| Eligibility |
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 cenral 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
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