Pazopanib, Docetaxel, Prednisone Prostate

This Phase I study will consist of a dose escalation portion which includes a dose escalation
phase of 10 dose levels: (1a) docetaxel 60 mg/m2, pazopanib 400 mg daily, prednisone 5 mg
BID; (2a) docetaxel 75 mg/m2, pazopanib 400 mg daily, prednisone 5 mg BID; and (3a) docetaxel
75 mg/m2, pazopanib 600 mg daily, prednisone 5 mg BID; (4a) docetaxel 75mg/m2, pazopanib 800
mg daily, (5a) docetaxel 75mg/m2, pazopanib 1000mg daily, prednisone 5 mg; (1b) docetaxel 60
mg/m2, pazopanib 400 mg daily x 17 days, prednisone 5 mg BID; (2b) docetaxel 75 mg/m2,
pazopanib 400 mg daily x 17 days, prednisone 5 mg BID; and (3b) docetaxel 75 mg/m2, pazopanib
600 mg daily x 17 days, prednisone 5 mg BID; (4b) docetaxel 75mg/m2, pazopanib 800 mg daily x
17 days, (5b) docetaxel 75mg/m2, pazopanib 1000mg daily x 17 days, prednisone 5 mg. If the
investigators see > 1 dose limiting toxicity (DLT) at Dose level 3 then the investigators
would investigate docetaxel 75 mg/m2, pazopanib 600 mg daily, prednisone 5 mg BID (Dose level
3a). If < 1 DLT are seen at Dose level 3 and Pharmacokinetic (PK) analysis is complete and
acceptable, then the investigators will proceed to dose level 4) docetaxel 75 mg/m2,
pazopanib 1000 mg daily, prednisone 5 mg BID.

The investigators will dose escalate in a classic 3+3 design. The maximum tolerated dose
(MTD) will be defined as the highest dose level that does not result in 2 or more dose
limiting toxicities (DLTs). A dose expansion at the MTD of 10-15 patients (up to a total of
36 patients) will be accrued in order to further describe the safety profile.

Inclusion Criteria:

- Histologically confirmed carcinoma of the prostate. Histologic evidence may be
confirmed through local or metastatic biopsy review. Non-adenocarcinomas are
permitted.

- Radiographic evidence of metastatic disease; non-evaluable, bone only metastasis is
permitted.

- Evidence of disease progression despite castrate levels of testosterone (<50 ng/dl).

- At the time of screening, at least 2 weeks since prior palliative radiation therapy
and 4 weeks from major surgery, and resolution of all toxic effects of prior therapy
to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI-CTCAE); version 4.0 Grade < 1.

- Age >18 years

- Adequate laboratory parameters

- Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 2

- Life expectancy greater than 3 months

- Written, signed and dated Institutional Review Board (IRB) approved informed consent
form.

Exclusion Criteria:

- History of or active central nervous system metastases

- The use of immunologic, biologic, or hormonal therapies within 2 weeks of study entry.

- Major surgery, open biopsy, traumatic injury within 4 weeks of the screening visit

- Subjects who have not recovered from prior biopsy, surgery, traumatic injury, and/or
radiation therapy.

- Previous treatment with docetaxel, including in the neo-adjuvant or adjuvant setting

- Presence of non-healing wound or ulcer

- Grade 3 or greater hemorrhage within the past month.

- Uncontrolled hypertension

- American Heart Association Class 2-4 heart disease or any history of congestive heart
failure with an ejection fraction <40%, recent cardiovascular event (within 12 months)
including unstable angina, any exertional angina, myocardial infarction, exertional or
rest claudication, or stroke/Cerebral Vascular Event/Transient Ischemic Attack.
Patients with known moderate to severe documented carotid or peripheral vascular
disease are excluded. Angioplasty or stenting of coronary or peripheral arteries are
exclusionary if within the past 12 months.

- Anticoagulation with warfarin (therapeutic doses of warfarin for catheter patency are
permitted up to 2 mg/day). Low molecular weight heparin is permitted.

- Diabetes mellitus with glycosylated hemoglobin A1c (HbgA1c) > 8% despite therapy

- Subjects with active autoimmune disorder(s) being treated with systemic
immunosuppressive agents within 4 weeks prior to the screening visit.

- Active infection(s), active antimicrobial therapy or serious intercurrent illness.

- Does not agree to use medically acceptable contraceptive methods while on study and
for 3 months after the last dose of pazopanib.

- Any other major medical or psychiatric illness that, in the investigator's judgment,
will substantially increase the risk associated with the subject's participation in
this study, including inability to absorb oral medications.

- Known hypersensitivity to any of the components in the docetaxel infusion or other
medical reasons for not being able to receive adequate premedication (for example,
antihistamine or anti-inflammatory agents).

- CalculatedQT (QTc) interval on baseline EKG > 500milliseconds

- History or presence of nephrotic syndrome