Primary Central Nervous System LymphomaPhase 1METHOGLUNCT05135858
Dose Dense Re-challenge of High Dose Methotrexate With Glucarpidase for Relapsed Primary Central Nervous System Lymphoma
A Phase 1 study testing Glucarpidase and Methotrexate (MTX) in people with Primary Central Nervous System Lymphoma, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Primary Central Nervous System Lymphoma
- What is being tested?
- Glucarpidase and Methotrexate (MTX)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteFrance
- Study dates
- 15 Sep 2022to 31 Jul 2025
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
France1 site, 1 recruiting
- Recruiting
Hôpital Pitié-Salpêtrière
Paris, 75013
Caroline HOUILLIER, MD, 01 42 16 41 60, caroline.houillier@aphp.fr
Caroline HOUILLIER, MD
About this study
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
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.
Read the 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
- Being tested
- Glucarpidase, Methotrexate (MTX)
- Keywords
- Primary CNS lymphoma, Relapse, High-dose methotrexate, Glucarpidase
- Medical subject headings
- Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GlucarpidaseDrug
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)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
| Study group | Role | What they receive |
|---|---|---|
| CPG2 | Experimental | 6 infusions of glucarpidase Receives: Drug: Glucarpidase; Drug: Methotrexate (MTX) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 25th day after the first injection of methotrexate
Secondary outcomes (10)
Frequency and grading of adverse event according to NCI-CTCAE v5.0
Measured: 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
Measured: 3 months after the end of HD-MTX treatment
Overall response rate according to IPCG criteria
Measured: 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)
Measured: At the first and the third cycles (each cycle is 5, 6 or 8 days)
Mean of dosage of anti-glucarpidase antibodies
Measured: 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
Measured: 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)
Measured: 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
Measured: From day 1 until discharge from hospital, an average of 4 to 7 weeks
Mean of dosage of CSF IL-10
Measured: 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
Measured: From day 1 until end of the treatment (up to 48 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Nov 2021
- Study start15 Sep 2022
- Primary completion31 Jan 2025 (estimated)
- Study completion31 Jul 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Primary Central Nervous System LymphomaStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- 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)
- Enrolment
- 18 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Collaborators
- BTG International Inc.
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05135858
- Sponsor's protocol ID
- APHP201186
- Other IDs
- 2021-000210-42
- Acronym
- METHOGLU
- Status last verified
- Oct 2022
- First submitted
- 15 Oct 2021
- Last updated
- 25 Oct 2022
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Study at a glance
From the registry record, last updated by the sponsor on 25 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT05135858
- Acronym / sponsor ID
- METHOGLU / APHP201186
- Conditions
- Primary Central Nervous System Lymphoma
- Keywords
- Primary CNS lymphoma, Relapse, High-dose methotrexate, Glucarpidase
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 18 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Collaborators
- BTG International Inc.
- Study start
- 15 Sep 2022 (actual)
- Primary completion
- 31 Jan 2025 (estimated)
- Study completion
- 31 Jul 2025 (estimated)
- First posted
- 26 Nov 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
- 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.
| Arm | Type | Receives |
|---|---|---|
| CPG2 | Experimental | Drug: Glucarpidase, Drug: Methotrexate (MTX)6 infusions of glucarpidase |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- 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
Key exclusion criteria (14 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GlucarpidaseGlucarpidase (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) | Drug | CPG2 |
| 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 | Drug | CPG2 |
Primary outcome
The occurrence of a dose schedule limiting toxicity (DLT)
Time frame: 25th day after the first injection of methotrexate
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.
10 secondary outcomes
Frequency and grading of adverse event according to NCI-CTCAE v5.0
Time frame: 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
Time frame: 3 months after the end of HD-MTX treatment
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)
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)
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)
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)]
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)
Median duration of treatment-related hospitalization in acute care unit
Time frame: From day 1 until discharge from hospital, an average of 4 to 7 weeks
Mean of dosage of CSF IL-10
Time frame: At baseline and at the end of the treatment (up to 48 days)
Median duration of hospitalization during the treatment
Time frame: From day 1 until end of the treatment (up to 48 days)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Oct 2022.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Glucarpidase and Methotrexate (MTX) in people with Primary Central Nervous System Lymphoma, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 25 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Caroline HOUILLIER, MD (01 42 16 41 60, caroline.houillier@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The occurrence of a dose schedule limiting toxicity (DLT) (time frame: 25th day after the first injection of methotrexate). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Oct 2022.