Cabozantinib-s-malate and Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Genitourinary Tumors

PRIMARY OBJECTIVES:

I. Determine the dose limiting toxicity (DLT) and recommended phase II dose (RP2D) of the
combination of cabozantinib (cabozantinib-s-malate) and nivolumab (cabo-nivo) and separately
the combination of cabozantinib, nivolumab and ipilimumab (cabo-nivo-ipi) in patients with
genitourinary tumors. (Phase I) II. Assess safety and tolerability of cabozantinib, nivolumab
and ipilimumab (cabo-nivo-ipi) in patients with genitourinary tumors at this novel dose.
(Dose Level 8 Cohort)

SECONDARY OBJECTIVES:

I. Preliminarily evaluate the activity, as determined by objective response rate using
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the modified Immune-Related
Response Criteria (irRC), derived from RECIST1.1, of cabo-nivo and cabo-nivo-ipi in patients
with advanced/refractory metastatic urothelial carcinoma (checkpoint inhibition therapy
naive) and with renal cell carcinoma in the second-line and beyond setting.

II. Preliminarily evaluate the activity, as determined by objective response rate using
RECIST 1.1 and the modified irRC, derived from RECIST 1.1, of cabo-nivo in patients with
adenocarcinoma and with rare histologies (including squamous or small cell carcinomas of the
bladder, renal medullary carcinoma, sarcomatoid bladder and renal cell carcinomas,
plasmacytoid carcinoma of the bladder and others) in the first line or beyond setting.

III. Preliminarily evaluate the activity, as determined by objective response rate using
RECIST 1.1 and the modified irRC, derived from RECIST 1.1, of cabo-nivo in patients with
urothelial carcinoma previously treated with checkpoint inhibition therapy in the second line
or beyond setting.

IV. Preliminarily evaluate the activity, as determined by objective response rate using
RECIST 1.1 and the modified irRC, derived from RECIST 1.1, of cabo-nivo-ipi in patients with
squamous cell carcinoma of the penis.

V. To evaluate the activity as determined by progression free survival (PFS) and overall
survival (OS) of: cabo-nivo and cabo-nivo-ipi in patients with advanced/refractory metastatic
urothelial carcinoma (checkpoint inhibition therapy naive) or with renal cell carcinoma in
the second-line and beyond setting.

VI. To evaluate the activity as determined by PFS and OS of: cabo-nivo in patients with
advanced adenocarcinoma and with rare histologies (including squamous or small cell
carcinomas of the bladder, renal medullary carcinoma, sarcomatoid bladder and renal cell
carcinomas, plasmacytoid carcinoma of the bladder and others) in the first-line and beyond
setting.

VII. To evaluate the activity as determined by PFS and OS of: cabo-nivo in patients with
urothelial carcinoma previously treated with checkpoint inhibition therapy in the second line
or beyond setting.

VIII. To evaluate the activity as determined by PFS and OS of: cabo-nivo-ipi in patients with
squamous cell carcinoma of the penis.

IX. To obtain additional data to evaluate the safety of both combinations in patients with
clear cell renal cell carcinoma (ccRCC).

X. To assess the number of malignant soft tissue and bone lesions on fludeoxyglucose F-18
(18F-FDG) positron emission tomography (PET)/computed tomography (CT) (scan 1) versus
combined fluorine F 18 sodium fluoride (18F-NaF) and 18F-FDG PET/CT (scan 2).

XI. To assess response assessment by RECIST 1.1 using CT of the chest, abdomen, and pelvis
with intravenous (IV) contrast versus assessment by combined 18F-NaF and 18F-FDG PET/CT (scan
2) using number of malignant and change (modified PET RECIST [PERCIST]) of soft tissue and
bone lesions.

XII. To test the feasibility of automated density and volume application (ADaVA) as a means
of assessing tumor response.

XIII. To assess PDL-1 and MET expression data and in exploratory fashion analyze their
association to response or clinical benefit.

EXPLORATORY OBJECTIVES:

I. To assess overall response rates (ORR) on patients who have been challenged or
re-challenged with ipilimumab therapy post disease progression.

II. To assess effects of treatment in patients with bone-only disease.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 treatment arms.

