Cabozantinib Plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced Urothelial Carcinoma

Pre-Screening Eligibility * Male or female subject aged ≥ 18 years. * Clinically, subject is a candidate for urothelial diagnostic procedure (fresh soft-tissue biopsy or TURBT). * Subject meets general medical criteria for consideration of treatment with immunotherapy using a checkpoint inhibitor. Treatment Inclusion Criteria: * Histologically proven transitional cell or urothelial carcinoma. * Patients with locally advanced or metastatic urothelial carcinoma must meet one of the following: * Patients who are not eligible for cisplatin-containing chemotherapy AND whose tumors express PD-L1 (Combined Positive Score (CPS) ≥ 10 as determined by an FDA-approved test; OR * Patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. * Metastatic (any N+ or M1) or locally advanced, unresectable (T4bN0) disease. * Measurable disease is required as determined by RECIST v1.1. * Performance Status ECOG 0-2 * Cisplatin-ineligibility based on ≥1 of the following: * Estimated creatinine clearance between ≥30 and \<60 ml/min (Cockcroft-Gault formula) * ECOG PS\>1 * Hearing loss * Baseline neuropathy \> grade 1. * Patient refusal * Be greater to or equal to 18 years of age on day of signing informed consent. * Serum albumin ≥ 2.8 g/dl * Alkaline phosphatase (ALP) ≤ 3 × upper limit of normal (ULN). ALP ≤ 5 × ULN with documented bone metastases. * Negative serum or urine pregnancy test at screening for women of childbearing potential. * Highly effective contraception for both male and female subjects throughout the study and for at least 120 days after last pembrolizumab treatment administration if the risk of conception exists. * Must have recovered from adverse effects of any prior surgery, radiotherapy or other antineoplastic therapy to grade ≤ 2. If notrecovered to grade ≤ 2, these must be deemed to be irreversible adverse events related to prior surgery and/or radiation therapy (such as incontinence or sexual dysfunction) per investigator clinical judgment. * Recovery to baseline or ≤ Grade 2 CTCAE v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. Alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable. * Last dose of any radiation therapy \> 2 weeks before first dose of study treatment. * Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines. * Adequate organ function as defined in the protocol Exclusion Criteria: * Prior chemotherapy for metastatic urothelial carcinoma. * Prior chemotherapy for localized urothelial carcinoma that has been completed less than 6 months before registration. * Variant histologies other than urothelial carcinoma will not be allowed. Patients with a component of variant histologies will be allowed to enroll, if urothelial carcinoma is the predominant histology per investigator judgement. Patients with any component of small cell will be excluded. * Has received prior treatment with cabozantinib. * Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment. * Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment. * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or other checkpoint inhibitors previously. * Radiation therapy for bone metastasis ≤ 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible. * Has 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 4 weeks prior to the first dose of trial treatment 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 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. * Concomitant anticoagulation with oral anticoagulants except for those specified below. Allowed anticoagulants are the following: * Prophylactic use of low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted. * Low-dose low molecular weight heparins (LMWH) are permitted. * Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban is allowed in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before the first dose of study treatment without, clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor. * The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 × ULN within 14 days before the first dose of study treatment. * The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders: * Ongoing congestive heart failure exacerbation or New York Heart Association Class 4, unstable angina pectoris, serious cardiac arrhythmias. * Uncontrolled hypertension defined as sustained blood pressure (BP) \> 150 mm Hg systolic or \> 100 mm Hg diastolic despite optimal antihypertensive treatment. Uncontrolled hypertension needs to be determined based on persistently high blood pressure readings over more than 24 hours and should NOT be based on the blood pressure readings from one clinic visit. Blood pressure readings done at home or by primary care providers are acceptable. If a blood pressure reading on the day of screening is high, but there are documented acceptable ( ≤150 mm Hg systolic and ≤100 mm Hg diastolic) blood pressure readings prior to or after the screening visit (with or without the use of anti-hypertensive medications), patient will not be considered to have uncontrolled hypertension. * Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or symptomatic thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) occurring less than or equal to 6 months before first dose of cabozantinib. \[Note: Subjects with a diagnosis of deep vein thrombosis (DVT) or incidentally detected asympotmatic and sub-segmental pulmonary embolism (PE) on routine scans are allowed if on a stable dose of anti-coagulation for at least 1 week before first dose of study treatment\]. * Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before first dose. * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: * The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction. * Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose. * Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation. * Lesions invading or encasing any major blood vessels. * Other clinically significant disorders that would preclude safe study participation per investigator clinical judgement. * Serious non-healing wound/ulcer/bone fracture. * Uncompensated/symptomatic hypothyroidism. * Moderate to severe hepatic impairment (Child-Pugh B or C). * Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. * Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before first dose and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications per investigator clinical judgement from prior surgery are not eligible. * Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms per electrocardiogram (ECG) within 28 days before first dose of study treatment. Note: If a single ECG shows a QTcF with an absolute value \> 500 ms, two additional ECGs at intervals of approximately 3 min must be performed after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility. * Diagnosis of another malignancy within 2 years before first dose of study treatment, with the exception of those determined by the treating investigator to have a negligible risk of metastasis or death (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, ductal carcinoma in situ treated surgically with curative intent, localized prostate cancer treated with curative intent and/or no intent for further treatment, or incidental prostate cancer) * Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). * Has active autoimmune disease currently requiring systemic treatment with high dose corticosteroids (dose more than physiologic replacement doses equivalent to prednisone 10 mg daily) or (disease modifying immunosuppressive agents). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, intranasal, inhaled, topical steroids, or local steroid injection) is not considered an exclusion. * Active autoimmune disease that might deteriorate significantly when receiving an immuno-stimulatory agent per treating physician's clinical judgment. Subjects with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. * Prior organ transplantation including allogenic stem-cell transplantation. * Has known history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. * Has an active infection currently requiring systemic (intravenous) antibiotic therapy. * Has a known history of active TB (Bacillus Tuberculosis). * Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). * Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). * Active and inactive vaccinations within 4 weeks of the first dose of pembrolizumab is prohibited. * Known prior severe hypersensitivity to investigational products or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3). * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. * Subjects taking prohibited medications as described in Section 6.8. A washout period of prohibited medications for a period of at least two weeks or as clinically indicated should occur prior to the start of treatment. * Inability to swallow tablets or evidence of impaired intestinal absorption Previous systemic chemotherapy treatment for urothelial carcinoma, with the exception of perioperative chemotherapy treatment alone or with concurrent radiation within 6 months prior to treatment.