Primary Outcomes:

Primary Outcome 1 - Measure: Objective response rate (ORR)

Primary Outcome 1 - Time Frame: Up to 5 years

Condition:

• Bladder Adenocarcinoma
• Bladder Clear Cell Adenocarcinoma
• Bladder Mixed Adenocarcinoma
• Bladder Neuroendocrine Carcinoma
• Bladder Small Cell Neuroendocrine Carcinoma
• Bladder Squamous Cell Carcinoma
• Bladder Urachal Adenocarcinoma
• Chromophobe Renal Cell Carcinoma
• Collecting Duct Carcinoma
• Infiltrating Bladder Lymphoepithelioma-Like Carcinoma
• Infiltrating Bladder Urothelial Carcinoma
• Infiltrating Bladder Urothelial Carcinoma With Giant Cells
• Infiltrating Bladder Urothelial Carcinoma, Nested Variant
• Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant
• Infiltrating Bladder Urothelial Carcinoma, Sarcomatoid Variant
• Kidney Medullary Carcinoma
• Large Cell Neuroendocrine Carcinoma
• Metastatic Bladder Carcinoma
• Metastatic Bladder Large Cell Neuroendocrine Carcinoma
• Metastatic Bladder Small Cell Neuroendocrine Carcinoma
• Metastatic Bladder Squamous Cell Carcinoma
• Metastatic Infiltrating Bladder Urothelial Carcinoma, Clear Cell Variant
• Metastatic Infiltrating Bladder Urothelial Carcinoma, Lipid-Rich Variant
• Metastatic Infiltrating Bladder Urothelial Carcinoma, Micropapillary Variant
• Metastatic Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant
• Metastatic Infiltrating Bladder Urothelial Carcinoma, Sarcomatoid Variant
• Metastatic Kidney Medullary Carcinoma
• Metastatic Malignant Genitourinary System Neoplasm
• Metastatic Penile Carcinoma
• Metastatic Prostate Small Cell Neuroendocrine Carcinoma
• Metastatic Sarcomatoid Renal Cell Carcinoma
• Metastatic Urethral Carcinoma
• Papillary Renal Cell Carcinoma
• Sarcomatoid Renal Cell Carcinoma
• Stage IV Bladder Cancer AJCC v8
• Stage IV Penile Cancer AJCC v8
• Stage IV Prostate Cancer AJCC v8
• Stage IV Renal Cell Cancer AJCC v8
• Stage IV Urethral Cancer AJCC v8
• Stage IVA Bladder Cancer AJCC v8
• Stage IVA Prostate Cancer AJCC v8
• Stage IVB Bladder Cancer AJCC v8
• Stage IVB Prostate Cancer AJCC v8
• Testicular Leydig Cell Tumor
• Testicular Sertoli Cell Tumor
• Urethral Clear Cell Adenocarcinoma

Eligibility

Criteria:
Inclusion Criteria:

- Metastatic disease defined as new or progressive lesions on cross-sectional imaging or
bone scan. Patients must have at least:

- One measurable site of disease as per Response Evaluation Criteria in Solid
Tumors (RECIST) version (v) 1.1

- One bone lesion on bone scan (tec99 or sodium fluoride [NaF] positron emission
tomography [PET]/computed tomography [CT], CT, or magnetic resonance imaging
[MRI]) for the bone-only cohort

- Histologically confirmed diagnosis of one of the following metastatic cohorts:

- Small cell/ neuroendocrine carcinoma of the bladder - All urothelial
carcinomas with any amount of neuroendocrine differentiation (including
small cell differentiation) will be included. If the tumor is purely
neuroendocrine, metastasis from another site of origin should be clinically
excluded.

- Adenocarcinoma of the bladder, or urachal adenocarcinoma, or bladder/urethra
clear cell adenocarcinoma - must be pure (per World Health Organization
[WHO] definition), (i.e. urothelial carcinoma with glandular differentiation
is not considered a pure adenocarcinoma.

- Squamous cell carcinoma of the bladder - must be pure (i.e. urothelial
carcinoma with squamous differentiation is not considered a pure squamous
cell carcinoma).

- Plasmacytoid urothelial carcinoma - Tumor should show predominantly > or
equal ~50% plasmacytoid histology (including all types of discohesive
growth, such as tumors with signet-ring and/or rhabdoid features as well).

- Any penile cancer

- Sarcomatoid renal cell carcinoma - Tumor should be predominantly sarcomatoid
~50% (including rhabdoid differentiation) is also unclassified renal cell
carcinomas (RCCs): all (assuming they are high grade with metastasis)
malignant angiomyolipomas are allowed.

- Sarcomatoid urothelial carcinoma - Tumor should show predominantly ~ 50%
sarcomatoid differentiation.

- Renal medullary carcinoma - Per WHO definition, ideally confirmed with
immunostains.

