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

NCT02795182 | Completed Phase 1 Results DMC

• 1 other identifier: BGB-3111_BGB-A317_Study_001
• Study Type: interventional
• Target: 75
• Locations: 2 countries
• Sites: 10

Brief 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.

Conditions

Lymphoma; Leukemia

Keywords

Relapsed; Refractory

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• Number of Participants With TEAEs and SAEs

  From the day of first dose of study drug until end of study (up to 4 years and 6 months)

• Overall Response Rate

  Up to 4 years and 6 months

• Duration of Response (DOR)

  Up to 4 years and 6 months

• Progression Free Survival (PFS)

  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)

Study Arms (1)

Zanubrutinib abd Tislelizumab

OTHER

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; Drug: Tislelizumab

Interventions

Zanubrutinib DRUG

Also known as: BGB-3111, Brukinsa

Zanubrutinib abd Tislelizumab

Tislelizumab DRUG

Also known as: BGB-A317

Zanubrutinib abd Tislelizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants may be entered in the study only if they meet all of the following criteria:
• 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).
• 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.
• Aged ≥ 18 years, able and willing to provide written informed consent and to comply with the study protocol.
• 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.
• 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.
• 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.
• Anticipated survival of at least 4 months.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• 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.
• Male participants must not donate sperm from initial study drug administration until 180 days after drug discontinuation.

You may not qualify if:

• Participants will not be entered in the study for any of the following reasons:
• Known, active, CNS lymphoma or leukemia, except for Cohorts 4.
• Diagnosis with Waldenstrom's macroglobulinemia (WM).
• 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.
• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
• History of stroke or cerebral hemorrhage within 6 months of enrollment.
• 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.
• Severe or debilitating pulmonary disease (dyspnea at rest, significant shortness of breath, congestive obstructive pulmonary disease).
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy.
• Prior Bruton's tyrosine kinase (BTK) inhibitor or anti-PD-1/anti-PD-L1 treatment.
• Any illness or condition that in the opinion of the investigator may affect safety of treatment or evaluation of any study endpoint.
• 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.
• 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).
• History of interstitial lung disease or noninfectious pneumonitis, except for those induced by radiation therapy.
• Requirement for medications which strong cytochrome P450 (CYP)3A inhibitors or inducers.

Sponsors & Collaborators

• BeiGene: lead

Study Sites (10)

St Vincent's Hospital

Darlinghurst, New South Wales, Australia

Location

Concord Hospital

Sydney, New South Wales, 2139, Australia

Location

Royal Hobart Hospital

Hobart, Tasmania, Australia

Location

Monash Hospital

Clayton, Victoria, 3168, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3002, Australia

Location

Epworth Healthcare

Richmond, Victoria, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

Location

Guangdong General Hospital

Guangzhou, Guangdong, China

Location

Harbin Medical University Cancer Hospital

Harbin, Heilongjiang, 150081, China

Location

Shanghai jiaotong university school of medicine Ruijin Hospital

Shanghai, Shanghai Municipality, 200025, China

Location

Related Publications (1)

• 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.

  PMID: 29439186 DERIVED

MeSH Terms

Conditions

Lymphoma; Leukemia; Recurrence

Interventions

zanubrutinib; tislelizumab

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Hematologic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Study Director
• Organization: BeiGene

clinicaltrials@beigene.com

+1-877-828-5568

Study Officials

• Study Director

  BeiGene

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 4, 2016
• First Posted: June 10, 2016
• Study Start: June 29, 2016
• Primary Completion: December 18, 2020
• Study Completion: December 18, 2020
• Last Updated: July 1, 2022
• Results First Posted: July 1, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

AU (7); CN (3)