Sacituzumab Govitecan Plus EV in Metastatic UC

Phase II Study Cohort A (dose expansion study to assess efficacy of Sacituzumab Govitecan (SG) and Enfortumab vedotin-ejfv (EV) combination) Inclusion Criteria: * Participants must have histologically documented confirmed predominant urothelial carcinoma (i.e. of the bladder, renal pelvis, ureter or urethra). Patients with squamous differentiation or mixed cell types are eligible if the urothelial component is more than 50%; small-cell carcinoma is not allowed. Patients with locally advanced unresectable disease are eligible. * Patient who are cisplatin eligible must have received prior treatment with platinum containing therapy defined as within the adjuvant/neoadjuvant setting with ≥ ypT2 disease at surgery or recurrent or progressive disease within 12 months or receiving treatment with platinum in locally advanced or metastatic setting. In addition, they must have received a checkpoint inhibitor (CPI) in locally advanced or metastatic urothelial cancer setting. Patients who received CPI therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease either during or within 12 months of therapy completion are eligible. A CPI is defined as a PD-1 or PD-L1 inhibitor. * Patients who are cisplatin-ineligible need only have progressed on or since one line of therapy defined as therapy given in the adjuvant/neoadjuvant setting within 12 months of progression or receiving therapy for locally advanced or metastatic disease * Patient must be progressing on or since most recent therapy * Age ≥18 years. Children are excluded from this study, but will be eligible for future pediatric trials. * ECOG performance status 0-1. * Participants must have adequate organ and marrow function as defined below: * Leukocytes ≥3,000/mcL * Absolute neutrophil count ≥1,500/mcL * Platelets ≥100,000/mcL * Total bilirubin ≤ institutional upper limit of normal (ULN) * AST(SGOT)/ALT(SGPT) ≤2.5x institutional ULN OR * ≤5x ULN with liver metastases and serum albumin \> 3 g/dL * Glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 (by Cockcroft Gault formula) * Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. * For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. * Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better. * Have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) as per response evaluation criteria in solid tumors version 1.1 (RECIST 1.1 criteria). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions * Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 6 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \>2 years * The effects of SG and EV on the developing human fetus are unknown. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 6 months after last study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study and up to 6 months after last study drug dose, 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 4 months after completion of SG administration. * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Subjects meeting any of the following exclusion criteria at Screening/Day 1 of treatment will not be enrolled in the study. * Women who are pregnant or lactating. Pregnant women are excluded from this study because SG and EV have potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with EV or SG, breastfeeding should be discontinued if the mother is treated on protocol. * Have had a prior anti-cancer biologic agent (including immune checkpoint inhibitors) within 4 weeks prior to Cycle 1 Day 1 (C1D1) or have had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to C1D1. Subjects participating in observational studies are eligible. * Presence of any toxicities attributed to prior anti-cancer therapy that are not resolved to Grade 1 or baseline that could impose serious risk for complications before administration of study drug agent * Note: If subjects received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. * Have previously received topoisomerase 1 inhibitors, SG or EV * Have an active second malignancy. Subjects with a history of malignancy that have been completely treated, with no evidence of active cancer for 3 years prior to start of therapy on trial (Cycle 1 Day 1 \[C1D1\]), or subjects with surgically-cured tumors with low risk of recurrence are allowed to enroll. * Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable CNS disease for at least 4 weeks prior to the first dose of study drug and all neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases, and are taking ≤20 mg/day of prednisone or its equivalent. All subjects with carcinomatous meningitis are excluded regardless of clinical stability. * Have active cardiac disease, defined as: * Myocardial infarction or unstable angina pectoris within 6 months prior to C1D1 * History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation * New York Heart Association (NYHA) Class III or greater congestive heart failure or left ventricular ejection fraction of \< 40% * Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or gastrointestinal (GI) perforation within 6 months of C1D1 * Have active serious infection requiring antibiotics (Contact sponsor-investigator for clarification) * Have other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations. * Patients with conditions requiring high doses of steroids (\>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. * History of idiopathic pulmonary fibrosis; organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. * Participants who are receiving any other investigational agents. