Zanubrutinib + CAR T-Cell Therapy for Non-Hodgkin's Lymphoma

Recruiting at 2 trial locations

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must not be taking: CYP3A inducers, Corticosteroids

Disqualifiers: Active CNS disease, HIV, 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: 2

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of zanubrutinib and CAR T-cell therapy in treating patients with aggressive B-cell non-Hodgkin's lymphoma or transformed indolent B-cell lymphoma that has come back (recurrent) or does not respond to treatment (refractory). Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. T cells are infection fighting blood cells that can kill tumor cells. The T cells given in this study will come from the patient and will have a new gene put in them that makes them able to recognize CAR, a protein on the surface of cancer cells. These CAR-specific T cells may help the body's immune system identify and kill cancer cells. Giving zanubrutinib together with CAR T-cell therapy may kill more cancer cells.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take certain medications like moderate or strong CYP3A inducers or high-dose corticosteroids shortly before starting the trial. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment Zanubrutinib + CAR T-Cell Therapy for Non-Hodgkin's Lymphoma?

CAR T-cell therapies like axicabtagene ciloleucel and tisagenlecleucel have shown to improve outcomes for patients with aggressive B-cell lymphomas that are resistant to other treatments. These therapies have been approved for use in patients with relapsed or refractory large B-cell lymphoma, demonstrating their effectiveness in targeting and eliminating cancerous B cells. ^{1 2 3 4 5}

What is the safety profile of CAR T-cell therapies like axicabtagene ciloleucel and tisagenlecleucel?

CAR T-cell therapies, such as axicabtagene ciloleucel and tisagenlecleucel, have been associated with some serious side effects, including cytokine release syndrome (a severe immune reaction) and neurological issues. These side effects are generally manageable with proper medical care, but they can require hospitalization and intensive monitoring. ^{2 3 6 7 8}

What makes the treatment Zanubrutinib + CAR T-Cell Therapy unique for Non-Hodgkin's Lymphoma?

This treatment combines Zanubrutinib, a drug that targets specific proteins in cancer cells, with CAR T-cell therapy, which uses modified immune cells to attack cancer. This combination aims to enhance the effectiveness of treatment for aggressive B-cell lymphomas, especially when other options have failed. ^{1 4 9 10 11}

Research Team

Reem Karmali

Principal Investigator

Northwestern University

Eligibility Criteria

Adults with certain aggressive B-cell non-Hodgkin's lymphoma or transformed indolent B-cell lymphoma that is resistant to standard treatments. Participants must have a life expectancy over 12 weeks, acceptable organ function, and no active infections or severe heart conditions. Pregnant women, nursing mothers, HIV patients, and those unable to swallow pills are excluded.

Inclusion Criteria

I agree to use effective birth control during and for 6 months after the study.

Patients must have a life expectancy of greater than 12 weeks

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

I have active disease in my brain or spinal cord.

I cannot swallow pills or capsules.

I do not have stomach or intestine problems that affect medication absorption.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in Phase

Participants receive zanubrutinib orally twice daily for 7-14 days

1-2 weeks

1 visit (in-person)

CAR T-Cell Therapy

Participants receive standard of care CAR T-cell therapy intravenously

4 weeks

1 visit (in-person)

Maintenance Phase

Participants receive zanubrutinib orally twice daily on days 1-28, with cycles repeating every 28 days for 12 months

12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Chimeric Antigen Receptor T-Cell Therapy
• Zanubrutinib

Trial Overview The trial studies the combination of zanubrutinib (a drug blocking enzymes for cell growth) with CAR T-cell therapy (patient's T cells engineered to target cancer cells). It aims to see if this combo is more effective in treating specific types of recurrent or unresponsive B-cell lymphomas.

