Diffuse Large B-cell Lymphoma
Conditions
Keywords
Relapsed/refractory non-GCB type
Brief summary
Screening (up to 28 days); daily treatment until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow-up, or study termination from sponsor; treatment (up to 2 years), safety follow-up (30 days); survival follow-up until data cutoff for final analysis.
Detailed description
This is a single-arm, multicenter, open-label Phase 2 study to evaluate efficacy, safety, tolerability of BGB-3111 (zanubrutinib) in participants with relapsed/refractory non-germinal center B-cell (GCB) type diffuse large B-cell lymphoma (DLBCL). The study will enroll approximately 40 participants treated with zanubrutinib (160 milligrams \[mg\]) twice daily (BID). All participants in the study were treated until disease progression, unacceptable toxicity, death, withdrawal of consent, or the study was terminated by the sponsor for final analysis. At the time of final analysis, participants who remained on treatment were considered for participation in the extension study when eligible. A treatment cycle consisted of 28 days.
Interventions
DRUGZanubrutinib
Administered at a dose of 160 mg BID orally.
Sponsors
BeiGene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Histologically confirmed non-germinal center DLBCL, by immunohistochemistry using the Hans algorithm: 1. Cluster of differentiation 10 (CD10)- and B-cell lymphoma 6 protein (BCL6)-, 2. CD10-, BCL6+, but maximal unique match+ 2. Men and women ≥ 18 years of age. 3. Eastern Cooperative Oncology Group performance status of 0-2. 4. Measurable disease was defined as at least 1 lymph node \> 1.5 centimeters in longest diameter and measurable in 2 perpendicular dimensions. 5. All participants must have provided fresh tumor biopsy or recent tumor tissue samples (within 2 years of study entry \[informed consent form signed\]). 6. Received at least one prior therapy for DLBCL that included anthracycline-based chemotherapy. 7. Participant not eligible for or refused intensive chemotherapy and hematopoietic stem cell transplant. 8. Documented failure to achieve at least partial response with, or documented disease progression after response to, the most recent treatment regimen. 9. Neutrophils ≥ 1 x 10\^9/liter (L) independent of growth factor support within 7 days of study entry. 10. Platelets ≥ 75 x 10\^9/L, independent of growth factor support or transfusion within 7 days of study entry. 11. Creatinine clearance of ≥ 30 milliliters/minute (as estimated by the Cockcroft-Gault equation or estimated glomerular filtration rate). 12. Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal (ULN). 13. Bilirubin ≤ 2 x ULN (unless documented Gilbert's syndrome), then up to 5 x ULN allowed. 14. Independent of erythropoietin support or transfusion within 7 days of first dose of study drug. 15. International normalized ratio ≤ 1.5 and activated partial thromboplastin time ≤ 1.5 x ULN. 16. Participants may be enrolled who relapsed after autologous stem cell transplant if they are at least 6 months after transplant, participants should have had no active infections (that is, fungal or viral). 17. Females of childbearing potential must have agreed 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 were 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. Males must have undergone sterilization-vasectomy, or utilized a barrier method where the female partner utilized the effective forms of birth control noted above. 18. Life expectancy of \> 3 months. 19. Able to provide written informed consent and could understand and comply with the requirements of the study. Key
Exclusion criteria
1. Current or history of central nervous system lymphoma. 2. Prior exposure to a BTK inhibitor. 3. Prior corticosteroids (at dosages equivalent to prednisone \> 20 mg/day) given with anti-neoplastic intent within 7 days, prior chemotherapy, targeted therapy, or radiation therapy within 3 weeks, or antibody-based therapies or Chinese anti-cancer herbal therapies within 4 weeks of the start of study drug. 4. Major surgery within 4 weeks of screening. 5. Toxicity of ≥ Grade 2 from prior anti-cancer therapy (except for alopecia, absolute neutrophil count \[ANC\]) and platelets. For ANC and platelets, please follow inclusion criteria #9 \[neutrophils\] and #10 \[platelets\]). 6. 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. 7. Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months of screening. Left ventricular ejection fraction is lower than 50% measured by echocardiography. 8. QTcF (Fridericia's correction) \> 450 milliseconds or other significant electrocardiogram abnormalities including second degree atrioventricular (AV) block Type II, or third-degree AV block. 9. 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. 10. Uncontrolled systemic infection or infection requiring parenteral anti-microbial therapy. 11. Known human immunodeficiency virus, or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction). 12. Pregnant or lactating women. 13. Any life-threatening illness, medical condition or organ system dysfunction, which, in the investigator's opinion, could compromise the participant's safety, or put the study at risk. 14. On medications that were strong cytochrome P450 (CYP), family 3, subfamily A (CYP3A) inhibitors or CYP3A inducers. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Up to approximately 23 months | Overall response rate was defined as the percentage of participants achieving either a partial response (PR) or complete response (CR) as determined by investigator according to the 2014 modification of the International Working Group (IWG) in Non-Hodgkin's lymphoma (NHL) Criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Up to 3 years and 2 months | Progression-free survival was defined as the time from first dose of zanubrutinib until first documentation of progression (by IWG on NHL criteria) or death, whichever occurred first. |
| Duration Of Response | Up to 3 years and 2 months | Duration of response was defined as the time from the date that the response criteria were first met to the date that progressive disease was objectively documented or death, whichever occurred first. Duration of response was summarized for responders (with a best overall response of CR or PR) only. |
| Time To Response | Up to 3 years and 2 months | Time to response was defined as the time from the first dose of zanubrutinib to the documentation of first response. Time to response was summarized for responders (with a best overall response of CR or PR) only. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From the time of informed consent to 30 days after the last dose of study drug (approximately Up to 3 years and 2 months) | A treatment-emergent adverse event was defined as an adverse event 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 occurred first. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 3 years and 2 months | Overall survival was defined as the time from first dose of zanubrutinib until death due to any cause. |
Countries
China
Participant flow
Recruitment details
This study was conducted at 11 centers in China, all of which enrolled participants. The first participant was dosed on 30 June 2017. Since the primary and secondary objectives were met and the analysis was complete, the sponsor ended the study on 03 September 2020 (Last patient last visit). As of the final database lock (15 October 2020), 41 participants were enrolled and treated with zanubrutinib.
