Trial of Cabozantinib (XL184) in Castrate-Resistant Prostate Cancer Metastatic to Bone

A significant proportion of patients with prostate cancer develop metastatic disease, which
most commonly affects the skeleton. Bone metastases are the cause of significant morbidity
and mortality in these patients, and require long-term management. Study participants in this
research study will have a diagnosis of castration-resistant prostate cancer metastatic to
bone.

Cabozantinib is not approved by the United States Food and Drug Administration (FDA) to treat
people for castration-resistant prostate cancer metastatic to bone or for any other type of
cancer. Giving cabozantinib to human cancer patients is experimental. Cabozantinib is
currently being given to patients on other studies. Cabozantinib is known to have anti-tumor
effects and to reduce bone metastases based on early clinical studies in prostate cancer and
other cancers. The drug is known to have side effects. The most common side effects were
fatigue, diarrhea, anorexia, rash, and palmar-plantar erythrodysesthesia (PPE) syndrome. To
date, it is not known if cabozantinib is safe and/or effective.

Inclusion Criteria:

- Pathologically and radiologically confirmed castrate-resistant prostate cancer
metastatic to bone

- Bone metastases which are accessible for biopsy under CT guidance.

- Willingness to undergo sequential biopsy of bone lesions.

- No prior standard chemotherapy for metastatic disease (neoadjuvant, adjuvant and
hormonal treatments are excluded).

- Participant must have discontinued antiandrogen therapy at least 4 weeks (for
flutamide and megestrol acetate) or 6 weeks (for bicalutamide or nilutamide) prior to
the first dose of XL184. Participants currently on LHRH or GnRH agonists can be
maintained on these agents.

- Greater than or equal to 18 years old on day of consent

- Participants must be able to care for themselves

- Adequate organ and bone marrow function

- Participants must be capable of understanding and complying with the protocol
requirements and has signed the informed consent document.

- Men capable of sexual activity will be required to agree to use a condom during sexual
contact with women having the potential to bear children during their participation in
the study and for six months after participation.

Exclusion Criteria:

- Prior therapy with cabozantinib

- Any other type of investigational agent within 28 days before the first dose of study
treatment or 5 half-lives of the compound or active metabolite, whichever is longer

- No radiation therapy within 14 days of study treatment. No radionuclide treatment
within two months.

- No known brain metastases.

- Test results that measure how quickly blood clots need to be adequate for the study

- Participants who require concomitant treatment, in therapeutic doses, with
anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or
Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (≤
81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular weight
heparin (LMWH) are permitted.

- Participants must not have uncontrolled significant illness including but not limited
to: ongoing or active infection requiring systemic treatment, symptomatic congestive
heart failure, uncontrolled hypertension , history of hypertensive emergency
(e.g.encephalopathy) or hypertensive urgency within 6 months of study treatment,
clinically significant wounds including osteonecrosis, history of organ transplant,
unstable angina pectoris, stroke within 3 months of study drug, heart attack within 3
months of study drug, development of clots within blood vessels within 6 months of
study drug, bleeding from distended veins within 3 months of study drug, any other
severe or life threatening hemorrhage/bleeding, major surgery within 4 weeks of study
treatment, clinically significant cardiac arrhythmias, history of bowel obstruction
within 6 months of study drug or unresolved malabsorption syndrome, untreated bone
fracture including tumor-related pathologic fracture, anticipated need for major
surgery during the period of the study.

- Corrected QT interval, as measured by an ECG, must be within acceptable protocol
limits within 28 days of entering the study

- Unable to swallow capsules

- Unable to undergo MRI

- History of another malignant disease within two years with the exception of
superficial skin or bladder cancer which has been completely resected or carcinoma in
situ without evidence of invasion.