Zanubrutinib Combination Therapy for Central Nervous System Lymphoma

Overseen By Juan P Alderuccio, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Miami

Must not be taking: CYP3A inducers, Warfarin

Disqualifiers: Primary CNS lymphoma, Cardiovascular disease, Autoimmune anemia, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to test the effects of a new treatment combination for individuals with secondary central nervous system lymphoma, a cancer affecting the brain and spinal cord. Researchers seek to evaluate how the drug Zanubrutinib (Brukinsa) performs when combined with other cancer-fighting medications. The trial seeks participants with a confirmed diagnosis of large B-cell lymphoma and cancer involvement in both the body and central nervous system. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on medications that strongly induce CYP3A (a liver enzyme that processes drugs) or if you require treatment with warfarin or similar blood thinners.

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

Research has shown that zanubrutinib, the main treatment in this trial, is generally safe. Studies have found that combining zanubrutinib with high-dose methotrexate results in a safety profile acceptable for treating primary central nervous system lymphoma. Additionally, the FDA has approved zanubrutinib for some types of lymphoma, indicating it is well-tolerated.

Although information on side effects from these combinations is limited, previous studies have not reported any severe unexpected side effects. However, as this trial is in an early stage, it is specifically designed to further assess safety, with close monitoring of any risks. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for central nervous system lymphoma, which typically include chemotherapy regimens like R-CHOP, Zanubrutinib is unique because it is a Bruton’s tyrosine kinase (BTK) inhibitor. This means it targets a specific enzyme crucial for the survival and proliferation of lymphoma cells. Researchers are excited about Zanubrutinib because it offers a more targeted approach, potentially leading to fewer side effects and improved effectiveness. By combining Zanubrutinib with Pola-R-CHP and Methotrexate, there's hope for a synergistic effect that could enhance treatment outcomes.

What evidence suggests that this treatment might be an effective treatment for CNS Lymphoma?

Studies have shown that zanubrutinib, when combined with high-dose methotrexate (HD-MTX), effectively treats central nervous system lymphoma. One study demonstrated strong positive responses in patients newly diagnosed with primary CNS lymphoma using this combination. For recurrent or hard-to-treat CNS lymphoma, zanubrutinib-based treatments proved both effective and safe. A review of several studies found zanubrutinib had an overall response rate of 85%, indicating most patients responded well. In this trial, participants will receive zanubrutinib with Pola-R-CHP and methotrexate. These findings suggest that zanubrutinib, especially when combined with treatments like methotrexate, could be a promising option for managing CNS lymphoma. ^{5 6 7 8 9}

Who Is on the Research Team?

Juan P Alderuccio, MD

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

This trial is for patients with secondary CNS lymphoma. Specific eligibility criteria are not provided, but typically participants would need a confirmed diagnosis and may have to meet certain health standards.

Inclusion Criteria

Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments (SoA)

Life expectancy of greater than ≥ 3 months

Agreement to use contraception during study participation

Exclusion Criteria

I have a severe lung condition.

I am currently receiving treatment for another cancer.

Breastfeeding or pregnant women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Zanubrutinib in combination with Pola-R-CHP and Methotrexate

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Zanubrutinib

Trial Overview The study tests the effectiveness of Zanubrutinib combined with Pola-R-CHP (Rituximab, Cyclophosphamide, Doxorubicin, Prednisone) and high-dose Methotrexate in treating secondary CNS lymphoma.

How Is the Trial Designed?

Group I: Zanubrutinib in combination with Pola-R-CHP and in combination with Methotrexate Group Experimental Treatment 7 Interventions

Participants will be in this group for up to 2 years

Zanubrutinib is already approved in United States, China for the following indications:

Approved in United States as Brukinsa for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)

Approved in China as Brukinsa for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)

Who Is Running the Clinical Trial?

University of Miami

Lead Sponsor

Trials

976

Recruited

423,000+

Juan P. Alderuccio, MD

Lead Sponsor

Trials

2

Recruited

120+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Published Research Related to This Trial

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]

Zanubrutinib is a next-generation BTK inhibitor that shows improved selectivity and reduced off-target toxicities compared to ibrutinib, making it a safer option for treating B-cell malignancies.

