Study of Atezolizumab as Monotherapy and in Combination With Platinum-Based Chemotherapy in Participants With Untreated Locally Advanced or Metastatic Urothelial Carcinoma
Condition: Urothelial Carcinoma
MeSH terms: Carcinoma; Carcinoma, Transitional Cell
Intervention: Atezolizumab; Carboplatin; Gemcitabine; Placebo; Cisplatin
Intervention description: 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.; 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.; 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.; 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.; 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.
Intervention MeSH terms: Carboplatin; Gemcitabine; Atezolizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 1213.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Urothelial carcinoma; Bladder cancer; Anti-PD-L1; Transitional carcinoma; Tecentriq; Atezolizumab; IMvigor130

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

Eligibility criteria:

        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