- Renal collecting duct carcinoma - Per WHO definition (medullary involvement,
predominant tubular morphology, desmoplastic stromal reaction, high grade
cytology, infiltrative growth pattern, and absence of other renal cell
carcinoma subtype or urothelial carcinoma).

- Bone only urothelial carcinoma or other non-prostate GU tumor

- Urethra carcinoma - May be of any histology but if urothelial carcinoma then
must be isolated to the urethra and not have metachronous or synchronous
urothelial carcinoma of the bladder.

- Other miscellaneous histologic variants of the urothelial carcinoma, such
as, but not limited to: micropapillary (Tumor should show predominantly > or
equal 50% micropapillary architecture), giant cell, lipid-rich, clear cell
and nested variants (Tumor should predominantly > or equal 50% show these
features), large cell neuroendocrine carcinoma, lymphoepithelioma-like
carcinoma and mixed patterns will be considered, as well as small cell
neuroendocrine prostate cancer (Only treatment-naïve primary small cell of
prostate with any amount of small cell component allowed. Post-treatment
small cell prostatic carcinomas are not allowed), Malignant testicular
Sertoli or Leydig cell tumors, and papillary and chromophobe RCC.

- Note: Translocation positive renal cell carcinoma patients are
eligible. However, AREN1721 should be considered before this trial.

- Hematoxylin and eosin (H&E) slides from diagnostic tumor tissue for retrospective
central pathology review

- Patients may have received up to 2 systemic anti-cancer treatments or be treatment
naive. Patients with small cell carcinoma should have received a platinum-based
combination regimen either as neoadjuvant, adjuvant or first-line treatment). Patients
in the bone-only cohort may be urothelial carcinoma histology but must receive
standard cisplatin-based chemotherapy (if cisplatin-eligible).

- Patients must be able to swallow oral formulation of the tablets

- Karnofsky performance status >= 80%

- Absolute neutrophil count (ANC) >= 1,000/mcL

- Platelet count >= 75,000/mcL

- Total bilirubin =< 1.5 x upper limit of normal (ULN). For subjects with known
Gilbert's disease or similar syndrome with slow conjugation of bilirubin, total
bilirubin =< 3.0 mg/dL

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x institutional
upper limit of normal (ULN) (or =< 5 x ULN for patients with liver metastases or
Gilbert's disease)

- Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 40
mL/min/1.73 m^2 (calculated using the Chronic Kidney Disease Epidemiology [CKD-EPI]
equation or Cockcroft-Gault formula) for patients with creatinine levels above
institutional normal

- Hemoglobin >= 9 g/dL (transfusion of packed red blood cells [PRBCs] allowed)

- Serum albumin >= 3.2 g/dL

- Lipase and amylase =< 2.0 x ULN and no radiologic (on baseline anatomical imaging) or
clinical evidence of pancreatitis

- Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib
will not be allowed. Also, patients that have received both prior MET or VEGF and
prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed

- Prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA-4/CTLA-4
inhibitors is allowed, either in the perioperative or in the metastatic setting.
However, patients that have received both prior MET or VEGF and prior
PD-1/PD-L1/CTLA-4 (sequentially or in combination) are not allowed

- Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of
highly active antiretroviral therapy (HAART), no clinically significant drug-drug
interactions are anticipated with the current HAART regimen, CD4 counts are greater
than 350 and viral load is undetectable

- Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's
syndrome and psoriasis controlled with topical medication only and patients with
positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies etc.
are eligible but should be considered for rheumatologic evaluation for the presence of
target organ involvement and potential need for systemic treatment

- Patients with vitiligo, endocrine deficiencies including thyroiditis managed with
replacement hormones or medications (e.g. thyroiditis managed with propylthiouracil
[PTU] or methimazole) including physiologic oral corticosteroids are eligible

- Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess,
and gastrointestinal (GI) obstruction, within 12 months are not eligible

- Women of childbearing potential must have a negative pregnancy test =< 7 days prior to
registration

- Women of childbearing potential include women who have experienced menarche and
who have not undergone successful surgical sterilization (hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post
menopause is defined as amenorrhea >= 12 consecutive months. Note: women who have
been amenorrheic for 12 or more months are still considered to be of childbearing
potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens,
ovarian suppression or any other reversible reason

- Pregnant women may not participate in this study because with cabozantinib, nivolumab,
and ipilimumab 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 cabozantinib, nivolumab, and ipilimumab, breastfeeding
should be discontinued if the mother is treated with these agents

- The patient has received no cytotoxic chemotherapy (including investigational
cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 2
weeks before the first dose of study treatment

- The patient has received no radiation therapy:

- To the lungs and mediastinum or abdomen within 4 weeks before the first dose of
study treatment, or has ongoing complications, or is healing from prior radiation
therapy

- To brain metastasis within 3 weeks for whole-brain radiotherapy (WBXRT), and 2
weeks for stereotactic body radiation therapy (SBRT) before the first dose of
study treatment

- To the abdomen within 4 weeks before the first dose of study treatment, or has
ongoing complications, or is healing from prior radiation therapy

