Vaccine Therapy With PROSTVAC/TRICOM and Flutamide Versus Flutamide Alone to Treat Prostate Cancer

Background:

- There is no standard of care for prostate cancer patients progressing on hormone therapy
with a rising serum PSA (prostatic specific antigen) level without evidence of
metastatic disease.

- We have completed a phase II trial in which men with this stage of disease were
randomized to receive a pox vector PSA vaccine vs. the antiandrogen nilutamide.

- The median time to treatment failure on nilutamide was 7.6 months.

- 12 patients on the vaccine arm had nilutamide added at the time of PSA progression.

- The median time for treatment failure after the addition of nilutamide was 13.9 months,
for a total of 25.9 months from initiation of vaccine therapy.

- This suggests that the combination of hormone therapy with vaccine therapy may lead to
an improved clinical benefit compared to hormone therapy alone.

- Due to the increased toxicity of nilutamide compared to other antiandrogens and the
patients prior exposure to bicalutamide therapy, we plan to use flutamide as a second
line hormonal manipulation in the below study.

Objectives (Primary):

-To determine if use of a combination of vaccine plus flutamide may be associated with a
trend toward improvement in time to treatment failure compared to flutamide alone.

Eligibility:

- Must have non metastatic androgen insensitive prostate cancer with a rising PSA with
castrate levels of testosterone and no evidence of metastatic disease on CT (computed
tomography) scan or bone scan.

- Hgb (hemoglobin) greater than or equal to 9 g/dL.

- Lymphocyte count greater than or equal to 500/mm(3).

- Hepatic function: Bilirubin less than or equal to 1.5 mg/dL, OR patients with Gilbert's
syndrome, a total bilirubin less than or equal to 3.0 mg/dL, AST (aspartate
aminotransferase) and ALT (alanine aminotransferase) less than 2.5 times upper limit of
normal

Design:

-Flutamide will be administered at a dose of 250 mg PO (by mouth) tid (three times a day)
every day in both arms A and B.

rV-PSATRICOM will be administered s.c. (subcutaneous) on day 1 in Arm B.

rF-PSATRICOM will be administered s.c. on day 29 & every 4 weeks in Arm B.

- For patients with declining PSA no restaging will be done unless they develop symptoms
consistent with metastatic disease.

- For patients with rising PSA, once 2 consecutive PSA rises are seen, a CT will be done
at their next scheduled visit. They will then be re-staged (CT and bone scans) at 3
month intervals as long as PSA continues to rise.

- After 3 months of therapy, patients receiving the flutamide alone (arm A) may cross over
to receive vaccine if they develop a rising PSA and scans are without metastatic
disease. The vaccine may commence 4 weeks after flutamide is stopped if the PSA
continues to rise. If there is an antiandrogen withdrawal response (a decline in PSA 28
days after the discontinuation of flutamide), PSA serum levels will be checked every 28
days and vaccine may commence when the serum PSA levels begin to rise (if scans are
negative for metastatsis). Patients on arm B will have flutamide discontinued and may
continue vaccine therapy. At this point patients may continue to receive treatment on
study until the development of disease on scans or a second occurrence of clinical
progression.

- Patients who have been on study for 2 years or more with stable disease and who are not
getting vaccine, clinic visits may be scheduled every 8 weeks. (Patients receiving
monthly vaccine will continue to have monthly visits.)

- For patients who have stable disease and attend clinic every 8 weeks, once 2 consecutive
PSA rises are seen, a CT and bone scan will be done at their next visit in 4 weeks. They
will then be restaged (CT and bone scans) at 3 month intervals as long as PSA continues
to rise.

- INCLUSION CRITERIA:

A. Histopathological documentation of prostate cancer confirmed in the Laboratory of
Pathology at the: National Institutes of Health (NIH) Clinical Center prior to starting
this study. If no pathologic specimen is available, patients may enroll with a pathologists
report showing a histologic diagnosis of prostate cancer and a clinical course consistent
with the disease.

B. Must have non-metastatic androgen insensitive prostate cancer with a rising PSA
(prostatic specific antigen) with castrate levels of testosterone and no evidence of
metastatic disease on CT (computed tomography) scan or bone scan. A rising PSA is defined
as two consecutively rising PSA levels, separated by at least 1 month apart, with the last
measurement that is greater than 1ng/ml. Patients on nilutamide therapy must undergo
nilutamide withdrawal for at least 4 weeks and still show evidence of a rising PSA.
Following treatment with bicalutamide, patients must undergo withdrawal for at least 6
weeks and still show evidence of a rising PSA.