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to EV or SG or any excipient contained in the drug formulations (including 2 (N morpholino) ethane sulfonic acid (MES), histidine, treahalose dihydrate polysorbate 80 and polysorbate 20). * Participants with uncontrolled intercurrent illness. * Participants with psychiatric illness/social situations that would limit compliance with study requirements. * Patients with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1C \>8% or 7-8% with associated diabetes symptoms that are otherwise not explained * Uncontrolled tumor related bone pain or impending spinal cord compression. Phase II Study Cohort B (assessing Sacituzumab Govitecan (SG) + Enfortumab vedotin-ejfv (EV) + Pembrolizumab combination) Inclusion Criteria: * Participants must have histologically documented confirmed predominant urothelial carcinoma (i.e. of the bladder, renal pelvis, ureter or urethra). Patients with squamous differentiation or mixed cell types are eligible if the transitional component is more than 50%; small-cell carcinoma is not allowed. Patients with locally advanced unresectable disease are eligible. * No prior therapy for metastatic urothelial carcinoma. Therapy in the perioperative setting is allowed with no time restrictions on platinum dosing. Prior immunotherapy is allowed provided it has been \> 6 months from last dose of immune checkpoint blockade. * Age ≥18 years; children are excluded from this study, but will be eligible for future pediatric trials. * ECOG performance status 0-1. * Participants must have adequate organ and marrow function as defined below: * Leukocytes ≥3,000/mcL * Absolute neutrophil count ≥1,500/mcL * Platelets ≥100,000/mcL * Total bilirubin ≤ institutional upper limit of normal (ULN) * AST(SGOT)/ALT(SGPT) ≤2.5x institutional ULN OR * ≤5x ULN with liver metastases and serum albumin \> 3 g/dL * Glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 (by Cockcroft Gault formula) * Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. * For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. * Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better. * Have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) as per response evaluation criteria in solid tumors version 1.1 (RECIST 1.1 criteria). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions * Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 6 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \>2 years * The effects of Pembrolizumab, SG and EV on the developing human fetus are unknown. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 6 months after last study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study and up to 6 months after last study drug dose, 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 4 months after completion of SG administration. * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Subjects meeting any of the following exclusion criteria at Screening/Day 1 of treatment will not be enrolled in the study. * Women who are pregnant or lactating. Pregnant women are excluded from this study because SG and EV have potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with EV or SG, breastfeeding should be discontinued if the mother is treated on protocol. * Have had a prior anti-cancer biologic agent (including immune checkpoint inhibitors) or chemotherapy within 26 weeks prior to Cycle 1 Day 1 (C1D1) Subjects participating in observational studies are eligible. * Have previously received topoisomerase 1 inhibitors, SG or EV * Have an active second malignancy. Subjects with a history of malignancy that have been completely treated, with no evidence of active cancer for 3 years prior to start of therapy on trial (Cycle 1 Day 1 \[C1D1\]), or subjects with surgically-cured tumors with low risk of recurrence are allowed to enroll. * Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable CNS disease for at least 4 weeks prior to the first dose of study drug and all neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases, and are taking ≤10 mg/day of prednisone or its equivalent. All subjects with carcinomatous meningitis are excluded regardless of clinical stability. * Have active cardiac disease, defined as: * Myocardial infarction or unstable angina pectoris within 6 months prior to C1D1 * History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation * New York Heart Association (NYHA) Class III or greater congestive heart failure or left ventricular ejection fraction of \< 40% * Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or gastrointestinal (GI) perforation within 6 months of C1D1 * Have active serious infection requiring antibiotics (Contact sponsor PI or Co-PI for clarification) * Have other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations. * Patients with conditions requiring high doses of steroids (\>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. * History idiopathic pulmonary fibrosis; organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. * Participants who are receiving any other investigational agents. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab, EV or SG or any excipient contained in the drug formulations (including 2 (N morpholino) ethane sulfonic acid (MES), histidine, treahalose dihydrate polysorbate 80 and polysorbate 20). * Participants with uncontrolled intercurrent illness. * Participants with psychiatric illness/social situations that would limit compliance with study requirements. * Patients with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1C \>8% or 7-8% with associated diabetes symptoms that are otherwise not explained * Uncontrolled tumor related bone pain or impending spinal cord compression. * History of autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 1. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 2. Brief (\<7 days) use of systemic corticosteroids is allowed when use is considered standard of care. 3. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy will not be excluded. 4. Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded. 5. Subjects with hypothyroidism that is stable with hormone replacement or Sjögren's syndrome will not be excluded.