Waldenström's Macroglobulinemia
Conditions
Brief summary
This study evaluated the safety, efficacy and clinical benefit of BGB-3111 (zanubrutinib) vs ibrutinib in participants with MYD88 Mutation Waldenström's Macroglobulinemia.
Detailed description
This open-label, randomized study compared the efficacy and safety of the Bruton's Tyrosine Kinase (BTK) inhibitors BGB-3111 and ibrutinib in participants with Waldenström's Macroglobulinemia who require therapy. Participants had baseline bone marrow samples assayed for sequencing of the MYD88 gene. 201 participants with the MYD88 mutation were enrolled and randomized to receive 160 mg BGB-3111 orally twice per day (PO BID) (treatment Arm A) or to receive 420mg ibrutinib orally once per day (PO QD) (treatment Arm B) until disease progression or unacceptable toxicity.
Interventions
DRUGBGB-3111
160 mg PO BID until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor
DRUGIbrutinib
420 mg PO QD until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor
Sponsors
BeiGene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Clinical and definitive histologic diagnosis of WM * Measurable disease, requiring treatment * Participants with no prior therapy for WM, must be considered inappropriate candidates for treatment with a standard chemoimmunotherapy regimen * Age ≥ 18 years old * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Adequate bone marrow function * Adequate renal and hepatic function * Electrocardiogram/multigated acquisition scan (ECHO/MUGA) demonstrating left ventricular ejection fraction (LVEF)≥ the lower limit of institutional normal * Participants may be enrolled who relapse after autologous stem cell transplant if they are at least 3 months after transplant, and after allogeneic transplant if they are at least 6 months post-transplant. * Females of childbearing potential must agree to use highly effective forms of birth control throughout the course of the study and at least up to 90 days after last dose of study drug. Males must have undergone sterilization- vasectomy, or utilize a barrier method * Life expectancy of \> 4 months Key
Exclusion criteria
* Prior exposure to a BTK inhibitor * Evidence of disease transformation at the time of study entry * Corticosteroids given with antineoplastic intent within 7 days, or chemotherapy given with antineoplastic intent, targeted therapy, or radiation therapy within 3 weeks, or antibody-based therapy within 4 weeks of the start of study drug * Major surgery within 4 weeks of study treatment * Toxicity of ≥ Grade 2 from prior anticancer therapy * History of other active malignancies within 2 years of study entry, with exception of (1) adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell carcinoma of skin; (3) previous malignancy confined and treated locally with curative intent * Currently active, clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease within 6 months of screening * QTcF prolongation (defined as a QTcF \> 480 msec) * Active, clinically significant Electrocardiogram (ECG) abnormalities * Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction * Uncontrolled active systemic infection or recent infection requiring parenteral anti-microbial therapy * Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C * Pregnant or lactating women * Any life-threatening illness, medical condition, organ system dysfunction, need for profound anticoagulation, or bleeding disorder, which, in the investigator's opinion, could compromise the subject's safety * Any medications which are strong or moderate cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong CYP3A inducers NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Either a Complete Response (CR) or Very Good Partial Response (VGPR) Using an Adaptation of the Response Criteria Updated at the Sixth International Workshop on WM as Assessed by an Independent Review Committee (IRC) | Up to approximately 2 years and 7 months | Percentage of participants with CR, defined as normal serum immunoglobulin M (IgM) levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, or VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) as Assessed by IRC | Up to approximately 2 years and 7 months | DOR defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first. CR is defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, VGPR, is defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values or partial response (PR) is defined as ≥50% reduction of serum IgM from baseline. |
| DOR as Assessed by IRC: Event -Free Rate | 12 and 18 months from the date of randomization (up to approximately 2 years and 7 months) | Estimated percentage of participants who were event-free based on Kaplan-Meier method. |
| Percentage of Participants Achieving Either CR or VGPR in as Assessed by the Investigator | Up to approximately 5 years and 5 months | Percentage of participants with CR, defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at Baseline, or VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values. |
