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

Assistance Publique - Hôpitaux de Paris

Status and phase: Enrolling; Phase 1

Conditions: Primary Central Nervous System Lymphoma

Treatments: Drug: Glucarpidase; Drug: Methotrexate (MTX)

Study type: Interventional

Funder types: Other

Identifiers

NCT05135858

2021-000210-42 (EudraCT Number)

APHP201186

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 18 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Cerebral relapse of primary CNS lymphoma (any line)

2. 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)

3. Absence of any systemic involvement confirmed by full body CT scan and/or FDG-PET scan

4. Age≥18 years

5. HD-MTX based chemotherapy in first line treatment, with complete response lasting at least 6 months after the end of the 1st line treatment

6. No administration of other anticancer therapy within the 3 weeks prior to inclusion

7. Karnofsky performance status (KPS) ≥ 50

8. Adequate haematological, renal and hepatic function (adequate Laboratory Parameters within 21 days):

   1. Absolute neutrophil count (ANC) >1000/mm3
   2. Platelets > 100,000/mm3 independent of transfusion support
   3. 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
   4. Estimated Glomerular Filtration Rate ≥ 60 mL/min/1.73m2) (MDRD)

9. All non-hematological adverse events (AEs) related to prior therapy completely resolved or improved to Grade 1-2 (except for alopecia or fatigue).

10. 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

1. Positive HIV serology
2. Active viral infection with Hepatitis B or C virus
3. Preexisting immunodeficiency (organ transplant recipient)
4. Relevant congestive heart failure interfering with hydration
5. Isolated CNS relapse of systemic non-Hodgkin's lymphoma (NHL)
6. 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.
7. Third space (i.e. pleural effusion, ascites, extended oedema).
8. Obesity (body mass index >30 kg/m2).
9. Any other active malignancy, except basocellular carcinoma and non-invasive cervix cancer
10. Absolute contraindication to MTX or leucovorin
11. Previous use of carboxypeptidase for delayed MTX excretion and kidney dysfunction after HD-MTX
12. No social security affiliation
13. Persons under legal protection (tutorship or curatorship) or safety measure
14. Participation in any other clinical trial (Jardé 1 and 2) either 1 month prior to or during this study.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Sequential Assignment

Masking: None (Open label)

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18 participants in 1 patient group

CPG2

Experimental group

Description:

6 infusions of glucarpidase

Treatment:

Drug: Glucarpidase

Drug: Methotrexate (MTX)