PART I: Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28 and
nivolumab intravenously (IV) over 30 minutes on days 1 and 15. Cycles repeat every 28 days in
the absence of disease progression or unacceptable toxicity. After 21 cycles, patients
receive nivolumab IV over 30 minutes every 4 weeks in the absence of disease progression or
unacceptable toxicity. After progression, patients may receive cabozantinib-s-malate PO,
nivolumab IV, and ipilimumab IV at the part II RP2D for 4 cycles followed by
cabozantinib-s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-cycle 21 in the
absence of disease progression or unacceptable toxicity.

PART II: Patients receive cabozantinib-s-malate PO QD on days 1-21, nivolumab IV over 30
minutes on day 1, and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days
for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After
completion of 4 cycles with ipilimumab, patients continue receiving cabozantinib-s-malate PO
QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28
days for up to 21 cycles in the absence of disease progression or unacceptable toxicity.
After 21 cycles, patients receive nivolumab IV over 30 minutes every 4 weeks in the absence
of disease progression or unacceptable toxicity. After progression, patients may receive
cabozantinib-s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 cycles
followed by cabozantinib-s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if
post-cycle 21 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 16 weeks or 100 days and
then every 2 months thereafter.

Inclusion Criteria:

- Patients in the phase I portion must have:

- Histologically confirmed diagnosis of metastatic, genitourinary solid tumor

- Metastatic disease defined as new or progressive lesions on cross-sectional
imaging; patients must have at least:

- One evaluable site of disease

- Or, appearance of one new bone lesion

- Patients in the expansion portion must have:

- Histologically confirmed diagnosis of metastatic:

- Urothelial carcinoma of the bladder, urethra, ureter, renal pelvis, OR

- Clear cell renal cell carcinoma OR

- Adenocarcinoma of the bladder OR

- Non-resectable squamous cell carcinoma of the penis OR

- Squamous or small cell carcinoma of the bladder, renal medullary carcinoma
(RMC), sarcomatoid bladder and renal cell carcinomas, plasmacytoid carcinoma
of the bladder or other rare bladder/kidney cancer histology AND

- Patients with urothelial cancer or renal cell carcinoma must have progressive
metastatic disease defined as new or progressive lesions on cross-sectional
imaging; patients must have at least:

- One measurable site of disease (according to RECIST criteria) or bone
disease by NaF PET/CT

- Patients must have either progressed on least one standard therapy or there must be no
standard treatment that has been shown to prolong survival for the patient's disease
(patients with urothelial carcinoma who are cisplatin-ineligible may receive protocol
therapy as a first line therapy); patients may have received any number of prior
cytotoxic agents

- Karnofsky performance status >= 70%

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,200/mcL

- Platelets >= 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) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3.0 x institutional upper limit of normal (ULN)

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

- Hemoglobin >= 9 g/dL

- Serum albumin >= 2.8 g/dL

- Lipase and amylase =< 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

- Urine protein/creatinine ratio (UPCR) =< 2

- Serum phosphorus >= lower limit of normal (LLN) (if below LLN, for asymptomatic
patients replacement may be initiated if clinically indicated without delaying the
start of study treatment)

- Serum calcium >= LLN (if below LLN, for asymptomatic patients replacement may be
initiated if clinically indicated without delaying the start of study treatment)

- Serum magnesium >= LLN (if below LLN, for asymptomatic patients replacement may be
initiated if clinically indicated without delaying the start of study treatment)

- Serum potassium >= LLN (if below LLN, for asymptomatic patients replacement may be
initiated if clinically indicated without delaying the start of study treatment)

- Women of childbearing potential must have a negative pregnancy test at screening;
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; postmenopause 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

- The effects of the drugs used in this trial on the developing human fetus are unknown;
however, cabozantinib was embryolethal in rats at exposures below the 140mg dose in
the label, with increased incidences of skeletal variations in rats and visceral
variations and malformations in rabbits; for this reason and because tyrosine kinase
inhibitors agents as well as other therapeutic agents used in this trial are known to
be teratogenic, women of child-bearing potential and men must agree to use adequate
contraception, as defined below, prior to study entry and for the duration of study
participation; should a woman become pregnant or suspect she is pregnant while she is
participating in this study, 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 31 weeks after
completion of all study medications; women treated or enrolled on this protocol must
also agree to use adequate contraception prior to the study, for the duration of study
participation, and for 23 weeks after completion of all study medications

- Sexually active subjects (men and women) must agree to use medically accepted barrier
methods of contraception (e.g., male or female condom) during the course of the study
and for 23 or 31 weeks for women or men respectively, after the last dose of study
drugs, even if oral contraceptives are also used; all subjects of reproductive
potential must agree to use both a barrier method and a second method of birth control
during the course of the study and for 23 or 31 weeks for women and men respectively
after the last dose of study drugs

