Atezolizumab and CYT107 in Treating Participants With Locally Advanced, Inoperable, or Metastatic Urothelial Carcinoma

Inclusion Criteria:

• Patients must have histologically or cytologically documented locallyadvanced/inoperable or metastatic urothelial bladder carcinoma (UBC), includingrenal pelvis, ureters, urinary bladder, and urethra

• Note: Mixed histology tumors allowed if predominant histology is urothelialcarcinoma

• Note: Small cell or neuroendocrine carcinoma is not allowed if predominant

• Patients must have recurrent disease after any prior platinum-based chemotherapyregimen

• Patients must have measurable disease per RECIST 1.1 assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI)

• ECOG performance status =< 2 (Karnofsky >= 60%)

• Patients must have a life expectancy of greater or equal to 12 weeks

• Leukocytes >= 2,500/mcL

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 8 g/dL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however,patients with known Gilbert's disease who have serum bilirubin level =< 3 x ULN maybe enrolled)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (AST and/or ALT=< 5 x ULN for patients with liver involvement)

• Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liverinvolvement or bone metastases)

• Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault

• At the discretion of the treating physician, a 24-hour urine creatinineclearance could be obtained and utilized as the gold standard if creatinineclearance by Cockcroft-Gault is < 30, and prevents patient enrollment on thetrial

• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (this applies only to patients who do not receive therapeuticanticoagulation; patients receiving therapeutic anticoagulation, such aslow-molecular-weight heparin or warfarin, should be on a stable dose)

• Patients must provide tissue from an archival tumor sample (obtained within 2 yearsfrom screening visit) or newly obtained core, punch, or excisional biopsy of a tumorlesion if deemed relatively safe and technically feasible

• Female patients of childbearing potential must have a negative urine or serumpregnancy test within 72 hours before receiving the first dose of study agent(s); ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required;

• Administration of atezolizumab may have an adverse effect on pregnancy andposes a risk to the human fetus, including embryo-lethality; CYT107 has notbeen tested for reproductive toxicity yet and may expose to the same risk;women of child-bearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) beforestudy entry, for the duration of study participation, and for 5 months (150days) after the last dose of study agent; should a woman become pregnant orsuspect she is pregnant while she or her partner is participating in thisstudy, she should inform her treating physician immediately

• Patients must have the ability to understand and the willingness to sign a writteninformed consent document

• Patients positive for human immunodeficiency virus (HIV) are allowed on study, butHIV-positive patients must have:

• A stable regimen of highly active antiretroviral therapy (HAART)

• No requirement for concurrent antibiotics or antifungal agents for theprevention of opportunistic infections

• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standardpolymerase chain reaction (PCR)-based tests

Exclusion Criteria:

• Patients with prior allogeneic bone marrow transplantation or prior solid organtransplantation

• Patients who have had chemotherapy or radiotherapy within 2 weeks (4 weeks fornitrosoureas or systemic mitomycin C) before the initiation of study treatment

• Patients who have received more than 2 systemic cytotoxic chemotherapy regimens formetastatic urothelial carcinoma

• Note: Prior perioperative chemotherapy is allowed and is not counted as a lineof therapy if patient relapsed >= 12 months later and received additionalplatinum-based chemotherapy for metastatic disease

• Patients who have not recovered from adverse events (other than alopecia) due toagents administered more than 4 weeks earlier (i.e., have residual toxicities >grade 1); however, the following therapies are allowed:

• Hormone-replacement therapy or oral contraceptives

• Herbal therapy >= 1 week before initiation of study treatment (herbal therapyintended as anticancer therapy must be discontinued at least 1 week beforeinitiation of study treatment)

• Palliative radiotherapy for bone metastases > 2 weeks before initiation ofstudy treatment

• Patients who have received prior treatment with anti-PD-1, or anti-PD-L1 therapeuticantibody, or pathway -targeting agents

• Patients who have received prior treatment with anti-CTLA-4 may be enrolled,provided the following requirements are met:

• Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks fromthe last dose

• No history of severe immune-related adverse effects from anti-CTLA-4 (National Cancer Institute [NCI] Common Terminology Criteria for AdverseEvents [CTCAE] grade 3 and 4)

• Patients who have received treatment with any other investigational agent within 4weeks before initiation of study treatment

• Patients who have received treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks before initiation of study treatment

• Patients who have received treatment with systemic immunosuppressive medications (including, but not limited to, oral prednisone ( > 10 mg/day or equivalent),cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosisfactor [anti TNF] agents) within 2 weeks before initiation of study treatment

• Patients who have received acute, low dose, systemic immunosuppressantmedications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled

• The use of inhaled corticosteroids, and mineralocorticoids (e.g.,fludrocortisone) for patients with orthostatic hypotension or adrenocorticalinsufficiency is allowed

