Waldenström's Macroglobulinemia (WM)
Conditions
Brief summary
This was a single-arm, multicenter Phase 2 study in Chinese participants with relapsed or refractory Waldenström's macroglobulinemia who exhibited one or more of the criteria for requiring treatment based on consensus guidelines from the Seventh International Workshop on Waldenström's Macroglobulinemia (IWWM). The study comprised an initial screening phase (up to 28 days), a single-arm treatment phase, and a follow-up phase.
Interventions
DRUGZanubrutinib
Oral administration using 80 mg capsules
Sponsors
BeiGene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Clinical and definitive histologic diagnosis of WM, meeting at least one criterion for treatment according to consensus panel criteria from the Seventh IWWM. 2. WM pathology confirmation by central lab prior to study enrollment. Previous pathology report, concurrently with newly generated central lab report to be reviewed to support WM diagnosis. 3. Men and women ≥ 18 years of age. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 5. Previously treated with a minimum of 1 prior line of standard chemotherapy-containing regimen (with completion of ≥ 2 continuous treatment cycles). 6. Documented failure to achieve at least minor response or documented disease progression after response to the most recent treatment regimen. 7. Neutrophils ≥ 0.75 x 10\^9/L independent of growth factor support within 7 days of first dose. 8. Platelets ≥ 50 x 10\^9/L, independent of growth factor support or transfusion within 7 days of first dose. 9. Hemoglobin ≥80 g/L, independent of erythropoietin (EPO) support or transfusion within 7 days of first dose of study drug. 10. Creatinine clearance of ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation or estimated glomerular filtration rate \[eGFR\] from the Modification of Diet in Renal Disease \[MDRD\]). 11. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN). 12. Bilirubin ≤ 2 x ULN (unless documented Gilbert's syndrome). 13. International normalized ratio ≤ 1.5 and activated partial thromboplastin time ≤ 1.5 x ULN. Participants with lupus anticoagulant or acquired von Willebrand disease due to WM may be enrolled after discussion with the medical monitor. 14. ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥50%. 15. Participants who relapse after autologous stem cell transplant may be enrolled if they are at least 6 months after transplant at screening. To be eligible after transplant, participants should have no active related infections. 16. 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. Highly effective forms of birth control can be defined as abstinence, hysterectomy, bilateral oophorectomy with no menstrual bleeding for up to 6 months, intrauterine contraception, hormonal methods such as contraceptive injection, oral contraceptive, etc. Males must have undergone sterilization-vasectomy, or use a barrier method where the female partner uses the effective forms of birth control noted above and must not donate sperm for at least 90 days after last dose of study drug. 17. Life expectancy of \> 4 months. 18. Able to provide written informed consent and can understand and comply with the requirements of the study. Key
Exclusion criteria
1. Central nervous system (CNS) involvement by WM. 2. Prior exposure to a BTK inhibitor. 3. Evidence of disease transformation. 4. Prior corticosteroids given in excess of prednisone 10 mg/day or its equivalent with antineoplastic intent within 7 days, prior chemotherapy, targeted therapy, or radiation therapy within 3 weeks, antineoplastic therapy with Chinese herbal medicine or antibody based therapies within 4 weeks of the start of study drug. 5. Major surgery within 4 weeks of randomization. 6. Toxicity of ≥ Grade 1 from prior anti-cancer therapy (except for absolute neutrophil count \[ANC\], platelets, and hemoglobin. For ANC, platelets, and hemoglobin, please follow inclusion criteria #7 \[neutrophils\], #8 \[platelets\], and #9 \[hemoglobin\]). 7. 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 (surgery or other modality) with curative intent. 8. Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, uncontrolled hypertension, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification, or history of myocardial infarction within 6 months of screening. 9. QTcF prolongation (defined as a QTc \>480 msecs based on Fridericia's formula) or other significant ECG abnormalities including second degree atrioventricular (AV) block Type II, or third degree AV block. 10. 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. 11. Active infection including infections requiring oral or intravenous anti-microbial therapy. 12. Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction \[PCR\]). 13. Pregnant or lactating women. 14. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, or put the study at risk. 15. On medications which are strong CYP3A inhibitors or strong CYP3A inducers. 16. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 17. Has received allogenic hematopoietic stem cell transplantation prior to enrollment. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Response Rate (MRR) as Assessed by the Independent Review Committee | Up to approximately 1 year and 9 months | MRR is defined as the percentage of participants who achieved complete response (CR) + very good partial response (VGPR) + partial response (PR), as assessed by an independent review committee according to modified Owen's criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS: Event-free Rate | Up to approximately 1 year and 9 months | Progression/death event-free rates were estimated by Kaplan-Meier method with 95% confidence intervals (CIs) estimated using Greenwood's formula |
