AZD2171 to Treat Prostate Cancer

Background:

- AZD2171 (Cediranib) is an oral potent inhibitor of receptor tyrosine kinases which
impact vascular endothelial growth factor-A (VEGF).

- VEGF appears important in blood vessel formation and disease progression in prostate
cancer.

- No known effective therapy in patients with progressive androgen-independent prostate
cancer after treatment with docetaxel.

Objectives:

- Primary objective of this study is to determine if AZD2171 is associated with a 30% 6
month probability of progression free survival in patients with metastatic androgen
independent prostate cancer (AIPC) as determined by clinical and radiographic criteria.

- Secondary objective of this study will be demonstration of biologic effect by the drug
in the patient and on the tumor (when possible). Correlative studies will be conducted
on serially obtained tissue biopsies and white blood cell collections.

- Laboratory correlates will include elucidation of activation of components of the VEGFR2
and angiogenesis pathways and evaluation of endothelial cell adhesion molecules
(released by damaged cells) using enzyme-linked immunosorbent assay (ELISA),
pharmacogenetic analysis of kinase insert domain receptor (KDR) variants and single
nucleotide polymorphisms, and pharmacokinetic characterization of AZD2171 activity.

Eligibility:

- Metastatic progressive androgen-independent prostate cancer.

- Prior treatment with docetaxel.

- May not have corrected QT interval (QTc ) greater than 470 msec or greater than 1+
proteinuria on 2 consecutive dipsticks no less than 1 week apart.

Design:

- Phase II trial with a two stage design. 12 patients enrolled in first cohort, if 2 or
more are progression free at 6 months than enroll up to 35 evaluable patients. The
ceiling will be set at 37 to allow for inevaluable patients.

- Starting dose 20 mg QD (every day) for all patients.

- Once two stage design is complete then prednisone 10 mg once per day will be given in
combination with AZD2171. The total number of patients will be 23 for this portion of
the protocol.

- INCLUSION CRITERIA:

1. Patients must have histopathological confirmation of prostate cancer by the
Laboratory of Pathology of the National Cancer Institute (NCI), Pathology
Department of the National Naval Medical Center or Pathology Department of Walter
Reed Army Medical Center prior to entering this study. Patients whose pathology
specimens are no longer available may be enrolled in the trial if the patient has
a clinical course consistent with prostate cancer and available documentation
from an outside pathology laboratory of the diagnosis. In cases where original
tissue blocks or archival biopsy material is available, all efforts should be
made to have the material forwarded to the research team for use in correlative
studies.

2. Patients must have metastatic progressive androgen-independent prostate cancer.
There must be radiographic evidence of disease that has continued to progress
despite hormonal agents. Progression requires that a measurable lesion is
expanding, new lesions have appeared, and/or that prostatic specific antigen
(PSA) is continuing to rise on successive measurements. Patients on flutamide
must have disease progression at least 4 weeks after withdrawal. Patients on
bicalutamide or nilutamide must have progression at least 6 weeks after
withdrawal.

3. Patients must have received prior therapy with docetaxel for androgen-independent
prostate cancer. Any number of prior treatments are acceptable.

4. Age greater than or equal to 18 years.

5. Life expectancy of greater than 3 months.

6. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal
to 2 (Karnofsky greater than or equal to 60%).

7. Patients must have normal organ and marrow function as defined below:

Absolute neutrophil count greater than or equal to 1,500/mcL

Platelets greater than or equal to 100,000/mcL

Hemoglobin greater than or equal to 8 g/dL

Total bilirubin within normal institutional limits (unless with clinical
Gilbert's syndrome)

Aspartate aminotransferase/serum glutamic oxaloacetic transaminase
(AST(SGOT))/alanine aminotransferase/serum glutamic pyruvic transaminase
(ALT(SGPT) less than or equal to 2.5 times institutional upper limit of normal

Creatinine less than or equal to 1.5 times institutional upper normal
institutional limits

OR

Creatinine clearance greater than 40 mL/min/1.3 m^2 for patients with creatinin
levels above institutional normal as calculated by the Cockcroft Gault formula.

8. Patients must have recovered from any acute toxicity related to prior therapy,
including surgery. Toxicity should be less than or equal to grade 1 or returned
to baseline.

9. All patients who have not undergone bilateral surgical castration must continue
suppression of testosterone production by appropriate usage of gonadotropin
releasing hormone (GnRH) agonists or antagonists.

10. Patients must not have other invasive malignancies (within the past three years
with the exception of non-melanoma skin cancers or non-invasive bladder cancer).

11. AZD2171 has been shown to terminate fetal development in the rat, as expected for
a process dependent on VEGF signaling. Enrolled patients must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry, the duration of study participation and 3 months after the
end of the treatment.

12. Ability to understand and the willingness to sign a written informed consent
document.

13. Patients must have a blood pressure of less than 140/90 at the time of
enrollment. Details of antihypertensive treatment, if required, will be left up
to the primary care physician.

EXCLUSION CRITERIA:

1. Patients who have had chemotherapy, radiotherapy, or major surgery within 4 weeks (6
weeks for nitrosoureas or mitomycin C) prior to entering the study.

2. Patients may not be receiving any agents not approved by the Food and Drug
Administration (FDA) within the past four weeks.

3. Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

4. Mean QTc greater than 470 msec (with Bazett's correction) in screening
electrocardiogram or history of familial long Q wave, T wave (QT) syndrome.

5. Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week
apart.

6. Uncontrolled intercurrent illness including, but not limited to hypertension, ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements.

7. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
AZD2171.