Refractory Mantle Cell Lymphoma, Relapsed Mantle Cell Lymphoma
Conditions
Brief summary
The primary objective of this study was to evaluate the efficacy of zanubrutinib in participants with centrally confirmed relapsed or refractory MCL.
Interventions
DRUGZanubrutinib
Administered as specified in the treatment arm.
Sponsors
BeiGene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Diagnostic report had to include evidence for morphological and cyclin D1 or t (11; 14). 2. Eastern Cooperative Oncology Group performance status of 0-2. 3. Measurable disease by computed tomography/magnetic resonance imaging. 4. Received prior regimens for MCL. 5. Documented failure to achieve any response, (stable disease or progressive disease during treatment) or documented progressive disease after response to the most recent treatment regimen. 6. Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal (ULN). 7. Total bilirubin ≤ 2 x ULN (unless documented Gilbert's syndrome). 8. Life expectancy of \> 4 months. Key
Exclusion criteria
1. Current or history of central nervous system lymphoma. 2. Prior exposure to a BTK inhibitor before enrollment. 3. Prior corticosteroids with anti-neoplastic intent within 7 days. 4. Major surgery within 4 weeks of screening. 5. Toxicity must have recovered from prior chemotherapy. 6. History of other active malignancies within 2 years of study entry. 7. Currently clinically significant active cardiovascular disease. 8. QT interval corrected with Fridericia's formula \> 450 microseconds or other significant electrocardiogram abnormalities. 9. Uncontrolled systemic infection or infection requiring parenteral anti-microbial therapy. 10. Known human immunodeficiency virus infection, or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction). Note: Other protocol-defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) As Assessed By Independent Review Committee | Up to 1 year and 11 months | The ORR was assessed in accordance with the 2014 modification of the International Working Group on non-Hodgkin Lymphoma Criteria. The ORR was defined as the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR). The BOR was defined as the best response recorded from the start of zanubrutinib until data cut or start of new antineoplastic treatment. Participants with no post-baseline response assessment (due to any reason) were considered non-responders for BOR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time To Response | Up to 3 years and 6 months | Time to response was defined as the time from treatment initiation to the first documentation of response. |
| Duration Of Response | Up to 3 years and 6 months | The duration of response was defined as the time from the date that the response criteria are first met to the date that Progressive Disease was objectively documented or death (whichever occurs first). Participants who did not have disease progression were censored at their last valid assessment. |
| Progression-free Survival | Up to 3 years and 6 months | Progression-free survival was defined as the time from the starting date of zanubrutinib to the date of first documentation of disease progression or death, whichever occurred first. Participants who did not have disease progression were censored at their last valid tumor assessment. A six-month progression-free survival rate was defined as no disease progression after treated with zanubrutinib for over six months (under control). The 95% confidence interval (CI) lower bound was 33.1 months while the upper bound could not be estimated. |
| Number Of Participants Experiencing Treatment -Emergent Adverse Events (AEs) | From the initiation of study drug until 30 days after the last dose (Up to 3 years and 6 months) | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date or a worsening in severity from baseline (pretreatment) on or after the date of first dose of study drug up to 30 days following study drug discontinuation (Safety Follow-up visit) or initiation of new anticancer therapy, whichever comes first. |
| Number Of Participants Experiencing AEs Leading To Treatment Discontinuation | From the initiation of study drug until 30 days after the last dose (Up to 3 years and 6 months) | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to the study drug or not. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. |
| ORR As Assessed By The Investigator | Up to 3 years and 6 months | The ORR was assessed in accordance with the 2014 modification of the International Working Group on non-Hodgkin Lymphoma Criteria. The ORR was defined as the percentage of participants achieving a BOR of CR or PR. The BOR was defined as the best response recorded from the start of zanubrutinib until data cut or start of new antineoplastic treatment. Participants with no post-baseline response assessment (due to any reason) were considered non-responders for BOR. For this outcome measure, only investigator-assessed data are analyzed and reported because of the high rate of concordance between the Independent Review Committee and investigator assessments for the primary outcome measure of ORR. |
Countries
China
Participant flow
Recruitment details
This study was conducted at 14 study centers in China; 13 study centers enrolled participants. Once the primary and secondary objectives were met and the analysis was complete, sponsor ended the study on 08 September 2020 and transferred all participants remaining on treatment to long term extension study.