- To any other site(s) within 2 weeks before the first dose of study treatment

- The patient has received no radionuclide treatment within 6 weeks of the first dose of
study treatment

- The patient has received no prior treatment with a small molecule kinase inhibitor
within 14 days or five half-lives of the compound or active metabolites, whichever is
longer, before the first dose of study treatment

- The patient has received no prior treatment with hormonal therapy within 14 days or
five half-lives of the compound or active metabolites, whichever is longer, before the
first dose of study treatment. Subjects receiving gonadotropin-releasing hormone
(GnRH) agonists and antagonists are allowed to participate

- The patient has not received any other type of investigational agent within 14 days
before the first dose of study treatment

- The patient must have recovered to baseline or Common Terminology Criteria for Adverse
Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia,
neuropathy and other non-clinically significant adverse events (AEs) defined as lab
elevation with no associated symptoms or sequelae

- The patient may not have active brain metastases or epidural disease. Patients with
brain metastases previously treated with whole brain radiation or radiosurgery who are
asymptomatic and do not require steroid treatment for at least 2 weeks before starting
study treatment are eligible. Neurosurgical resection of brain metastases or brain
biopsy is permitted if completed at least 3 months before starting study treatment.
Baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic
resonance imaging (MRI) scans for subjects with known brain metastases is required to
confirm eligibility

- No concomitant treatment with warfarin. Aspirin (up to 325 mg/day), thrombin or factor
Xa inhibitors, low-dose warfarin (=< 1 mg/day), prophylactic and therapeutic low
molecular weight heparin (LMWH) are permitted

- No chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone,
phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St.
John's wort) or strong CYP3A4 inhibitors

- Because the lists of these agents are constantly changing, it is important to
regularly consult medical reference texts such as the Physicians' Desk Reference
may also provide this information. As part of the enrollment/informed consent
procedures, the patient will be counseled on the risk of interactions with other
agents, and what to do if new medications need to be prescribed or if the patient
is considering a new over-the-counter medicine or herbal product

- The patient has not experienced any of the following:

- Clinically-significant gastrointestinal bleeding within 6 months before the first
dose of study treatment

- Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood per day within 1 months
before the first dose of study treatment

- Any other signs indicative of pulmonary hemorrhage within 3 months before the
first dose of study treatment

- The patient has no tumor invading any major blood vessels

- The patient has no evidence of tumor invading the GI tract (esophagus, stomach, small
or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial
tumor within 28 days before the first dose of cabozantinib. Patients with rectal tumor
masses are not eligible.

- The patient has no uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:

- Cardiovascular disorders including:

- Congestive heart failure (CHF): New York Heart Association (NYHA) class III
(moderate) or class IV (severe) at the time of screening.

- Concurrent uncontrolled hypertension defined as sustained blood pressure
(BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal
antihypertensive treatment within 7 days of the first dose of study
treatment

- The subject has a corrected QT interval calculated by the Fridericia formula
(QTcF) > 500 ms within 28 days before randomization. Note: if initial QTcF
is found to be > 500 ms, two additional electrocardiograms (EKGs) separated
by at least 3 minutes should be performed. If the average of these three
consecutive results for QTcF is =< 500 ms, the subject meets eligibility in
this regard

- Any history of congenital long QT syndrome

- Any of the following within 6 months before registration of study treatment:

- Unstable angina pectoris

- Clinically-significant cardiac arrhythmias (patients with atrial
fibrillation are eligible)

- Stroke (including transient ischemic attack [TIA], or other ischemic
event)

- Myocardial infarction

- Cardiomyopathy

- No significant gastrointestinal disorders particularly those associated with a
high risk of perforation or fistula formation including:

- Any of the following that have not resolved within 28 days before the first
dose of study treatment:

- Active peptic ulcer disease

- Acute diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis, or malabsorption syndrome

- None of the following within 2 years before the first dose of study
treatment:

- Abdominal fistula or genitourinary fistula

- Gastrointestinal perforation

- Bowel obstruction or gastric outlet obstruction

- Intra-abdominal abscess. Note: Complete resolution of an
intra-abdominal abscess must be confirmed prior to initiating treatment
with cabozantinib even if the abscess occurred more than 2 years before
the first dose of study treatment

- Disorders associated with a high risk of fistula formation including percutaneous
endoscopic gastrostomy (PEG) tube placement are not eligible

- No other clinically significant disorders such as:

- Severe active infection requiring IV systemic treatment within 14 days
before the first dose of study treatment

- Serious non-healing wound/ulcer/bone fracture within 28 days before the
first dose of study treatment

- History of organ or allogeneic stem cell transplant

- Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
before the first dose of study treatment (for asymptomatic patients with an
elevated thyroid-stimulating hormone [TSH], thyroid replacement may be
initiated if clinically indicated without delaying the start of study
treatment)

- No history of major surgery as follows:

- Major surgery within 3 months of the first dose of ca
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No