| Overall Response Rate (ORR) | Up to approximately 1 year and 9 months | ORR is defined as the percentage of participants with a minor, partial, very good partial, and complete response, as assessed by an independent review committee using modified Owen's criteria |
| Duration of Major Response (DOMR) | Up to approximately 1 year and 9 months | DOMR is defined as the time from the date that the major response criteria are first met to the date that progressive disease (PD) is objectively documented or death, whichever comes first, as assessed by an independent review committee using modified Owen's criteria |
| Progression Free Survival (PFS) | Up to approximately 1 year and 9 months | PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by an independent review committee using modified Owen's criteria |
| Number of Participants With Resolution of Treatment-precipitating Symptoms | Up to approximately 1 year and 9 months | Number of participants with resolution of treatment-precipitating symptoms, defined as any resolution (from Yes at baseline to No at any postbaseline point onwards during study) of the indications for initiation of therapy in WM signs and symptoms evaluation. |
| Number of Participants With an Anti-lymphoma Effect | Up to approximately 1 year and 9 months | Number of participants with an anti-lymphoma effect, defined as any reduction during the course of study in bone marrow involvement by lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly by computed tomography scan as assessed by an independent review committee; lymphadenopathy is defined as any node with longest diameter (LDi) \> 1.5 cm and splenomegaly is defined as vertical spleen length \> 13 cm |
| Number of Participants With Adverse Events | Up to approximately 3 years and 5 months | Number of participants with treatment-emergent adverse events (TEAEs), grade 3 or higher TEAEs, serious adverse events (SAEs), treatment-related adverse events (AEs), adverse events of special interest, and TEAEs leading to study drug discontinuation, dose reduction and treatment interruption |
| DOMR: Event-free Rate | Up to approximately 1 year and 9 months | DOMR event-free rates were estimated by Kaplan-Meier method with 95% CIs estimated using Greenwood's formula |
Countries
China
Participant flow
Recruitment details
This study enrolled participants at 10 study centers in China. The first participant was dosed on 31 August 2017, and the last participant enrolled and received their first dose of zanubrutinib on 08 May 2018. A total of 44 participants were enrolled and all received at least 1 dose of the study drug.
Pre-assignment details
The protocol-defined efficacy analyses were performed 12 months after the last patient received the first dose of study drug, with a data cutoff date of 08 May 2019.
Participants by arm
| Arm | Count |
|---|---|
| Zanubrutinib Zanubrutinib 160 mg orally twice daily with or without food until progressive disease or intolerable toxicity | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 7 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Transferred to long-term extension study | 29 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Zanubrutinib |
|---|---|
| Age, Continuous | 64.7 Years STANDARD_DEVIATION 8.1 |
| Race/Ethnicity, Customized Chinese | 44 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 44 |
| other Total, other adverse events | 44 / 44 |
| serious Total, serious adverse events | 25 / 44 |
Outcome results
Primary
Major Response Rate (MRR) as Assessed by the Independent Review Committee
MRR is defined as the percentage of participants who achieved complete response (CR) + very good partial response (VGPR) + partial response (PR), as assessed by an independent review committee according to modified Owen's criteria
Time frame: Up to approximately 1 year and 9 months
Population: Efficacy Analysis Set includes participants with confirmed Waldenström's macroglobulinemia based on central pathologic review among those who received at least one dose of study drug and with a baseline IgM (or M-protein) ≥ 5 g/L
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zanubrutinib | Major Response Rate (MRR) as Assessed by the Independent Review Committee | 69.8 Percentage of participants |
Comparison: Zanubrutinib versus historical control estimate of 30%p-value: <0.0001Exact binomial test
Secondary
DOMR: Event-free Rate
DOMR event-free rates were estimated by Kaplan-Meier method with 95% CIs estimated using Greenwood's formula
Time frame: Up to approximately 1 year and 9 months
Population: Efficacy Analysis Set includes participants with confirmed Waldenström's macroglobulinemia based on central pathologic review among those who received at least one dose of study drug and with a baseline IgM (or M-protein) ≥ 5 g/L
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zanubrutinib | DOMR: Event-free Rate | 6 months | 96.2 Percentage of participants |
| Zanubrutinib | DOMR: Event-free Rate | 9 months | 87.0 Percentage of participants |
| Zanubrutinib | DOMR: Event-free Rate | 12 months | 87.0 Percentage of participants |
Secondary
Duration of Major Response (DOMR)
