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BGB 3111 in Combination With Obinutuzumab in Participants With B-Cell Lymphoid 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: NCT02569476
Recruitment Status : Completed
First Posted : October 6, 2015
Results First Posted : November 3, 2021
Last Update Posted : March 3, 2022
Sponsor:
Information provided by (Responsible Party):
BeiGene

Study Description
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Brief Summary:
This study evaluated the safety and preliminary efficacy of BGB-3111 (zanubrutinib) in combination with obinutuzumab in participants with B-cell lymphoid malignancies.

Condition or disease Intervention/treatment Phase
B-cell Lymphoid Malignancies Drug: Zanubrutinib Drug: Obinutuzumab Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 119 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Study to Assess Safety, Tolerability and Antitumor Activity of the Combination of BGB 3111 With Obinutuzumab in Subjects With B-Cell Lymphoid Malignancies
Actual Study Start Date : January 13, 2016
Actual Primary Completion Date : September 2, 2020
Actual Study Completion Date : September 2, 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Zanubrutinib and Obinutuzumab
In the dose-escalation part, dose levels and regimens were evaluated. In the indication-specific expansion cohorts, participants were assigned to different cohorts based on histology type.
 Drug: Zanubrutinib
Other Name: BGB-3111

Drug: Obinutuzumab


Outcome Measures
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Primary Outcome Measures :
  1. Part 1 : Number Of Participants Experiencing Adverse Events [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]

    An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product (zanubrutinib in combination with obinutuzumab). An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of the study drug. A serious AE (SAE) was any untoward medical occurrence that, at any dose.

    • resulted in death,
    • was life threatening,
    • required hospitalization or prolongation of existing hospitalization,
    • resulted in disability/incapacity,
    • was a congenital anomaly/birth defect.

  2. Part 1: Number Of Participants With Clinical Laboratory Abnormalities [ Time Frame: Day -28 to -1 (predose) through 4 years and 8 months ]
    Laboratory results are reported as participants with shifts towards (high directionality) or away (low directionality) from Grade 3 or Higher Toxicity.

  3. Part 1: Number Of Deaths [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]

    An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product (zanubrutinib in combination with obinutuzumab). An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. An SAE was any untoward medical occurrence that, at any dose:

    • resulted in death,
    • was life threatening,
    • required hospitalization or prolongation of existing hospitalization,
    • resulted in disability/incapacity,
    • was a congenital anomaly/birth defect.

  4. Part 1: Number Of Participants Experiencing Dose-limiting Toxicity (DLT) [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]

    Dose-limiting toxicities were defined as a toxicity or AE occurring during the DLT assessment period (first 29 days of treatment), which is not clearly attributable to a cause other than zanubrutinib and/or obinutuzumab (such as disease progression, underlying illness, concurrent illness or concomitant medication) and meets one of the following criteria:

    • Grade 3 or 4 drug-related non-hematologic toxicity (excluding Grade 3 nausea, vomiting, hypertension, and asymptomatic laboratory abnormalities),
    • Grade 4 drug-related hematologic toxicity persisting for >14 days,
    • any grade toxicity, which in the judgment of the investigator or Sponsor, required removal of the participant from the study.

  5. Part 1 and Part 2: Number Of Participants Achieving A Best Response Of Partial Response [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]

    Partial response was defined as follows:

    • ≥ 50% reduction of serum IgM from baseline,
    • reduction in lymphadenopathy/splenomegaly (if present at baseline). For response assessments that occurred during cycles where a CT scan was not required, then results from prior scans (up to 12 weeks during the first 48 weeks and up to 24 weeks thereafter) could be carried forward in those participants with extramedullary disease at baseline.


Secondary Outcome Measures :
  1. Part 1 and Part 2: Number Of Participants Achieving A Best Response Of Complete Response [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]

    Complete response was defined as follows:

    • normal serum IgM values,
    • disappearance of monoclonal protein by immunofixation,
    • no histological evidence of bone marrow involvement,
    • complete resolution of lymphadenopathy/splenomegaly (if present at baseline) For response assessments that occurred during cycles where a computed tomography (CT) scan was not required, then results from prior scans (up to 12 weeks during the first 48 weeks and up to 24 weeks thereafter) could be carried forward in those participants with extramedullary disease at baseline.

  2. Part 1 and Part 2: Progression-free Survival (PFS) [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]
    Progression-free survival was defined as time (in months) from the start of treatment with zanubrutinib or obinutuzumab to the first documented disease progression or death due to any cause, whichever occurred first. Results are reported as the median months for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and non-germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL).

