Dose Dense Re-challenge of High Dose Methotrexate With Glucarpidase for Relapsed Primary Central Nervous System Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Dose Dense Re-challenge of High Dose Methotrexate (HD-MTX) With Glucarpidase (CPG2) for Relapsed Primary Central Nervous System Lymphoma (PCNSL): A Phase I Trial

Conditions
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Primary Central Nervous System Lymphoma

Intervention / Treatment
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* Drug: Glucarpidase
* Drug: Methotrexate (MTX)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cerebral relapse of primary CNS lymphoma (any line) Pathological diagnosis of diffuse large B cell lymphoma (or cytological diagnosis in the CSF or in the vitreous) at initial diagnosis (not mandatory at the time of the present relapse) Absence of any systemic involvement confirmed by full body CT scan and/or FDG-PET scan Age≥18 years HD-MTX based chemotherapy in first line treatment, with complete response lasting at least 6 months after the end of the 1st line treatment No administration of other anticancer therapy within the 3 weeks prior to inclusion Karnofsky performance status (KPS) ≥ 50 Adequate haematological, renal and hepatic function (adequate Laboratory Parameters within 21 days): Absolute neutrophil count (ANC) >1000/mm3 Platelets > 100,000/mm3 independent of transfusion support Alanine aminotransferase and aspartate aminotransferase ≤ 3 x upper limit of normal (ULN) and/or total bilirubin ≤ 1,5x ULN, unless related to Gilbert's or Meulengracht disease Estimated Glomerular Filtration Rate ≥ 60 mL/min/1.73m2) (MDRD) All non-hematological adverse events (AEs) related to prior therapy completely resolved or improved to Grade 1-2 (except for alopecia or fatigue). Written informed consent, which could be signed by the trustworthy person or close relatives in case the neurologic status of the patient does not allow him to sign. In case the patient is unable to sign the consent at baseline, but his neurological status improves during the treatment, he will be asked to give his written informed follow-up consent Exclusion Criteria: Positive HIV serology Active viral infection with Hepatitis B or C virus Preexisting immunodeficiency (organ transplant recipient) Relevant congestive heart failure interfering with hydration Isolated CNS relapse of systemic non-Hodgkin's lymphoma (NHL) Pregnancy or lactation. An effective contraception is mandatory for patients (men and women of childbearing potential) all along the study participation and during at least 6 months after the end of MTX. Men must not donate sperm all along the study participation and during at least 6 months after the end of MTX. Third space (i.e. pleural effusion, ascites, extended oedema). Obesity (body mass index >30 kg/m2). Any other active malignancy, except basocellular carcinoma and non-invasive cervix cancer Absolute contraindication to MTX or leucovorin Previous use of carboxypeptidase for delayed MTX excretion and kidney dysfunction after HD-MTX No social security affiliation Persons under legal protection (tutorship or curatorship) or safety measure Participation in any other clinical trial (Jardé 1 and 2) either 1 month prior to or during this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CPG2<br>6 infusions of glucarpidase | Drug: Glucarpidase<br>* 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)<br>Drug: Methotrexate (MTX)<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 25th day after the first injection of methotrexate | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and grading of adverse event according to NCI-CTCAE v5.0 |  | 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 |  | 3 months after the end of HD-MTX treatment | 
| Overall response rate according to IPCG criteria |  | 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) |  | At the first and the third cycles (each cycle is 5, 6 or 8 days) | 
| Mean of dosage of anti-glucarpidase antibodies |  | 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 |  | 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) |  | 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 | From day 1 until discharge from hospital, an average of 4 to 7 weeks | 
| Mean of dosage of CSF IL-10 |  | 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 | From day 1 until end of the treatment (up to 48 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary CNS lymphoma, Relapse, High-dose methotrexate, Glucarpidase