Neoadjuvant Atezolizumab in Localized Bladder Cancer

Inclusion Criteria

• 18 years of age or older
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1
• Histologically document transitional cell carcinoma with the presence of any of the following stages: Carcinoma in situ (CIS), high-grade Ta, any grade T1, or any grade cT2-T4, considered appropriate for radical cystectomy. Subjects with mixed histology are required to have a dominant transitional cell carcinoma (TCC) pattern.
• For subjects with non-muscle-invasive bladder cancer (NMIBC), Bacillus Calmette-Guerin (BCG) -refractory or BCG-resistant disease. BCG-refractory disease is defined as the absence of a complete response by 6 months in patients who have received induction and maintenance OR two induction courses of BCG. BCG-resistant disease is defined as persistent or recurrent disease after 2 induction courses of BCG within 1 year OR cancer recurrence within 1 year of initiation of therapy for patients who have received induction plus maintenance BCG therapy. Subjects with NMIBC must be suitable for and willing to undergo a radical cystectomy at the completion of study therapy.
• For subjects with muscle invasive disease: not suitable neoadjuvant cisplatin-based chemotherapy as determined by the following:
• Creatinine clearance less than 60ml/min. Glomerular filtration rate (GFR) should be assessed by calculation from serum/plasma creatinine (Cockcroft-Gault formula)
• Common Terminology Criteria for Adverse Events (CTCAE) Grade >/= 2 hearing loss
• CTCAE Grade >/= 2 neuropathy
• Subjects with nonmetastatic muscle-invasive bladder cancer (MIBC) not meeting the above criteria are still eligible provided the patient declines neoadjuvant cisplatin-based chemotherapy, after specific informed consent describing the known benefits of cisplatin-based chemotherapy. The reason for declining must be documented.
• Adequate bone marrow function defined as
• White Blood Cell count (WBC) > 2500 cells/mm3
• Absolute Neutrophil Count (ANC) > 1500 cells/mm3
• Hemoglobin > 9 g/dL. Patients may be transfused or receive erythropoietic treatment to meet this criterion.
• Platelet count > 100,000 cells/mm3
• Adequate renal function: Serum creatinine 30ml/min
• Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert's disease)
• aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN)
• Ability to understand and willingness to sign a written informed consent.
• Have available evaluable archival tumor tissue for PD-L1 biomarker assessment. Presence of PD-L1 antigen on tumors is NOT required for study entry.
• The effects of MPDL3280A on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception prior to study entry, during study participation, and for 90 days after study treatment discontinuation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 90 days after completion of study drug administration.

Exclusion Criteria

• Subjects with primary TCC of the ureter, urethra, or renal pelvis without TCC of the bladder are not allowed.
• Known distant metastatic disease (e.g. pulmonary or hepatic metastases).
• Subjects with malignant lymphadenectomy in the abdomen or pelvis considered appropriate for radical cystectomy and lymphadenectomy with the goal of complete resection of all malignant disease are allowed.
• Intravesical chemo- or biologic therapy within 6 weeks of first treatment.
• Prior systemic chemotherapy or radiation therapy for transitional cell carcinoma of the bladder.
• Subjects who have received prior intravesical chemotherapy are allowed.
• Prior treatment with CD137 agonists or immune checkpoint blo