Sacituzumab Govitecan With or Without Atezolizumab Immunotherapy in Rare Genitourinary Tumors (SMART) Such as High Grade Neuroendocrine Carcinomas, Adenocarcinoma, and Squamous Cell Bladder/Urinary Tract Cancer, Renal Medullary Carcinoma and Penile C...

• INCLUSION CRITERIA:

• Participants must have histologically confirmed diagnosis of a locally advancedunresectable or metastatic non-prostate genitourinary (GU) tumor of the followinghistologies:

• HGNEC, including, but not limited to, small cell carcinoma and large cellneuroendocrine carcinoma of the bladder or urinary tract

• Squamous cell carcinoma of the bladder or urinary tract

• Primary adenocarcinoma of the bladder or urinary tract (urachal or non-urachal)

• Renal medullary carcinoma

• Squamous cell carcinoma of the penis

Note: For the purposes of enrollment, the urinary tract is defined as the renal pelvis, ureter, bladder, and urethra.

• Pre-study treatment tissue availability (sufficient tissue for approximately 25unstained slides is mandatory for enrollment. If tissue is determined to beinsufficient/unsuitable, a fresh biopsy prior to study therapy will be required.

• Locally advanced unresectable or metastatic disease. Participants who have receivedprior treatment must have evidence of progressive disease (PD; i.e., defined as newor progressive lesions evident on cross-sectional imaging).

• Participants must have measurable disease, per RECIST 1.1.

• Age >= 18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status <= 1 (Karnofsky >= 70%.

• Adequate organ and marrow function as defined below:

• Hemoglobin (Hgb) >= 9.0 g/dL

• Absolute neutrophil count (ANC) >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin <= 1.5 x upper limit of normal (ULN) (<= 3 x ULN inparticipants with known/suspected Gilbert s disease)

• AST/ ALT <= 2.5 x ULN (or <= 5 x ULN if considered to be related to livermetastases by the PI)

• Serum creatinine <= 2 x ULN or creatinine clearance >= 30 ml/min/1.73 m^2 (glomerular filtration rate [GFR] may be used in place of CrCl. Creatinineclearance or eGFR should be calculated per institutional standard)

• Alkaline phosphatase <= 2.5 x ULN (or <= 5 x ULN if considered to be related toliver or bone metastases by the PI)

• Serum albumin >= 25g/L

• For participants not receiving therapeutic anticoagulation: internationalnormalized ratio (INR) or activated partial thromboplastin time (aPTT) <= 1.5 xULN

• For participants receiving therapeutic anticoagulation: stable anticoagulantregimen

• Participants may have received any number of prior anti-cancer treatments or betreatment na(SqrRoot) ve (except for participants with HGNEC of the bladder/urinarytract cancer, whom must have received a platinum-based combination regimen either asneoadjuvant, adjuvant or first-line treatment in the locally advanced/metastaticsetting).

• Treated central nervous system (CNS) lesions, provided that all of the followingcriteria are met:

• Measurable disease, per RECIST v1.1, must be present outside the CNS.

• The participant has no history of intracranial hemorrhage or spinal cordhemorrhage.

• The participant has not undergone stereotactic radiotherapy within 1 week priorto initiation of study treatment, whole-brain radiotherapy (WBXRT) within 2weeks prior to initiation of study treatment, or neurosurgical resection within 4 weeks prior to initiation of study treatment.

• The participant has no ongoing requirement for corticosteroids as therapy forCNS disease.

• The participant may be receiving anti-convulsant therapy if appropriate and thedose is considered stable.

Prior treatment as follows:

• Prior radionuclide treatment must have a washout period of at least 6 weeks prior tothe first dose of study treatment.

• Prior treatment with chemotherapy must have a washout period of 2 weeks prior to thefirst dose of study treatment.

• Prior treatment with non-CNS-directed radiotherapy must have a washout period of 2weeks prior to the first dose of study treatment (except palliative bone-directedradiotherapy which does not require any washout).

• Prior treatment with a small molecule kinase inhibitor must have a washout period ofat least 2 weeks or five half-lives of the compound or active metabolites, prior tothe first dose of study treatment.

• Prior treatment with systemic immunostimulatory agents (including, but not limitedto, interferon and interleukin 2 [IL-2]) must have a washout period of at least 4weeks or 5 half-lives of the drug (whichever is longer) prior to the first dose ofstudy treatment.

• Major surgical procedure, other than for diagnosis, must not occur within 4 weeksprior to the first dose of study treatment.

• Prior treatment with systemic immunosuppressive medication (including, but notlimited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate,thalidomide, and anti-TNF-alpha agents) must have a washout period of at least 2weeks prior to initiation of study treatment or anticipation of need for systemicimmunosuppressive medication during study treatment, with the following exceptions:

• Participants who received acute, low-dose systemic immunosuppressant medicationor a one-time pulse dose of systemic immunosuppressant medication (e.g., 48hours of corticosteroids for a contrast allergy) are eligible for the study.

