Back to results

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

Primary Purpose

Primary Central Nervous System Lymphoma

Status

Recruiting

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

Glucarpidase

Methotrexate (MTX)

About this trial

This is an interventional treatment trial for Primary Central Nervous System Lymphoma focused on measuring Primary CNS lymphoma, Relapse, High-dose methotrexate, Glucarpidase

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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):
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)
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.

Sites / Locations

Hôpital Pitié-SalpêtrièreRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CPG2

Arm Description

6 infusions of glucarpidase

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Frequency and grading of adverse event according to NCI-CTCAE v5.0

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

Overall response rate according to IPCG criteria

Mean of dosages of MTX and its metabolites in the blood, urine and cerebrospinal fluid (CSF)

Mean of dosage of anti-glucarpidase antibodies

Mean global score of quality of life assessment measured with EORTC QLQ-C30 scale

Mean global score of quality of life assessment measured with Brain Module (BM 20)

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

Mean of dosage of CSF IL-10

Median duration of hospitalization during the treatment

Duration of treatment-related hospitalization in acute care unit

Full Information

NCT ID

NCT05135858

First Posted

October 15, 2021

Last Updated

October 24, 2022

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

BTG International Inc.

1. Study Identification

Unique Protocol Identification Number

NCT05135858

Brief Title

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

Acronym

METHOGLU

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Recruiting

Study Start Date

September 15, 2022 (Actual)

Primary Completion Date

January 31, 2025 (Anticipated)

Study Completion Date

July 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

BTG International Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Primary Central Nervous System Lymphoma

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

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)

Allocation

N/A

Enrollment

18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

CPG2

Arm Type

Experimental

Arm Description

6 infusions of glucarpidase

Intervention Type

Drug

Intervention Name(s)

Glucarpidase

Intervention Description

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)

Intervention Type

Drug

Intervention Name(s)

Methotrexate (MTX)

Intervention Description

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

Primary Outcome Measure Information:

Title

The occurrence of a dose schedule limiting toxicity (DLT)

Description

Time Frame

25th day after the first injection of methotrexate

Secondary Outcome Measure Information:

Title

Frequency and grading of adverse event according to NCI-CTCAE v5.0

Time Frame

through study completion, an average of 4 months

Title

Time Frame

3 months after the end of HD-MTX treatment

Title

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)

Title

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)

Title

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)

Title

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)]

Title

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)

Title

Median duration of treatment-related hospitalization in acute care unit

Description

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

Title

Mean of dosage of CSF IL-10

Time Frame

At baseline and at the end of the treatment (up to 48 days)

Title

Median duration of hospitalization during the treatment

Description

Duration of treatment-related hospitalization in acute care unit

Time Frame

From day 1 until end of the treatment (up to 48 days)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Caroline HOUILLIER, MD

Phone

01 42 16 41 60

caroline.houillier@aphp.fr

First Name & Middle Initial & Last Name or Official Title & Degree

Khê HOANG-XUAN, MD,PhD

Phone

01 42 16 03 81

khe.hoang-xuan@aphp.fr

Facility Information:

Facility Name

Hôpital Pitié-Salpêtrière

City

Paris

ZIP/Postal Code

75013

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Caroline HOUILLIER, MD

Phone

01 42 16 41 60

caroline.houillier@aphp.fr

First Name & Middle Initial & Last Name & Degree

Caroline HOUILLIER, MD

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

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.

IPD Sharing 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.

IPD Sharing Access Criteria

Researchers who provide a methodologically sound proposal.

Learn more about this trial

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

We'll reach out to this number within 24 hrs