Locally Advanced or Metastatic Urothelial Bladder Cancer
Conditions
Brief summary
This was a single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of the anti- programmed cell death-1(PD-1) monoclonal antibody BGB-A317 in participants with PD-L1+, locally advanced or metastatic Urothelial Bladder Cancer (UBC) who have progressed during or following a platinum-containing regimen
Interventions
DRUGTislelizumab
200mg intravenously (IV) every 3 weeks (Q3W)
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. Participants with histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium 2. Disease progression during or following treatment with at least one platinum-containing regimen for inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence 3. Participants must submit archival tumor tissue for determination of program death ligand-1 (PD-L1) expression and other biomarker analyses. PD-L1 expression will be assessed centrally, and participants who are tested as PD-L1 high are eligible. 4. Participants must have at least one measurable lesion as defined per RECIST version 1.1 assessed by the investigator 5. Male or female, aged ≥18 years on day of signing informed consent 6. Participants have voluntarily agreed to participate by giving written informed consent 7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 8. Life expectancy ≥12 weeks 9. Participant must have adequate organ function as indicated by the following screening laboratory values obtained within 7 days prior to the first study treatment 1. Absolute neutrophil count (ANC) ≥1.5×109/L 2. Platelets ≥100×109/L 3. Hemoglobin ≥9 g/dL or ≥5.6 mmol /L (Note: Criteria must be met without a transfusion within 14 days of obtaining the sample) 4. Calculated creatinine clearance ≥ 30 milliliter (mL)/min (Cockcroft-Gault formula, see Appendix 5) 5. Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) (total bilirubin must be \<4 X ULN for participants with Gilbert's syndrome) 6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for participants with liver metastases 10. Female participants are eligible to enter and participate in the study if they are of: 1. Non-childbearing potential (ie, physiologically incapable of becoming pregnant), including any female who i) Has had a hysterectomy ii) Has had a bilateral oophorectomy (ovariectomy) iii) Has had a bilateral tubal ligation iv) Is post menopausal (total cessation of menses for ≥1 year) 2. Childbearing potential, has a negative serum pregnancy test at screening (within 7 days before the first investigational product administration), not be breast feeding, and agree to remain abstinent (refrain from heterosexual intercourse) or uses adequate contraceptive methods that result in a failure rate of \<1% per year before study entry and throughout the study until 120 days after the last investigational product administration 11. Male participants are eligible to participate in the study if they are vasectomized or agree to use contraception during the study treatment period and for at least 120 days after the last dose of study drug Key
Exclusion criteria
1. History of severe hypersensitivity reactions to other humanized monoclonal antibodies 2. Prior active malignancy within 2 years prior to Cycle 1 Day 1. 3. Prior therapies targeting PD-1 or PD-L1. 4. Active brain or leptomeningeal metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments. 5. Participants with active autoimmune diseases or history of autoimmune diseases that may relapse should be excluded. 6. Participants should be excluded if they have conditions requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. 7. Has history of interstitial lung disease or non-infectious pneumonitis except for those induced by radiation therapies 8. With severe chronic or active infections (including tuberculosis infection, etc) requiring systemic antibacterial, antifungal or antiviral therapy within 14 days prior to first dose of study drug. 9. With uncontrollable pleural effusion, pericardial effusion or ascites requiring pleurocentesis or abdominal tapping less than 4 weeks 10. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina 11. Known history of Human Immunodeficiency Virus (HIV) 12. Participants with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carrier with HBV deoxyribonucleic acid (DNA) ≥500 IU/mL (or 2.5 × 103 cps/mL), or active hepatitis C should be excluded. Participant with inactive hepatitis B surface antigen (HBsAg) carrier, active HBV infection with sustained anti-HBV suppression (HBV DNA \<500 IU/mL or 2.5 × 103 cps/mL) and participants whose hepatitis C has been cured (hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] is lower than detection limit) can be enrolled 13. Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events (AEs) 14. Prior chemotherapy, radiotherapy, immunotherapy or any investigational therapies (including Chinese herbal medicine and Chinese patent medicines) used to control cancer within 2 weeks of Cycle 1 Day 1. AEs associated with these therapies must be Grade 0-1, baseline or stabilized (except for alopecia) 15. Prior allogeneic stem cell or solid organ transplant 16. Administration of a live or attenuated vaccine within 4 weeks prior to study drug administration 17. Major surgical procedure other than for diagnosis within 28 days prior to study drug administration NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) as Assessed by Independent Review Committee (IRC) | From the date of first dose up to approximately 2 years and 2 months | ORR is defined as the percentage of participants who had confirmed complete response (CR) or partial response (PR) assessed by Independent Review Committee (IRC) using RECIST version 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) as Assessed by IRC | From the date of first dose up to approximately 2 years and 2 months | PFS is defined as the time from the date of first dose of study drug to the date of first documentation of disease progression assessed by IRC using RECIST version 1.1 or death, whichever occurs first |
