Glucarpidase for Central Nervous System Lymphoma

Recruiting in Palo Alto (17 mi)

+10 other locations

Overseen by Lauren Schaff, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Methotrexate, Rituximab

Must not be taking: Antineoplastic agents

Disqualifiers: HIV, Hepatitis B/C, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the effects of a drug called Voraxaze when it's routinely given in combination with methotrexate and rituximab, the standard treatment for CNSL.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, you cannot use other approved or investigational cancer treatments while participating in the trial.

What data supports the effectiveness of the drug Glucarpidase for Central Nervous System Lymphoma?

Research shows that a combination of rituximab and high-dose methotrexate is effective for treating primary central nervous system lymphomas, with studies indicating good response rates and improved survival outcomes. ^{1 2 3 4 5}

Is Glucarpidase safe for humans?

Rituximab, a drug often used with methotrexate for treating central nervous system lymphoma, can cause side effects like fever, chills, and rigors (shaking). ^{1 3 6 7 8}

How is the drug Glucarpidase for Central Nervous System Lymphoma different from other treatments?

Glucarpidase is unique because it is used to rapidly break down methotrexate, a drug that can be toxic at high levels, especially in the central nervous system. This approach is different from other treatments that primarily focus on directly attacking the lymphoma cells with chemotherapy or radiation. ^{3 4 9 10 11}

Eligibility Criteria

Adults with B-cell non-Hodgkin's lymphoma in the brain, spinal cord, or leptomeningeal space can join. They must be able to handle certain procedures and have recovered from previous treatments. Women of childbearing age need a negative pregnancy test and agree to birth control; men must also use contraception.

Inclusion Criteria

Patients must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests

Women of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 30 days after the last dose of the study drug

I am at least 18 years old.

Exclusion Criteria

You are allergic to any part of the study drug.

You have serious and ongoing health problems.

You had a severe allergic reaction to the study drugs in the past that cannot be treated with medicine.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive up to 8 cycles of treatment with rituximab, methotrexate, and glucarpidase. Each cycle is 14 days long.

16 weeks

Multiple visits per cycle for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Glucarpidase (Enzyme)
• Leucovorin (Antidote)
• Methotrexate (Antimetabolite)
• Rituximab (Monoclonal Antibody)
• Voraxaze (Enzyme)

Trial Overview The trial is testing Voraxaze (Glucarpidase) combined with standard CNSL treatments methotrexate and rituximab. It aims to see if routine administration of Voraxaze improves outcomes for patients with central nervous system lymphoma.

Participant Groups

Group I: Arm E-glucarpidase 1000u + MTX Experimental Treatment 2 Interventions

Study treatment consists of glucarpidase 1000u, to be administered at least 24 hours after start of standard of care MTX. Patients will have a standard of care methotrexate level drawn within 6 hours of planned glucarpidase administration to confirm eligibility (must reflect MTX \> 100 nmol/L)

Group II: Arm D -Rituximab + MTX + Glucarpidase Experimental Treatment 3 Interventions

Up to 12 patients will be included in Arm D of this study. Cycles will be 14 days long. All patients will receive MTX 3.5 g/m2 administered Day 1 of each cycle (+/- 7 days, a minimum of 14 days required between doses). Glucarpidase will be administered 24 hours (+/- 2 hr) after start of MTX infusion except in cycles 1-2 of Cohort B. Dose of glucarpidase will be 2000 units in Cohort A (first 4 patients) and 1000 units in Cohort B (remaining 8 patients). Patients in Arm D will receive 8 cycles of treatment. Cycles 1 and 2 will be administered in patient while Cycles 3-8 may be in the outpatient setting. Concurrent chemotherapy such as vincristine, procarbazine, and/or ibrutinib may be administered at the investigator's discretion and in accordance with standard of care. In Cohort B, all cycles will be administered with rituximab 500 mg/m2. Rituximab should be administered prior to glucarpidase (window -4 days).

Group III: Arm C - HD-MTX (Arm Outpatient MTX Therapy in times of COVID-19) Experimental Treatment 2 Interventions

MTX ≤ 3.5 g/m2 will be administered on Day 1, along with pre- and post- hydration. Patients will return on Day 2 for continued hydration and glucarpidase 2000 units. Glucarpidase rapidly and sustainably reduces serum MTX levels \>95% without crossing the blood brain barrier, effectively resulting in systemic MTX clearance. Patients will return for bloodwork on Day 3 to document MTX clearance. Arm Outpatient MTX Therapy in times of COVID-19 will only be a single-institution arm, only open at Memorial Sloan Kettering Cancer Center.

