A Study of Atezolizumab Versus Observation as Adjuvant Therapy in Participants With High-Risk Muscle-Invasive Urothelial Carcinoma (UC) After Surgical Resection

Study Overview
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Brief Summary
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This Phase III, open-label, randomized, multicenter study is to evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared with observation in participants with muscle-invasive UC who are at high risk for recurrence following resection. Eligible participants were randomized by a 1:1 ratio into atezolizumab group or control group.

Official Title
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A Phase III, Open-Label, Multicenter, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Versus Observation as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Urothelial Carcinoma After Surgical Resection

Conditions
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Carcinoma, Transitional Cell

Intervention / Treatment
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* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed muscle-invasive UC (also termed transitional cell carcinoma) of the bladder or upper urinary tract (i.e., renal pelvis or ureters) For participants treated with prior neoadjuvant chemotherapy: tumor stage of ypT2-4a or ypN+ (ypT2-4 or ypN+ for participants with upper urinary tract UC) and M0 For participants who have not received prior neoadjuvant chemotherapy: tumor stage of pT3-4a or pN+ (pT3-4 or pN+ for participants with upper urinary tract UC) and M0 Representative formalin-fixed paraffin-embedded tumor specimens from surgical resection (i.e., radical cystectomy, nephroureterectomy, or lymph node dissection) in paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to be evaluable for tumor programmed death-ligand 1 (PD-L1) expression prior to study enrollment Absence of residual disease and absence of metastasis, as confirmed by a negative baseline computed tomography (CT) or magnetic resonance imaging scan of the pelvis, abdomen, and chest no more than 4 weeks prior to randomization Full recovery from cystectomy or nephroureterectomy within 14 weeks following surgery Eastern Cooperative Oncology Group performance status of less than or equal to (</=) 2 Life expectancy greater than or equal to (>/=) 12 weeks Adequate hematologic and end-organ function For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use contraceptive methods that result in a failure rate of less than (<) 1 percent (%) per year during the treatment period and for at least 5 months after the last dose of atezolizumab Exclusion Criteria: Any approved anti-cancer therapy within 3 weeks prior to initiation of study treatment Adjuvant chemotherapy or radiation therapy for UC following surgical resection Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or five half-lives of the drug prior to enrollment Malignancies other than UC within 5 years prior to Cycle 1, Day 1 Pregnancy or breastfeeding Significant cardiovascular disease Severe infections within 4 weeks prior to Cycle 1, Day 1 Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation History of autoimmune disease Prior allogeneic stem cell or solid organ transplant History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan Positive test for human immunodeficiency virus and/or active hepatitis B or hepatitis C or tuberculosis Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1 Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, including anti-CD40, anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab<br>Participants will receive intravenous (IV) atezolizumab on Day 1 of each 21-day cycle for 16 cycles (up to 1 year). | Drug: Atezolizumab<br>* Atezolizumab will be administered at a dose of 1200 milligrams (mg).<br>* Other names: TECENTRIQ®; MPDL3280A;|
| No Intervention: Observation<br>Participants will undergo observation starting on Day 1 for 16 cycles (up to 1 year). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS), as Assessed by Investigator | DFS is defined as the time from randomization to the time of first occurrence of a DFS event. DFS events include: local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes); urinary tract recurrence of UC (including all pathological stages and grades); distant metastasis of UC; or death from any cause. Tumor assessment will be performed using radiographic evaluations. | Randomization up to first occurrence of DFS event (up to approximately 50 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is defined as the time from randomization to the date of death from any cause, regardless of whether the death occurs during study treatment or following treatment discontinuation. | Randomization until death due to any cause (up to approximately 80 months) | 
| Disease-Specific Survival (DSS), as Assessed by Investigator | DSS is defined as the time from randomization until the date of death from UC. | Randomization until death due to UC (up to approximately 50 months) | 
| Distant Metastasis-Free Survival (DMFS) | DMFS is defined as the time from randomization to the date of diagnosis of distant (that is, non-locoregional) metastases or death from any cause. Tumor assessment will be performed using radiographic evaluations. | Randomization up to diagnosis of distant metastases or death from any cause (up to approximately 50 months) | 
| Non-Urinary Tract Recurrence-Free Survival (NURFS) | NURFS is defined as the time from randomization to the time of first occurrence of a NURFS event. NURFS events include: local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes); distant metastasis of UC; or death from any cause. Tumor assessment will be performed using radiographic evaluations. | Randomization up to time of first occurrence of a NURFS event (up to approximately 50 months) | 
| Percentage of Participants With Adverse Events (AEs) | Percentage of participants with at least one Adverse Event. | Screening up to approximately 80 months | 
| Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab | Percentage of participants with anti-therapeutic antibodies to atezolizumab. | Baseline up to approximately 50 months | 
| EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | The EQ-5D-5L is a generic preference-based HRQoL questionnaire that provides a single index value for health status and is used to inform pharmacoeconomic evaluations and to measure general health status. Visual analog scale (VAS) allows the patient to indicate, on a scale of 0-100, how his or her health is on the day of assessment, with 100 being the best imaginable health state and 0 being the worst imaginable health state. | Day 1 of Cycle 1 up to approximately 50 months (Cycle length = 21 days) | 
| Minimum Observed Serum Atezolizumab Concentration (Cmin) | Minimum observed serum atezolizumab concentration (Cmin) prior to infusion on Day 1 of Cycles 1, 2, 3, and 4; every 8 cycles starting on Cycle 8; at treatment discontinuation; and at 120 days after the last dose of atezolizumab. | Pre-dose (Hour 0) on Day 1 of Cycles 1, 2, 3, 4, every 8 cycles from Cycle 8, at treatment discontinuation, 120 days after treatment discontinuation (up to approximately 50 months))(Cycle length = 21 days) | 
| Maximum Observed Serum Atezolizumab Concentration (Cmax) | Maximum observed serum atezolizumab concentration (Cmax) after infusion on Day 1 of Cycle 1. | Day 1 of Cycle 1 (Cycle length = 21 days) |