| DOR as Assessed by the Investigator | Up to approximately 5 years and 5 months | DOR is defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first |
| DOR as Assessed by the Investigator: Event-Free Rate | 24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months) | Estimated percentage of participants who were event-free based on Kaplan-Meier method. |
| Progression Free Survival (PFS) as Assessed by the IRC | Up to approximately 2 years and 7 months | PFS as assessed by the IRC, defined as time from randomization to the first documentation of progression (per modified International Workshop on Waldenström macroglobulinemia \[IWWM criteria\]) or death, whichever occurs first |
| Percentage of Participants Achieving Major Response Rate (MRR) as Assessed by IRC | Up to approximately 2 years and 7 months | MRR defined as the percentage of participants achieving a best response of response of CR, defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values or partial response (PR) defined as ≥50% reduction of serum IgM from baseline. |
| PFS as Assessed by the Investigator | Up to approximately 5 years and 5 months | PFS as assessed by the Investigator, defined as time from randomization to the first documentation of progression (per modified IWWM criteria) or death, whichever occurs first. |
| PFS as Assessed by the Investigator: Event-Free Rate | 24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months) | Percentage of participants who were event-free based on Kaplan-Meier method. |
| Percentage of Participants With Resolution of All Treatment-precipitating Symptoms | Up to approximately 5 years and 5 months | — |
| Percentage of Participants With an Anti-Lymphoma Effect | Up to approximately 5 years and 5 months | Anti-Lymphoma Effect is defined as any reduction in bone marrow involvement by lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly by CT scan, at any time during the course of study treatment. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Up to approximately 5 years and 5 months | — |
| PFS as Assessed by IRC: Event-Free Rate | 12 and 18 months from the date of randomization (up to approximately 2 years and 7 months) | Estimated percentage of participants who were event-free based on Kaplan-Meier method |
Countries
Australia, Czechia, France, Germany, Greece, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
A total of 201 participants were randomized to Arm A and Arm B in 12 countries in Australia, Europe, United Kingdom and United States.
Pre-assignment details
The screening period consisted of Days -35 to -1.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Ibrutinib Participants diagnosed with WM with mutated MYD88 gene received 420 mg ibrutinib once daily orally until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor | 99 |
| Arm B: Zanubrutinib Participants diagnosed with WM with mutated MYD88 gene received 160 mg zanubrutinib twice daily orally until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor | 102 |
| Total | 201 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 18 | 14 |
| Overall Study | Enrolled in Long-term Extension Study | 48 | 66 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Participant Randomized but died before dosing | 1 | 0 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Sponsor's Decision to End the Study | 20 | 13 |
| Overall Study | Withdrawal by Subject | 9 | 8 |
Baseline characteristics
| Characteristic | Arm B: Zanubrutinib | Total | Arm A: Ibrutinib |
|---|---|---|---|
| Age, Continuous | 69.2 years STANDARD_DEVIATION 10.26 | 69.5 years STANDARD_DEVIATION 9.46 | 69.9 years STANDARD_DEVIATION 8.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 8 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 82 Participants | 173 Participants | 91 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 20 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 15 Participants | 5 Participants |
| Race (NIH/OMB) White | 88 Participants | 182 Participants | 94 Participants |
| Sex: Female, Male Female | 33 Participants | 67 Participants | 34 Participants |
| Sex: Female, Male Male | 69 Participants | 134 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 19 / 99 | 14 / 102 |
| other Total, other adverse events | 96 / 98 | 99 / 101 |
| serious Total, serious adverse events | 50 / 98 | 59 / 101 |
Outcome results
Primary
Percentage of Participants Achieving Either a Complete Response (CR) or Very Good Partial Response (VGPR) Using an Adaptation of the Response Criteria Updated at the Sixth International Workshop on WM as Assessed by an Independent Review Committee (IRC)
Percentage of participants with CR, defined as normal serum immunoglobulin M (IgM) levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, or VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values.