Group IV: Arm B - Rituximab + MTX + Glucarpidase Experimental Treatment 2 Interventions

Patients will receive up to 8 cycles of treatment consisting of rituximab Day 1 (+/- 7 days) and MTX Day 2 (+/- 7 days) as per standard of care. Voraxaze will be administered each cycle 24 hours (+/- 2 h) after start of MTX infusion. Dose of Voraxaze will be 2000 units during cycles 1-4, and 1000 units during cycles 5-8. Patients will be treated with rituximab 500 mg/m\^2. (Cohort B) will receive MTX 8 g/m2. Patients will also receive standard of care leucovorin rescue starting at least 24 hours after MTX and 2 hours after Voraxaze. Cycles will be 14 days long.

Group V: Arm A - Rituximab + MTX + Glucarpidase Experimental Treatment 4 Interventions

Patients will receive rituximab Day 1 (+/- 7 days) and MTX Day 2 (+/- 7 days) as per standard of care. Voraxaze will be administered each cycle 24 hours (+/- 2 h) after start of MTX infusion. Dose of Voraxaze will be 2000 units during cycles 1-4, and 1000 units during cycles 5-8. Patients will be treated with rituximab 500 mg/m\^2. (Cohort A) will receive MTX 3 g/m2. Patients will also receive standard of care leucovorin rescue starting at least 24 hours after MTX and 2 hours after Voraxaze. Cycles will be 14 days long.

Methotrexate is already approved in United States, Canada, European Union for the following indications:

🇺🇸 Approved in United States as Trexall for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

🇨🇦 Approved in Canada as Mexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

🇪🇺 Approved in European Union as Methotrexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis
• Crohn's disease
• Ulcerative colitis

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Memorial Sloan Kettering Commack Commack, NY

Memorial Sloan Kettering Cancer Center New York, NY

Memorial Sloan Kettering Basking Ridge Basking Ridge, NJ

Memorial Sloan Kettering Nassau Uniondale, NY

More Trial Locations

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center Lead Sponsor

University of Alabama at Birmingham Collaborator

References

1. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of High Dose Methotrexate, Temozolomide and Rituximab in the Treatment of Patients with Primary Central Nervous System Lymphoma]. [2021] To investigate the clinical efficacy of high dose methotrexate (HD-MTX), temozolomide (TMZ), and rituximab (R) in the treatment of patients with primary central nervous system lymphoma (PCNSL).

2. England pubmed.ncbi.nlm.nih.gov

Rituximab with high-dose methotrexate is effective and cost-effective in newly diagnosed primary central nervous system lymphoma. [2023] Induction chemotherapy based on high-dose methotrexate is considered as the standard approach for newly diagnosed primary central nervous system lymphomas (PCNSLs). However, the best combination chemotherapeutic regimen remains unclear. This study aimed to determine the efficacy and toxicities of rituximab with methotrexate (R-M regimen). Consecutive 37 Chinese patients receiving R-M regimen as induction chemotherapy were retrospectively identified from January 2015 to June 2020 from our center in eastern China. Fourteen patients receiving rituximab plus methotrexate with cytarabine (R-MA regimen) at the same period were identified as the positive control group. The response rates, survival, toxicities, length of hospital stay (LOS), and cost were compared. Compared with the R-MA regimen, the R-M regimen showed comparable response rate and survival outcomes, but had fewer grade 3-4 hematological toxicities, shorter LOS, lower mean total hospitalization cost and lower mean total antibiotic cost. Complete remission at the end of induction chemotherapy and ECOG > 3 were independent prognostic factors for overall survival. In conclusion, R-M regimen is an effective and cost-effective combination treatment for PCNSLs, which warrants further evaluation in randomized trials.

3. England pubmed.ncbi.nlm.nih.gov

Interstitial pneumonitis during rituximab-containing chemotherapy for primary central nervous system lymphomas: a case report and review of literature. [2022] Primary central nervous system lymphoma(PCNSL) is a rare kind of non-Hodgkin lymphoma. Rituximab combined with high-dose methotrexate, cytarabine and dexamethasone (R-MAD regimen) were reported effective for PCNSL patients. Rituximab can cause several side effects, including fever, chills and rigors.

4. England pubmed.ncbi.nlm.nih.gov

Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. [2022] The optimal treatment strategy in patients with aggressive B cell central nervous system lymphoma suitable to receive intensive therapy is unknown. The benefit of incorporating rituximab in systemic therapy remains unclear. We performed a retrospective study examining the impact of rituximab in the context of concomitant therapies, including methotrexate, cytarabine, and radiotherapy, in patients treated with curative intent at 4 university teaching hospitals during 1996-2011.