C. Life expectancy greater than or equal to 6 months.

D. ECOG (Eastern Cooperative Oncology Group) performance status of 0-1.

E. No systemic steroid or steroid eye drop use within 2 weeks prior to initiation of
experimental therapy.

F. Hematological eligibility parameters:

- Granulocyte count greater than or equal to 1,500/mm(3).

- Platelet count greater than or equal to 100,000/mm(3)

- Hgb (Hemoglobin) greater than or equal to 9 Gm/dL

- Lymphocyte count greater than or equal to 500/mm(3).

G. Biochemical eligibility parameters (within 16 days of starting therapy)

-Hepatic function: Bilirubin less than or equal to 1.5 mg/dl, OR patients with Gilbert's
syndrome, a total bilirubin less than or equal to 3.0 mg/dL, AST (aspartate
aminotransferase) and ALT (alanine aminotransferase) less than 2.5 times upper limit of
normal

H. No other active malignancies within the past 3 years (with the exception of non-melanoma
skin cancers or carcinoma in situ of the bladder) or life threatening illnesses.

I. Willing to travel to the NIH for follow-up visits.

J. 18 years of age or greater.

K. Able to understand and sign informed consent.

L. Must agree to use effective birth control (such as a condom) or abstinence during and
for a period of 4 months after the last vaccination therapy. Patients must be willing to
remain on chemical castration therapy, unless they have had surgical castration.

M. Patients must have recovered from acute toxicities related to prior therapy or surgery.

N. Parameters for assessment of baseline renal function:

Serum creatinine less than or equal to 1.5 times the upper limit of normal OR creatinine
clearance on a 24-h urine collection of greater than or equal to 60 mL/min.

EXCLUSION CRITERIA:

A. Patients should have no evidence of being immunocompromised as listed below.

- Human immunodeficiency virus positivity due to the potential for decreased tolerance
and may be at risk for severe side effects.

- Concurrent use of topical steroids (including steroid eye drops) or systemic steroids.
Nasal or inhaled steroid use is permitted.

- Patients who have undergone allogenic peripheral stem cell transplantation or solid
organ transplantation requiring immunosuppression.

B. Patients who test positive for active Hepatitis B or Hepatitis C infection.

C. Patients should have no autoimmune diseases that have required treatment such as,
Addison's disease, Hashimoto's thyroiditis, or systemic lupus erythematous, Sjogren
syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome, active Grave's disease.

D. History of allergy or untoward reaction to prior vaccination with vaccinia virus or to
any component of the vaccinia vaccine regimen.

E. Do not administer the recombinant vaccinia vaccine if the recipient, or for at least
three weeks after vaccination, their close household contacts (close household contacts are
those who share housing or have close physical contact) are: persons with active or a
history of eczema or other eczematoid skin disorders; those with other acute, chronic or
exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, varicella zoster,
severe acne, or other open rashes or wounds) until condition resolves; pregnant or nursing
women; children 3 years of age and under; and immunodeficient or immunosuppressed persons
(by disease or therapy), including HIV (human immunodeficiency virus) infection.

F. Serious intercurrent medical illness (e.g., one that requires treatment) which would
interfere with the ability of the patient to carry out the treatment program, including,
but not limited to, inflammatory bowel disease, Crohn's disease, ulcerative colitis, or
active diverticulitis.

G. Patients with cardiac disease that have fatigue, palpitation, dyspnea or angina with
ordinary physical activity (New York Heart Association class 2 or greater) are not
eligible.

H. Patients with a history of congestive heart failure or who have objective evidence of
congestive heart failure by physical exam or imaging are not eligible.

I. Patients with pulmonary disease that have fatigue or dyspnea with ordinary physical
activity are not eligible.

J. Concurrent chemotherapy.

K. No known brain metastasis, or with a history of seizures, encephalitis, or multiple
sclerosis.

L. Patients with a serious hypersensitivity reaction to egg products are not eligible.

M. Prior splenectomy.

N. Patients who have received prior flutamide therapy in the last year. (Patients treated
with flutamide in the neoadjuvant or adjuvant setting or those previously treated with
flutamide who did not have a rising PSA on treatment would be allowed to enroll on the
protocol.)