Time frame: Up to approximately 2 years and 7 months
Population: Intent To Treat (ITT) Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Ibrutinib | Percentage of Participants Achieving Either a Complete Response (CR) or Very Good Partial Response (VGPR) Using an Adaptation of the Response Criteria Updated at the Sixth International Workshop on WM as Assessed by an Independent Review Committee (IRC) | 19.2 Percentage of Participants |
| Arm B: Zanubrutinib | Percentage of Participants Achieving Either a Complete Response (CR) or Very Good Partial Response (VGPR) Using an Adaptation of the Response Criteria Updated at the Sixth International Workshop on WM as Assessed by an Independent Review Committee (IRC) | 28.4 Percentage of Participants |
p-value: 0.092195% CI: [-1.5, 22]Cochran-Mantel-Haenszel
Secondary
DOR as Assessed by IRC: Event -Free Rate
Estimated percentage of participants who were event-free based on Kaplan-Meier method.
Time frame: 12 and 18 months from the date of randomization (up to approximately 2 years and 7 months)
Population: ITT Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Ibrutinib | DOR as Assessed by IRC: Event -Free Rate | 12 Months | 87.9 Percentage of Participants |
| Arm A: Ibrutinib | DOR as Assessed by IRC: Event -Free Rate | 18 Months | 87.9 Percentage of Participants |
| Arm B: Zanubrutinib | DOR as Assessed by IRC: Event -Free Rate | 18 Months | 85.2 Percentage of Participants |
| Arm B: Zanubrutinib | DOR as Assessed by IRC: Event -Free Rate | 12 Months | 94.4 Percentage of Participants |
Secondary
DOR as Assessed by the Investigator
DOR is defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first
Time frame: Up to approximately 5 years and 5 months
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Ibrutinib | DOR as Assessed by the Investigator | NA Months |
| Arm B: Zanubrutinib | DOR as Assessed by the Investigator | NA Months |
Secondary
DOR as Assessed by the Investigator: Event-Free Rate
Estimated percentage of participants who were event-free based on Kaplan-Meier method.
Time frame: 24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months)
Population: ITT Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Ibrutinib | DOR as Assessed by the Investigator: Event-Free Rate | 36 Months | 77.5 Percentage of Participants |
| Arm A: Ibrutinib | DOR as Assessed by the Investigator: Event-Free Rate | 48 Months | 73.9 Percentage of Participants |
| Arm A: Ibrutinib | DOR as Assessed by the Investigator: Event-Free Rate | 24 Months | 87.7 Percentage of Participants |
| Arm B: Zanubrutinib | DOR as Assessed by the Investigator: Event-Free Rate | 24 Months | 89.7 Percentage of Participants |
| Arm B: Zanubrutinib | DOR as Assessed by the Investigator: Event-Free Rate | 36 Months | 81.1 Percentage of Participants |
| Arm B: Zanubrutinib | DOR as Assessed by the Investigator: Event-Free Rate | 48 Months | 81.1 Percentage of Participants |
Secondary
Duration of Response (DOR) as Assessed by IRC
DOR defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first. CR is defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, VGPR, is defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values or partial response (PR) is defined as ≥50% reduction of serum IgM from baseline.
Time frame: Up to approximately 2 years and 7 months
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Ibrutinib | Duration of Response (DOR) as Assessed by IRC | NA Months |
| Arm B: Zanubrutinib | Duration of Response (DOR) as Assessed by IRC | NA Months |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Up to approximately 5 years and 5 months
Population: Safety Analysis Set includes all participants who received any dose of zanubrutinib or ibrutinib
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Ibrutinib | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with At Least 1 TEAE | 98 Number of Participants |
| Arm A: Ibrutinib | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 50 Number of Participants |
| Arm B: Zanubrutinib | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with At Least 1 TEAE | 101 Number of Participants |
| Arm B: Zanubrutinib | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 59 Number of Participants |
Secondary
Percentage of Participants Achieving Either CR or VGPR in as Assessed by the Investigator
Percentage of participants with CR, defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at Baseline, or VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values.
Time frame: Up to approximately 5 years and 5 months
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Ibrutinib | Percentage of Participants Achieving Either CR or VGPR in as Assessed by the Investigator | 25.3 Percentage of Participants |
| Arm B: Zanubrutinib | Percentage of Participants Achieving Either CR or VGPR in as Assessed by the Investigator | 38.2 Percentage of Participants |
Secondary
Percentage of Participants Achieving Major Response Rate (MRR) as Assessed by IRC
MRR defined as the percentage of participants achieving a best response of response of CR, defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values or partial response (PR) defined as ≥50% reduction of serum IgM from baseline.
