Relapsed or Refractory Chronic Lymphocytic Leukemia, Relapsed or Refractory Small Lymphocytic Lymphoma
Conditions
Keywords
Bruton's tyrosine kinase, Chronic lymphocytic leukemia, Relapsed/refractory, Zanubrutinib
Brief summary
This was a single-arm, open-label, multi-center Phase 2 study in participants with histologically documented CLL/SLL who have relapsed after or refractory to ≥ 1 prior treatment regimen(s). The study is composed of an initial screening phase, a single-arm treatment phase, and a follow-up phase.
Interventions
DRUGZanubrutinib
Zanubrutinib 160 mg (two - 80 mg white opaque capsules) taken by mouth (PO) twice a day (BID)
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. Confirmed diagnosis with at least one criterion for treatment according to International workshop on chronic lymphocytic leukemia (IWCLL) 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 3. Measurable disease by contrast enhanced computerized tomography / magnetic resonance imaging (CT/MRI). 4. Previously treated with a minimum of 1 prior line of standard chemotherapy-containing regimen (with completion of ≥2 treatment cycles). 5. Documented failure to achieve at least partial response (PR) or documented disease progression after response to the most recent treatment regimen. Refractory disease is defined as treatment failure (stable disease, non-response, progressive disease \[PD\]) or disease progression within 6 months after the most recent prior therapy (Hallek et al, 2008). 6. Neutrophils ≥ 0.75 x 109/L independent of growth factor support within 7 days of study entry 7. Platelets ≥ 50 x 109/L, independent of growth factor support or transfusion within 7 days of study entry 8. 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 \[MDRD\]) 9. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN 10. Bilirubin ≤2 x ULN (unless documented Gilbert's syndrome) 11. International normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5 x ULN. 12. Participants may be enrolled who relapse after autologous stem cell transplant if they are at least 6 months after transplant. 13. Life expectancy of \>4 months 14. Echocardiogram (ECHO) must demonstrate left ventricular ejection fraction (LVEF) ≥50%; (AHA, 2016) Key
Exclusion criteria
1. Current or history of central nervous system (CNS) lymphoma 2. Prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor 3. Prior corticosteroids given in excess of prednisone 10 mg/day or its equivalent with antineoplastic intent within 7 days. 4. Major surgery within 4 weeks of screening 5. Not recovered from toxicity of any prior anti-cancer therapy to \<Grade 1 (except for alopecia, absolute neutrophil count (ANC) and 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 8. QTcF \>480 msecs based on Fridericia's formula 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. Active infection including infections requiring oral or intravenous anti-microbials 11. Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction \[PCR\]). 12. Has received allogenic hematopoietic stem cell transplantation prior to enrollment 13. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the participants's safety, or put the study at risk 14. Requires ongoing treatment with any medication which is a strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitor or strong CYP3A inducer 15. Known or clinically suspected Richter's transformation at the time of study entry 16. History of stroke or intracranial hemorrhage within 6 months prior to enrollment NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) by Independent Review Committee (IRC) | Up to 1 year and 4 months | ORR is defined as the number of participants who achieve a best response of CR or, CRi, Nodular Partial Response, PR, and PR with Lymphocytosis as assessed by IRC per the modified IWCLL Guidelines in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with SLL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS): Percentage of Participants Progression/Death Event Free | 6, 12, 24, and 36 months | PFS is defined as the time from treatment initiation to first documentation of progression by International workshop on chronic lymphocytic leukemia (IWCLL) criteria/revised criteria for response for malignant lymphoma or death, whichever is earlier. |
| Duration of Response (DOR): Event Free Rate - Percentage of Participants Who Remained Event Free | 6, 12, 24, and 36 months | DOR is defined as the time from the date that response criteria are first met to the date that progressive disease (PD) is objectively documented or death, whichever occurs first |
| Time to Response (TTR) | Up to 3.5 years | TTR is defined as the time from treatment initiation to first signs of response |
| Overall Response Rate as Determined by the Investigator | up to 3.5 years | Overall response was defined as achieving a best overall response of CR, CRi, nodular partial response (nPR), PR, or partial response with lymphocytosis (PR-L). |
| Number of Participants Experiencing Adverse Events (AEs) | Up to 3.5 years | An adverse event (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. All AEs were monitored per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version \[v\] 4.03 2010). A treatment emergent adverse event (TEAE) is defined as an adverse event that has 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 or initiation of new anticancer therapy, whichever occurs first. |
Countries
China
Participant flow
Recruitment details
91 participants were enrolled at 11 sites in China. The first participant was dosed on 09 March 2017. Database lock date for the primary outcome measure was 14 December 2018. Final database lock date was 16 October 2020.
Participants by arm
| Arm | Count |
|---|---|
| Zanubrutinib 160 mg administered orally (two - 80 mg white opaque capsules) twice a day (BID) for up to three years or until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by the sponsor. | 91 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 11 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Study terminated by sponsor | 12 |
| Overall Study | Transferred to extension study BGB-3111-LTE1 (NCT04170283) | 60 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Zanubrutinib |
|---|---|
| Age, Continuous | 60.9 years STANDARD_DEVIATION 9.73 |
| Age, Customized <65 | 60 Participants |
| Age, Customized ≥65 | 31 Participants |
| Race/Ethnicity, Customized Chinese | 91 participants |
| Race/Ethnicity, Customized Other | 0 participants |
| Sex: Female, Male Female | 39 Participants |
| Sex: Female, Male Male | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 11 / 91 |
| other Total, other adverse events | 91 / 91 |
| serious Total, serious adverse events | 47 / 91 |
Outcome results
Primary
Overall Response Rate (ORR) by Independent Review Committee (IRC)
ORR is defined as the number of participants who achieve a best response of CR or, CRi, Nodular Partial Response, PR, and PR with Lymphocytosis as assessed by IRC per the modified IWCLL Guidelines in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with SLL.
