Glucarpidase for Central Nervous System Lymphoma

Recruiting at 10 trial locations

Overseen By Christian Grommes, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

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 All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

64 Participants Needed

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}

Research Team

Lauren Schaff, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

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 have received two treatments for CNS lymphoma.

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.

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
• Leucovorin
• Methotrexate
• Rituximab
• Voraxaze

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

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

University of Alabama at Birmingham

Collaborator

Trials

1,677

Recruited

2,458,000+

Findings from Research

The combination treatment of high dose methotrexate (HD-MTX), temozolomide (TMZ), and rituximab (R) significantly improved progression-free survival (PFS) and overall survival (OS) in patients with primary central nervous system lymphoma (PCNSL), with median PFS of 56.7 months compared to 7.3 months for those receiving only HD-MTX and TMZ.

The treatment was generally well-tolerated, with only mild side effects such as grade 1-2 nausea and vomiting reported during the induction phase, and no severe grade 3/4 toxicities observed during consolidation treatment.

NCBI (Pubmed)

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]. Pang, DW., Chen, FL., Guo, HG., et al.[2021]

The R-M regimen (rituximab with methotrexate) for treating primary central nervous system lymphomas showed similar response rates and survival outcomes compared to the R-MA regimen (rituximab with methotrexate and cytarabine) in a study of 37 patients.

The R-M regimen resulted in fewer severe hematological toxicities, shorter hospital stays, and lower overall treatment costs, suggesting it is a more cost-effective option for patients with PCNSLs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab with high-dose methotrexate is effective and cost-effective in newly diagnosed primary central nervous system lymphoma. Yuan, X., Yu, T., Huang, Y., et al.[2023]

Rituximab, part of the R-MAD regimen for treating primary central nervous system lymphoma (PCNSL), can cause rare but serious side effects, such as interstitial pneumonitis, as demonstrated in a case report of a patient who recovered after treatment.

This case highlights the need for increased awareness among physicians regarding the potential for rituximab-induced lung complications, emphasizing the importance of early detection and management in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interstitial pneumonitis during rituximab-containing chemotherapy for primary central nervous system lymphomas: a case report and review of literature. Wu, Y., Sun, X., Liu, J., et al.[2022]

In a retrospective study of 120 patients with aggressive B cell central nervous system lymphoma, the addition of rituximab to high-dose methotrexate-based chemotherapy was associated with improved overall survival, suggesting it may enhance treatment efficacy.

Key factors predicting better survival included younger age (≤60 years), good performance status, normal lactate dehydrogenase levels, and receiving treatment after 2004, highlighting the importance of these variables in patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. Gregory, G., Arumugaswamy, A., Leung, T., et al.[2022]

In a study of seven patients with CNS lymphoma, the combination of rituximab and temozolomide was well tolerated, with no toxicity reported from rituximab and manageable side effects from temozolomide, indicating a safer alternative to traditional chemotherapy regimens.

The treatment showed promising efficacy, with five patients achieving a complete response and two achieving a partial response, although the median survival was 8 months, suggesting that this regimen could be beneficial for elderly patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Wong, ET., Tishler, R., Barron, L., et al.[2018]

Adding rituximab to methotrexate-based chemotherapy for primary CNS lymphoma significantly increased the complete response (CR) rate, with 44% achieving CR after five cycles and 78% after seven cycles, indicating improved treatment efficacy.

Reduced-dose whole-brain radiotherapy (23.4 Gy) after achieving CR did not lead to neurocognitive decline, suggesting it is a safe option for patients, while the most common toxicities observed were manageable, such as neutropenia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. Shah, GD., Yahalom, J., Correa, DD., et al.[2022]

In a study of 479 patients with relapsing-remitting and progressive multiple sclerosis, rituximab treatment led to an impressive 85.7% reduction in annualized relapse rate and an 82.9% decrease in gadolinium-enhanced lesions after a median follow-up of 14.2 months.

Rituximab was found to be safe, with mild infusion-related symptoms being the most common side effect, and only 18 patients reported relevant infections, indicating a favorable safety profile for this treatment in MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of multiple sclerosis with rituximab: A Spanish multicenter experience. Gascón-Giménez, F., Alcalá, C., Ramió-Torrentà, L., et al.[2023]

In a study of 100 patients with primary central nervous system lymphoma, the combination of high-dose methotrexate and rituxan resulted in a higher complete remission rate (66% vs. 58%) compared to traditional treatment with high-dose methotrexate and whole brain radiotherapy.

The targeted treatment group also experienced significantly longer median progression-free survival (28 months) compared to the traditional treatment group (11 months), indicating that the methotrexate and rituxan combination is not only effective but also has fewer adverse reactions, making it a safer option, especially for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Curative Efficacy of High Dose MTX Combined with Rituxan for Treatment Primary CNS Lymphoma]. Mou, K., Gu, WW., Gu, CH., et al.[2018]

Standard chemotherapy for malignant lymphoma is ineffective for cerebral involvement due to the inability of drugs like cyclophosphamide and doxorubicin to cross the blood-brain barrier, leading to the exploration of alternative treatments.

The combination of cladribine and rituximab has shown promising results in two patient cases, with survival times of 30 and 52 months, suggesting it may be an effective salvage therapy for secondary central nervous system lymphoma and initial therapy for primary central nervous system lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two Cases of Cerebral Involvement in Malignant Lymphoma (CD20+) That Responded to Combination Therapy with Rituximab and Cladribine. Jo, T., Matsuo, M., Horio, K., et al.[2021]

In a study of 22 patients with relapsed central nervous system lymphoma, high-dose methotrexate treatment resulted in a remarkable overall response rate of 91% for the first salvage therapy and 100% for the second salvage therapy.

The median survival after the first relapse was 61.9 months, suggesting that high-dose methotrexate is an effective treatment option for patients who initially responded to methotrexate, potentially allowing for the deferral of more toxic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Plotkin, SR., Betensky, RA., Hochberg, FH., et al.[2013]

A 62-year-old male with mantle cell lymphoma (MCL) and meningeal lymphomatosis achieved tumor clearance after just three doses of intrathecal rituximab (IT-R), highlighting its efficacy in treating central nervous system involvement in MCL.

Following IT-R, the patient underwent a comprehensive systemic therapy regimen and an autologous stem cell transplant, resulting in a sustained remission for 23 months, suggesting a potential effective treatment strategy for MCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid complete response using intrathecal rituximab in a patient with leptomeningeal lymphomatosis due to mantle cell lymphoma. Villela, L., García, M., Caballero, R., et al.[2021]

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]

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]

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]

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

Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. [2022]

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

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. [2018]

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

Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. [2022]

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

Treatment of multiple sclerosis with rituximab: A Spanish multicenter experience. [2023]

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

[Curative Efficacy of High Dose MTX Combined with Rituxan for Treatment Primary CNS Lymphoma]. [2018]

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]

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

Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. [2013]

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]