Time frame: Up to approximately 2 years and 7 months
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Ibrutinib | Percentage of Participants Achieving Major Response Rate (MRR) as Assessed by IRC | 77.8 Percentage of Participants |
| Arm B: Zanubrutinib | Percentage of Participants Achieving Major Response Rate (MRR) as Assessed by IRC | 77.5 Percentage of Participants |
Secondary
Percentage of Participants With an Anti-Lymphoma Effect
Anti-Lymphoma Effect is defined as any reduction in bone marrow involvement by lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly by CT scan, at any time during the course of study treatment.
Time frame: Up to approximately 5 years and 5 months
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Ibrutinib | Percentage of Participants With an Anti-Lymphoma Effect | 84.2 Percentage of Participants |
| Arm B: Zanubrutinib | Percentage of Participants With an Anti-Lymphoma Effect | 78.8 Percentage of Participants |
Secondary
Percentage of Participants With Resolution of All Treatment-precipitating Symptoms
Time frame: Up to approximately 5 years and 5 months
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Ibrutinib | Percentage of Participants With Resolution of All Treatment-precipitating Symptoms | 78.6 Percentage of Participants |
| Arm B: Zanubrutinib | Percentage of Participants With Resolution of All Treatment-precipitating Symptoms | 79.2 Percentage of Participants |
Secondary
PFS as Assessed by IRC: Event-Free Rate
Estimated percentage of participants who were event-free based on Kaplan-Meier method
Time frame: 12 and 18 months from the date of randomization (up to approximately 2 years and 7 months)
Population: ITT Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Ibrutinib | PFS as Assessed by IRC: Event-Free Rate | 12 Months | 87.2 Percentage of Participants |
| Arm A: Ibrutinib | PFS as Assessed by IRC: Event-Free Rate | 18 Months | 83.8 Percentage of Participants |
| Arm B: Zanubrutinib | PFS as Assessed by IRC: Event-Free Rate | 12 Months | 89.7 Percentage of Participants |
| Arm B: Zanubrutinib | PFS as Assessed by IRC: Event-Free Rate | 18 Months | 85.0 Percentage of Participants |
Secondary
PFS as Assessed by the Investigator
PFS as assessed by the Investigator, defined as time from randomization to the first documentation of progression (per modified IWWM criteria) or death, whichever occurs first.
Time frame: Up to approximately 5 years and 5 months
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Ibrutinib | PFS as Assessed by the Investigator | NA Months |
| Arm B: Zanubrutinib | PFS as Assessed by the Investigator | NA Months |
Secondary
PFS as Assessed by the Investigator: Event-Free Rate
Percentage of participants who were event-free based on Kaplan-Meier method.
Time frame: 24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months)
Population: ITT Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Ibrutinib | PFS as Assessed by the Investigator: Event-Free Rate | 24 Months | 80.6 Percentage of Participants |
| Arm A: Ibrutinib | PFS as Assessed by the Investigator: Event-Free Rate | 36 Months | 74.8 Percentage of Participants |
| Arm A: Ibrutinib | PFS as Assessed by the Investigator: Event-Free Rate | 48 Months | 67.3 Percentage of Participants |
| Arm B: Zanubrutinib | PFS as Assessed by the Investigator: Event-Free Rate | 24 Months | 88.5 Percentage of Participants |
| Arm B: Zanubrutinib | PFS as Assessed by the Investigator: Event-Free Rate | 36 Months | 78.3 Percentage of Participants |
| Arm B: Zanubrutinib | PFS as Assessed by the Investigator: Event-Free Rate | 48 Months | 78.3 Percentage of Participants |
Secondary
Progression Free Survival (PFS) as Assessed by the IRC
PFS as assessed by the IRC, defined as time from randomization to the first documentation of progression (per modified International Workshop on Waldenström macroglobulinemia \[IWWM criteria\]) or death, whichever occurs first
Time frame: Up to approximately 2 years and 7 months
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Ibrutinib | Progression Free Survival (PFS) as Assessed by the IRC | NA Months |
| Arm B: Zanubrutinib | Progression Free Survival (PFS) as Assessed by the IRC | NA Months |