Participants by arm
| Arm | Count |
|---|---|
| Zanubrutinib Participants received 160 mg of zanubrutinib BID. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 24 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Other: Transferred to Long term Extension (LTE) study BGB-3111-LTE1 (NCT04170283) | 4 |
| Overall Study | Study ended by sponsor once primary/ secondary analysis was complete and participants discontinued | 4 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Zanubrutinib |
|---|---|
| Age, Continuous | 57.2 years STANDARD_DEVIATION 12.45 |
| Eastern Cooperative Oncology Group Performance Status Grade 0 | 10 Participants |
| Eastern Cooperative Oncology Group Performance Status Grade 1 | 27 Participants |
| Eastern Cooperative Oncology Group Performance Status Grade 2 | 4 Participants |
| Hepatitis B Core Antibody Negative | 28 Participants |
| Hepatitis B Core Antibody Positive | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 41 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 24 / 41 |
| other Total, other adverse events | 34 / 41 |
| serious Total, serious adverse events | 12 / 41 |
Outcome results
Primary
Overall Response Rate
Overall response rate was defined as the percentage of participants achieving either a partial response (PR) or complete response (CR) as determined by investigator according to the 2014 modification of the International Working Group (IWG) in Non-Hodgkin's lymphoma (NHL) Criteria.
Time frame: Up to approximately 23 months
Population: The Safety Analysis Set, which included all participants who received any dose of study drug, was the analysis set used for the efficacy and safety analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zanubrutinib | Overall Response Rate | 29.3 percentage of participants |
Secondary
Duration Of Response
Duration of response was defined as the time from the date that the response criteria were first met to the date that progressive disease was objectively documented or death, whichever occurred first. Duration of response was summarized for responders (with a best overall response of CR or PR) only.
Time frame: Up to 3 years and 2 months
Population: The Safety Analysis Set, which included all participants who received any dose of study drug, was the analysis set used for the efficacy and safety analyses
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Duration Of Response | 4.5 months |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
A treatment-emergent adverse event was defined as an adverse event 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 occurred first.
Time frame: From the time of informed consent to 30 days after the last dose of study drug (approximately Up to 3 years and 2 months)
Population: The Safety Analysis Set included all participants who received any dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zanubrutinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Serious TEAE | 12 Participants |
| Zanubrutinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE leading to treatment discontinuation | 4 Participants |
| Zanubrutinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with at least1 TEAE | 36 Participants |
Secondary
Progression-free Survival
Progression-free survival was defined as the time from first dose of zanubrutinib until first documentation of progression (by IWG on NHL criteria) or death, whichever occurred first.
Time frame: Up to 3 years and 2 months
Population: The Safety Analysis Set, which included all participants who received any dose of study drug, was the analysis set used for the efficacy and safety analyses
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Progression-free Survival | 2.8 months |
Secondary
Time To Response
Time to response was defined as the time from the first dose of zanubrutinib to the documentation of first response. Time to response was summarized for responders (with a best overall response of CR or PR) only.
Time frame: Up to 3 years and 2 months
Population: The Safety Analysis Set, which included all participants who received any dose of study drug, was the analysis set used for the efficacy and safety analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Time To Response | 2.83 months |
Other Pre-specified
Overall Survival
Overall survival was defined as the time from first dose of zanubrutinib until death due to any cause.
Time frame: Up to 3 years and 2 months
Population: The Safety Analysis Set, which included all participants who received any dose of study drug, was the analysis set used for the efficacy and safety analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Overall Survival | 8.4 months |