will be preceded by a prehydration and will be followed by a posthydration
The occurrence of a dose schedule limiting toxicity (DLT)
defined as any of the following events assessed as related or possibly related to methotrexate: * Any grade V toxicity (according to NCI-CTCAE v 5.0) * Grade IV non-haematological toxicity excluding fatigue, alopecia, nausea, vomiting (according to NCI-CTCAE v 5.0) * Creatinine \> 3 X baseline (grade III toxicity according to NCI-CTCAE v 5.0) * Grade IV thrombopenia, grade III thrombopenia with bleeding, grade IV neutropenia or grade III neutropenia with fever,lasting \> 3 days (according to NCI-CTCAE v 5.0) * Delay in MTX administration \> 36 hours due to any adverse effect.
Time frame: 25th day after the first injection of methotrexate
Frequency and grading of adverse event according to NCI-CTCAE v5.0
Time frame: through study completion, an average of 4 months
Mean score of neurocognition assessed by neuropsychological testing at baseline and within the - Neurocognition assessed by neuropsychological testing at baseline and within the 3 months after the end of HD-MTX treatment
Time frame: 3 months after the end of HD-MTX treatment
Overall response rate according to IPCG criteria
Time frame: After 3 cycles (each cycle is 5, 6 or 8 days), at the end of treatment (up to 48 days) and at 3 months after the end of treatment (up to 48 days)
Mean of dosages of MTX and its metabolites in the blood, urine and cerebrospinal fluid (CSF)
Time frame: At the first and the third cycles (each cycle is 5, 6 or 8 days)
Mean of dosage of anti-glucarpidase antibodies
Time frame: At baseline, then prior to each CPG2 dose, at the end of HD-MTX treatment (up to 48 days) and at 3 months after the end of HD-MTX treatment.(up to 48 days)
Mean global score of quality of life assessment measured with EORTC QLQ-C30 scale
Time frame: At baseline, at the end of HD-MTX treatment (up to 48 days) and at 3 months after the end of HD-MTX treatment (up to 48 days)]
Mean global score of quality of life assessment measured with Brain Module (BM 20)
Time frame: At baseline, at the end of HD-MTX treatment (up to 48 days) and at 3 months after the end of HD-MTX treatment (up to 48 days)
Median duration of treatment-related hospitalization in acute care unit
Defined as the cumulative time from start of the HD MTX protocol (including the pre-hydration) to its elimination
Time frame: From day 1 until discharge from hospital, an average of 4 to 7 weeks
Mean of dosage of CSF IL-10
Time frame: At baseline and at the end of the treatment (up to 48 days)
Median duration of hospitalization during the treatment
Duration of treatment-related hospitalization in acute care unit
Time frame: From day 1 until end of the treatment (up to 48 days)
Plan to share: Yes — The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients. Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.
Supporting information: Study protocol, Sap, Icf
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Assistance Publique - Hôpitaux de Paris