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

NCT ID: NCT05135858

Last Updated: 2022-10-25

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-09-15
• Study Completion Date: 2025-07-31

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.

Conditions

Primary Central Nervous System Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CPG2

6 infusions of glucarpidase

Group Type: EXPERIMENTAL

Glucarpidase

Intervention Type: 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)

Methotrexate (MTX)

Intervention Type: 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

Interventions

Glucarpidase

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

Methotrexate (MTX)

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

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

BTG International Inc.

OTHER

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Hôpital Pitié-Salpêtrière

Paris, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Caroline HOUILLIER, MD

Role: CONTACT

caroline.houillier@aphp.fr

01 42 16 41 60

Khê HOANG-XUAN, MD,PhD

Role: CONTACT

khe.hoang-xuan@aphp.fr

01 42 16 03 81

Facility Contacts

Caroline HOUILLIER, MD

Role: primary

caroline.houillier@aphp.fr

01 42 16 41 60

Other Identifiers

2021-000210-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

APHP201186

Identifier Type: -

Identifier Source: org_study_id