Zanubrutinib + Tislelizumab for Lymphoma

(OZUHN-024 Trial)

Overseen By John Kuruvilla, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: BTK inhibitors, PD-1 inhibitors

Disqualifiers: Uncontrolled autoimmune disease, CNS involvement, organ transplant, 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

Duration: Variable, based on individual response and safety assessment

76 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have taken BTK or PD-1 inhibitors before, or if you are on high doses of prednisone. It's best to discuss your current medications with the trial team to see if they might affect your eligibility.

What data supports the effectiveness of the drug Tislelizumab for treating lymphoma?

Tislelizumab has shown promising results in treating various types of lymphoma, including classical Hodgkin's lymphoma and B-cell non-Hodgkin lymphoma, with high response rates and some patients achieving complete remission. It has been approved in China for relapsed or refractory classical Hodgkin's lymphoma and has demonstrated effectiveness in combination with other therapies for B-cell non-Hodgkin lymphoma. ^{1 2 3 4 5}

Is the combination of Zanubrutinib and Tislelizumab safe for treating lymphoma?

Tislelizumab has been studied in various cancers and generally has an acceptable safety profile, with common side effects like fatigue and low blood cell counts, and more serious risks like respiratory infections. In studies with lymphoma patients, it was well tolerated, with some experiencing infusion-related reactions and immune-related side effects, but no deaths were reported due to treatment. ^{1 4 6 7 8}

How is the drug Tislelizumab unique for treating lymphoma?

Tislelizumab, when combined with zanubrutinib, offers a novel approach by combining a PD-1 inhibitor with a BTK inhibitor, which has shown promising results in treating aggressive forms of lymphoma like Richter transformation, with a good response rate and tolerability. ^{9 10 11 12 13}

What is the purpose of this trial?

This study is designed to see how well two new drugs work, either alone or with the usual treatment, for patients whose lymphoma (a type of cancer) has gotten worse after they've already received a special type of immune therapy called anti-CD19 CAR-T cell therapy. It's a planned, multi-site clinical trial. This means that patients from several different medical centers will be involved in the study. The study will test two specific drugs: Zanubrutinib: A new drug that targets certain cancer cells and blocks a specific protein involved in cancer cell survival, known as a BTK inhibitor. Tislelizumab: Another new drug that helps the immune system attack cancer cells by blocking a protein that prevents immune cells from doing their job, known as a PD-1 inhibitor. We have already seen that this combination of drugs is safe and shows early promise in treating patients with aggressive B cell cancers that have come back or didn't respond well to previous treatments. Additionally, research in the lab suggests that adding either a BTK or a PD-1 inhibitor might make CAR-T therapy, a type of treatment where modified immune cells are used to target cancer, even more effective. Since there isn't much experience with using the drugs tislelizumab and zanubrutinib on their own for this specific group of patients, the first part of our trial will test each drug alone to make sure they're safe to use. If these drugs are found to be safe when used by themselves, we'll then try a new treatment approach that combines both drugs together. Here's what we're hoping to achieve: Combining zanubrutinib and tislelizumab might work well because: Zanubrutinib helps to directly attack lymphoma cells (a type of cancer cell). Tislelizumab helps the immune system (or CAR-T therapy) work better against cancer cells. We want to see if this combination is effective and safe for patients whose lymphoma has continued to progress or come back after they've already had anti-CD19 CAR-T therapy.

Eligibility Criteria

This trial is for lymphoma patients whose cancer has worsened after anti-CD19 CAR-T cell therapy. Specific eligibility details are not provided, but typically include factors like age, health status, and previous treatments.

Inclusion Criteria

My large B-cell lymphoma returned or didn't respond to CAR-T therapy within the last 6 weeks.

Intervention arm: Hemoglobin ≥ 80 g/L at screening

Serum total bilirubin < 1.5x ULN, except in patients with documented Gilberts syndrome at screening

Exclusion Criteria

Prior anaphylactic reaction to monoclonal antibody therapy at any time prior to enrollment

Life expectancy < 30 days at the time of enrollment

I have been treated with BTK or PD-1 inhibitors before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either zanubrutinib or tislelizumab alone initially, followed by a combination of both drugs if deemed safe

Variable, based on individual response and safety assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Tislelizumab

Trial Overview The study tests Zanubrutinib (a BTK inhibitor) and Tislelizumab (a PD-1 inhibitor), alone or combined with standard care. It's a multi-site trial to see if these drugs can make CAR-T therapy more effective against aggressive B cell cancers.

Participant Groups

Group I: Interventional Arm Experimental Treatment 1 Intervention

Patients will receive a combination of tislelizumab and zanubrutinib.

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Findings from Research

Tislelizumab is a modified PD-1 antibody that effectively inhibits tumor growth in various cancers, including Hodgkin's lymphoma and lung cancer, and has received multiple approvals in China for its use.

It has a favorable safety profile with common side effects like fatigue and anemia, and it offers economic advantages over other PD-1 inhibitors, making it a promising option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab: A Modified Anti-tumor Programmed Death Receptor 1 Antibody. Zhang, L., Geng, Z., Hao, B., et al.[2023]

Tislelizumab is an anti-PD-1 monoclonal antibody developed as an immunotherapy for cancer, specifically approved in December 2019 in China for relapsed or refractory classical Hodgkin's lymphoma after at least two prior chemotherapy treatments.

