Study of Atezolizumab as Monotherapy and in Combination With Platinum-Based Chemotherapy in Participants With Untreated Locally Advanced or Metastatic Urothelial Carcinoma

Study Overview
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Brief Summary
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A Phase III, randomised study of atezolizumab alone and in combination with chemotherapy versus chemotherapy alone in participants with untreated advanced urothelial cancer.

Official Title
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A Phase III, Multicenter, Randomized, Placebo-Controlled Study of Atezolizumab (Anti-PD-L1 Antibody) as Monotherapy and in Combination With Platinum-Based Chemotherapy in Patients With Untreated Locally Advanced or Metastatic Urothelial Carcinoma

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Carboplatin
* Drug: Gemcitabine
* Other: Placebo
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Considered to be eligible to receive platinum-based chemotherapy, in the investigator's judgment Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to (</=) 2 Histologically documented, locally advanced (T4b, any N; or any T, N2-3) or metastatic urothelial carcinoma (mUC) (M1, Stage IV) (also termed transitional cell carcinoma [TCC] or urothelial cell carcinoma [UCC] of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra) Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens 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 PD-L1 expression prior to study enrollment; participants who have fewer than 15 unstained slides available at baseline (but no less than [<] 10) may be eligible following discussion with the Medical Monitor No prior chemotherapy for inoperable locally advanced or mUC For participants who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval more than (>) 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment naive in the metastatic setting Prior local intravesical chemotherapy or immunotherapy is allowed if completed at least 4 weeks prior to the initiation of study treatment Measurable disease, as defined by RECIST v1.1 Adequate hematologic and end-organ function For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 6 months after the last dose of carboplatin, cisplatin, or gemcitabine or for 5 months after the last dose of atezolizumab For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm Exclusion Criteria: Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to enrolment Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic resonance imaging evaluation during screening and prior radiographic assessments Participants with treated asymptomatic central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria: * Evaluable or measurable disease outside the CNS * No metastases to midbrain, pons, medulla, or within 10 mm of the optic apparatus (optic nerves and chiasm) * No history of intracranial or spinal cord hemorrhage * No ongoing requirement for corticosteroid as therapy for CNS disease; anti-convulsants at a stable dose are allowed * No evidence of significant vasogenic edema * No stereotactic radiation, whole-brain radiation or neurosurgical resection within 4 weeks prior to Cycle 1, Day 1 * Radiographic demonstration of interim stability (i.e., no progression) between the completion of CNS-directed therapy and the screening radiographic study * Screening CNS radiographic study >/=4 weeks since completion of radiotherapy or surgical resection and >/=2 weeks since discontinuation of corticosteroids Prior treatment with CD137 agonists, anti-CTLA-4, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to Cycle 1, Day 1 or anticipated requirement for systemic immunosuppressive medications during the study Leptomeningeal disease Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) Uncontrolled tumour-related pain or hypercalcemia Significant cardiovascular disease including known left ventricular ejection fraction (LVEF) <40% Severe infections within 4 weeks before randomization or therapeutic oral or IV antibiotics within 2 weeks before randomization Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis Malignancies other than urothelial carcinoma within 5 years prior to Cycle 1, Day 1 Life expectancy of <12 weeks Pregnant or lactating, or intending to become pregnant during the study Serum albumin <25 gram per liter (g/L) History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation History of autoimmune disease Participants with prior allogeneic stem cell or solid organ transplantation History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan Positive test for human immunodeficiency virus (HIV) Active hepatitis B or hepatitis C Active tuberculosis Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab+Gemcitabine+Carboplatin/Cisplatin<br>Participants will receive blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). | Drug: Atezolizumab<br>* Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) by intravenous (IV) infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1. In specific circumstances treatment may continue beyond disease progression.<br>* Other names: Tecentriq;Drug: Carboplatin<br>* Carboplatin will be administered at doses to achieve area under the concentration-time curve (AUC) of 4.5 milligram per milliliter into minute (mg/mL*min) by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered at a dose of 1000 milligrams per square meter (mg/m^2) by IV infusion on Day 1 and Day 8 of each 21-day cycle, until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.<br>Drug: Cisplatin<br>* Cisplatin will be administered at a dose of 70 mg/m^2 by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.<br>|
| Placebo Comparator: Placebo+Gemcitabine+Carboplatin/Cisplatin<br>Participants will receive blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). | Drug: Carboplatin<br>* Carboplatin will be administered at doses to achieve area under the concentration-time curve (AUC) of 4.5 milligram per milliliter into minute (mg/mL*min) by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered at a dose of 1000 milligrams per square meter (mg/m^2) by IV infusion on Day 1 and Day 8 of each 21-day cycle, until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.<br>Other: Placebo<br>* Placebo matched to atezolizumab will be administered by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1. In specific circumstances treatment may continue beyond disease progression.<br>Drug: Cisplatin<br>* Cisplatin will be administered at a dose of 70 mg/m^2 by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.<br>|