| Disease Control Rate (DCR) as Assessed by IRC | From the date of first dose up to approximately 2 years and 2 months | DCR is defined as the percentage of participants who achieve CR, PR and stable disease (SD) assessed by IRC using RECIST version 1.1 |
| Overall Survival (OS) | From the date of first dose up to approximately 2 years and 2 months | OS - defined as the time from the date of first dose of study drug until the date of death from any cause |
| ORR as Assessed by the Investigators | From the date of first dose up to approximately 2 years and 2 months | ORR is defined as the percentage of participants who had confirmed complete response (CR) or partial response (PR) as assessed by the investigators per RECIST version 1.1 and immune related RECIST (irRECIST) |
| Duration of Response (DOR) as Assessed by IRC | From the date of first dose up to approximately 2 years and 2 months | DOR - defined as the time from the first determination of a confirmed objective response by IRC according to RECIST version 1.1 until the first documentation of progression or death, whichever comes first |
| PFS as Assessed by Investigators Per RECIST Version 1.1 and irRECIST | From the date of first dose up to approximately 2 years and 2 months | PFS is defined as the time from the date of first dose of study drug to the date of first documentation of disease progression assessed by the investigator according to RECIST version 1.1 and irRECIST until the first documentation of progression or death, whichever comes first |
| DCR as Assessed by Investigators Per RECIST Version 1.1 and irRECIST | From the date of first dose up to approximately 2 years and 2 months | DCR is defined as the percentage of participants who achieve CR, PR and stable disease (SD) assessed by investigators per RECIST version 1.1 and irRECIST |
| Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From the date of first dose until End of Study (approximately 3 years and 9 months) | TEAE is defined as an adverse event (AE) that had an onset date or a worsening in severity from baseline pre-treatment) on or after the first dose of study drug up to 30 days following study drug .discontinuation. An SAE is any untoward medical occurrence that, at any dose that results in death or is life-threatening. |
| DOR as Assessed by Investigators Per RECIST Version 1.1 and irRECIST | From the date of first dose up to approximately 2 years and 2 months | DOR is defined as the time from the first determination of a confirmed objective response by the investigator according to RECIST version 1.1 and irRECIST until the first documentation of progression or death, whichever comes first |
Countries
China, South Korea
Participant flow
Recruitment details
113 participants were enrolled in 27 centers in China and 3 centers in South Korea. All efficacy evaluations were done until 16 September 2019, the primary data cut-off date. Safety evaluations were done until 11 March 2021, the study completion date.
Participants by arm
| Arm | Count |
|---|---|
| Tislelizumab Participants received 200mg tislelizumab intravenously (IV) every 3 weeks (Q3W) until disease progression or death | 113 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 89 |
| Overall Study | Participant refused to enter LTE | 1 |
| Overall Study | Participants transferred to Long-Term Extension (LTE) study | 9 |
| Overall Study | Sponsor Decision | 9 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Tislelizumab | — |
|---|---|---|
| Age, Continuous | 62.1 years STANDARD_DEVIATION 7.85 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment China | 108 participants | — |
| Region of Enrollment South Korea | 5 participants | — |
| Sex: Female, Male Female | 29 Participants | — |
| Sex: Female, Male Male | 84 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 89 / 113 |
| other Total, other adverse events | 110 / 113 |
| serious Total, serious adverse events | 49 / 113 |
Outcome results
Primary
Objective Response Rate (ORR) as Assessed by Independent Review Committee (IRC)
ORR is defined as the percentage of participants who had confirmed complete response (CR) or partial response (PR) assessed by Independent Review Committee (IRC) using RECIST version 1.1
Time frame: From the date of first dose up to approximately 2 years and 2 months
Population: The Efficacy Evaluable Analysis Set includes all participants who received any dose of tislelizumab and had measurable disease per IRC according to RECIST version 1.1 at baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tislelizumab | Objective Response Rate (ORR) as Assessed by Independent Review Committee (IRC) | 24.0 Percentage of participants |
p-value: <0.0001Exact Binomial Test
