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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two drugs, pemetrexed (a chemotherapy drug) and zanubrutinib, to determine their effectiveness in treating certain brain-related lymphomas that have recurred or resisted previous treatments. The researchers aim to assess whether this treatment can reduce or control the disease and evaluate its safety for patients. Suitable candidates for this trial include those diagnosed with primary CNS lymphoma or a specific type of B cell lymphoma affecting the brain, who have experienced issues with previous treatments. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering patients a chance to contribute to important findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that zanubrutinib is generally safe for people with central nervous system lymphoma. It effectively reaches the brain, which is crucial for treating brain-related conditions. In past studies, patients taking zanubrutinib with other treatments tolerated it well, experiencing no severe side effects.

For pemetrexed, research indicates it is also safe when used alone in patients with recurring central nervous system lymphoma. Most side effects were manageable, even for those who had undergone many previous treatments.

In summary, past studies have demonstrated that both zanubrutinib and pemetrexed are safe and well-tolerated in people with conditions like yours. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Zanubrutinib and Pemetrexed for CNS Lymphoma because it offers a novel approach compared to traditional treatments like chemotherapy and radiation. Zanubrutinib is a Bruton's tyrosine kinase inhibitor, which targets and blocks specific pathways that cancer cells use to grow, potentially offering a more targeted attack on lymphoma cells. Additionally, the combination with Pemetrexed, a chemotherapy that disrupts cancer cell metabolism, could enhance the overall effectiveness. This dual approach may offer more precise and effective treatment, potentially with fewer side effects than standard therapies.

What evidence suggests that this trial's treatments could be effective for CNS lymphoma?

Research shows that zanubrutinib, included in this trial's induction therapy, may effectively treat central nervous system lymphoma. Studies indicate it helps about 85% of patients, with most experiencing some improvement. Additionally, around 54% of patients achieve a complete response, where no cancer is detectable. Pemetrexed, also part of the induction therapy, proves effective on its own, especially for recurrent cases. It is manageable and suitable, particularly for older patients. Together, these treatments could offer a strong approach against this type of cancer. ^{1 3 4 6 7}

Who Is on the Research Team?

Yuliya Linhares, M.D.

Principal Investigator

Miami Cancer Institute at Baptist Health, Inc.

Are You a Good Fit for This Trial?

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.

Patients with prior participation in specified therapies within 2 weeks of protocol treatment

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7485351/

Pemetrexed in Recurrent or Progressive Central Nervous ... Pemetrexed administered at 900 mg/m 2 every 2 weeks exhibits single‐agent activity in patients with recurrent CNSL; it is well tolerated, and side effects are ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8983235/

Pemetrexed for Recurrent Primary Central Nervous System ... Results demonstrate that using high-dose pemetrexed might be a feasible and effective treatment for recurrent PCNSL in the elderly.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT00916630?tab=table

Treatment of Recurrent Primary or Secondary Central ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

4. asco.org asco.org/abstracts-presentations/ABSTRACT488552

Efficacy of pemetrexed-based regimens in primary central ... Efficacy of pemetrexed-based regimens in primary central nervous system lymphoma: A single-center experience. ; Age/Sex, ECOG, Regimen, Cycles, Best Response ; 74 ...

5. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.26709

Pemetrexed in the treatment of relapsed/refractory primary ... Pemetrexed has single-agent activity in relapsed/refractory PCNSL. Toxicities were seen likely because of the higher than standard dose used.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT00712062

Study of Pemetrexed to Treat Recurrent or Progressive ... The purpose of this study is to determine if pemetrexed is effective in the treatment of primary central nervous system lymphoma (PCNSL) that has either ...

7. neurology.org neurology.org/doi/10.1212/WNL.94.15_supplement.2809

Alimta (Pemetrexed) in recurrent or progressive primary ... Pemetrexed exhibits single-agent activity in heavily pre-treated patients with recurrent CNSL, is well tolerated and side effects are manageable.