DOMR is defined as the time from the date that the major response criteria are first met to the date that progressive disease (PD) is objectively documented or death, whichever comes first, as assessed by an independent review committee using modified Owen's criteria
Time frame: Up to approximately 1 year and 9 months
Population: Efficacy Analysis Set includes participants with confirmed Waldenström's macroglobulinemia based on central pathologic review among those who received at least one dose of study drug and with a baseline IgM (or M-protein) ≥ 5 g/L
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Duration of Major Response (DOMR) | NA Months |
Secondary
Number of Participants With Adverse Events
Number of participants with treatment-emergent adverse events (TEAEs), grade 3 or higher TEAEs, serious adverse events (SAEs), treatment-related adverse events (AEs), adverse events of special interest, and TEAEs leading to study drug discontinuation, dose reduction and treatment interruption
Time frame: Up to approximately 3 years and 5 months
Population: The Safety Analysis Set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Zanubrutinib | Number of Participants With Adverse Events | At least one TEAE | 44 Participants |
| Zanubrutinib | Number of Participants With Adverse Events | Grade 3 or higher TEAEs | 34 Participants |
| Zanubrutinib | Number of Participants With Adverse Events | Serious TEAEs | 25 Participants |
| Zanubrutinib | Number of Participants With Adverse Events | Treatment-related TEAEs | 41 Participants |
| Zanubrutinib | Number of Participants With Adverse Events | TEAEs of special interest | 43 Participants |
| Zanubrutinib | Number of Participants With Adverse Events | TEAEs leading to study drug discontinuation | 5 Participants |
| Zanubrutinib | Number of Participants With Adverse Events | TEAEs leading to treatment interruption | 17 Participants |
| Zanubrutinib | Number of Participants With Adverse Events | TEAEs leading to dose reduction | 1 Participants |
Secondary
Number of Participants With an Anti-lymphoma Effect
Number of participants with an anti-lymphoma effect, defined as any reduction during the course of study in bone marrow involvement by lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly by computed tomography scan as assessed by an independent review committee; lymphadenopathy is defined as any node with longest diameter (LDi) \> 1.5 cm and splenomegaly is defined as vertical spleen length \> 13 cm
Time frame: Up to approximately 1 year and 9 months
Population: Efficacy Analysis Set includes participants with confirmed Waldenström's macroglobulinemia based on central pathologic review among those who received at least one dose of study drug and with a baseline IgM (or M-protein) ≥ 5 g/L
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib | Number of Participants With an Anti-lymphoma Effect | 34 Participants |
Secondary
Number of Participants With Resolution of Treatment-precipitating Symptoms
Number of participants with resolution of treatment-precipitating symptoms, defined as any resolution (from Yes at baseline to No at any postbaseline point onwards during study) of the indications for initiation of therapy in WM signs and symptoms evaluation.
Time frame: Up to approximately 1 year and 9 months
Population: Efficacy Analysis Set includes participants with confirmed Waldenström's macroglobulinemia based on central pathologic review among those who received at least one dose of study drug and with a baseline IgM (or M-protein) ≥ 5 g/L
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib | Number of Participants With Resolution of Treatment-precipitating Symptoms | 35 Participants |
Secondary
Overall Response Rate (ORR)
ORR is defined as the percentage of participants with a minor, partial, very good partial, and complete response, as assessed by an independent review committee using modified Owen's criteria
Time frame: Up to approximately 1 year and 9 months
Population: Efficacy Analysis Set includes participants with confirmed Waldenström's macroglobulinemia based on central pathologic review among those who received at least one dose of study drug and with a baseline IgM (or M-protein) ≥ 5 g/L
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zanubrutinib | Overall Response Rate (ORR) | 79.1 Percentage of participants |
Secondary
PFS: Event-free Rate
Progression/death event-free rates were estimated by Kaplan-Meier method with 95% confidence intervals (CIs) estimated using Greenwood's formula
Time frame: Up to approximately 1 year and 9 months
Population: Efficacy Analysis Set includes participants with confirmed Waldenström's macroglobulinemia based on central pathologic review among those who received at least one dose of study drug and with a baseline IgM (or M-protein) ≥ 5 g/L
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zanubrutinib | PFS: Event-free Rate | 6 months | 89.8 Percentage of participants |
| Zanubrutinib | PFS: Event-free Rate | 9 months | 87.0 Percentage of participants |
| Zanubrutinib | PFS: Event-free Rate | 12 months | 77.8 Percentage of participants |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by an independent review committee using modified Owen's criteria
Time frame: Up to approximately 1 year and 9 months
Population: Efficacy Analysis Set includes participants with confirmed Waldenström's macroglobulinemia based on central pathologic review among those who received at least one dose of study drug and with a baseline IgM (or M-protein) ≥ 5 g/L
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Progression Free Survival (PFS) | NA Months |