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

NCT05135858 | Unknown Phase 1

• 2 other identifiers: APHP2011862021-000210-42
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Primary Central Nervous System Lymphoma

Keywords

Primary CNS lymphoma; Relapse; High-dose methotrexate; Glucarpidase

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• 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)

Study Arms (1)

CPG2

EXPERIMENTAL

6 infusions of glucarpidase

Drug: Glucarpidase; Drug: Methotrexate (MTX)

Interventions

Glucarpidase DRUG

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)

CPG2

Methotrexate (MTX) DRUG

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

CPG2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• BTG International Inc.: collaborator

Study Sites (1)

Hôpital Pitié-Salpêtrière

Paris, 75013, France

RECRUITING

MeSH Terms

Conditions

Recurrence

Interventions

glucarpidase; Methotrexate

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Central Study Contacts

Caroline HOUILLIER, MD

CONTACT

01 42 16 41 60; caroline.houillier@aphp.fr

Khê HOANG-XUAN, MD,PhD

CONTACT

01 42 16 03 81; khe.hoang-xuan@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: October 15, 2021
• First Posted: November 26, 2021
• Study Start: September 15, 2022
• Primary Completion: January 31, 2025
• Study Completion: July 31, 2025
• Last Updated: October 25, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor.
• Access Criteria: Researchers who provide a methodologically sound proposal.

Locations

FR (1)