• Patients taking bisphosphonate therapy for symptomatic hypercalcemia

• Note: Use of bisphosphonate therapy for other reasons (e.g., bone metastasis orosteoporosis) is allowed

• Patients with known primary central nervous system (CNS) malignancy or symptomaticCNS metastases are excluded, with the following exceptions:

• Patients with asymptomatic untreated CNS disease may be enrolled, provided allof the following criteria are met:

• Evaluable or measurable disease outside the CNS

• No metastases to brain stem, midbrain, pons, medulla, cerebellum, orwithin 10 mm of the optic apparatus (optic nerves and chiasm)

• No history of intracranial hemorrhage or spinal cord hemorrhage

• No ongoing requirement for dexamethasone for CNS disease; patients on astable dose of anticonvulsants are permitted

• No neurosurgical resection or brain biopsy within 28 days beforeinitiation of study treatment

• Patients with asymptomatic treated CNS metastases may be enrolled, provided allthe criteria listed above are met as well as the following:

• Radiographic demonstration of improvement upon the completion of CNSdirected therapy and no evidence of interim progression between thecompletion of CNS directed therapy and the screening radiographic study

• No stereotactic radiation or whole-brain radiation within 28 days beforeinitiation of study treatment

• Screening CNS radiographic study >= 4 weeks from completion ofradiotherapy and >= 2 weeks from discontinuation of corticosteroids

• Note: Patients with CNS metastases enrolled on trial must also have a brain MRIimaging at all standard radiologic evaluation timepoints

• Patients with known hypersensitivity to Chinese hamster ovary cell products or otherrecombinant human antibodies

• Patients who have a history of severe allergic, anaphylactic, or otherhypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

• Patients with known clinically significant liver disease, including active viral,alcoholic, or other hepatitis; cirrhosis; fatty liver/nonalcoholic fatty liverdisease (NAFLD)/nonalcoholic steatohepatitis (NASH); and inherited liver disease

• Patients with past or resolved hepatitis B infection (defined as having anegative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible

• Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction is negative for HCV ribonucleic acid (RNA)

• Patients with active underlying autoimmune disease requiring systemicimmunosuppressive medication (oral prednisone > 10 mg/day or equivalent). Topical,inhaled, or intra-articular steroids or physiologic endocrine replacement (insulin,levothyroxine, etc.) are permitted. Patients with a history of autoimmune diseasethat is not currently active require consultation with the protocol principalinvestigator (PI) and/or Cancer Immunotherapy Trials Network (CITN) CoordinatingCenter

• Patients who have a history of idiopathic pulmonary fibrosis, pneumonitis (includingdrug induced), organizing pneumonia (bronchiolitis obliterans, cryptogenicorganizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CTscan; history of radiation pneumonitis in the radiation field (fibrosis) ispermitted

• Patients who have known additional malignancies other than UBC within 2 years beforeinitiation of study treatment; exceptions include malignancies with a negligiblerisk of metastasis or death and treated with expected curative outcome (e.g.,non-melanomatous skin cancers), or localized prostate cancer treated with curativeintent and absence of prostate-specific antigen (PSA) relapse or incidental prostatecancer

• Patients with active tuberculosis (TB)

• Patients who have leptomeningeal disease

• Patients who have severe infections within 4 weeks before initiation of studytreatment, including, but not limited to, hospitalization for complications ofinfection, bacteremia, or severe pneumonia;

• Exception: Uncomplicated urinary tract infection will not be considered as asevere infection in these patients

• Patients who have signs or symptoms of infection within 2 weeks before initiation ofstudy treatment

• Patients who have received oral or IV antibiotics within 2 weeks before initiationof study treatment; patients receiving prophylactic antibiotics (e.g., forprevention of a urinary tract infection or chronic obstructive pulmonary disease)are eligible

• Patients who have major surgical procedure, other than for diagnosis, within 28 daysbefore initiation of study treatment or anticipation of need for a major surgicalprocedure during the course of the study

• Patients who have had a live, attenuated vaccine within 4 weeks before initiation ofstudy treatment or anticipation that such a live, attenuated vaccine will berequired during the study and up to 5 months after the last dose of atezolizumab.

• Influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuatedinfluenza vaccine within 4 weeks before initiation of study treatment or at anytime during the study

• Uncontrolled intercurrent illness including, but not limited to, symptomaticcongestive heart failure (New York Heart Association class III or IV), unstableangina pectoris, cardiac arrhythmia, recent myocardial infarction (within the last 6months), or psychiatric illness/social situations that would limit compliance withstudy requirements

• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) fortreatment of either a psychiatric or medical (e.g., infectious) illness