Zanubrutinib + Pemetrexed for CNS Lymphoma

Overseen By Allison Miller

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yuliya Linhares

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Uncontrolled illness, Active malignancy, Immunosuppression, Cardiovascular disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

15 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use warfarin or other vitamin K antagonists, and you should not be on strong CYP3A inhibitors or inducers. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination Zanubrutinib and Pemetrexed for CNS Lymphoma?

Research shows that Pemetrexed has been explored for its effectiveness in treating relapsed primary central nervous system lymphoma (PCNSL), suggesting it may have potential benefits. However, there is no direct evidence from the provided studies about the combination of Zanubrutinib and Pemetrexed specifically for CNS Lymphoma. ^{1 2 3 4 5}

Is the combination of Zanubrutinib and Pemetrexed safe for treating CNS Lymphoma?

Zanubrutinib has been used safely in patients with central nervous system lymphoma, showing good tolerance and effectiveness in some cases. Pemetrexed has also been evaluated for safety in treating relapsed primary central nervous system lymphoma, indicating it can be used safely in humans. ^{1 4 6 7 8}

What makes the drug combination of Zanubrutinib and Pemetrexed unique for treating CNS lymphoma?

The combination of Zanubrutinib and Pemetrexed is unique for treating CNS lymphoma because Zanubrutinib, a Bruton's tyrosine kinase inhibitor, can effectively penetrate the blood-brain barrier, making it suitable for CNS involvement, while Pemetrexed has shown efficacy in relapsed cases, offering a novel approach for patients who cannot tolerate standard high-dose methotrexate regimens. ^{1 6 7 8 9}

What is the purpose of this trial?

This study is being conducted to evaluate the safety and efficacy of the combination of pemetrexed and zanubrutinib (called induction therapy) followed by zanubrutinib treatment alone (also called maintenance therapy) in people who have relapsed or refractory (RR) primary central nervous system lymphoma (PCNSL) or isolated central nervous system relapse of B cell lymphoma (SCNSL). Assessments include how well people respond to this treatment, whether their disease gets better or worse, and their survival. Safety of this treatment and its side effects also will be assessed.

Research Team

Yuliya Linhares, M.D.

Principal Investigator

Miami Cancer Institute at Baptist Health, Inc.

Eligibility Criteria

This trial is for people with relapsed or refractory primary or secondary central nervous system lymphoma. Participants must have certain types of B cell lymphoma, measurable disease, and adequate organ function. They should not be pregnant, use effective contraception, and have a life expectancy of at least 2 months. Excluded are those with recent other treatments, significant heart issues, active infections requiring treatment within the last week, or known bleeding disorders.

Inclusion Criteria

I have a confirmed diagnosis of CNS lymphoma or secondary CNS involvement by diffuse large B cell lymphoma.

I am mostly independent in my daily activities.

I have B cell non-Hodgkin's lymphoma that can be measured.

Exclusion Criteria

I do not have any serious illnesses that are not under control.

I do not have any other active cancer except for allowed exceptions.

I understand and can follow the study's requirements.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Participants receive oral zanubrutinib and IV pemetrexed as induction therapy

6 months

Maintenance Therapy

Participants receive oral zanubrutinib maintenance therapy, with cycles continuing until disease progression

28-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Pemetrexed
• Zanubrutinib

Trial Overview The study tests pemetrexed combined with zanubrutinib (induction therapy), followed by maintenance therapy with zanubrutinib alone in patients whose CNS lymphoma has returned after treatment or didn't respond well to previous therapies. It aims to assess how well patients respond to this regimen and monitor their survival rates as well as any side effects.

Participant Groups

Group I: Induction Therapy + SOC Treatment Experimental Treatment 4 Interventions

Participants will receive the induction therapy (oral zanubrutinib + IV pemetrexed) and be placed into one of the cohorts according to standard of care (SOC) treatment: Cohort 1: Induction Therapy + Autologous Stem Cell Transplant (ASCT) After completion of the induction therapy, ASCT candidates will undergo transplant as per SOC. If the transplant is delayed and 8 induction cycles have been completed, oral zanubrutinib maintenance will proceed until transplant, but will not occur after transplant. Cohort 2: Induction Therapy + Whole Brain Radiation Therapy (WBRT) After completion of the induction therapy, WBRT candidates will undergo WBRT as per SOC. Oral zanubrutinib maintenance will start 7-10 days after the completion of WBRT. 28-d maintenance cycles will continue until disease progression. Cohort 3: Induction Therapy Alone After completion of the induction therapy, 28-day oral zanubrutinib maintenance cycles will begin and continue until disease progression

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

Approved in United States as Alimta for:

• Malignant pleural mesothelioma
• Non-small cell lung cancer

Approved in European Union as Alimta for:

• Malignant pleural mesothelioma
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

Yuliya Linhares

Lead Sponsor

Trials

1

Recruited

20+

Baptist Health South Florida

Lead Sponsor

Trials

54

Recruited

8,100+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Findings from Research

In a study of 7 patients with relapsed primary central nervous system lymphoma (PCNSL), high-dose pemetrexed (900 mg/m²) resulted in an overall response rate of 71.4%, with 2 patients achieving complete remission and 3 achieving partial remission.