Participant Groups

Group I: Treatment (zanubrutinib and CAR T-cell therapy) Experimental Treatment 4 Interventions

LEAD- IN PHASE: Patients receive zanubrutinib PO BID for 7-14 days in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive standard of care CAR T-cell therapy IV at 4 weeks. MAINTENANCE PHASE: Patients receive zanubrutinib PO BID on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.

Chimeric Antigen Receptor T-Cell Therapy is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Tisagenlecleucel for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in United States as Tisagenlecleucel for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Axicabtagene ciloleucel for:

• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in United States as Axicabtagene ciloleucel for:

• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Tecartus for:

• Mantle cell lymphoma
• Acute lymphoblastic leukemia

Approved in United States as Tecartus for:

• Mantle cell lymphoma
• Acute lymphoblastic leukemia

Approved in European Union as Brexucabtagene autoleucel for:

• Mantle cell lymphoma

Approved in United States as Brexucabtagene autoleucel for:

• Mantle cell lymphoma

Approved in European Union as Lisocabtagene maraleucel for:

• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in United States as Lisocabtagene maraleucel for:

• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in Canada as CAR T-cell therapy for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in Japan as CAR T-cell therapy for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

CAR T-cell therapies have significantly changed treatment options for patients with relapsed or refractory aggressive B-cell lymphomas, with three products currently approved or nearing approval.

Selecting the right CAR T-cell product for a patient involves careful consideration of various factors, including the patient's age, health status, previous treatments, and the specific characteristics of each CAR T-cell product.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient selection for chimeric antigen receptor (CAR) T-cell therapy for aggressive B-cell non-Hodgkin lymphomas. Johnson, PC., Abramson, JS.[2021]

CAR-T cell therapies, specifically axicabtagene ciloleucel and tisagenlecleucel, have significantly improved outcomes for patients with relapsed or refractory aggressive B-cell lymphomas, with approvals based on pivotal trials demonstrating their efficacy after multiple prior treatments.

Despite their similar CAR technologies, differences in manufacturing and clinical trial designs exist between these therapies, highlighting the need for ongoing monitoring of patient responses and potential long-term side effects in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: Observations from the JULIET, ZUMA-1, and TRANSCEND trials. Westin, JR., Kersten, MJ., Salles, G., et al.[2022]

The three CAR-T cell therapies (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel) show promising efficacy in treating large B cell lymphoma, with overall response rates of nearly 70% and complete response rates exceeding 50% across 33 studies involving 2,172 patients.

However, axicabtagene ciloleucel and tisagenlecleucel are associated with significant risks of severe neurotoxicity and life-threatening cytokine release syndrome, necessitating careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of CAR-T Cell Products Axicabtagene Ciloleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel for the Treatment of Hematologic Malignancies: A Systematic Review and Meta-Analysis. Meng, J., Wu, X., Sun, Z., et al.[2022]

Tisagenlecleucel and axicabtagene ciloleucel are groundbreaking CAR-T cell therapies that have shown high effectiveness in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and certain types of B-cell non-Hodgkin lymphomas.

This review highlights the challenges faced by physicians in administering these therapies and discusses future directions for research and treatment in the field of immune and cellular therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19 chimeric antigen receptor-T cells in B-cell leukemia and lymphoma: current status and perspectives. Mohty, M., Gautier, J., Malard, F., et al.[2022]

In a pivotal phase 2 study involving 93 adult patients with relapsed or refractory diffuse large B-cell lymphoma, CAR T-cell therapy with tisagenlecleucel achieved a best overall response rate of 52%, with 40% of patients experiencing complete responses.

The treatment demonstrated durable responses, with a 12-month relapse-free survival rate of 65%, and no deaths were attributed to the therapy itself, although some patients experienced significant adverse events like cytokine release syndrome and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Schuster, SJ., Bishop, MR., Tam, CS., et al.[2019]

Cytokine release syndrome (CRS) is the most common adverse reaction reported after CAR-T therapy, with significantly higher reports for axicabtagene ciloleucel compared to tisagenlecleucel, indicating a need for careful monitoring of this side effect.

