Cabozantinib and Androgen Ablation in Patients With Androgen-Dependent Metastatic Prostate Cancer

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take 1 capsule of
cabozantinib by mouth 1 time every day while you are on study. You should not eat or drink
anything other than water for 2 hours before and 1 hour after taking the study drug. You
should take the capsule with at least 1 cup (8 ounces) of water. You will also be given
separate directions about how to take the study drug.

You will also receive hormone therapy. The hormone drug you receive will be standard of care
hormone therapy. The study doctor will decide what hormone therapy you will receive and will
explain when and how you should take the hormone therapy, as well as its risks.

You will be given a drug diary where you will record when you take cabozantinib. You should
return this diary to the study staff when you come into the clinic.

Study Visits:

At every visit, you will be asked about any side effects you may have had and any other drugs
you may be taking.

If you are receiving Coumadin, every week for the first 3 weeks, you will have blood drawn
(about 1 teaspoon) to test your blood clotting function.

Every 3 weeks for the first 12 weeks of the study, and then every 6 weeks after that:

- You will have a physical exam.

- Blood (about 3-4 teaspoons) will be drawn for routine tests.

Every 3 weeks for the first 12 weeks of the study, and then every 12 weeks after that, blood
(about 1 teaspoon) will be drawn to check your thyroid and pancreatic function. The frequency
of the testing may change if the study doctor thinks it is needed.

Every 6 weeks, you will have the following tests performed:

- Blood (about 2-3 teaspoons) will be drawn to measure your PSA levels and for biomarker
testing.

- Urine will be collected for routine tests.

- You may have these test performed near your home if the study doctor thinks you are
tolerating the treatment.

Every 12 weeks, you will have a bone scan and CT scans of the chest, abdomen, and pelvis to
check the status of the disease.

Length of Study:

You may continue receiving the study drug for as long as the study doctor thinks it is in
your best interest. You will be taken off study early if the disease gets worse, if you have
intolerable side effects, or if your study doctor thinks it is in your best interest to stop.

Long-Term Follow-Up:

You will be contacted every 6 months after you stop taking the study drug to check on how you
are feeling and the status of the disease. This will consist of a phone call, e-mail, or
medical record review. If you are called, each call should last about 5 minutes.

This is an investigational study. Cabozantinib is FDA approved to treat patients with certain
types of thyroid cancer. Its use in this study is investigational.

Up to 60 participants will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Histologic proof of prostate adenocarcinoma

2. Newly diagnosed Androgen-Dependent Prostate Cancer. Patients already on ADT are
eligible as long as the time from initiation of LHRH analog or antagonist is not
greater than 3 months.

3. Metastatic disease on bone scan and/or involvement of soft tissues (lymph nodes and/or
viscera) by CT scan, PET/CT, or MRI

4. PSA > 1 ng/ml, unless anaplastic features are present (according to eligibility 10)

5. Life expectancy from a co-morbid illness > 3 years

6. Eastern Cooperative Oncology Group (ECOG) performance status
7. Patients must have adequate organ function as defined by: Absolute Neutrophil Count
(ANC) >/= 1,500/ul (unless due to bone marrow infiltration by tumor in which case ANC
>/=500/ml are allowed) Hemoglobin (Hgb) >/= 9 gm/dL (unless due to bone marrow
infiltration by tumor in which case Hgb>8 gm/dL); Total bilirubin upper limit of normal (ULN). For patients with known Gilbert's disease, total
bilirubin should be /= 100,000/mm^3 (unless due to bone
marrow infiltration by tumor in which case >/=50,000/ml are allowed); Alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) involvement, or normal; Urine protein/creatinine ratio (UPCR) /= lower limits
of normal (LLN); estimated creatinine clearance of >/=40 ml/min.

8. Prior ADT is allowed if it was an adjunct to definite local therapy, was given for
metastatic disease.

9. Prior therapy with other tyrosine kinase inhibitors (TKI) inhibitors or any other type
of investigational agent is allowed if it was an adjunct to definitive local therapy,
was given for therapy for metastatic disease.

10. Patients with "anaplastic" features are eligible for this trial as defined by at least
one of the following: a) Any of the following metastatic presentations: exclusive
visceral metastases, radiographically predominant lytic bone metastases identified by
plain X-ray or CT scan, bulky (>5 cm in longest dimension) lymphadenopathy or
high-grade (gleason >8) tumor mass in the prostate/pelvis.; b) Low PSA ( at initial presentation (prior to androgen ablation or at symptomatic progression in
the castrate-setting) plus high volume (>/=20) bone metastases.; c) Elevated serum LDH
(>/= 2 x ULN) or elevated serum CEA (>/= 2 x ULN) in the absence of other etiologies.;
d) Short interval ( initiation of hormonal therapy.

11. Sexually active fertile subjects, and their partners, must agree to use medically
accepted methods of contraception (eg, barrier methods, including male condom, female
condom, or diaphragm with spermicidal gel) during the course of the study and for 4
months after the last dose of study drug(s).

Exclusion Criteria:

1. Biological agents (antibodies, immune modulators, cytokines, or vaccines) or
radionuclide treatment within 6 weeks of the first dose of study treatment.

2. Radiation therapy within 2 weeks prior to initiation of study treatment.

3. Symptomatic or uncontrolled brain metastasis or epidural disease requiring current
treatment including steroids and anti-convulsant.

4. The subject has had another diagnosis of malignancy requiring systemic treatment
within the last two years, unless non-melanoma skin cancer, or superficial bladder
cancer.

5. The subject has uncontrolled or significant intercurrent illness including, but not
limited to, the following conditions: Chronically uncontrolled hypertension, defined
conventionally as consistent and repeated systolic pressures above 140 mmHg or
diastolic pressures above 90 mmHg despite anti-hypertensive therapy. This may be
better established with home BP readings than with clinic visit results. There is no
criterion related to a specific BP result required for eligibility, nor are acute BP
elevations that are related to iatrogenic causes, acute pain, or other transient
reversible causes considered to be an exclusion criteria. The intent is to exclude
patients with chronically uncontrolled hypertension that might be further exacerbated
by Cabozantinib.

6. Continued from # 5) Other cardiovascular disorders such as symptomatic congestive
heart failure (CHF), unstable angina pectoris, clinically-significant cardiac
arrhythmias, history of stroke (including transient ischemic attack [TIA], or other
ischemic event) within 6 months of study treatment, myocardial infarction within 6
months of study treatment, history of thromboembolic event requiring therapeutic
anticoagulation within 6 months of study treatment or main portal vein or vena cava
thrombosis or occlusion. ;Gastrointestinal (GI) disorders particularly those
associated with a high risk of perforation or fistula formation including: Any of the
following at the time of screening; a) intra-abdominal tumor/metastases invading GI
mucosa b) active peptic ulcer disease, c) inflammatory bowel disease (including
ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic
cholangitis or appendicitis

7. Continued from # 6) Any of the following within 6 months before the first dose of
study treatment: a) history of abdominal fistula b) gastrointestinal perforation c)
bowel obstruction or gastric outlet obstruction; d) 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 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
PEG tube placement within 3 months before the first dose of study therapy or
concurrent evidence of intraluminal tumor involving the trachea and esophagus.

8. The subject is unable to swallow capsules tablets

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

10. Oral corticosteroids >/= 7.5mg/day prednisone (or prednisone equivalents).

11. Prior treatment with cabozantinib.

12. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF)
>500 ms within 28 days before randomization.