5. United States pubmed.ncbi.nlm.nih.gov

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. [2018] Methotrexate-based and alkylator-based chemotherapy regimens are associated with renal and bone marrow toxicities, which limit their use in patients with central nervous system (CNS) lymphomas. The authors report their experience with an immunochemotherapy regimen consisting of rituximab and temozolomide in patients with primary or metastatic CNS lymphoma.

6. United States pubmed.ncbi.nlm.nih.gov

Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. [2022] Our goals were to evaluate the safety of adding rituximab to methotrexate (MTX)-based chemotherapy for primary CNS lymphoma, determine whether additional cycles of induction chemotherapy improve the complete response (CR) rate, and examine effectiveness and toxicity of reduced-dose whole-brain radiotherapy (WBRT) after CR.

7. Switzerland pubmed.ncbi.nlm.nih.gov

Treatment of multiple sclerosis with rituximab: A Spanish multicenter experience. [2023] Rituximab (RTX) is considered a potential therapeutic option for relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). The main objective of this work was to investigate the effectiveness and safety of rituximab in MS.

8. China pubmed.ncbi.nlm.nih.gov

[Curative Efficacy of High Dose MTX Combined with Rituxan for Treatment Primary CNS Lymphoma]. [2018] To explore the curative efficacy of methotrexate(MTX) combined with rituxan for treating patients with primary central nervous system(CNS) lymphoma.

9. Switzerland pubmed.ncbi.nlm.nih.gov

Two Cases of Cerebral Involvement in Malignant Lymphoma (CD20+) That Responded to Combination Therapy with Rituximab and Cladribine. [2021] Cerebral involvement frequently occurs in association with progression or relapse of malignant lymphoma. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone, the standard chemotherapy for malignant lymphoma, is an ineffective treatment for cerebral involvement because these drugs cannot cross the blood-brain barrier. Therefore, various alternative strategies have been attempted. Although high-dose methotrexate combined with whole-brain radiotherapy is widely used to treat primary central nervous system lymphoma, there is no standard therapy to treat cerebral involvement in malignant lymphoma. Furthermore, high-dose methotrexate in combination with whole-brain radiotherapy is not always effective, and high rates of neurotoxicity are often observed, particularly in the elderly. To expand the therapeutic options for central nervous system involvement in recent years, systemic chemotherapies, including rituximab, high-dose methotrexate, and other agents that act during the S, G2, and M phases of the cell cycle, have been attempted. In our hospital, cladribine, a purine analogue with a cytocidal effect on resting malignant cells (G0/G1 phase of the cell cycle), has been used in combination with rituximab, which exhibits antitumor effects on nodal and extranodal lesions of relapsed and/or refractory B cell lymphomas, particularly cerebral lesions. Here, we report 2 representative cases of patients who were treated with cladribine plus rituximab and survived for 30 months (died of sepsis) and 52 months (still alive), respectively. The outcomes of these cases suggest that cladribine plus rituximab combination therapy with whole-brain radiotherapy may be very useful as salvage therapy for secondary central nervous system lymphoma and as initial therapy for primary central nervous system lymphoma.

10. United States pubmed.ncbi.nlm.nih.gov

Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. [2013] Over the past decade, high-dose methotrexate has emerged as the single most effective agent in the initial treatment of primary nervous system lymphoma. However, the majority of patients who respond initially to treatment relapse. The optimal management of these patients has not been determined. We performed a multicenter, retrospective study of high-dose methotrexate in patients with relapsed central nervous system lymphoma.

11. England pubmed.ncbi.nlm.nih.gov

Rapid complete response using intrathecal rituximab in a patient with leptomeningeal lymphomatosis due to mantle cell lymphoma. [2021] Mantle cell lymphoma (MCL) is a B-cell lymphoid tumor that expresses CD20 and is associated with a poor prognosis. Central nervous system involvement has been associated with particularly dismal outcome. We report a 62-year-old male with MCL and meningeal lymphomatosis. The patient was treated with intrathecal rituximab (IT-R) 25 mg every third day for five doses with clearance of tumor after the third dose. Systemic therapy consisted of R-HyperCVAD alternating with rituximab, high-dose methotrexate, and cytarabine every 21 days, with IT-R on day 1 of each chemotherapy cycle. The patient was consolidated with an autologous stem cell transplant and remains in remission 23 months later. The use of IT-R and conventional intrathecal chemotherapy in MCLs is discussed here.