A Study of Dovitinib With Androgen Deprivation Therapy (ADT) in Patients With Metastatic Prostate Cancer Receiving Primary ADT

In 2010, an estimated 217,730 new cases of prostate cancer occurred with 32,050 deaths in
the United States of America. Prostate cancer exhibits a unique natural history that is a
function of therapies rendered. Initially, the disease is treated with androgen deprivation
therapy (ADT) with substantial regression of disease in the vast majority of patients.
However, the response is short-lived, on the order of 18-24 months, with subsequent
resumption of cancer growth manifesting as an increasing PSA, radiographic disease
progression, and progressive symptoms related to the increasing disease burden, so called
metastatic castration-resistant prostate cancer (CRPC). Almost all prostate cancer deaths
occur in men with metastatic castration-resistant disease (CRPC).

An appropriate therapeutic strategy would be to utilize agents in combination with ADT that
could serve to extend the sensitivity of the disease to primary ADT. The hormonal sensitive
state, when the tumor burden is dramatically lowered due to therapeutic response, could
represent the optimal context to introduce novel agents, leading to cytoreduction and/or
maintenance of the hormone-sensitive state.

It has been demonstrated that the proangiogenic factor FGF-2 appears to play a central role
in angiogenesis in hormone sensitive prostate cancer (HSPC). Thus targeting FGF-2 in
conjunction with primary ADT may represent a novel therapeutic strategy in the initial
treatment of metastatic HSPC.

Dovitinib is a broad-targeted-profiled RTK inhibitor active against VEGF, FGF and PDGF.
Anti-tumor effects for this agent may, therefore, be secondary to anti-angiogenesis,
anti-proliferative activity against tumor cells, and anti-stromal activity.

The study will enroll patients with metastatic prostate disease receiving initial ADT.
Participants will be randomized to receive ADT alone, or in combination with Dovitinib.
Participants will be stratified based on ECOG PS, Prior ADT > or < 30 days, and disease
location (bone only vs. other).

ADT will be administered per standard of care on both treatment arms. Patients randomized to
the combination arm will receive ADT plus Dovitinib at a dose of 500 mg/day given on a
five-days-on-two-days-off schedule. One cycle equals 28 days. Dovitinib cycles will repeat
continuously until disease progression, or removal from study for other reasons. Patients
must begin Dovitinib within 120 days after the start of ADT. Thereafter, patients will be
allowed to remain on the study until unacceptable side effect(s) occur, or until there is
disease progression to castration-resistance status.

Quality of life will be assessed during the course of the study utilizing the Functional
Assessment of Cancer Therapy-Prostate (self administered FACT-P).

Blood samples obtained at specified time points will be collected for research purposes from
participants who provide consent to do so. Biomarkers pertinent to the hypothesized
mechanism of action will be evaluated. Circulating tumor cells (CTC) will be enumerated at
baseline (CellSearch™), and every 3 months thereafter. An additional citrate tube of blood
will be collected for CTC-based ex-vivo culture analysis with each CTC draw. Samples of
archival prostate biopsy specimens will also be analyzed for specific proteins related to
Dovitinib's mechanism of action.

Inclusion Criteria:

- Men with metastatic hormone-sensitive metastatic prostate cancer

- ECOG (WHO) performance status 0-2

- Age ≥ 18 years old

- PSA > 4.0

- Patients must have the following laboratory values:

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Platelets ≥ 100 x 109/L

- Hemoglobin (Hgb) > 9 g/dL

- Serum total bilirubin: ≤ 1.5 x ULN

- ALT and AST ≤ 3.0 x ULN (for patients with or without liver metastases)

- Serum creatinine ≤ 1.5 x ULN or serum creatinine > 1.5 - 3 x ULN if calculated
creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockroft-Gault equation

- Urine dipstick reading negative for proteinuria, or if 1+, then total urinary
protein must be less than 500 mg and measured creatinine cleaners ≥ 50
mL/min/1.73m2 from a 24 hour urine collection

- Histologically or cytologically confirmed prostate cancer.

- Urine dipstick reading negative for proteinuria, or, if documentation of +1 results
for protein on dipstick reading, then total urinary protein ≤ 500 mg and measured
creatinine clearance ≥ 50 mL/min/1.73m2 from a 24 hour urine collection.

- Patients may have begun hormonal therapy, but must have done so within 120 days of
study treatment.

- Patients must have metastatic disease (extensive or limited).

- Scans (CT chest, abdomen, and pelvis) and bone scan must be obtained within 4 weeks
of treatment.

- Written informed consent obtained according to local guidelines

Exclusion Criteria:

- Patients with brain metastases

- Patients with another primary malignancy within 3 years prior to starting study drug,
with the exception of adequately treated in-situ carcinoma of the uterine cervix, or
skin cancer (such as basal cell carcinoma, squamous cell carcinoma, or
non-melanomatous skin cancer)

- Patients who have received prior cytotoxic chemotherapy within 3 years of starting
study drug.

- Patients who have received targeted therapy (e.g., sunitinib, sorafenib, pazopanib) ≤
4 weeks prior to starting study drug, or who have not recovered from the side effects
of such therapy.

- Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or ≤ 2
weeks prior to starting study drug in the case of localized radiotherapy (e.g., for
analgesic purpose or for lytic lesions at risk of fracture), or who have not
recovered from radiotherapy toxicities.

- Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal or
intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to
starting study drug, or patients who have had minor procedures, percutaneous biopsies
or placement of vascular access device ≤ 1 week prior to starting study drug, or who
have not recovered from side effects of such procedure or injury.

- Patients with any of the following concurrent severe and/or uncontrolled medical
conditions which could compromise participation in the study:

- Impaired cardiac function or clinically significant cardiac diseases

- Neurological compromise or dysfunction due to metastases

- Ureteral or bladder outlet obstruction due to metastases or local invasion

- Impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of dovitinib (e.g., ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
resection)

- Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

- Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is
not mandatory)

- Patients who are currently receiving anticoagulation treatment with therapeutic
doses of warfarin

- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.
active or uncontrolled infection, uncontrolled diabetes) that could cause
unacceptable safety risks or compromise compliance with the protocol

- Rising PSA meeting criteria for progression to CRPC

- Patients unwilling or unable to comply with the protocol