- Tissue availability for programmed cell death ligand 1 (PD-L1) expression is mandatory
for enrollment; however if archived tissue is unavailable the patient will be given
the option to consent to pre and post treatment tissue biopsies; tissue biopsies will
be collected pretreatment (prior to the first dose of therapy) and post treatment
(after at least 1 dose, preferably 2 doses of nivolumab)

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- The subject has received cytotoxic chemotherapy (including investigational cytotoxic
chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or
nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment

- Patients who have been previously treated with MET or vascular endothelial growth
factor receptor (VEGFR) inhibitors (except for patients on renal cell cancer [RCC]
cohort) are not eligible for the expansion cohorts but can enroll in the phase I
portion

- Prior treatment with any therapy on the programmed cell death 1 (PD-1)/PD-L1 axis or
anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors unless enrolling
the urothelial carcinoma with previous checkpoint inhibition therapy expansion cohort

- The subject has received radiation therapy:

- To the thoracic cavity or abdomen within 3 months before the first dose of study
treatment, or has ongoing complications, or is without complete recovery and
healing from prior radiation therapy

- To bone or brain metastasis within 3 weeks before the first dose of study
treatment

- To any other site(s) within 28 days before the first dose of study treatment

- The subject has received radionuclide treatment within 6 weeks of the first dose of
study treatment

- The subject has received 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 subject has received 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 subject has received any other type of investigational agent within 28 days before
the first dose of study treatment

- The subject has not recovered to baseline or Common Terminology Criteria for Adverse
Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and
other non-clinically significant adverse events (AEs) defined as lab elevation with no
associated symptoms or sequelae

- The subject has active brain metastases or epidural disease; subjects with brain
metastases previously treated with whole brain radiation or radiosurgery or subjects
with epidural disease previously treated with radiation or surgery 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 CT or magnetic resonance imaging (MRI)
scans for subjects with known brain metastases is required to confirm eligibility

- The subject has prothrombin time (PT)/international normalized ratio (INR) or partial
thromboplastin time (PTT) test >= 1.5 x the laboratory ULN within 7 days before the
first dose of study treatment

- The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
such as warfarin or warfarin-related agents, thrombin or factor Xa inhibitors; aspirin
(up to 325 mg/day), low-dose warfarin (=< 1 mg/day), prophylactic and therapeutic low
molecular weight heparin (LMWH) are permitted

- The subject requires chronic concomitant treatment of strong cytochrome P450, family
3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin,
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)

- The subject has 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 within 3 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 subject has tumor invading any major blood vessels

- The subject has evidence of tumor invading the gastrointestinal (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

- The subject has 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) >
140 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 the first dose of study treatment:

- Unstable angina pectoris

- Clinically-significant cardiac arrhythmias

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

- Myocardial infarction

- Cardiomyopathy

- 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

- Intra-abdominal tumor/metastases invading GI mucosa

- Active peptic ulcer disease, diverticulitis, cholecystitis, symptomatic
cholangitis or appendicitis

- Malabsorption syndrome

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

- Abdominal 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 6 months before the first dose of
study treatment

- Other disorders associated with a high risk of fistula formation including
percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the
first dose of study therapy

- Other clinically significant disorders such as:

- Severe active infection requiring 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 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)

- History of major surgery as follows:

- Major surgery within 3 months of the first dose of cabozantinib; however, if
there were no wound healing complications, patients with rapidly growing
aggressive cancers, may start as soon as 6 weeks if wound has completely
healed post-surgery

- Minor surgery within 1 month of the first dose of cabozantinib if there were
no wound healing complications or within 3 months of the first dose of
cabozantinib if there were wound complications excluding core biopsies and
Mediport placement

- In addition, complete wound healing from prior surgery must be confirmed at least
28 days before the first dose of cabozantinib irrespective of the time from
surgery

- The subject is unable to swallow tablets

- History of severe hypersensitivity reaction to any monoclonal antibody

- The subject is unable or unwilling to abide by the study protocol or cooperate fully
with the investigator or designee

- For disease specific studies: the subject has had evidence within 2 years of the start
of study treatment of another malignancy which required systemic treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cabozantinib, nivolumab, ipilimumab or other agents used in study

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with cabozantinib

- Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of
highly active antiretroviral therapy (HAART), cluster of differentiation (CD)4 counts