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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02795182
Recruitment Status : Active, not recruiting
First Posted : June 10, 2016
Last Update Posted : January 23, 2020
Sponsor:
Information provided by (Responsible Party):
BeiGene

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.

Condition or disease Intervention/treatment Phase
Lymphoma Leukemia Drug: BGB-3111 Drug: BGB-A317 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 29, 2016
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
BGB-3111 and BGB-A317
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 tiselisumab 200mg given every 21 days, to be continued until disease progression, unacceptable toxicity, treatment consent withdrawal, or study termination
Drug: BGB-3111
Drug: BGB-A317



Primary Outcome Measures :
  1. Dose Escalation: Maximum Tolerated Dose (MTD) [ Time Frame: Up to 28 Days ]
    The MTD is considered the dose level below that at which at least 2 participants (or at least 33%) experience a dose-limiting toxicity.

  2. Dose Escalation: Recommended Phase 2 Dose (RP2D) [ Time Frame: Approximately 1.5 years ]
    The RP2D of tislelizumab in combination with zanubrutinib will be selected by taking into account the MTD, safety, tolerability, and PK profile

  3. Dose Expansion: Safety and tolerability: CTCAE v.4.03 [ Time Frame: Approximately 1.5 years ]
    Safety and tolerability of tislelizumab in combination with zanubrutinib as assessed by the occurrence and severity of Adverse Reactions (AEs) using Common Terminology Criteria for Adverse Events (CTCAE v.4.03).


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: Approximately 1.5 years ]
    ORR is defined as the proportion of participants who had complete response (CR) or partial response (PR) by standard disease-specific response criteria.

  2. Duration of response (DOR) [ Time Frame: Approximately 1.5 years ]
    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.

  3. Progression free survival (PFS) [ Time Frame: Approximately 1.5 years ]
    PFS is defined as the time from the first dose of study medication to objective disease progression or death.

  4. Pharmacokinetic (PK) Parameter [ Time Frame: Approximately 56 days ]
    PK Parameter: Area Under the Curve (AUC), area under zanubrutinib plasma concentration

  5. PK Parameter [ Time Frame: Approximately 1.5 years ]
    PK Parameter: Trough Concentration of zanubrutinib and tislelizumab (Ctrough)

  6. PK Parameter [ Time Frame: Approximately 56 days ]
    PK Parameter: Maximum Concentration (Cmax) of zanubrutinib

  7. PK Parameter [ Time Frame: Approximately 56 days ]
    PK Parameter: terminal half-life (t1/2) of zanubrutinib

  8. Immunogenicity [ Time Frame: Approximately 1.5 years ]
    Immunogenicity as assessed by the presence of anti-drug antibodies of tislelizumab



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02795182


Locations
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Australia, New South Wales
St Vincent's Hospital
Darlinghurst, New South Wales, Australia
Concord Hospital
Sydney, New South Wales, Australia, 2139
Australia, Tasmania
Royal Hobart Hospital
Hobart, Tasmania, Australia
Australia, Victoria
Monash Hospital
Clayton, Victoria, Australia, 3168
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia, 3002
Epworth Healthcare
Richmond, Victoria, Australia
Australia, Western Australia
Sir Charles Gairdner Hospital
Nedlands, Western Australia, Australia, 6009
China, Guangdong
Guangdong General Hospital
Guangzhou, Guangdong, China
China, Heilongjiang
Harbin Medical University Cancer Hospital
Harbin, Heilongjiang, China, 150081
China, Shanghai
Shanghai jiaotong university school of medicine Ruijin Hospital
Shanghai, Shanghai, China, 200025
Sponsors and Collaborators
BeiGene
Investigators
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Principal Investigator: Constantine Tam, MD Peter MacCallum Cancer Centre, Australia

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: BeiGene
ClinicalTrials.gov Identifier: NCT02795182    
Other Study ID Numbers: BGB-3111_BGB-A317_Study_001
CTR20180193 ( Registry Identifier: Center for drug evaluation, CFDA )
First Posted: June 10, 2016    Key Record Dates
Last Update Posted: January 23, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Keywords provided by BeiGene:
Relapsed
Refractory
Additional relevant MeSH terms:
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Neoplasms
Zanubrutinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action