Time frame: Up to 1 year and 4 months
Population: Modified Safety Analysis Set: All participants in the safety analysis set who had confirmed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib | Overall Response Rate (ORR) by Independent Review Committee (IRC) | 80 Participants |
p-value: <0.000195% CI: [79.4, 93.81]Exact Binomial Test
Secondary
Duration of Response (DOR): Event Free Rate - Percentage of Participants Who Remained Event Free
DOR is defined as the time from the date that response criteria are first met to the date that progressive disease (PD) is objectively documented or death, whichever occurs first
Time frame: 6, 12, 24, and 36 months
Population: The Safety Analysis Set included all participants who received ≥ 1 doses of study drug. Duration of response was summarized for responders (with Best Overall Response of partial response with lymphocytosis (PR-L) or above) only
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zanubrutinib | Duration of Response (DOR): Event Free Rate - Percentage of Participants Who Remained Event Free | 36 Months | 69.9 Percentage of participants |
| Zanubrutinib | Duration of Response (DOR): Event Free Rate - Percentage of Participants Who Remained Event Free | 6 Months | 97.5 Percentage of participants |
| Zanubrutinib | Duration of Response (DOR): Event Free Rate - Percentage of Participants Who Remained Event Free | 12 Months | 92.5 Percentage of participants |
| Zanubrutinib | Duration of Response (DOR): Event Free Rate - Percentage of Participants Who Remained Event Free | 24 Months | 83.4 Percentage of participants |
Secondary
Number of Participants Experiencing Adverse Events (AEs)
An adverse event (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. All AEs were monitored per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version \[v\] 4.03 2010). A treatment emergent adverse event (TEAE) is defined as an adverse event that has 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 or initiation of new anticancer therapy, whichever occurs first.
Time frame: Up to 3.5 years
Population: The Safety Analysis Set included all participants who received ≥ 1 doses of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Zanubrutinib | Number of Participants Experiencing Adverse Events (AEs) | At Least 1 TEAE | 91 Participants |
| Zanubrutinib | Number of Participants Experiencing Adverse Events (AEs) | Grade 3 or higher TEAE | 76 Participants |
| Zanubrutinib | Number of Participants Experiencing Adverse Events (AEs) | Serious TEAEs | 47 Participants |
| Zanubrutinib | Number of Participants Experiencing Adverse Events (AEs) | TEAE leading to death | 6 Participants |
| Zanubrutinib | Number of Participants Experiencing Adverse Events (AEs) | TEAE leading to treatment discontinuation | 14 Participants |
| Zanubrutinib | Number of Participants Experiencing Adverse Events (AEs) | TEAE leading to treatment modification | 42 Participants |
| Zanubrutinib | Number of Participants Experiencing Adverse Events (AEs) | TEAE leading to treatment interruption | 42 Participants |
| Zanubrutinib | Number of Participants Experiencing Adverse Events (AEs) | TEAE leading to dose reduction | 8 Participants |
| Zanubrutinib | Number of Participants Experiencing Adverse Events (AEs) | Treatment-related TEAE | 90 Participants |
Secondary
Overall Response Rate as Determined by the Investigator
Overall response was defined as achieving a best overall response of CR, CRi, nodular partial response (nPR), PR, or partial response with lymphocytosis (PR-L).
Time frame: up to 3.5 years
Population: The Safety Analysis Set included all participants who received ≥ 1 doses of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Overall Response Rate as Determined by the Investigator | 92.3 Percentage of participants |
Secondary
Progression-free Survival (PFS): Percentage of Participants Progression/Death Event Free
PFS is defined as the time from treatment initiation to first documentation of progression by International workshop on chronic lymphocytic leukemia (IWCLL) criteria/revised criteria for response for malignant lymphoma or death, whichever is earlier.
Time frame: 6, 12, 24, and 36 months
Population: The Safety Analysis Set included all participants who received ≥ 1 doses of study drug. All efficacy analyses were based on the Safety Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zanubrutinib | Progression-free Survival (PFS): Percentage of Participants Progression/Death Event Free | 6 months | 93.3 Percentage of participants |
| Zanubrutinib | Progression-free Survival (PFS): Percentage of Participants Progression/Death Event Free | 12 months | 88.7 Percentage of participants |
| Zanubrutinib | Progression-free Survival (PFS): Percentage of Participants Progression/Death Event Free | 24 months | 80.5 Percentage of participants |
| Zanubrutinib | Progression-free Survival (PFS): Percentage of Participants Progression/Death Event Free | 36 months | 68.1 Percentage of participants |
Secondary
Time to Response (TTR)
TTR is defined as the time from treatment initiation to first signs of response
Time frame: Up to 3.5 years
Population: The Safety Analysis Set included all participants who received ≥ 1 doses of study drug. Time to response was summarized for responders (those who achieved a best overall response of at least PR-L) only
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Time to Response (TTR) | 2.79 Months |