While pemetrexed shows promise as a treatment option for relapsed PCNSL, the main side effects included myelosuppression and gastrointestinal reactions, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Curative effect of pemetrexed on the treatment of relapsed primary central nervous system lymphoma]. Wang, Y., Wang, X., Zhao, Y., et al.[2015]

A combination of (90)Y-Ibritumomab Tiuxetan (Zevalin) and Temozolomide has shown promising efficacy as a maintenance therapy for recurrent Primary Central Nervous System Lymphoma (PCNSL), with two patients achieving complete remission after 9 and 10 months.

This treatment approach may be particularly beneficial for older patients with progressive PCNSL, suggesting it could be a viable alternative for those who do not respond to initial therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage therapy for primary central nervous system lymphoma with (90)Y-Ibritumomab and Temozolomide. Pitini, V., Baldari, S., Altavilla, G., et al.[2022]

The combination of rituximab and temozolomide (TMZ) showed promising efficacy in two patients with recurrent and refractory primary central nervous system lymphoma (PCNSL), achieving complete and partial responses after treatment cycles.

This therapy was effective regardless of the patients' different tumor profiles, suggesting it could be a viable option for diverse cases of PCNSL, although further research in larger populations is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with rituximab and temozolomide for recurrent and refractory primary central nervous system lymphoma. Murakami, M., Fujimaki, T., Asano, S., et al.[2021]

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 addition of temozolomide (TMZ) to the standard treatment of high-dose methotrexate (HD-MTX) and whole-brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL) did not improve overall survival, with a 2-year survival rate of 71.4% in the TMZ group compared to 86.8% in the standard treatment group.

The study, which included 134 patients and was terminated early due to futility, found that the methylation status of the MGMT promoter did not predict response to TMZ, indicating that this treatment may not be effective for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C. Mishima, K., Nishikawa, R., Narita, Y., et al.[2023]

In a retrospective study of two elderly patients with primary central nervous system lymphoma (PCNSL), treatment with zanubrutinib, a Bruton's tyrosine kinase inhibitor, after middle-dose methotrexate led to significant improvements in their condition, with one patient achieving complete remission and the other partial remission.

Both patients are alive, indicating that zanubrutinib may effectively extend progression-free survival (PFS) and overall survival (OS) in elderly patients with PCNSL who cannot tolerate standard methotrexate regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib in the Maintenance Treatment of Elderly People with Primary Central Nervous System Lymphoma: A Report of 2 Cases. Liu, Y., Sun, J., Tuo, K.[2023]

A 53-year-old man with refractory primary central nervous system lymphoma (PCNSL) achieved complete remission after being treated with zanubrutinib combined with a high-dose methotrexate-based chemotherapy regimen, demonstrating the potential efficacy of this treatment approach.

Zanubrutinib, a Bruton's tyrosine kinase inhibitor, was well tolerated and suggests that integrating such small molecules into first-line treatments for PCNSL could improve outcomes and reduce the risk of recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Management of a Patient with Refractory Primary Central Nervous System Lymphoma by Zanubrutinib. Cheng, Q., Wang, J., Lv, C., et al.[2021]

Zanubrutinib, a Bruton's tyrosine kinase inhibitor, showed a high overall response rate of 84.5% in patients with diffuse large B-cell lymphoma (DLBCL), including 81.8% in those with central nervous system (CNS) involvement, indicating its effectiveness in treating this condition.

The study demonstrated that zanubrutinib effectively crosses the blood-brain barrier, with a mean cerebrospinal fluid concentration of 2941.1 pg/ml, suggesting it could be a promising treatment option for CNS lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary Evaluation of Zanubrutinib-Containing Regimens in DLBCL and the Cerebrospinal Fluid Distribution of Zanubrutinib: A 13-Case Series. Zhang, Y., Li, Y., Zhuang, Z., et al.[2022]

Ibrutinib, a Bruton tyrosine kinase inhibitor, presents a promising treatment option for patients with relapsed and refractory primary CNS lymphoma (PCNSL) who cannot tolerate or respond to high-dose methotrexate regimens.

This review highlights the need for alternative therapies in PCNSL, as current treatments primarily rely on high-dose methotrexate, which may not be suitable for all patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in primary central nervous system diffuse large B-cell lymphoma. T Low, J., B Peters, K.[2021]

References

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

[Curative effect of pemetrexed on the treatment of relapsed primary central nervous system lymphoma]. [2015]

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

Salvage therapy for primary central nervous system lymphoma with (90)Y-Ibritumomab and Temozolomide. [2022]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

Combination therapy with rituximab and temozolomide for recurrent and refractory primary central nervous system lymphoma. [2021]

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Zanubrutinib in the Maintenance Treatment of Elderly People with Primary Central Nervous System Lymphoma: A Report of 2 Cases. [2023]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Successful Management of a Patient with Refractory Primary Central Nervous System Lymphoma by Zanubrutinib. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Preliminary Evaluation of Zanubrutinib-Containing Regimens in DLBCL and the Cerebrospinal Fluid Distribution of Zanubrutinib: A 13-Case Series. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Ibrutinib in primary central nervous system diffuse large B-cell lymphoma. [2021]