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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of two new drugs, zanubrutinib and tislelizumab, either alone or together, for treating lymphoma that has worsened after previous therapy. Zanubrutinib directly targets cancer cells, while tislelizumab, an immunotherapy drug, boosts the immune system's ability to fight cancer. The trial aims to determine if these drugs can offer a new treatment option for patients whose lymphoma has returned or progressed after anti-CD19 CAR-T cell therapy. Individuals with large B cell lymphoma that has relapsed or been resistant to treatment following CAR-T therapy may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that the combination of zanubrutinib and tislelizumab is generally safe for individuals with certain B-cell cancers. Studies indicate that the most common side effects include infections, stomach issues, and blood-related problems. These side effects occur in a small percentage of participants: infections in about 18%, stomach issues in 13%, and blood issues in 11.4%. Overall, participants tolerate the combination well, meaning most can manage any side effects they experience. This suggests the treatment is safe enough for further testing in clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of zanubrutinib and tislelizumab for lymphoma because it offers a novel approach that differs from standard treatments like chemotherapy and traditional immunotherapy. Zanubrutinib is a Bruton's tyrosine kinase (BTK) inhibitor, which specifically targets and blocks BTK, a protein essential for the growth and survival of certain cancer cells. Tislelizumab, on the other hand, is a PD-1 inhibitor that helps the immune system recognize and attack cancer cells more effectively. Together, these drugs aim to improve outcomes by combining targeted attack on cancer cell growth with enhanced immune response, potentially offering a more effective and less toxic alternative to existing therapies.

What evidence suggests that this trial's treatments could be effective for lymphoma?

Studies have shown that combining zanubrutinib and tislelizumab holds promise for treating certain cancers. One study found that individuals with Richter transformation had a 74.7% chance of living for at least a year. This combination also proved effective in extending survival when used with CAR-T therapy, which employs specially altered immune cells. The combination appears to enhance the immune system's ability to fight cancer. Overall, early research suggests this treatment could benefit patients whose lymphoma has worsened after other treatments. Participants in this trial will receive the combination of tislelizumab and zanubrutinib to further evaluate its effectiveness. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

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

Intervention arm: Hemoglobin ≥ 80 g/L at screening

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. nature.com nature.com/articles/s41591-023-02722-9

Tislelizumab plus zanubrutinib for Richter transformation Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4–91.0). The most common adverse events were ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12017895/

Response‐adapted zanubrutinib and tislelizumab as a ... The superior PFS observed in our study highlights the potential of zanubrutinib and tislelizumab to improve the outcomes of CAR T‐cell therapy.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265025018944

CLL-1340: Outcomes With Bruton Tyrosine Kinase ... The zanubrutinib/tislelizumab combination showed the highest response rates and survival, whereas acalabrutinib and pirtobrutinib monotherapy had more ...

4. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/204/502086/Tislelizumab-Plus-Zanubrutinib-in-Patients-with

Tislelizumab Plus Zanubrutinib in Patients with Richter ... The median DOR was not reached, the 6-month DOR rate was 70.6%. Median PFS was 10 months (95% CI 3.8 -16.3) with a 12-month rate of 46.9% (Fig B) ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06167785

A Study to Evaluate Zanubrutinib and Tislelizumab in ... The purpose of the study is to to evaluate the efficacy of zanubrutinib and tislelizumab in patients with progressive lymphoma post anti-CD 19 CAR-T failure.

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118595112

An Update on Safety and Preliminary Efficacy of Highly ... Conclusions: The combination of zanubrutinib and tislelizumab has shown a generally manageable toxicity profile in B-cell malignancies. IR-AEs, consistent with ...

7. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/1594/427339/An-Update-on-Safety-and-Preliminary-Efficacy-of

An Update on Safety and Preliminary Efficacy of Highly ... Conclusions: The combination of zanubrutinib and tislelizumab has shown a generally manageable toxicity profile in B-cell malignancies. IR-AEs, ...

8. esmoiotech.org esmoiotech.org/article/S2590-0188(22)00141-1/fulltext

106P Zanubrutinib in combination with tislelizumab ... This combination of zanubrutinib and tislelizumab is well-tolerated with promising clinical response in refractory DLBCL patients.