Zanubrutinib (BGB-3111) in Combination With Tislelizumab (BGB-A317) in Participants With B-cell Malignancies

A Phase 1b, Open Label, Multiple Dose, Dose Escalation and Expansion Study to Assess Safety, Tolerability and Antitumor Activities of the Combination of BGB-3111 With BGB-A317 in Subjects With B-Cell Lymphoid Malignancies

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

Study Overview

• Status: Completed
• Conditions: Lymphoma; Leukemia
• Intervention / Treatment: Drug: Zanubrutinib; Drug: Tislelizumab

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia
      • St Vincent's Hospital
    • Sydney, New South Wales, Australia, 2139
      • Concord Hospital
  • Tasmania
    • Hobart, Tasmania, Australia
      • Royal Hobart Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Hospital
    • Melbourne, Victoria, Australia, 3002
      • Peter Maccallum Cancer Centre
    • Richmond, Victoria, Australia
      • Epworth Healthcare
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • Guangdong General Hospital
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150081
      • Harbin Medical University Cancer Hospital
  • Shanghai
    • Shanghai, Shanghai, China, 200025
      • Shanghai Jiaotong University School of Medicine Ruijin Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Zanubrutinib abd Tislelizumab; Based on results of the dose escalation cohorts and the identified recommended Phase 2 dose, all patients will receive zanubrutinib at 160 mg orally twice daily in combination with intravenous infusion of tislelizumab 200mg given every 21 days, to be continued until disease progression, unacceptable toxicity, treatment consent withdrawal, or study termination	Drug: Zanubrutinib; Other Names: Brukinsa; BGB-3111; Drug: Tislelizumab; Other Names: BGB-A317

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Escalation: Maximum Tolerated Dose (MTD) of Tislelizumab	The MTD of tislelizumab is considered the dose level below that at which at least 2 participants (or at least 33%) experience a dose-limiting toxicity (DLT).	From the date of first dose of study drugs until RP2D was determined (Approximately 1 year and 10 months)
Dose Escalation: RP2D of Tislelizumab	The RP2D of tislelizumab in combination with zanubrutinib will be selected by taking into account the safety, tolerability, and pharmacokinetic (PK) profile.	From the date of first dose of study drugs until final R2PD was decided (Approximately 1 year and 10 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With TEAEs and SAEs	A treatment-emergent adverse event (TEAE) was defined as an AE that had an onset date during the treatment emergent period, defined as from the first dose date of zanubrutinib or tislelizumab (whichever is earlier) through 30 days after the last dose (permanent discontinuation of study drug) of zanubrutinib or 90 days after the last dose of tislelizumab, whichever is later, or prior to initiation of new anti-cancer therapy. Treatment-related serious adverse events (SAEs) and any worsening of a TEAE by PT post treatment-emergent period were also counted as TEAEs.	From the day of first dose of study drug until end of study (up to 4 years and 6 months)
Overall Response Rate	ORR, is defined as the percentage of participants who had complete response (CR) or partial response (PR) by standard disease-specific response criteria. for WM participants ORR includes minor response (MR) and very good partial response (VGPR).	Up to 4 years and 6 months
Duration of Response (DOR)	DOR is defined as the time from the date that a confirmed objective response is first documented to the date of progressive disease (PD) or death due to any cause for those participants with a confirmed PR or CR.	Up to 4 years and 6 months
Progression Free Survival (PFS)	PFS, is defined as the time from the first dose of study medication to objective disease progression or death	Up to 4 years and 6 months
Number of Participants With Anti-Drug Antibodies (ADAs) to Tislelizumab		From the day of first dose of study drug until end of study (up to 4 years and 6 months)

Collaborators and Investigators

• Sponsor: BeiGene

Publications and helpful links

General Publications

• Othman J, Verner E, Tam CS, Huang J, Lin L, Hilger J, Trotman J, Gasiorowski R. Severe hemolysis and transfusion reactions after treatment with BGB-3111 and PD-1 antibody for Waldenstrom macroglobulinemia. Haematologica. 2018 May;103(5):e223-e225. doi: 10.3324/haematol.2017.186817. Epub 2018 Feb 8. No abstract available.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2016
• Primary Completion (Actual): December 18, 2020
• Study Completion (Actual): December 18, 2020

Study Registration Dates

• First Submitted: June 4, 2016
• First Submitted That Met QC Criteria: June 8, 2016
• First Posted (Estimate): June 10, 2016

Study Record Updates

• Last Update Posted (Actual): July 1, 2022
• Last Update Submitted That Met QC Criteria: March 16, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Relapsed; Refractory
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Zanubrutinib
• Other Study ID Numbers: BGB-3111_BGB-A317_Study_001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No