• Participants who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenal insufficiencyare eligible for the study.

• FDA-approved hormonal therapy for the treatment or prevention of other malignancies (e.g., breast cancer, prostate cancer) are allowed to be continued where in theopinion of the treating investigator stopping such therapies may increase the riskof disease progression. Potential drug-drug interactions with the hormonal agentwill be assessed by the treating investigator prior to enrollment and hormonalagents that inhibit or induce UGT1A1 will be excluded while on trial.

• Human immunodeficiency virus (HIV)-infected participants are eligible if on stabledose of highly active antiretroviral therapy (HAART), a CD4 count >= 200cells/microL, and an undetectable viral load.

• Hepatitis B virus (HBV) positive participants are eligible if they have been treatedor are on an appropriate course of antivirals at study entry and with plannedmonitoring and management according to appropriate guidance. For previously treatedpatients or those with prior infection that has been cleared, prophylaxis ispermitted, and hepatology consultation recommended.

• Participants with a history of hepatitis C virus (HCV) infection (i.e., positive HCVantibody test) must have been treated and cured (negative HCV RNA test atscreening). Participants with HCV infection who are currently on treatment areeligible if they have an undetectable HCV viral load.

• Individuals of child-bearing potential (IOCBP) and individuals able to father achild must agree to use an effective method of contraception as follows:

• IOCBP must agree to use one (1) highly effective methods of contraception (e.g., intrauterine device [IUD], hormonal, surgical sterilization) prior tostudy entry, for the duration of study participation, and for up to 6 monthsafter discontinuation of the study drug(s). Participants must refrain fromdonating eggs during this same period.

• Individuals able to father children must agree to use an effective method ofcontraception (barrier, surgical sterilization) for the duration of the studytreatment and up to 6 months after the last dose of the study drug(s) and mustrefrain from donating sperm during this same period.

• Nursing participants must discontinue nursing and/or not begin nursing until 1 monthafter the last dose of study drug(s).

• Ability of participants to understand and the willingness to sign a written informedconsent document.

EXCLUSION CRITERIA:

• History of severe hypersensitivity or allergic reactions attributed to compounds ofsimilar chemical or biologic composition to SG, SN-38, irinotecan, or atezolizumab,or hypersensitivity to Chinese hamster ovary cell products.

• Symptomatic or untreated brain/CNS metastases.

• Positive serum or urine Beta-human chorionic gonadotropin (Beta-hCG) test atscreening.

• Participants unwilling to accept blood products as medically indicated.

• Active or history of autoimmune disease or immune deficiency that might recur, whichmight affect vital organ function or require immune suppressive treatment includingsystemic corticosteroids. These conditions include myasthenia gravis, myositis,autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, antiphospholipid antibody syndrome, Wegenergranulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis,with the following exceptions:

• Participants with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone are eligible for the study.

• Participants with controlled Type 1 diabetes mellitus who are on an insulinregimen are eligible for the study.

• Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., participants with psoriatic arthritisare excluded) are eligible for the study provided all of following conditionsare met:

• Rash must cover < 10% of body surface area.

• Disease is well controlled at baseline and requires only low-potencytopical corticosteroids.

• There has been no occurrence of acute exacerbations of the underlyingcondition requiring psoralen plus ultraviolet A radiation, methotrexate,retinoids, biologic agents, oral calcineurin inhibitors, or high-potencyor oral corticosteroids within the previous 12 months.

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest computed tomography (CT) scan. History ofradiation pneumonitis in the radiation field (fibrosis) is permitted.

• Anticipation of need for a major surgical procedure during the study.

• Prior allogeneic stem cell or solid organ transplantation.

• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation ofstudy treatment, or anticipation of need for such a vaccine during SG oratezolizumab treatment or within 5 months after the final dose of SG oratezolizumab. Note: Seasonal flu vaccines that do not contain a live virus andlocally authorized/approved COVID-19 vaccines are permitted.

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently) with the exception ofparticipants with indwelling catheters (e.g., PleurX(R)) who are allowed.

• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN).

• Significant cardiovascular disease (such as New York Heart Association Class II orgreater cardiac disease, myocardial infarction, cerebrovascular accident, unstablearrhythmia, or unstable angina) within 3 months prior to initiation of studytreatment.

• Prior treatment with immune checkpoint blockade therapies, including anti-PD-1, andanti-PD-L1 therapeutic antibodies (for Arm 2 only).

• Participants with prior malignancy within the previous 2 years except for locallycurable cancers that have been apparently cured such as basal or squamous cell skincancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, orlow risk Gleason 6 prostate cancer, among others. Participants with a prior orconcurrent malignancy whose natural history or treatment does not have the potentialto interfere with the safety or efficacy assessment of the investigational regimenare eligible for the study.

• Participants with severe uncontrolled intercurrent illness that would limitcompliance with study requirements, evaluated by history, physical exam, andchemistry panel.