Study of Atezolizumab as Monotherapy and in Combination With Platinum-Based Chemotherapy in Participants With Untreated Locally Advanced or Metastatic Urothelial Carcinoma
- Conditions
- Urothelial Carcinoma
- Interventions
- Registration Number
- NCT02807636
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
A Phase III, randomised study of atezolizumab alone and in combination with chemotherapy versus chemotherapy alone in participants with untreated advanced urothelial cancer.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1213
Not provided
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Gemcitabine Participants will receive blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Cisplatin Participants will receive blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). Placebo+Gemcitabine+Carboplatin/Cisplatin Carboplatin Participants will receive blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). Placebo+Gemcitabine+Carboplatin/Cisplatin Placebo Participants will receive blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). Atezolizumab Monotherapy Atezolizumab Eligible participants will receive open-label atezolizumab as monotherapy. Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Participants will receive blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Carboplatin Participants will receive blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). Placebo+Gemcitabine+Carboplatin/Cisplatin Gemcitabine Participants will receive blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). Placebo+Gemcitabine+Carboplatin/Cisplatin Cisplatin Participants will receive blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
- Primary Outcome Measures
Name Time Method Investigator Assessed Progression-Free Survival (PFS) in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm Baseline up to first documented disease progression or death, whichever occurs first (up to approximately 35 months) 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.
Overall Survival (OS) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Baseline until death due to any cause (up to approximately 73 months) OS is defined as the time from randomization to death due to any cause.
Overall Survival (OS) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Baseline until death due to any cause (up to approximately 73 months) OS is defined as the time from randomization to death due to any cause.
- Secondary Outcome Measures
Name Time Method OS Event Free Rate Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Year 1 Overall Survival (OS) Event Free Rate at 1 Year.
Objective Response Rate (ORR) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months) 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.
Objective Response Rate (ORR) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months) 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.
Duration of Response (DOR) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm 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) 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.
Duration of Response (DOR) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm 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) 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.
IRF-PFS Randomization to first documented disease progression or death from any cause (up to 35 months) 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.
OS Event Free Rate in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Year 1 Overall Survival (OS) Event Free Rate at 1 Year.
PFS Event Free Rate Year 1 Progression Free Survival (PFS) Event Free Rate at 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 Up to approximately 73 months 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.
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 Up to approximately 73 months 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.
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 Up to approximately 73 months 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.
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 Up to approximately 73 months Median time to deterioration in physical function as measured by the QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab Monotherapy Arm.
Maximum Atezolizumab Serum Concentration Cycle 1 Day 1 Maximum 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 Minimum atezolizumab serum concentration.
Percentage of Participants With Anti-Therapeutic (Anti-Atezolizumab) Antibodies (ATAs) Up to approximately 35 months Percentage of participants with Anti-Therapeutic (Anti-Atezolizumab) Antibodies (ATAs).
Investigator-Assessed Progression-Free Survival (INV-PFS) in Participants Treated With Atezolizumab Monotherapy Arm Compared With Placebo+Gemcitabine+Carboplatin/Cisplatin Arm 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) 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.
Percentage of Participants With Grade 3-4 Adverse Events (AEs) Baseline up to 93 months Percentage of participants with Grade 3-4 Adverse Events (AEs) assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Percentage of Participants With Grade 5 Adverse Events (AEs) Baseline up to 93 months Percentage of participants with Grade 5 Adverse Events (AEs) assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Percentage of Participants With Serious Adverse Events (SAEs) Baseline up to 93 months Percentage of participants with Serious Adverse Events (SAEs) assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Percentage of Participants With Adverse Events (AEs) Leading to Withdrawal of Any Study Treatment Baseline up to 93 months Percentage of participants with Adverse Events (AEs) leading to withdrawal of any study treatment assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Percentage of Participants With Atezolizumab-Specific Adverse Events of Special Interest (AESIs) Baseline up to 93 months Percentage of participants with atezolizumab-specific Adverse Events of Special Interest (AESIs) Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Trial Locations
- Locations (204)
Highlands Oncology Group
🇺🇸Rogers, Arkansas, United States
Coastal Integrative Cancer Care
🇺🇸San Luis Obispo, California, United States
Yale School of Medicine
🇺🇸New Haven, Connecticut, United States
Norwalk Hospital
🇺🇸Norwalk, Connecticut, United States
Christina Care Institutional Review Board
🇺🇸Newark, Delaware, United States
Florida Cancer Specialists
🇺🇸Fort Myers, Florida, United States
UF Health Cancer Center at Orlando Health
🇺🇸Orlando, Florida, United States
Florida Cancer Specialists (St. Petersburg ? St. Anthony?s Professional Building)
🇺🇸Saint Petersburg, Florida, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Parkview Research Center
🇺🇸Fort Wayne, Indiana, United States
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