Docetaxel, Thalidomide, Prednisone, and Bevacizumab to Treat Metastatic Prostate Cancer

This is a Phase II study of docetaxel, bevacizumab, prednisone and thalidomide in patients
with androgen independent metastatic prostate cancer who are previously untreated with
chemotherapy. The primary objective of this study is to determine if the combination of
docetaxel, thalidomide and bevacizumab is able to be associated with a sufficiently high
proportion of patients with a PSA response to be worthy of further investigation in
metastatic prostate cancer. We will also be looking at multiple secondary endpoints. These
will include possible pharmacokinetic interactions among the study agents, potential
correlation between patient genotype and efficacy of treatment. We will also be looking for
circulating endothelial cells in blood before and after treatment. Additionally we will be
monitoring the tolerability of the regimen, time to disease progression, and survival
duration as endpoints as well. We hope to use this trial to build on the promising results
seen in our thalidomide/docetaxel protocol where there was a significant PSA decline and a
trend toward survival benefit.

- INCLUSION CRITERIA:

Androgen-independent metastatic adenocarcinoma of the prostate defined as progressive
metastatic disease while on gonadotropin releasing hormone (GnRH) agonists or post surgical
castration

Histopathological documentation of prostate cancer confirmed in the National Cancer
Institute (NCI) Laboratory of Pathology at the National Institutes of Health, the Pathology
Department at Walter Reed Medical Center or the Pathology Department at National Naval
Medical Center, prior to starting this study. In addition, patients whose slides are lost
or unavailable will be eligible for the study if they provide documentation of prostate
cancer and if they meet criteria of clinically progressive prostate cancer as outlined in
section 3.1.1.3.

Clinically progressive prostate cancer documented prior to entry. Progression must be
documented by at least one of the following parameters:

- Two consecutively rising prostate-specific antigen (PSA) levels. The first rising PSA
must be a minimum of one week from a reference value. It is recognized that PSA
fluctuations are such that the confirmatory PSA value might be less than the previous
one. In these cases, that patient would still be eligible provided the next PSA was
greater than the first rising PSA value. Patients must have PSA greater than or equal
to 5.0.

- At least one new lesion on bone scan.

- Progressive measurable disease.

Patients must have undergone bilateral surgical castration or must continue on GNRH
agonist.

Those patients receiving an anti-androgen agent and are entering the trial due to a rise in
PSA must demonstrate a continued rise in PSA 4 weeks after stopping flutamide and 6 weeks
after stopping bicalutamide or nilutamide.

Patients may not have received any chemotherapy for metastatic prostate cancer

Age greater than or equal to 18 years

Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2

Life expectancy of greater than 3 months

Patients must have adequate organ and marrow function as defined below:

Leukocytes- greater than or equal to 3,000/microliter

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

Platelets- greater than or equal to 100,000/microliter

Hemoglobin- greater than or equal to 8.0g/L - transfusions acceptable

Total bilirubin- less than or equal to 1.5 times the institutional upper limits of normal

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

Creatinine or Creatinine clearance- less than or equal to 1.5 times the institutional upper
limits of normal or greater than or equal to 40 mL/min/1.73 m^2 for patients with
creatinine levels above institutional normal.

Recovered from any toxicity from surgery or radiotherapy

Must be willing to travel from their home to the National Institutes of Health (NIH) for
follow-up visits

Able and willing to follow instructions and conform to protocol.

Patients may have had no other active malignancy within the past 2 years with the exception
of non-melanoma skin cancer and superficial bladder carcinoma

No history of myocardial infarction within the past 6 months, uncontrolled congestive heart
failure (CHF) or uncontrolled angina pectoris

Patients must agree to use adequate contraception (abstinence; hormonal or barrier method
of birth control) for the study and at least 2 months after completion.

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

EXCLUSION CRITERIA:

Present clinical signs or symptoms of brain and/or leptomeningeal metastases confirmed by
computed tomography (CT) or magnetic resonance imaging (MRI) brain scan.

Uncontrolled, intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure (American Heart Association (AHA) Class II
or worse), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements

Persistent systolic blood pressure greater than or equal to 170 mmHg or diastolic blood
pressure greater than or equal to 100 mmHg.

Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral
therapy are excluded from the study because of possible pharmacokinetic interactions with
docetaxel, bevacizumab, and/or the combination.

Proteinuria, as demonstrated by a urine, protein, creatinine (UPC) ratio greater than or
equal to 1.0 at screening, required to be assessed if urine dipstick is greater than or
equal to 1+.

Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC)
ratio. For UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should
be < 1000 mg for patient enrollment. Note: UPC ratio of spot urine is an estimation of the
24 urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine
protein of 1 gm. UPC ratio is calculated using one of the following formula:

- [urine protein]/[urine creatinine] - if both protein and creatinine are reported in
mg/dL

- [(urine protein) x 0.088]/[urine creatinine] - if urine creatinine is reported in
mmol/L

Therapeutic anticoagulation with coumadin, heparins, or heparinoids.

Greater than Grade 2 peripheral neuropathy at baseline.

History of transient ischemic attacks (TIA) or cerebrovascular accident (CVA) within the
past 2 years.

History of allergic reaction to docetaxel, prednisone, thalidomide and/or bevacizumab or
related products.

Patients who are on concurrent investigational agent(s)

Patients who are unable to ingest oral medication.

INCLUSION OF WOMEN AND MINORITIES

Men of all races and ethnic groups are eligible for this trial. Every effort will be made
to recruit minorities in this study. Women are ineligible for this study.