  3. Part 1 and Part 2: Duration Of Response (DOR) [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]
    Duration of response for responders was defined as the time (in months) from the date of the earliest qualifying response to the date of progressive disease or death due to any cause (whichever occurred earlier). Duration of response was analyzed using the same methods as the analysis for PFS. Responses after initiating new anticancer therapy, roll over to the long-term extension (LTE) study, or the first occurrence of disease progression were not considered in the analysis.

  4. Part 1 and Part 2: Time To Response (TTR) [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]
    The TTR for responders was defined as time (in months) from the start of the study treatment to the date of the earliest qualifying response. The TTR was summarized using descriptive statistics. Responses after initiating new anticancer therapy, roll over to the LTE study, or the first occurrence of disease progression were not considered in the analysis of TTR.

  5. Part 1 and Part 2: Overall Survival (OS) [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]
    Overall survival was defined as the time (in months) from the date of the start of the study treatment to death due to any cause. Participants who were alive before final database lock or discontinuation of the study (discontinued study due to reasons other than death) were censored at their last known alive date on or before database lock.

  6. Part 1 and Part 2: Hematologic Improvement In Participants With CLL [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]
    The number and percentage of participants with CLL with anemia (hemoglobin ≤110 grams/liter [g/L]), neutropenia (absolute neutrophil count ≤1.5 x 10^9/L), or thrombocytopenia (platelet count ≤100 x 10^9/L) at baseline were estimated.

  7. Part 1: Area Under The Plasma Concentration-time Curve From Time 0 To The Time Of The Last Measurable Concentration (AUClast) Of Zanubrutinib [ Time Frame: Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 ]
  8. Part 1: Area Under The Plasma Concentration-time Curve From Time 0 To Infinity Time (AUC) Of Zanubrutinib [ Time Frame: Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 ]
  9. Part 1: Maximum Plasma Concentration (Cmax) Of Zanubrutinib [ Time Frame: Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 ]
  10. Part 1: Time To Maximum Plasma Concentration (Tmax) Of Zanubrutinib [ Time Frame: Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 ]
  11. Part 1: Terminal Elimination Half-life (t1/2) Of Zanubrutinib [ Time Frame: Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 ]
  12. Part 1: Apparent Clearance (CL/F) Of Zanubrutinib [ Time Frame: Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 ]
  13. Part 1: Apparent Volume Of Distribution (Vz/F) Of Zanubrutinib [ Time Frame: Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 ]
  14. Part 1 and Part 2: Steady State AUClast Of Zanubrutinib [ Time Frame: Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 ]
  15. Part 1 and Part 2: Steady State Cmax of Zanubrutinib [ Time Frame: Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 ]
  16. Part 1 and Part 2: Steady State Tmax Of Zanubrutinib [ Time Frame: Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 ]
  17. Part 2: Number Of Participants Experiencing Adverse Events [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]

    An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product (zanubrutinib in combination with obinutuzumab). An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. An SAE was any untoward medical occurrence that, at any dose,:

    • resulted in death,
    • was life threatening,
    • required hospitalization or prolongation of existing hospitalization,
    • resulted in disability/incapacity,
    • was a congenital anomaly/birth defect.

  18. Part 2: Number Of Participants With Clinical Laboratory Abnormalities [ Time Frame: Day -28 to -1 (predose) through 4 years and 8 months ]
    Results are reported as participants with shifts towards (high directionality) or away (low directionality) from Grade 3 or Higher Toxicity.

  19. Part 2: Number Of Deaths [ Time Frame: Day 1 (first dose) through 4 years and 8 months ]

    An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product (zanubrutinib in combination with obinutuzumab). An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. An SAE was any untoward medical occurrence that, at any dose,:

    • resulted in death,
    • is life threatening,
    • required hospitalization or prolongation of existing hospitalization,
    • resulted in disability/incapacity,
    • was a congenital anomaly/birth defect.


Eligibility Criteria
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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

Inclusion Criteria:

  • Aged ≥18 years, able and willing to provide written informed consent and to comply with the study protocol.

