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

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. 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.

What data supports the effectiveness of the drug Zanubrutinib for treating central nervous system lymphoma?

Research shows that Zanubrutinib, a type of drug called a Bruton's tyrosine kinase inhibitor, has been effective in treating central nervous system lymphoma. In one study, patients with this condition showed an 81.8% response rate, and the drug was able to reach the brain effectively, which is important for treating this type of cancer. ^{1 2 3 4 5}

Is zanubrutinib safe for use in humans?

Zanubrutinib has been generally well tolerated in various studies, with common side effects including infections, bruising, and diarrhea. Serious side effects like low white blood cell counts and pneumonia have been reported in some cases, but overall, it has shown a good safety profile in patients with different types of lymphoma. ^{1 2 4 6 7}

What makes the drug zanubrutinib unique for treating central nervous system lymphoma?

Zanubrutinib is unique because it is a second-generation Bruton's tyrosine kinase inhibitor that can effectively cross the blood-brain barrier, making it particularly suitable for treating central nervous system lymphoma. It also has a more selective action with fewer side effects compared to similar drugs like ibrutinib, and it has shown promising results in achieving remission in patients with this condition. ^{1 2 4 5 8}

What is the purpose of this trial?

The purpose of this study is to is to determine the effects (good and bad) of Zanubrutinib in Combination with Pola-R-CHP and High-dose Methotrexate in patients with Secondary Central Nervous System (CNS) Lymphoma.

Research Team

Juan P Alderuccio, MD

Principal Investigator

University of Miami

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

References

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

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

2. 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]

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

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. [2018]

4. China pubmed.ncbi.nlm.nih.gov

Bruton's tyrosine kinase inhibitors in primary central nervous system lymphoma-evaluation of anti-tumor efficacy and brain distribution. [2022]

5. 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]

6. Italy pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. [2021]

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

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. [2021]

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

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. [2023]