Participants by arm
| Arm | Count |
|---|---|
| Zanubrutinib Zanubrutinib (160 mg) administered BID until Zanubrutinib (160 milligrams \[mg\]) administered orally twice daily (BID) until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow up, or study termination by sponsor, which comes first. | 86 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 21 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Primary and secondary objectives were met and remaining participants transferred to LTE by sponsor | 49 |
| Overall Study | Withdrawal by Subject | 13 |
Baseline characteristics
| Characteristic | Zanubrutinib |
|---|---|
| Age, Continuous | 59.0 years STANDARD_DEVIATION 8.18 |
| Age, Customized < 65 years | 64 Participants |
| Age, Customized ≥ 65 years | 22 Participants |
| Disease Status Refractory Disease | 45 Participants |
| Disease Status Relapsed Disease | 41 Participants |
| Eastern Cooperative Oncology Group Performance Status Grade 0 | 60 Participants |
| Eastern Cooperative Oncology Group Performance Status Grade 1 | 22 Participants |
| Eastern Cooperative Oncology Group Performance Status Grade 2 | 4 Participants |
| Mantle Cell Lymphoma (MCL) Disease Stage at Study Entry MCL Stage I | 1 Participants |
| Mantle Cell Lymphoma (MCL) Disease Stage at Study Entry MCL Stage II | 7 Participants |
| Mantle Cell Lymphoma (MCL) Disease Stage at Study Entry MCL Stage III | 14 Participants |
| Mantle Cell Lymphoma (MCL) Disease Stage at Study Entry MCL Stage IV | 64 Participants |
| Race/Ethnicity, Customized Chinese | 86 Participants |
| Region of Enrollment China | 86 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 86 |
| other Total, other adverse events | 82 / 86 |
| serious Total, serious adverse events | 25 / 86 |
Outcome results
Primary
Overall Response Rate (ORR) As Assessed By Independent Review Committee
The ORR was assessed in accordance with the 2014 modification of the International Working Group on non-Hodgkin Lymphoma Criteria. The ORR was defined as the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR). The BOR was defined as the best response recorded from the start of zanubrutinib until data cut or start of new antineoplastic treatment. Participants with no post-baseline response assessment (due to any reason) were considered non-responders for BOR.
Time frame: Up to 1 year and 11 months
Population: Safety Analysis Set: All participants who received any dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib | Overall Response Rate (ORR) As Assessed By Independent Review Committee | 72 Participants |
Comparison: A binomial exact test was performed to test against the null hypothesis H0: ORR=0.40 using the significant level of 0.025 (1-sided)p-value: <0.000195% CI: [74.2, 90.8]Binomial Exact Test
Secondary
Duration Of Response
The duration of response was defined as the time from the date that the response criteria are first met to the date that Progressive Disease was objectively documented or death (whichever occurs first). Participants who did not have disease progression were censored at their last valid assessment.
Time frame: Up to 3 years and 6 months
Population: Safety Analysis Set: All participants who received any dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Duration Of Response | NA months |
Secondary
Number Of Participants Experiencing AEs Leading To Treatment Discontinuation
An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to the study drug or not. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time frame: From the initiation of study drug until 30 days after the last dose (Up to 3 years and 6 months)
Population: Safety Analysis Set: All participants who received any dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib | Number Of Participants Experiencing AEs Leading To Treatment Discontinuation | 8 Participants |
Secondary
Number Of Participants Experiencing Treatment -Emergent Adverse Events (AEs)
An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date or a worsening in severity from baseline (pretreatment) on or after the date of first dose of study drug up to 30 days following study drug discontinuation (Safety Follow-up visit) or initiation of new anticancer therapy, whichever comes first.
Time frame: From the initiation of study drug until 30 days after the last dose (Up to 3 years and 6 months)
Population: Safety Analysis Set: All participants who received any dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib | Number Of Participants Experiencing Treatment -Emergent Adverse Events (AEs) | 83 Participants |
Secondary
ORR As Assessed By The Investigator
The ORR was assessed in accordance with the 2014 modification of the International Working Group on non-Hodgkin Lymphoma Criteria. The ORR was defined as the percentage of participants achieving a BOR of CR or PR. The BOR was defined as the best response recorded from the start of zanubrutinib until data cut or start of new antineoplastic treatment. Participants with no post-baseline response assessment (due to any reason) were considered non-responders for BOR. For this outcome measure, only investigator-assessed data are analyzed and reported because of the high rate of concordance between the Independent Review Committee and investigator assessments for the primary outcome measure of ORR.
Time frame: Up to 3 years and 6 months
Population: Safety Analysis Set: All participants who received any dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib | ORR As Assessed By The Investigator | 72 Participants |
Comparison: A binomial exact test was performed to test against the null hypothesis H0: ORR=0.40 using the significant level of 0.025 (1-sided)p-value: <0.000195% CI: [74.2, 90.8]Binomial Exact Test
Secondary
Progression-free Survival
Progression-free survival was defined as the time from the starting date of zanubrutinib to the date of first documentation of disease progression or death, whichever occurred first. Participants who did not have disease progression were censored at their last valid tumor assessment. A six-month progression-free survival rate was defined as no disease progression after treated with zanubrutinib for over six months (under control). The 95% confidence interval (CI) lower bound was 33.1 months while the upper bound could not be estimated.
Time frame: Up to 3 years and 6 months
Population: Safety Analysis Set: All participants who received any dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Progression-free Survival | 33.0 months |
Secondary
Time To Response
Time to response was defined as the time from treatment initiation to the first documentation of response.
Time frame: Up to 3 years and 6 months
Population: Safety Analysis Set: All participants who received any dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zanubrutinib | Time To Response | 2.72 months | Standard Deviation 0.105 |