Secondary
DCR as Assessed by Investigators Per RECIST Version 1.1 and irRECIST
DCR is defined as the percentage of participants who achieve CR, PR and stable disease (SD) assessed by investigators per RECIST version 1.1 and irRECIST
Time frame: From the date of first dose up to approximately 2 years and 2 months
Population: Efficacy Evaluable Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tislelizumab | DCR as Assessed by Investigators Per RECIST Version 1.1 and irRECIST | RECIST | 41.3 Percentage of participants |
| Tislelizumab | DCR as Assessed by Investigators Per RECIST Version 1.1 and irRECIST | irRECIST | 46.2 Percentage of participants |
Secondary
Disease Control Rate (DCR) as Assessed by IRC
DCR is defined as the percentage of participants who achieve CR, PR and stable disease (SD) assessed by IRC using RECIST version 1.1
Time frame: From the date of first dose up to approximately 2 years and 2 months
Population: Efficacy Evaluable Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tislelizumab | Disease Control Rate (DCR) as Assessed by IRC | 38.5 Percentage of participants |
Secondary
DOR as Assessed by Investigators Per RECIST Version 1.1 and irRECIST
DOR is defined as the time from the first determination of a confirmed objective response by the investigator according to RECIST version 1.1 and irRECIST until the first documentation of progression or death, whichever comes first
Time frame: From the date of first dose up to approximately 2 years and 2 months
Population: Efficacy Evaluable Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tislelizumab | DOR as Assessed by Investigators Per RECIST Version 1.1 and irRECIST | RECIST | NA Months |
| Tislelizumab | DOR as Assessed by Investigators Per RECIST Version 1.1 and irRECIST | irRECIST | NA Months |
Secondary
Duration of Response (DOR) as Assessed by IRC
DOR - defined as the time from the first determination of a confirmed objective response by IRC according to RECIST version 1.1 until the first documentation of progression or death, whichever comes first
Time frame: From the date of first dose up to approximately 2 years and 2 months
Population: Efficacy Evaluable Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tislelizumab | Duration of Response (DOR) as Assessed by IRC | NA Months |
Secondary
Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
TEAE is defined as an adverse event (AE) that had an onset date or a worsening in severity from baseline pre-treatment) on or after the first dose of study drug up to 30 days following study drug .discontinuation. An SAE is any untoward medical occurrence that, at any dose that results in death or is life-threatening.
Time frame: From the date of first dose until End of Study (approximately 3 years and 9 months)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tislelizumab | Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with At Least 1 TEAE | 112 Number of participants |
| Tislelizumab | Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Grade 3 or Higher | 64 Number of participants |
| Tislelizumab | Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Serious TEAEs | 49 Number of participants |
Secondary
ORR as Assessed by the Investigators
ORR is defined as the percentage of participants who had confirmed complete response (CR) or partial response (PR) as assessed by the investigators per RECIST version 1.1 and immune related RECIST (irRECIST)
Time frame: From the date of first dose up to approximately 2 years and 2 months
Population: Efficacy Evaluable Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tislelizumab | ORR as Assessed by the Investigators | RECIST | 24.0 Percentage of participants |
| Tislelizumab | ORR as Assessed by the Investigators | irRECIST | 24.0 Percentage of participants |
Secondary
Overall Survival (OS)
OS - defined as the time from the date of first dose of study drug until the date of death from any cause
Time frame: From the date of first dose up to approximately 2 years and 2 months
Population: Safety Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tislelizumab | Overall Survival (OS) | 9.8 Months |
Secondary
PFS as Assessed by Investigators Per RECIST Version 1.1 and irRECIST
PFS is defined as the time from the date of first dose of study drug to the date of first documentation of disease progression assessed by the investigator according to RECIST version 1.1 and irRECIST until the first documentation of progression or death, whichever comes first
Time frame: From the date of first dose up to approximately 2 years and 2 months
Population: Efficacy Evaluable Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tislelizumab | PFS as Assessed by Investigators Per RECIST Version 1.1 and irRECIST | RECIST | 2.1 Months |
| Tislelizumab | PFS as Assessed by Investigators Per RECIST Version 1.1 and irRECIST | irRECIST | 2.6 Months |
Secondary
Progression-Free Survival (PFS) as Assessed by IRC
PFS is defined as the time from the date of first dose of study drug to the date of first documentation of disease progression assessed by IRC using RECIST version 1.1 or death, whichever occurs first
Time frame: From the date of first dose up to approximately 2 years and 2 months
Population: Efficacy Evaluable Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tislelizumab | Progression-Free Survival (PFS) as Assessed by IRC | 2.1 Months |