  • Laboratory parameters as specified below:

    • Hematologic: Platelet count >40x10^9/liter (L) (may be post-transfusion); absolute neutrophil count >1.0x10^9/L (growth factor use is allowed to bring pre-treatment neutrophils to >1.0x10^9 cells/L if marrow infiltration is involved).
    • Hepatic: Total bilirubin <3 x upper limit normal (ULN); and aspartate aminotransferase and alanine transaminase ≤3 x ULN.
    • Renal: Creatinine clearance ≥50 milliliters/minute (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 6 months.
  • Eastern Cooperative Oncology Group performance status of 0 to 2.
  • Female participants of childbearing potential and non-sterile males must have agreed to practice at least one of the following methods of birth control with partner(s) throughout the study and for ≥3 months after discontinuing zanubrutinib or ≥18 months following obinutuzumab treatment, whichever was longer: total abstinence from sexual intercourse, double barrier contraception, intra uterine device or hormonal contraceptive initiated at least 3 months prior to first administration of study drug.
  • Male participants must have not donated sperm from first study drug administration, until 3 months after zanubrutinib discontinuation or 18 months following obinutuzumab treatment, whichever is longer.

Exclusion Criteria:

  • Known central nervous system lymphoma or leukemia.
  • Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome.
  • Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
  • History of significant cardiovascular disease.
  • Severe or debilitating pulmonary disease.
  • History of severe allergic or anaphylactic reactions to monoclonal antibody therapy.
  • Prior Bruton tyrosine kinase inhibitor treatment.
  • Used medications which were strong cytochrome P450 (CYP) 3A inhibitors and strong CYP3A inducers.
  • Vaccination with a live vaccine within 28 days of the initiation of treatment.
  • Allogeneic stem cell transplantation within 6 months, or had active graft versus host disease requiring ongoing immunosuppression.
  • Receipt of the following treatment prior to first administration of zanubrutinib, corticosteroids given with anti-neoplastic intent within 7 days, chemotherapy or radiotherapy within 3 weeks, monoclonal antibody within 4 weeks.
  • Participated in any investigational drug study within 28 days of study entry, or not recovered from non-hematologic toxicity of any prior chemotherapy up to ≤ Grade 1 (except for alopecia).
  • History of other active malignancies within 2 years of study entry.
  • Major surgery in the past 4 weeks.
  • Active symptomatic fungal, bacterial and/or viral infection including evidence of infection with human immunodeficiency virus, human T cell lymphotropic virus seropositive status.
  • Inability to comply with the study procedures.
  • Pregnant or nursing women.
  • Any illness or condition that in the opinion of the investigator may have affected the safety of treatment or evaluation of any study's endpoints.
Contacts and Locations
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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): NCT02569476


Locations
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United States, Florida
Florida Cancer Specialists
Fort Myers, Florida, United States, 33916
Florida Cancer Specialists
Saint Petersburg, Florida, United States, 33705
United States, Tennessee
Tennessee Oncology, PLLC - Nashville
Nashville, Tennessee, United States, 37203
Australia, New South Wales
Border Medical Oncology
Albury, New South Wales, Australia, 2640
St George Hospital
Kogarah, New South Wales, Australia, 2217
Australia, Queensland
Brisbane Clinic for Lymphoma, Myeloma and Leukaemia
Greenslopes, Queensland, Australia, 4120
Australia, South Australia
Ashford Cancer Centre Research
Kurralta Park, South Australia, Australia, 5037
Australia, Victoria
St Vincent's Hospital Melbourne
East Melbourne, Victoria, Australia, 3002
University Hospital Geelong
Geelong, Victoria, Australia, 3220
St Frances Xavier Cabrini Hospital
Malvern, Victoria, Australia, 3144
The Alfred Hospital
Melbourne, Victoria, Australia, 3181
Australia, Western Australia
Royal Perth Hospital
Perth, Western Australia, Australia, 6000
Korea, Republic of
Severance Hospital, Yonsei University
Seoul, Korea, Republic of, 03722
Asan Medical Center
Seoul, Korea, Republic of, 05505
Samsung Medical Center
Seoul, Korea, Republic of, 06351
Sponsors and Collaborators
BeiGene
Investigators
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Principal Investigator: Study Director BeiGene
  Study Documents (Full-Text)

Documents provided by BeiGene:
Study Protocol  [PDF] January 3, 2019
Statistical Analysis Plan  [PDF] August 3, 2020

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: BeiGene
ClinicalTrials.gov Identifier: NCT02569476    
Other Study ID Numbers: BGB-3111_GA101_Study_001
First Posted: October 6, 2015    Key Record Dates
Results First Posted: November 3, 2021
Last Update Posted: March 3, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Keywords provided by BeiGene:
BGB-3111
Zanubrutinib
Obinutuzumab
Lymphoma
 Leukemia
Therapeutic uses
B-cell
Additional relevant MeSH terms:
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Neoplasms
Obinutuzumab
Zanubrutinib
Antineoplastic Agents, Immunological
 Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action