Evaluating Zanubrutinib and Tislelizumab for Progressive Lymphoma After CAR-T Therapy

A Prospective, Multicenter, Phase II Trial to Evaluate the Efficacy of Zanubrutinib and Tislelizumab as Well as Standard of Care for the Treatment of Patients With Progressive Lymphoma Post Anti-CD19 CAR-T Cell Therapy

This study is testing whether a combination of zanubrutinib and tislelizumab can help people with large B-cell lymphoma who have not responded well after CAR-T therapy.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 76 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University Health Network, Toronto (Academic / other)
• Drugs / interventions: tislelizumab, zanubrutinib, CAR-T, radiation, prednisone, Chimeric antigen receptor
• Locations: 1 site (Toronto, Ontario)
• Trial ID: NCT06167785 on ClinicalTrials.gov

What this trial studies

This phase II study focuses on patients with large B-cell lymphoma who have experienced disease progression after anti-CD19 CAR-T therapy. It consists of two parts: an initial safety run-in period to assess the tolerability and safety of zanubrutinib and tislelizumab monotherapy, followed by an expanded cohort phase if the initial results are promising. Patients who meet the eligibility criteria can also enroll in a standard of care arm during the study. The aim is to evaluate the efficacy of the combination therapy in this heavily pre-treated population.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with relapsed or refractory large B-cell lymphoma post-CD19 CAR-T therapy.

Not a fit: Patients who do not have measurable disease or are not within the specified eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide a new treatment option for patients with progressive lymphoma after CAR-T therapy.

How similar studies have performed: While this approach is novel for this specific patient population, similar studies evaluating combination therapies in lymphoma have shown promising results.

Eligibility criteria

Inclusion Criteria:

1. Age ≥ 18 years
2. Able and willing to provide written informed consent and to comply with the study protocol
3. Radiologically measurable disease (≥ 1 nodal lesion \> 2.0 cm in the longest diameter, and/or extranodal lesion \> 1.0cm in the longest diameter)
4. Intervention arm: Radiological measureable disease per inclusion criterion #3 with more than one site of disease.
5. Relapse or refractory Large B cell Lymphoma post-CD19 directed CAR-T cell therapy within 6 weeks prior to enrollment (histological confirmation highly recommended although not mandatory)
6. Intervention arm: Hemoglobin ≥ 80 g/L at screening\*
7. Intervention arm: Platelet count ≥ 50 x 109/L at screening\*
8. Intervention arm: Neutrophil count ≥ 1.0 x 109/L at screening\*
9. Intervention arm: performance status ≤ 2 at screening
10. AST and ALT \< 2.5 x upper limit of normal (ULN) at screening
11. Serum total bilirubin \< 1.5 x ULN, or \< 3 x ULN in patients with documented Gilberts syndrome at screening
12. Creatinine clearance ≥ 30 mL/min as estimated by Cockcroft-gault equation at screening \* Counts can be supported with growth factors or transfusions as per standard transfusion protocols

Exclusion Criteria:

1. Life expectancy \< 30 days at the time of enrollment
2. Prior exposure to bruton tyrosine kinase (BTK) or Programmed cell death (PD)-1 inhibitor at any time prior to enrollment
3. Prior anaphylactic reaction to monoclonal antibody therapy at any time prior to enrollment
4. On higher than physiologic doses (10mg daily) of prednisone daily at least 7 days prior to initiation of trial treatment
5. Uncontrolled autoimmune disease
6. Known active central nervous system (CNS) involvement disease
7. History of prior allogeneic transplant or organ transplant
8. Active bleeding or history of bleeding diathesis including, but not limited to,

   * History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
   * History of stroke or intracranial hemorrhage within 180 days before first dose of study drug
9. Difficulty with or unable to swallow oral medication, or known conditions that would significantly affect gastrointestinal function that would limit absorption of oral medication
10. History of chronic or active, uncontrolled bacterial, viral or fungal infection; human T- cell lymphotropic virus type 1 seropositive status.
11. Serologic status reflecting active viral hepatitis B or C infection as follows: (a) presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is undetectable (\< 20IU), and if they are willing to be on appropriate prophylaxis and undergo monitoring for HBV reactivation if clinically indicated.

    (b) Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV ribonucleaic acid (RNA) is undetectable.
12. Individuals with known active human immunodeficiency (HIV) infection are eligible if CD4 and viral titres are controlled
13. Any serious intercurrent illness, life threatening condition, organ system dysfunction including:

    * (1) Clinically significant cardiovascular including:

      1. prolonged QTc \> 480ms,
      2. history of Mobitz II second degree or third degree heart block without a permanent pacemaker in situ,
      3. uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure reading on 2 separate occasions showing systolic blood pressure (BP) \> 170 mmHg and/or diastolic BP \> 105mmHg at screening,
      4. uncontrolled or history of symptomatic arrhythmias (ie. sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes),
      5. congestive heart failure or NYHA class ≥ 3,
      6. myocardial infarction within 6 months prior to enrollment;
    * (2) History of significant cerebrovascular events including stroke or intracranial hemorrhage within 6 months prior to enrollment
    * (3) History of interstitial lung disease or non-infectious pneumonitis (excluding radiation induced), or severe/ debilitating pulmonary disease prior to enrollment
14. History of other active malignancies within 2 years prior to enrollment, with the exception of adequately treated in-situ carcinoma of cervix; localized basal cell or squamous cell carcinoma of skin; or previous malignancy confined and treated locally (surgery or other modality) with curative intent.
15. Female patients of childbearing potential must practice highly effective methods (Section 6.7.1.1) of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib or tislelizumab
16. Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with highly effective methods during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib or tislelizumab.
17. Major surgery within 4 weeks of the first dose of study drug
18. Vaccination with a live vaccine within 28 days prior to the first dose of study drug
19. Patient requires treatment with warfarin or other vitamin K antagonists
20. Severe or debilitating pulmonary disease (dyspnea at rest, significant shortness of breath, congestive obstructive pulmonary disease).
21. History of interstitial lung disease or noninfectious pneumonitis, except for those induced by radiation therapy.
22. Active and symptomatic fungal, bacterial, and/or viral infection; human T-cell lymphotropic virus type 1 seropositive status.
23. Any illness or condition that in the opinion of the investigator may affect safety of treatment or evaluation of any study endpoint.
24. Active autoimmune diseases or history of severe autoimmune diseases; these include but are not limited to a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, connective tissue diseases, scleroderma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, or clinically manifest antiphospholipid syndrome. Note: Subjects are permitted to enroll if they have vitiligo, eczema, type I diabetes mellitus, or endocrine deficiencies, including thyroiditis managed with replacement hormones including physiologic doses of corticosteroids. Subjects with Sjögren's syndrome and psoriasis controlled with topical medication and subjects with positive serology, such as antinuclear antibodies or antithyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
25. A condition requiring systemic treatment with either corticosteroids (\> 20 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration, except for primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL). Note: adrenal replacement doses ≤ 20 mg daily prednisone or equivalents are permitted in the absence of active autoimmune disease; subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption).
26. Major surgery in the past 4 weeks prior to the first day of screening.
27. Intervention arm: Live vaccines within 28 days of screening
28. Patients with contraindications for zanubrutinib

Where this trial is running

Toronto, Ontario

• University Health Network (UHN) — Toronto, Ontario, Canada (Recruiting)

Study contacts

• Principal investigator: John Kuruvilla, FRCPC — University Health Network, Toronto
• Study coordinator: John Kuruvilla, FRCPC

Conditions Large B-cell Lymphoma