The study analyzed 1426 reports of adverse drug reactions from real clinical settings, supporting the overall safety profile of CAR-T therapies while confirming CRS as a major concern.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice. Bonaldo, G., Montanaro, N., AlbertoVaccheri, ., et al.[2021]

Tisagenlecleucel, an anti-CD19 CAR-T cell therapy, has been approved for treating pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), showing significant long-term effectiveness and overall survival benefits.

While CAR-T cell therapy can lead to serious adverse events like cytokine release syndrome and neurological toxicities, these effects are manageable with proper medical training and protocols, highlighting the importance of specialized care in administering this innovative treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T Cell Therapy: Practical Considerations for Implementation in Europe. Buechner, J., Kersten, MJ., Fuchs, M., et al.[2020]

CAR T-cell therapy, particularly with products like tisagenlecleucel and axicabtagene ciloleucel, has shown significant efficacy in treating CD19-expressing blood cancers, leading to complete responses in patients who have not responded to previous treatments.

Despite its effectiveness, CAR T-cell therapy carries risks such as cytokine release syndrome and neurotoxicity, necessitating careful monitoring and management by healthcare providers during follow-up care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond CAR T-Cell Therapy: Continued Monitoring and Management of Complications. Reiser, V.[2021]

CAR T-cell therapy, particularly with anti-CD19 targeting, has shown significant effectiveness in treating aggressive B-cell non-Hodgkin's lymphoma (NHL), leading to long-term remissions in patients with diffuse large B-cell lymphoma (DLBCL) who have not responded to other treatments.

Two CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved by the FDA for refractory DLBCL, while a third product, liso-cel, is showing promising results in ongoing trials, although potential side effects like cytokine-release syndrome and neurotoxicity are important considerations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. Chavez, JC., Bachmeier, C., Kharfan-Dabaja, MA.[2020]

CAR T-cell therapy targeting CD19 has transformed the treatment landscape for relapsed or refractory B-cell lymphomas, leading to rapid FDA approval for multiple lymphoma subtypes due to high response rates and durability.

Three second-generation anti-CD19 CAR T-cell products have been approved for use in aggressive non-Hodgkin's lymphoma, and ongoing research is focused on understanding treatment failures and improving outcomes for patients who do not respond to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for B-cell lymphoma. Denlinger, N., Bond, D., Jaglowski, S.[2022]

Chimeric antigen receptor (CAR) T-cell therapy, specifically anti-CD19 CAR T-cell therapies like axicabtagene ciloleucel and tisagenlecleucel, have been approved for treating relapsed or refractory aggressive B-cell lymphoma, marking a significant advancement after decades of limited treatment options.

These therapies have shown promising efficacy in clinical trials, but they also come with potential toxicities, highlighting the need for ongoing research to enhance their safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The promise of CAR T-cell therapy in aggressive B-cell lymphoma. Nair, R., Neelapu, SS.[2021]

References

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

Patient selection for chimeric antigen receptor (CAR) T-cell therapy for aggressive B-cell non-Hodgkin lymphomas. [2021]

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

Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: Observations from the JULIET, ZUMA-1, and TRANSCEND trials. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of CAR-T Cell Products Axicabtagene Ciloleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel for the Treatment of Hematologic Malignancies: A Systematic Review and Meta-Analysis. [2022]

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

CD19 chimeric antigen receptor-T cells in B-cell leukemia and lymphoma: current status and perspectives. [2022]

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

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice. [2021]

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

Chimeric Antigen Receptor-T Cell Therapy: Practical Considerations for Implementation in Europe. [2020]

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

Beyond CAR T-Cell Therapy: Continued Monitoring and Management of Complications. [2021]

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

CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. [2020]

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

CAR T-cell therapy for B-cell lymphoma. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

The promise of CAR T-cell therapy in aggressive B-cell lymphoma. [2021]