| Experimental: Atezolizumab Monotherapy<br>Eligible participants will receive open-label atezolizumab as monotherapy. | Drug: Atezolizumab<br>* Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) by intravenous (IV) infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1. In specific circumstances treatment may continue beyond disease progression.<br>* Other names: Tecentriq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator Assessed Progression-Free Survival (PFS) in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm | PFS is defined as the time from randomization to the first documented disease progression as determined by the investigator with the use of RECIST v1.1, or death from any cause, whichever occurs first. | Baseline up to first documented disease progression or death, whichever occurs first (up to approximately 35 months) | 
| Overall Survival (OS) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm | OS is defined as the time from randomization to death due to any cause. | Baseline until death due to any cause (up to approximately 73 months) | 
| Overall Survival (OS) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm | OS is defined as the time from randomization to death due to any cause. | Baseline until death due to any cause (up to approximately 73 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm | Objective response rate (ORR) is defined as the proportion of participants with a confirmed objective response, either complete response (CR) or partial response (PR), observed on two assessments >= 28 days apart per RECIST v1.1, based on investigator assessment. The analysis population for ORR will be all randomized participants with measurable disease at baseline. | Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months) | 
| Objective Response Rate (ORR) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm | Objective response rate (ORR) is defined as the proportion of participants with a confirmed objective response, either complete response (CR) or partial response (PR), observed on two assessments >= 28 days apart per RECIST v1.1, based on investigator assessment. The analysis population for ORR will be all randomized participants with measurable disease at baseline. | Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months) | 
| Duration of Response (DOR) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm | Duration of response (DOR) is defined for participants with an objective response as the time from the first documented objective response to documented disease progression per RECIST v1.1, based on investigator assessment, or death due to any cause, whichever occurs first. | From first documented objective response (CR or PR) to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months) | 
| Duration of Response (DOR) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm | Duration of response (DOR) is defined for participants with an objective response as the time from the first documented objective response to documented disease progression per RECIST v1.1, based on investigator assessment, or death due to any cause, whichever occurs first. | From first documented objective response (CR or PR) to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months) | 
| IRF-PFS | Independent review facility PFS (IRF-PFS) is defined as the time from randomization to the first documented disease progression as determined by blinded independent central review with use of RECIST v1.1, or death due to any cause, whichever occurs first. | Randomization to first documented disease progression or death from any cause (up to 35 months) | 
| OS Event Free Rate Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm | Overall Survival (OS) Event Free Rate at 1 Year. | Year 1 | 
| OS Event Free Rate in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm | Overall Survival (OS) Event Free Rate at 1 Year. | Year 1 | 
| PFS Event Free Rate | Progression Free Survival (PFS) Event Free Rate at Year 1 | Year 1 | 
| Time to Deterioration in Global Health Status as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm | Time to deterioration in global health status as measured by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm. | Up to approximately 73 months | 
| Time to Deterioration in Global Health Status as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab Monotherapy Arm | Time to deterioration in global health status as measured by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 in the Placebo+Chemo Arm versus Atezolizumab Monotherapy Arm. | Up to approximately 73 months | 
| Time to Deterioration in Physical Function as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm | Median time to deterioration in physical function as measured by the QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm. | Up to approximately 73 months | 
| Time to Deterioration in Physical Function as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab Monotherapy Arm | Median time to deterioration in physical function as measured by the QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab Monotherapy Arm. | Up to approximately 73 months | 
| Maximum Atezolizumab Serum Concentration | Maximum atezolizumab serum concentration. | Cycle 1 Day 1 | 
| Minimum Atezolizumab Serum Concentration | Minimum atezolizumab serum concentration. | Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 8 Day 1, Cycle 16 Day 1, Cycle 24 Day 1, Cycle 32 Day 1, Day 120 post dose of last blinded atezolizumab treatment, and study drug early discontinuation | 
| Percentage of Participants With Anti-Therapeutic (Anti-Atezolizumab) Antibodies (ATAs) | Percentage of participants with Anti-Therapeutic (Anti-Atezolizumab) Antibodies (ATAs). | Up to approximately 35 months | 
| Investigator-Assessed Progression-Free Survival (INV-PFS) in Participants Treated With Atezolizumab Monotherapy Arm Compared With Placebo+Gemcitabine+Carboplatin/Cisplatin Arm | PFS is defined as the time from randomization to the first documented disease progression as determined by the investigator with the use of RECIST v1.1, or death from any cause, whichever occurs first. | Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (assessed at baseline, every 9 weeks for 54 weeks and every 12 weeks thereafter up to 35 months) | 
| Percentage of Participants With Adverse Events (AEs) Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 |  | Baseline up to 90 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urothelial carcinoma, Bladder cancer, Anti-PD-L1, Transitional carcinoma, Tecentriq, Atezolizumab, IMvigor130