BGB 3111 in Combination With Obinutuzumab in Participants With B-Cell Lymphoid Malignancies

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

Official Title
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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

Conditions
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B-cell Lymphoid Malignancies

Intervention / Treatment
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* Drug: Zanubrutinib
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zanubrutinib and Obinutuzumab<br>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<br> <br> * Other names: BGB-3111;Drug: Obinutuzumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 : Number Of Participants Experiencing Adverse Events | 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. | Day 1 (first dose) through 4 years and 8 months | 
| Part 1: Number Of Participants With Clinical Laboratory Abnormalities | Laboratory results are reported as participants with shifts towards (high directionality) or away (low directionality) from Grade 3 or Higher Toxicity. | Day -28 to -1 (predose) through 4 years and 8 months | 
| Part 1: Number Of Deaths | 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. | Day 1 (first dose) through 4 years and 8 months | 
| Part 1: Number Of Participants Experiencing Dose-limiting Toxicity (DLT) | 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. | Day 1 (first dose) through 4 years and 8 months | 
| Part 1 and Part 2: Number Of Participants Achieving A Best Response Of Partial Response | 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. | Day 1 (first dose) through 4 years and 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2: Number Of Participants Achieving A Best Response Of Complete Response | 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. | Day 1 (first dose) through 4 years and 8 months | 
| Part 1 and Part 2: Progression-free Survival (PFS) | 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). | Day 1 (first dose) through 4 years and 8 months | 
| Part 1 and Part 2: Duration Of Response (DOR) | 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. | Day 1 (first dose) through 4 years and 8 months | 
| Part 1 and Part 2: Time To Response (TTR) | 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. | Day 1 (first dose) through 4 years and 8 months | 
| Part 1 and Part 2: Overall Survival (OS) | 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. | Day 1 (first dose) through 4 years and 8 months | 
| Part 1 and Part 2: Hematologic Improvement In Participants With CLL | 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. | Day 1 (first dose) through 4 years and 8 months | 
| Part 1: Area Under The Plasma Concentration-time Curve From Time 0 To The Time Of The Last Measurable Concentration (AUClast) Of Zanubrutinib |  | Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 | 
| Part 1: Area Under The Plasma Concentration-time Curve From Time 0 To Infinity Time (AUC) Of Zanubrutinib |  | Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 | 
| Part 1: Maximum Plasma Concentration (Cmax) Of Zanubrutinib |  | Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 | 
| Part 1: Time To Maximum Plasma Concentration (Tmax) Of Zanubrutinib |  | Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 | 
| Part 1: Terminal Elimination Half-life (t1/2) Of Zanubrutinib |  | Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 | 
| Part 1: Apparent Clearance (CL/F) Of Zanubrutinib |  | Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 | 
| Part 1: Apparent Volume Of Distribution (Vz/F) Of Zanubrutinib |  | Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 | 
| Part 1 and Part 2: Steady State AUClast Of Zanubrutinib |  | Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 | 
| Part 1 and Part 2: Steady State Cmax of Zanubrutinib |  | Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 | 
| Part 1 and Part 2: Steady State Tmax Of Zanubrutinib |  | Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7 | 
| Part 2: Number Of Participants Experiencing Adverse Events | 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. | Day 1 (first dose) through 4 years and 8 months | 
| Part 2: Number Of Participants With Clinical Laboratory Abnormalities | Results are reported as participants with shifts towards (high directionality) or away (low directionality) from Grade 3 or Higher Toxicity. | Day -28 to -1 (predose) through 4 years and 8 months | 
| Part 2: Number Of Deaths | 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. | Day 1 (first dose) through 4 years and 8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BGB-3111, Zanubrutinib, Obinutuzumab, Lymphoma, Leukemia, Therapeutic uses, B-cell