The drug has shown promise in treating both hematological cancers and advanced solid tumors, indicating its potential for future approvals in additional cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab: First Approval. Lee, A., Keam, SJ.[2020]

In a phase IA/IB study involving 451 patients with advanced solid tumors, tislelizumab demonstrated an acceptable safety profile, with most adverse events being mild (grade 1-2), and only 5.3% of patients discontinuing treatment due to side effects.

Tislelizumab showed promising antitumor activity, with 18% of patients in phase IA and 12% in phase IB achieving confirmed objective responses, leading to the recommendation of a dosing schedule of 200 mg every 3 weeks for future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors. Desai, J., Deva, S., Lee, JS., et al.[2021]

Tislelizumab, a PD-1 inhibitor, significantly improved the overall response rate (ORR) and disease control rate (DCR) in patients with malignant solid tumors, with odds ratios of 2.59 and 1.78, respectively, based on a meta-analysis of seven phase III trials involving 3478 participants.

The treatment also demonstrated improved overall survival (OS) and progression-free survival (PFS), with hazard ratios of 0.71 and 0.68, indicating that tislelizumab is an effective option for patients with solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of tislelizumab for malignant solid tumor: a systematic review and meta-analysis of phase III randomized trials. Abushanab, AK., Mustafa, MT., Mousa, MT., et al.[2023]

Monoclonal antibody therapies for advanced primary cutaneous lymphomas show promising efficacy and a more manageable safety profile compared to traditional polychemotherapy, which often has severe side effects.

Despite their advantages, the safety of these monoclonal antibodies must be carefully evaluated, as adverse effects can arise from targeting not only tumor cells but also benign T and B cells, and many patients have undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Reactions of Antibody-Therapy for Primary Cutaneous Lymphomas: Rituximab, Brentuximab Vedotin, Alemtuzumab, and Mogamulizumab. Saulite, I., Guenova, E., Hoetzenecker, W.[2019]

Zanubrutinib is a highly selective second-generation BTK inhibitor that has shown deep and sustained remissions in patients with relapsed and refractory B-cell lymphoma, indicating its efficacy as a targeted therapy.

The drug has a favorable safety profile, making it a promising option for precision therapy in the treatment of B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Application of Zanubrutinib in B-Cell Lymphoma --Review]. Tang, X., Zou, WR., Peng, P., 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]

A 75-year-old patient developed a severe disseminated cryptococcal infection, leading to pneumonia and meningitis, four months after starting zanubrutinib for Waldenström's macroglobulinemia, highlighting a potential risk of serious infections associated with BTK inhibitors.

Despite initial treatment, the patient's condition worsened, resulting in septic shock and multiorgan failure, suggesting that while zanubrutinib can be effective for certain cancers, it may also compromise immune function, increasing vulnerability to invasive fungal infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fatal disseminated cryptococcal infection in a patient treated with zanubrutinib for Waldenström's macroglobulinemia. Patel, D., Sidana, M., Mdluli, X., et al.[2022]

In a phase 2 study involving 59 patients with Richter transformation of chronic lymphocytic leukemia, the combination of the PD-1 inhibitor tislelizumab and the BTK inhibitor zanubrutinib resulted in a significant overall response rate of 58.3%, surpassing the predefined threshold of 40%.

The treatment was well-tolerated, with a 12-month overall survival rate of 74.7%, indicating that this combination therapy is both effective and safe for patients with this aggressive form of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. Al-Sawaf, O., Ligtvoet, R., Robrecht, S., et al.[2023]

In a study of 27 patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), the combination of zanubrutinib and salvage chemotherapy resulted in a high overall response rate of 74.1% and a complete remission rate of 33.3%, indicating significant efficacy.

The most common severe side effects were neutropenia and thrombocytopenia, but the treatment was generally manageable, suggesting that zanubrutinib plus chemotherapy could be a viable option for R/R DLBCL patients, especially those with poor responses to initial treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib plus salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma. Yuan, X., Li, X., Huang, Y., et al.[2022]

References

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

Tislelizumab: A Modified Anti-tumor Programmed Death Receptor 1 Antibody. [2023]

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

Tislelizumab: First Approval. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors. [2021]

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

Tislelizumab augment the efficacy of CD19/22 dual-targeted chimeric antigen receptor T cell in advanced stage relapsed or refractory B-cell non-Hodgkin lymphoma. [2023]

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

Treating relapsed/refractory mature T- and NK-cell neoplasms with tislelizumab: a multicenter open-label phase 2 study. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of tislelizumab for malignant solid tumor: a systematic review and meta-analysis of phase III randomized trials. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Treatment of relapsed or refractory classical Hodgkin lymphoma with the anti-PD-1, tislelizumab: results of a phase 2, single-arm, multicenter study. [2021]

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

Adverse Reactions of Antibody-Therapy for Primary Cutaneous Lymphomas: Rituximab, Brentuximab Vedotin, Alemtuzumab, and Mogamulizumab. [2019]

9. China pubmed.ncbi.nlm.nih.gov

[Clinical Application of Zanubrutinib in B-Cell Lymphoma --Review]. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

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

11. England pubmed.ncbi.nlm.nih.gov

A fatal disseminated cryptococcal infection in a patient treated with zanubrutinib for Waldenström's macroglobulinemia. [2022]

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

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. [2023]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Zanubrutinib plus salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma. [2022]