Effects of IAS in Men With Localized Biochemical Relapsed Prostate Cancer

The standard first line treatment for men with early stage newly diagnosed localized prostate
cancer is a surgical removal of the prostate, localized external beam radiation,
brachytherapy, or a combination of surgery and radiation. In most patients Prostate Specific
Antigen (PSA) levels will decline after these localized treatments, demonstrating a response
to these therapies. However despite an initial response to localized treatment, some men will
go on to later develop a rise in PSA levels, an indicator of Biochemical Relapsed Prostate
Cancer (BRPC). For BRPC patients who have not yet developed metastasis, the standard
treatment is Androgen Deprivation Therapy (ADT) to decrease levels of Testosterone,
subsequently decreasing PSA levels. A low value for the PSA is more desirable as it may
indicate no tumor growth.

ADT may be administered as a continuous treatment (Continuous Androgen Suppression, or CAS)
or as intermittent treatment (Intermittent Androgen Suppression, or IAS). This treatment is
continued until the development of Castration Resistant Prostate Cancer (CRPC), indicated by
a rise in PSA despite ADT. Giving the hormone therapy intermittently (in cycles of treatment
and off treatment periods) appears to delay the change of prostate cancer to a type of
prostate cancer that resists hormone therapy, prolonging efficacy of ADT monotherapy. IAS may
also decrease the impact of ADT on mental status.

This study evaluated the effect of intermittent androgen suppression on time to androgen
independent progression (the development of castration resistant disease) and overall
survival in men with localized prostate cancer. Subjects were also evaluated for the effects
of intermittent androgen suppression on a variety of neuro-psychiatric assessments and on
bone density.

The subjects in this study had a rising PSA value after definitive therapy either with
radical prostatectomy or external beam irradiation for the treatment of prostate cancer. All
subjects were males at or over the age of 21 years.

New subjects were introduced to this study protocol (along with other non-study treatment
options) during a clinic visit with Dr. Higano or another sub-investigator. After informed
consent was obtained, subjects underwent the following screening procedures before starting
treatment: Bone density scan (DEXA), Technetium-99 bone scan, CT scan of the chest, abdomen,
and pelvis, blood draw, and neuro-psychiatric assessments. Subjects then began androgen
suppression with a two-week lead-in of Flutamide, followed by 9 monthly injections of
Leuprolide Acetate. During the treatment, they had quarterly clinic visits and blood draws.
Their PSA levels were monitored monthly, and if their PSA reached the appropriate nadir at by
month 9, the androgen suppression was interrupted. At the end of each treatment cycle,
subjects underwent another bone density test, blood draw, problem solving test, and
neuro-psychiatric assessments.

During the "off treatment" phase, the subject will again had quarterly clinic visits, blood
draws, and neuro-psychiatric assessments. PSA and testosterone were be monitored monthly.
Once the PSA reached the appropriate threshold, the subject performed another set of
screening procedures and resumed treatment for another 9 months. This cycle continued until
the patient withdrew from the study, was taken off the study due to toxicities or the
decision of the investigator, or until the treatment with IAS was no longer effective in
controlling the prostate cancer. The neuro-psychiatric assessments were only performed during
the subject's first cycle of treatment (consisting of the 9 months on treatment, and at month
3 of the off treatment period afterwards).

Inclusion Criteria:

- Biochemical relapse (rising PSA) after initial treatment (radiation therapy,
brachytherapy, or radical prostatectomy) for histologically or cytologically confirmed
adenocarcinoma of the prostate

- Clinical stage A2, B, C, D1

- Age: older than 21 years old

- Performance status of 0 or 1

- Pretreatment serum testosterone, normal range (or no clinical evidence of testosterone
deficiency).

- If less than 30 months since completion of radiation therapy, biopsy of prostate
suggested within 6 months of study entry. If more than or equal to 30 months since
completion of radiation therapy, biopsy of prostate suggested within 1 year.

- Written informed consent.

Exclusion Criteria:

- Abnormal bone scan suggestive of metastatic osseous disease.

- Previous hormonal manipulation including orchiectomy or any medication with
significant antiandrogenic activity (combined androgen suppression over 9 months,
monotherapy antiandrogens, estrogens, ketoconazole). *Neoadjuvant androgen suppression
therapy of less than or equal to 3 months is allowed, if this androgen suppression
therapy was completed more than or equal to 1 year prior to study enrollment AND if
the Testosterone level is within the normal ranges.

- Any systemic chemotherapy or curative radiotherapy within 6 months.

- Hepatic dysfunction:

- Total bilirubin greater than 2.0 mg/dl

- Aspartate transaminase (AST; SGOT) greater than 3 times the upper limit of normal
range

- Lactate dehydrogenase (LDH) greater than 3 times the upper limit of normal
range).

- Renal dysfunction:

- Blood urea nitrogen (BUN) greater than 40 mg/dl

- Serum Creatinine greater than 2.0 mg/dl.

- History or presence of other malignancy within the last 5 years (except treated
squamous/basal cell carcinoma of the skin or superficial bladder carcinoma).

- Hypersensitivity to flutamide or leuprolide.