Cabozantinib-S-Malate in Treating Patients With Hormone-Resistant Metastatic Prostate Cancer

PRIMARY OBJECTIVES:

I. To evaluate the timing, pathophysiology, and magnitude of changes in tumor imaging and
pharmacodynamic markers with XL184 (cabozantinib-s-malate) treatment in metastatic castrate
resistant prostate cancer.

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) achieved with XL184 in metastatic castrate
resistant prostate cancer (CRPC) patients.

II. To evaluate the feasibility of the therapy, and the toxicities associated. III. To
evaluate overall survival (OS) in metastatic CRPC patients post androgen deprivation therapy
(ADT) treated with XL-184.

OUTLINE:

Patients receive cabozantinib-s-malate orally (PO) daily in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks and then
periodically thereafter.

Inclusion Criteria:

- The subject has histologically confirmed prostate adenocarcinoma with radiologic
evidence of metastases

- If patient are on anti-androgens, these should be discontinued, at least 4 weeks prior
for flutamide and at least 6 weeks for bicalutamide or nilutamide

- At least 14 days should have elapsed from prior radiation therapy to bone metastases
from prostate cancer

- The patient has received a maximum of one prior chemotherapy regimen for metastatic
prostate cancer

- Patients must demonstrate disease progression on or after most recent systemic
therapy, either by prostate-specific antigen (PSA), new bone metastases or by
measurable disease criteria per Response Evaluation Criteria in Solid Tumors (RECIST)
guidelines

- Patients should have received either luteinizing hormone-releasing hormone (LHRH)
analogue, or LHRH analogue and anti- androgen for metastatic prostate cancer

- The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1

- Bisphosphonate therapy can be continued if started prior to protocol enrollment

- Patients must have blood pressure (BP) readings < 150/90 prior to enrollment

- Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support

- Platelets >= 100,000/mm^3

- Hemoglobin >= 9 g/dL

- Bilirubin =< 1.5 x the upper limit of normal (ULN); for subjects with known Gilbert's
disease, bilirubin =< 3.0 mg/dL

- Serum albumin >= 2.8 g/dl

- Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 50 mL/min; for
creatinine clearance estimation, the Cockcroft and Gault equation should be used

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN if no
liver involvement, or =< 5 x ULN with liver involvement

- Lipase < 1.5 x the upper limit of normal (except for subjects with adenocarcinoma of
the pancreas)

- Urine protein/creatinine ratio (UPCR) =< 1

- Serum phosphorus >= lower limit of normal (LLN)

- The subject is capable of understanding and complying with the protocol requirements
and has signed the informed consent document

- Patients participating in this trial must also be eligible and willing to sign consent
for participation in [2'-18F]-1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymine
(FMAU) and 18F-flouride positron emission tomography (PET) scans done under separate
protocols

- Sexually active subjects (men) must agree to use medically accepted barrier methods of
contraception (eg, male condom, or diaphragm with spermicidal gel) during the course
of the study and for 4 months after the last dose of study drug(s), even if oral
contraceptives are also used by the female partner; all subjects of reproductive
potential must agree to use both a barrier method and a second method of birth control

- Projected life expectancy of at least 6 months

- No prior history of other malignancies in the last 3 years, except for squamous and
basal cell skin cancer

Exclusion Criteria:

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

- Prior treatment with cabozantinib

- The subject has received radiation therapy:

- To the thoracic cavity or gastrointestinal tract within 3 months of the first
dose of study treatment

- To bone or brain metastasis within 14 days of the first dose of study treatment

- To any other site(s) within 28 days of 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 or a
hormonal therapy (including investigational kinase inhibitors or hormones) within 14
days or five half-lives of the compound or active metabolites, whichever is longer,
before the first dose of study treatment; patients receiving LHRH or
gonadotropin-releasing hormone (GnRH) agonists to maintain castrate levels of
testosterone or patients on bisphosphonate/denosumab, may be maintained on these
agents

- 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)

- The subject has a primary brain tumor

- The subject has active brain metastases or epidural disease (Note: 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 scans are not required to confirm eligibility)

- The subject has prothrombin time (PT)/international normalized ratio (INR) or partial
thromboplastin time (PTT) test results at screening >= 1.3 x the laboratory ULN

- The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
such as warfarin or warfarin-related agents, heparin, thrombin or Factor xabans (Xa)
inhibitors, or antiplatelet agents (eg, clopidogrel); low dose aspirin (=< 81 mg/day),
low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH)
are permitted

- The subject has experienced any of the following within 3 months before the first dose
of study treatment:

- Clinically-significant hematemesis or gastrointestinal bleeding

- Hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood

- Any other signs indicative of pulmonary hemorrhage

- The subject has radiographic evidence of cavitating pulmonary lesion(s)

- The subject has tumor in contact with, invading or encasing major blood vessels

- 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 BP > 140 mmHg
systolic, or > 90 mmHg diastolic despite optimal antihypertensive treatment
(BP must be controlled at screening)

- 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

- Thromboembolic event requiring therapeutic anticoagulation (Note:
subjects with a venous filter (e.g. vena cava filter) are not eligible
for this study)

- Gastrointestinal disorders particularly those associated with a high risk of
perforation or fistula formation including:

- Any of the following at the time of screening

- Intra-abdominal tumor/metastases invading gastrointestinal (GI) mucosa

- Active peptic ulcer disease

- Inflammatory bowel disease (including ulcerative colitis and Crohn's
disease), diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis

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

- History of abdominal fistula

- Gastrointestinal perforation

- Bowel obstruction or gastric outlet obstruction

- Intra-abdominal abscess. Note: Complete resolution of an intraabdominal
abscess must be confirmed prior to initiating treatment with
cabozantinib even if the abscess occurred more that 6 months ago

- GI surgery (particularly when associated with delayed or incomplete healing)
within 28 days; Note: Complete healing following abdominal surgery must be
confirmed prior to initiating treatment with cabozantinib even if surgery
occurred more that 28 days ago

- 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 or concurrent evidence of intraluminal tumor
involving the trachea and esophagus

- Other clinically significant disorders such as:

- Active infection requiring systemic treatment

- Serious non-healing wound/ulcer/bone fracture

- History of organ transplant

- Concurrent uncompensated hypothyroidism or thyroid dysfunction

- History of major surgery within 4 weeks or minor surgical procedures within
1 week before randomization

- The subject is unable to swallow tablets

- The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >
470 ms within 28 days before randomization

- The subject has a previously identified allergy or hypersensitivity to components of
the study treatment formulation

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

- The subject has had evidence within 2 years of the start of study treatment of another
malignancy, which required systemic treatment