Zanubrutinib (BGB-3111) in Combination With Tislelizumab (BGB-A317) in Participants With B-cell Malignancies
Condition: Lymphoma; Leukemia
MeSH terms: Neoplasms
Intervention: Zanubrutinib; Tislelizumab
Intervention MeSH terms: Tislelizumab; Zanubrutinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 75.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Relapsed; Refractory

Summary:

      This study is evaluating the safety and preliminary efficacy of BGB-3111 in combination with
      BGB-A317 in participants with B-cell lymphoid malignancies.
    

Eligibility criteria:

        Key Inclusion Criteria

        Participants may be entered in the study only if they meet all of the following criteria:

          1. Dose escalation for Dose Levels 1, 2, and 3: participants with relapsed or refractory
             World Health Organization (WHO) classification-defined B-lymphoid malignancy following
             at least 1 line of therapy, with no therapy of higher priority available, including
             chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell
             lymphoma (MCL), follicular lymphoma (FL), human cultured lymphoblast (HCL), Marginal
             zone lymphoma (MZL), non-germinal center B-cell (GCB) DLBCL, GCB DLBCL, transformed
             FL, and Richter's transformation (NOTE: participants with WM are excluded from
             enrollment as of Amendment 3).

          2. Dose expansion for Cohorts 1 to 4: participants with either of the following relapsed
             or refractory WHO-classified lymphoid malignancies who have received at least 1 prior
             line of standard therapy: a. Cohort 1: GCB DLBCL, with cell of origin defined by
             either immunohistochemistry or gene expression profiling. b. Cohort 2: non-GCB DLBCL,
             with cell of origin defined by either immunohistochemistry or gene expression
             profiling. participants who have transformed to DLBCL from another histology may be
             enrolled into Cohort 3. c. Cohort 3: Transformed lymphoid malignancy, including but
             not limited to: i. Large cell transformation of chronic lymphocytic leukemia
             (Richter's transformation). ii. Large cell transformation of other WHO-classified
             indolent non-Hodgkin's lymphoma, including FL, or MZL. d. Cohort 4: Histologically
             confirmed primary central nervous system lymphoma (PCNSL) or secondary central nervous
             system lymphoma (SCNSL) of breast or testicular origin: i. Must be able to tolerate
             lumbar puncture and/or Ommaya taps. ii. Must have received at least 1 prior central
             nervous system (CNS)-directed therapy. iii. Presence of brain parenchymal and/or
             leptomeningeal disease.

          3. Aged ≥ 18 years, able and willing to provide written informed consent and to comply
             with the study protocol.

          4. Measurable disease for non-Hodgkin lymphoma defined as ≥ 1 nodal lesion that is > 15
             mm in the longest diameter and can be accurately measured in at least 2 dimensions
             with computed tomography (CT) scan, or ≥ 1 extra-nodal lesion that is > 10 mm in the
             longest diameter and can be accurately measured in at least 2 dimensions with CT scan,
             except for PCNSL or SCNSL.

          5. Participants with an accessible tumor lesion must agree to a tumor biopsy at screening
             and another before the drug administration on Cycle 1 Day 8, ideally taken from the
             same tumor lesion, for biomarker analysis (up to first 12 qualified participants),
             except for PCNSL. Additionally, participants with DLBCL must have archival tumor
             tissue or agree to a tumor biopsy for confirmation of the DLBCL subtype.

          6. Laboratory parameters as specified below: a. Hematologic: Platelet count ≥ 50 × 109/L;
             absolute neutrophil count ≥ 1.0 × 109 cells/L; participants with neutrophils < 1.0 ×
             109/L unless cytopenias are a direct result of active leukemia or lymphoma, in which
             case platelet count ≥ 35 × 109/L, absolute neutrophil count ≥ 0.75 × 109/L are
             allowed. (Note: Platelet transfusion administered ≤ 7 days of screening to raise
             pre-treatment platelet count to ≥ 35 x 109/L is prohibited.) b. Hepatic: Total
             bilirubin ≤ 1.5 the upper limit of normal (ULN) or ≤ 2.0 × ULN for participants with
             Gilbert syndrome, aspartate transaminase (AST), and alanine aminotransaminase (ALT) ≤
             3 × ULN. c. Renal: Creatinine clearance ≥ 30 mL/min (as estimated by the
             Cockcroft-Gault equation or as measured by nuclear medicine scan or 24-hour urine
             collection). participants requiring hemodialysis will be excluded.

          7. Anticipated survival of at least 4 months.

          8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

          9. Female participants of childbearing potential and nonsterile males must practice at
             least 1 of the following methods of birth control with partner(s) throughout the study
             and for ≥ 3 months after discontinuing study drug: total abstinence from sexual
             intercourse, double-barrier contraception, intrauterine device or hormonal
             contraceptive initiated at least 3 months prior to first dose of study drug.

         10. Male participants must not donate sperm from initial study drug administration until
             180 days after drug discontinuation.