In recent clinical trials, zanubrutinib demonstrated significant efficacy in improving progression-free survival in patients with chronic lymphocytic leukemia (CLL) and showed better safety profiles, including a lower risk of serious side effects like atrial fibrillation and major bleeding compared to ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. Wolska-Washer, A., Robak, T.[2023]

Zanubrutinib, a selective Bruton tyrosine kinase inhibitor, showed a high overall response rate of 94.5% in treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma carrying the del(17p) mutation, indicating its efficacy in a challenging patient population.

The treatment was well tolerated, with an estimated 18-month progression-free survival rate of 88.6% and an overall survival rate of 95.1%, although some patients experienced adverse events, including neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. Tam, CS., Robak, T., Ghia, P., et al.[2021]

A combination treatment of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the BTK inhibitor ibrutinib showed promising responses in patients with primary central nervous system lymphoma.

However, this treatment regimen was linked to significant toxicity, including serious infections like pulmonary and cerebral aspergillosis, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. Grommes, C., Younes, A.[2018]

In a retrospective study of patients with primary central nervous system lymphoma (PCNSL), three patients showed good clinical responses to ibrutinib-based therapy, indicating its potential effectiveness in treating this aggressive cancer, especially in those unfit for traditional chemotherapy.

In vitro and pharmacokinetic studies revealed that ibrutinib demonstrated the strongest anti-tumoral effects compared to other BTK inhibitors, and both ibrutinib and tirabrutinib effectively penetrated the blood-brain barrier, making them promising candidates for targeted therapy in PCNSL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bruton's tyrosine kinase inhibitors in primary central nervous system lymphoma-evaluation of anti-tumor efficacy and brain distribution. Yu, H., Kong, H., Li, C., et al.[2022]

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 selective Bruton tyrosine kinase inhibitor, was found to be generally well tolerated when combined with obinutuzumab in a phase 1 study involving 81 patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

The combination therapy showed high efficacy, achieving a 100% overall response rate in treatment-naïve CLL patients and a 92% response rate in relapsed/refractory CLL patients, with a 72% response rate in relapsed/refractory FL patients over a median follow-up of 20 to 29 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Tam, CS., Quach, H., Nicol, A., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10762531/

Clinical outcomes of newly diagnosed primary central nervous ... Zanubrutinib combined with HD-MTX resulted in effective clinical responses in newly diagnosed PCNSL patients. The study highlighted the potential of CSF ctDNA ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1735/532484/Updated-Results-from-a-Multicenter-Phase-II-Study

Updated Results from a Multicenter, Phase II Study of ... This study aims to evaluate the efficacy and safety of R-MTX-Zebrutinib in patients with relapsed or refractory central nervous system lymphoma (SCNSL)

3. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.70083?af=R

Meta‐analysis evaluating the efficacy and safety of various ... Among patients with PCNSL, zanubrutinib achieved pooled ORR and CR rates of 85% and 54%, respectively. Ibrutinib had pooled ORR and CR rates of ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.23_suppl.30

Bruton's tyrosine kinase inhibitor zanubrutinib-based ... Conclusions: Our study demonstrates that zanubrutinib-based therapy is effective and safe for the treatment of R/R PCNSL. We advocate for the ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S000649712409311X

Zanubrutinib in Combination with R-MTX for Newly ... Zanubrutinib combined with H-MTX showed promising efficacy and acceptable safety in Primary Central Nervous System Lymphoma (PCNSL).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8739956/

Preliminary Evaluation of Zanubrutinib-Containing Regimens ... This preliminary study revealed the effectiveness of zanubrutinib-containing regimens in DLBLC, especially CNS-involved cases, for the first time.

7. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6484/527496/Zanubrutinib-in-Combination-with-R-MTX-for-Newly

Zanubrutinib in Combination with R-MTX for Newly Diagnosed ... Zanubrutinib combined with H-MTX showed promising efficacy and acceptable safety in Primary Central Nervous System Lymphoma (PCNSL).

8. clinicaltrials.gov clinicaltrials.gov/study/NCT05681195

NCT05681195 | Zanubrutinib With Pemetrexed to Treat ... Zanubrutinib is an oral drug that is approved by the Food and Drug Administration (FDA) as safe and effective to treat certain lymphoma types. Official Title.

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123126930

Efficacy and Safety of Zanubrutinib-Containing Regimens ... We performed a multicenter retrospective study to evaluate the efficacy and safety of Zanubrutinib-containing regimens for salvage treatment in 28 relapsed ...