A Study of Atezolizumab in Participants With Locally Advanced or Metastatic Urothelial Bladder Cancer (Cohort 1)

Study Overview
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Brief Summary
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This Phase II, single-arm study is designed to evaluate the effect of atezolizumab treatment in participants with locally advanced or metastatic urothelial bladder cancer. Participants will be enrolled into 1 of 2 cohorts. Cohort 1 (reported here) will consist of participants who are treatment-naïve and ineligible for cisplatin-containing chemotherapy. Cohort 2 will contain participants who have progressed during or following a prior platinum-based chemotherapy regimen. The results of the second cohort are reported separately (NCT02108652). Participants in both cohorts will be given a 1200 milligrams (mg) intravenous (IV) dose of atezolizumab on Day 1 of 21-day cycles. Treatment of participants in Cohort 1 will continue until disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) or unmanageable toxicity. Treatment of participants in Cohort 2 will continue until loss of clinical benefit or unmanageable toxicity.

Official Title
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A Phase II, Multicenter, Single-Arm Study of Atezolizumab in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, urethra) Representative tumor specimens as specified by the protocol Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Life expectancy greater than or equal to (>=) 12 weeks Measurable disease, as defined by RECIST v1.1 Adequate hematologic and end organ function Cohort 1-Specific Inclusion Criteria No prior chemotherapy for inoperable locally advanced or metastatic or recurrent urothelial carcinoma Ineligible for cisplatin-based chemotherapy due to one of the following: Impaired renal function, a hearing loss of 25 decibels (dB) at two contiguous frequencies, Grade 2 or greater peripheral neuropathy, or ECOG performance score of 2 Exclusion Criteria: Any approved anti-cancer therapy within 3 weeks prior to initiation of study treatment Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment Active or untreated central nervous system (CNS) metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments Leptomeningeal disease Uncontrolled tumor-related pain Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) Uncontrolled hypercalcemia (greater than [>] 1.5 millimoles per liter [mmol/L] ionized calcium or Ca > 12 milligrams per deciliter [mg/dL] or corrected serum calcium > upper limits of normal [ULN]) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab Malignancies other than urothelial bladder cancer within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome or incidental prostate cancer Pregnant and lactating women History of autoimmune disease History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan Serum albumin less than (<) 2.5 grams per deciliter (g/dL) Positive test for human immunodeficiency virus (HIV) and/or active hepatitis B or hepatitis C or tuberculosis Severe infections within 4 weeks prior to Cycle 1, Day 1 Significant cardiovascular disease Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 Prior allogeneic stem cell or solid organ transplant Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4), anti-programmed death-1 receptor (anti-PD-1), and anti-programmed death-ligand 1 (anti-PD-L1) therapeutic antibodies

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Treatment-naive Cisplatin Ineligible Participants<br>Participants with advanced disease who are treatment-naive for advanced urothelial carcinoma and cisplatin ineligible will receive atezolizumab 1200 mg via IV infusion on Day 1 of 21-day cycles until disease progression per RECIST v1.1 criteria or unmanageable toxicity. | Drug: Atezolizumab<br>* Atezolizumab 1200 mg will be given by IV infusion on Day 1 of 21-day cycles until disease progression per RECIST v1.1 criteria or unmanageable toxicity.<br>* Other names: Tecentriq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Confirmed Objective Response of Complete Response (CR) or Partial Response (PR) as Assessed by the Independent Review Facility (IRF) According to RECIST v1.1 | Tumor response was assessed by the IRF according to RECIST v1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm). PR was defined as greater than or equal to (≥) 30 percent (%) decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR. The percentage of participants with a confirmed objective response of CR or PR was reported. The exact 95% confidence interval (CI) was calculated using the Clopper-Pearson method. | Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) as Assessed by the IRF According to RECIST v1.1 | DOR was defined as the time from the initial occurrence of documented CR or PR (whichever occurred first) until documented disease progression or death due to any cause on study, whichever occurred first. Tumor response was assessed by the IRF according to RECIST v1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR. | Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 
| DOR as Assessed by the Investigator According to RECIST v1.1 | DOR was defined as the time from the initial occurrence of documented CR or PR (whichever occurred first) until documented disease progression or death due to any cause on study, whichever occurred first. Tumor response was assessed by the investigator according to RECIST v1.1. CR was defined as disappearance of all target and non-target lesions and no new measurable or unmeasurable lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to Baseline sum LD. | Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 
| Percentage of Participants With Death or Disease Progression as Assessed by the IRF According to RECIST v1.1 | Tumor response was assessed by the IRF according to RECIST v1.1. Disease progression or PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 
| Progression-Free Survival (PFS) as Assessed by the IRF According to RECIST v1.1 | PFS was defined as the time from start of treatment to the first event of death or PD. Tumor response was assessed by the IRF according to RECIST v1.1. Disease progression or PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 
| Percentage of Participants With Death or Disease Progression as Assessed by the Investigator According to RECIST v1.1 | Tumor response was assessed by the investigator according to RECIST v1.1. Disease progression or PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The percentage of participants who died or experienced PD was reported. | Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 
| PFS as Assessed by the Investigator According to RECIST v1.1 | PFS was defined as the time from start of treatment to the first event of death or PD. Tumor response was assessed by the investigator according to RECIST v1.1. Disease progression or PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 
| Percentage of Participants With a Confirmed Objective Response of CR or PR as Assessed by the Investigator According RECIST v1.1 | Tumor response was assessed by the investigator according to RECIST v1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR. The percentage of participants with a confirmed objective response of CR or PR was reported. The exact 95% CI was calculated using the Clopper-Pearson method. | Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 
| Percentage of Participants Who Died | The percentage of participants who died from any cause was reported. | Baseline until death (data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 
| Overall Survival (OS) | OS was defined as the time from start of treatment to the time of death from any cause on study. | Baseline until death (data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 
| Percentage of Participants Alive at 1-year |  | 1-year | 
| Maximum Serum Concentration (Cmax) of Atezolizumab |  | Pre-dose (0 hours) and 30 minutes post-dose on Day 1 of Cycle 1 (Cycle length = 21 days) | 
| Minimum Serum Concentration (Cmin) of Atezolizumab |  | Pre-dose (0 hours) on Day 1 of Cycles 1, 2, 3, 4, 8 (Cycle length = 21 days) | 
| Percentage of Participants Positive for Anti-therapeutic Antibodies (ATA) to Atezolizumab |  | Day 1 of all cycles (Cycle length = 21 days) and at treatment discontinuation (data cutoff date 04 July 2016, up to maximum length of follow-up of 23.52 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-PD-L1, PD-L1, MPDL3280A, PD-1, bladder cancer, atezolizumab, Tecentriq