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

Hoffmann-La Roche1,213 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

1,213

Conditions

Urothelial Carcinoma

Interventions

AtezolizumabDRUG

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.

CarboplatinDRUG

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.

GemcitabineDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (204)

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline until death due to any cause (up to approximately 73 months)

Secondary Outcomes

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.

Time frame: 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

Data from ClinicalTrials.gov

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PlaceboOTHER

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.

CisplatinDRUG

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.

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)

St. Petersburg, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

Parkview Research Center

Fort Wayne, Indiana, United States

...and 194 more locations

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Year 1

PFS Event Free Rate

Progression Free Survival (PFS) Event Free Rate at Year 1

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Up to approximately 73 months

Maximum Atezolizumab Serum Concentration

Maximum atezolizumab serum concentration.

Time frame: Cycle 1 Day 1

Minimum Atezolizumab Serum Concentration

Minimum atezolizumab serum concentration.

Time frame: 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).

Time frame: 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

Time frame: 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 Grade 3-4 Adverse Events (AEs)

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.