        Key Exclusion Criteria

        Participants will not be entered in the study for any of the following reasons:

          1. Known, active, CNS lymphoma or leukemia, except for Cohorts 4.

          2. Diagnosis with Waldenstrom's macroglobulinemia (WM).

          3. For PCNSL and SCNSL (Cohorts 4): a. Require corticosteroid therapy > 16 mg
             dexamethasone daily or equivalent. b. Corticosteroid therapy ≤ 16 mg dexamethasone
             daily or equivalent at study entry from which, in the Investigator's opinion, it is
             expected that the participant cannot be tapered off after the first 4 weeks of study
             treatment. c. Intraocular PCNSL without evidence of brain disease. d. SCNSL actively
             receiving treatment for extra-CNS disease. e. PCNSL actively receiving concomitant
             local or systemic therapy for CNS disease.

          4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.

          5. History of stroke or cerebral hemorrhage within 6 months of enrollment.

          6. History of significant cardiovascular disease, defined as: a. Congestive heart failure
             greater than New York Heart Association (NYHA) class II according to the NYHA
             functional classification. b. Unstable angina or myocardial infarction with 6 months
             of enrollment. c. Serious cardiac arrhythmia or clinically significant ECG
             abnormality: corrected QT wave (QTcF) > 480 msec based on the Fridericia's formula or
             other ECG abnormalities including second-degree atrioventricular block type II,
             third-degree atrioventricular block. Participants who have a pacemaker will be allowed
             on study despite ECG abnormalities or the inability to calculate the QTc.

          7. Severe or debilitating pulmonary disease (dyspnea at rest, significant shortness of
             breath, congestive obstructive pulmonary disease).

          8. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy.

          9. Prior Bruton's tyrosine kinase (BTK) inhibitor or anti-PD-1/anti-PD-L1 treatment.

         10. Any illness or condition that in the opinion of the investigator may affect safety of
             treatment or evaluation of any study endpoint.

         11. 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: Participants 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. Participants with Sjögren's syndrome and
             psoriasis controlled with topical medication and participants 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.

         12. 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 PCNSL and SCNSL. Note: adrenal replacement doses
             ≤ 20 mg daily prednisone or equivalents are permitted in the absence of active
             autoimmune disease; Participants are permitted to use topical, ocular,
             intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic
             absorption).

         13. History of interstitial lung disease or noninfectious pneumonitis, except for those
             induced by radiation therapy.

         14. Requirement for medications which strong cytochrome P450 (CYP)3A inhibitors or
             inducers.

         15. Vaccination with a live vaccine within 28 days of the initiation of treatment.

         16. A candidate for hematopoietic stem cell transplantation. Participants are excluded if
             they had received an allogeneic stem cell transplantation within 6 months or have
             active graft-versus-host-disease requiring ongoing immunosuppression.

         17. Participated in any investigational drug study within 28 days or not recovered from
             toxicity of any prior chemotherapy to Grade ≤ 1.

         18. History of other active malignancies within 2 years of study entry, 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.

         19. Major surgery in the past 4 weeks prior to the first day of screening.

         20. Active and symptomatic fungal, bacterial, and/or viral infection; human T-cell
             lymphotropic virus type 1 seropositive status.

         21. Human immunodeficiency virus (HIV) infection, or active hepatitis B (e.g., hepatitis B
             surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV]
             ribonucleic acid [RNA] detected. • Hepatitis B/C serologic markers and viral load will
             be tested at screening. The hepatitis B testing includes HBsAg, HBcAb, and HBsAb as
             well as hepatitis B virus (HBV) DNA by Polymerase chain reaction (PCR) if the
             participant is negative for HBsAg but HBcAb positive (regardless of HBsAb status). The
             hepatitis C testing includes Hepatitis C virus (HCV) antibody as well as HCV RNA by
             PCR if the Participant is HCV antibody positive. Participants with positive HBsAg
             and/or detectable level of HBV DNA or detectable level of HCV RNA (≥ 15 IU/mL) are not
             eligible. Participants negative for HBsAg, HBcAb positive, and HBV DNA negative must
             undergo monthly HBV DNA screening by PCR. Participants positive for HCV antibody but
             negative for HCV RNA (defined as < 15 IU) must undergo monthly HCV RNA screening.

         22. Inability to comply with study procedures.

         23. Pregnant or nursing women.

         24. Men or women of childbearing potential who refuse to use an adequate measure of
             contraception, unless they have past medical history of surgical sterilization.

         25. Currently taking or plan to take CNS penetrant therapy such as thiotepa, cytarabine,
             or partially CNS penetrant agents known to be active in lymphoid tumors, such as
             rituximab.

         26. Has taken or plans to take any chemotherapy, immunotherapy (eg, interleukin,
             interferon, thymoxin), or any investigational therapies to treat leukemia or lymphoma
             within 28 days or 5 half-lives (whichever is shorter) of the first study drug
             administration, including CNS penetrating agents.

        NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.