Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II, Multicenter, Single-Arm Study of Atezolizumab in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer
Brief Summary: This Phase II, single-arm study is designed to evaluate the effect of atezolizumab treatment in participants with locally advanced or metastatic urothelial bladder cancer. Participants will be enrolled into 1 of 2 cohorts. Cohort 1 will consist of participants who are treatment-naïve and ineligible for cisplatin-containing chemotherapy. The results of Cohort 1 are reported separately (NCT02951767). Cohort 2 (reported here) will contain participants who have progressed during or following a prior platinum-based chemotherapy regimen. Participants in both cohorts will be given a 1200 milligrams (mg) intravenous (IV) dose of atezolizumab on Day 1 of 21-day cycles. Treatment of participants in Cohort 1 will continue until disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) or unmanageable toxicity. Treatment of participants in Cohort 2 will continue until loss of clinical benefit or unmanageable toxicity.


Options:
A: Inclusion Criteria:

* Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
* Age ≥ 18 years at the time of consent.
* ECOG Performance Status (PS) of ≤ 1 within fourteen days of registration for protocol therapy.
* Histological or cytological evidence of urothelial cancer of the bladder, urethra, ureter, or renal pelvis. Differentiation with variant histologies (e.g., squamous cell differentiated) will be permitted provided that the predominant histology is urothelial carcinoma.
* Metastatic and/or unresectable (cT4b) disease
* Must have achieved an objective response (CR/PR) or stable disease (SD) after 4 to 6 cycles of standard first-line platinum-based chemotherapy for mUC (e.g., as per NCCN guidelines). Able to commence study treatment within 2 to 6 weeks of receiving last dose of first-line chemotherapy.
* All subjects must have adequate archival tissue available prior to registration (i.e., at least 20 unstained slides or paraffin block). If acceptable archival tissue is not available, the subject must be willing to consent to providing a core or excisional biopsy for research prior to registration for protocol therapy. If archival tissue is not available and there are no sites amenable to biopsy, enrollment must be discussed with the sponsor-investigator on a case by case basis.
* Female subjects of childbearing potential must have a negative serum pregnancy within three days prior to registration for protocol therapy
* Sexually active, pre-menopausal women of childbearing potential must be willing to use an adequate method of contraception or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study drug. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> one year.
* Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug.

Exclusion Criteria:

* More than one line of prior chemotherapy for metastatic or locally advanced disease, with the following exception:

  * Prior neoadjuvant/adjuvant chemotherapy will not count as line of therapy if completed greater than 12 months prior to initiation of chemotherapy regimen for metastatic or unresectable disease.
* Current or past participation in a study of an investigational agent or using an investigational device within four weeks of registration for protocol therapy.
* A diagnosis of immunodeficiency or is receiving treatment with systemic steroid therapy or any other form of immunosuppressive therapy within seven days prior to registration for protocol therapy.
* Prior chemotherapy, targeted small molecule therapy, or radiation therapy within two weeks prior to registration for protocol therapy. Note: If the subjects have undergone major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting protocol therapy.
* A known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
* A known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to registration for protocol therapy and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least seven days prior to registration for protocol therapy.
* Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Has evidence of active, non-infectious pneumonitis.
* Has a history of interstitial lung disease.
* An active infection requiring systemic therapy.
* A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening period through 120 days after the last dose of protocol therapy.
* Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). Examples include nivolumab, MPDL3280, etc.
* A known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
* A known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
* Receipt of a live vaccine within 30 days prior to registration for protocol therapy.
* Unresolved toxicity (i.e., \> Grade 1 or above baseline) due to previously administered agents. Exception includes: subjects with ≤ Grade 2 neuropathy are eligible for the study.
B: Inclusion Criteria:

* Histologically- or cytologically-confirmed diagnosis of advanced/unresectable (inoperable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell and mixed transitional/non-transitional cell histologies)
* Ineligible for cisplatin therapy
* No prior systemic chemotherapy for metastatic disease (adjuvant or neoadjuvant platinum-based chemotherapy with recurrence \>12 months since completion of therapy is allowed)
* Available tissue from a newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
* Measurable disease
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
* Adequate organ function
* Female participants of childbearing potential have a negative urine or serum pregnancy test; surgically sterile, or willing to use 2 acceptable methods of birth control, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study treatment
* Male participants must be willing to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of study treatment

Exclusion Criteria:

* Disease that is suitable for local therapy administered with curative intent
* Currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study treatment
* Prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to study Day 1 or who has not recovered from adverse events due to agents administered more than 4 weeks earlier
* Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or not recovered from AEs due to a previously administered agent
* Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cancer
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Active autoimmune disease that has required systemic treatment in past 2 years
* Evidence of interstitial lung disease or active non-infectious pneumonitis
* Active infection requiring systemic therapy
* Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study treatment
* Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another co-inhibitory T-cell receptor
* Known human immunodeficiency virus (HIV)
* Known active Hepatitis B or C
* Received a live virus vaccine within 30 days of planned start of study treatment
C: Inclusion Criteria:

* Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, urethra)
* Representative tumor specimens as specified by the protocol
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Life expectancy greater than or equal to (\>=) 12 weeks
* Measurable disease, as defined by RECIST v1.1
* Adequate hematologic and end organ function

Cohort 2-Specific Inclusion Criteria

* Disease progression during or following treatment with at least one platinum-containing regimen (e.g., gemcitabine and cisplatin \[GC\], methotrexate, vinblastine, doxorubicin, and cisplatin \[MVAC\], CarboGem, etc.) for inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence.
* A regimen was defined as participants receiving at least two cycles of a platinum-containing regimen. Participants who had received one cycle of a platinum-containing regimen but discontinued due to Grade 4 hematologic toxicity or Grade 3 or 4 non-hematologic toxicity could also be eligible.
* Participants who received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing adjuvant/neoadjuvant regimen were considered as second-line participants.

Exclusion Criteria:

* Any approved anti-cancer therapy within 3 weeks prior to initiation of study treatment
* Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment
* Active or untreated central nervous system (CNS) metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments
* Leptomeningeal disease
* Uncontrolled tumor-related pain
* Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
* Uncontrolled hypercalcemia (greater than \[\>\] 1.5 millimoles per liter \[mmol/L\] ionized calcium or Ca \> 12 milligrams per deciliter \[mg/dL\] or corrected serum calcium \> upper limits of normal \[ULN\]) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
* Malignancies other than urothelial bladder cancer within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome or incidental prostate cancer
* Pregnant and lactating women
* History of autoimmune disease
* History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
* Serum albumin less than (\<) 2.5 grams per deciliter (g/dL)
* Positive test for human immunodeficiency virus (HIV) and/or active hepatitis B or hepatitis C or tuberculosis
* Severe infections within 4 weeks prior to Cycle 1, Day 1
* Significant cardiovascular disease
* Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1
* Prior allogeneic stem cell or solid organ transplant
* Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1
* Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
* Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4), anti-programmed death-1 receptor (anti-PD-1), and anti-programmed death-ligand 1 (anti-PD-L1) therapeutic antibodies
D: 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

Answer: C