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

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how a new combination of treatments can assist individuals with certain types of non-Hodgkin's lymphoma that have recurred or are resistant to standard treatment. The study examines the use of zanubrutinib, a drug that inhibits cancer cell growth, in combination with CAR T-cell therapy (Chimeric Antigen Receptor T-Cell Therapy), which employs specially modified immune cells to target cancer. This trial may suit those with specific types of aggressive B-cell lymphoma unresponsive to standard treatments. As a Phase 2 trial, it focuses on assessing the treatment's effectiveness in an initial, smaller group of participants, offering them a chance to benefit from innovative therapies.

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.

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

Research has shown that both zanubrutinib and CAR T-cell therapy have been studied for their safety in humans. CAR T-cell therapy, which uses a person's own immune cells to fight cancer, has received FDA approval for other types of B-cell lymphoma, indicating it has been tested and deemed safe for these conditions. However, it can cause serious side effects, such as a strong immune reaction called cytokine release syndrome and some brain-related effects.

Zanubrutinib is a drug that inhibits certain enzymes aiding cancer cell growth. It is generally well-tolerated, with common side effects including mild low blood counts and some stomach issues. Its approval for other conditions suggests it is generally safe.

Combining zanubrutinib with CAR T-cell therapy might increase the risk of side effects, but this combination is under study to better understand its safety. So far, research has shown that this combination can be used safely with careful monitoring by healthcare professionals. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Zanubrutinib with CAR T-cell therapy for treating non-Hodgkin's lymphoma because it offers a unique approach compared to existing treatments like chemotherapy and radiation. Zanubrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor, which works by blocking signals that help cancer cells survive, offering a targeted method to potentially reduce cancer growth. CAR T-cell therapy, on the other hand, involves modifying a patient's own T-cells to better recognize and attack cancer cells. Together, these treatments might provide a more effective and personalized strategy, especially for patients who have not responded well to traditional therapies.

What evidence suggests that zanubrutinib and CAR T-cell therapy could be effective for non-Hodgkin's lymphoma?

Research has shown that zanubrutinib effectively treats relapsed or hard-to-treat mantle cell lymphoma, a type of blood cancer. Studies found that 84% of patients responded to the treatment, and 25% achieved complete remission, meaning no cancer was detected. Additionally, CAR T-cell therapy successfully targets a protein called CD19, found in many B-cell lymphomas, including non-Hodgkin's lymphoma. CAR T-cells not only attack cancer cells but also remain in the body to help prevent the cancer from returning. In this trial, participants will receive a combination of zanubrutinib and CAR T-cell therapy, offering a promising approach to addressing aggressive and treatment-resistant lymphomas. ^{2 6 7 8 9}

Who Is on the Research Team?

Reem Karmali

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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