Docetaxel and Prednisone With or Without Cediranib in Treating Patients With Metastatic Prostate Cancer That Did Not Respond to Hormone Therapy

PRIMARY OBJECTIVE:

I. To determine the 6-month progression-free survival rate of patients with hormone
refractory metastatic adenocarcinoma of the prostate treated with docetaxel and prednisone
with vs without cediranib.

SECONDARY OBJECTIVES:

I. To evaluate the safety profile of cediranib, docetaxel, and prednisone in patients with
metastatic hormone-refractory prostate cancer.

II. To determine the duration of prostate-specific antigen (PSA) response and PSA control in
patients with metastatic hormone-refractory prostate cancer treated with cediranib,
docetaxel, and prednisone.

III. To determine the partial and complete response rate in patients with measurable disease
treated with cediranib, docetaxel, and prednisone.

IV. To determine time to progression in patients with metastatic hormone-refractory prostate
cancer treated with cediranib, docetaxel, and prednisone.

V. To determine overall survival in patients with metastatic hormone-refractory prostate
cancer.

VI. To perform correlative marker studies measuring serum levels of VEGF, PDGF, sICAM, bFGF,
interleukin (IL)-6, and IL-8.

VII. To perform a pilot study of [F18]FMAU positron emission test (PET) imaging on patients
receiving cediranib, docetaxel, and prednisone.

OUTLINE: This is a multicenter study. Patients are stratified by participating institution.
Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral cediranib once daily on days 1-21, docetaxel IV over 1 hour on
day 1, and oral prednisone twice daily on days 1-21.

ARM II: Patients receive docetaxel and prednisone as in arm I.

In both arms, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity. Archival paraffin-embedded tissue blocks or slides from time of
diagnosis (or subsequent, but prior to therapy) are evaluated for expression of molecular
targets relevant to this study. Blood specimens from baseline, after courses 1 and 2, and
after completion of study treatment are analyzed for protein markers. Samples are analyzed by
ELISA and IHC for angiogenesis-associated plasma proteins, plasma levels of VEGF, tumor
expression of PDGFR, and interleukin (IL)-6 and IL-8 plasma levels. Patients also undergo
positron emission test (PET) scans utilizing fluorodeoxyglucose (FDG) at baseline and after
course 1.

After completion of study treatment, patients are followed every 3 months for 52 weeks.

Inclusion Criteria:

- Clinical/radiologic metastases with objective evidence of disease progression by
imaging or by rising prostate-specific antigen (PSA) despite androgen deprivation
therapy

- Rising PSA must be determined based on a rising trend with 2 successive elevations at
a minimum interval of 1 week

- Meets 1 of the following criteria: Measurable disease, with any level of PSA, at least
1 unidimensionally measurable lesion (longest diameter to be recorded) >= 20 mm by
conventional techniques or >= 10 mm by spiral CT scan, nonmeasurable disease, PSA >= 5
ng/mL OR new areas of bony metastases on bone scan

- Castrate levels of testosterone < 50 ng/dL must be maintained and documented

- Luteinizing hormone-releasing hormone (LHRH) agonist therapy must be continued, if
required to maintain castrate levels of testosterone

- Total bilirubin normal

- Patients with radiological evidence of stable brain metastases are eligible provided
they are asymptomatic and do not require corticosteroids or have been treated with
corticosteroids and show clinical and radiological evidence of stabilization at least
10 days after discontinuation of steroids

- ECOG performance status (PS) =< 2 or Karnofsky PS 60-100%

- Life expectancy > 12 weeks

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Histologically confirmed adenocarcinoma of the prostate

- AST and ALT =< 2.5 times upper limit of normal

- Creatinine normal OR creatinine clearance >= 60 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Proteinuria =< 1+ and urine protein:creatinine ratio =< 1.0 OR 24-hour urine protein <
1,000 mg

- Peripheral neuropathy >= grade 2

- Uncontrolled intercurrent illness including, but not limited to, any of the following:
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, psychiatric illness/social situations that would limit
compliance with study requirements

- Congestive heart failure, second or third degree heart block, or recent myocardial
infarction within the past 6 months

- QTc prolongation > 500 msec OR other ECG abnormality noted within 14 days of treatment

- New York Heart Association class III or IV cardiac disease; Class II disease
controlled with treatment and monitoring allowed

- History of poorly controlled hypertension (e.g., resting blood pressure > 150/90 mm Hg
with or without hypertensive therapy)

- History of a curatively treated malignancy with a survival prognosis of less than 5
years or concurrent malignancy except for adequately treated basal cell or squamous
cell skin cancer or carcinoma in situ

- History of significant gastrointestinal impairment, as judged by the investigator,
that would significantly affect the absorption of cediranib

- History of severe hypersensitivity reaction to docetaxel or other drugs formulated
with polysorbate 80

- Significant hemorrhage (30 mL bleeding/episode in previous 3 months) or hemoptysis (5
mL fresh blood in previous 4 weeks)

- Prior enrollment or randomization of treatment in the present study

- Patients must be off flutamide antiandrogen therapy for ≥ 4 weeks (6 weeks for
bicalutamide or nilutamide)

- No prior chemotherapy for metastatic prostate cancer

- No major surgery within the past 14 days or a surgical incision that is not fully
healed

- No HIV-positive patients on combination antiretroviral therapy

- No conditions requiring concurrent use of drugs or biologics with proarrhythmic
potential

- No other investigational agents within 30 days prior to study enrollment

- No untreated unstable brain or meningeal metastases

- Known hypersensitivity to cediranib or any of its excipients