Phase II High Risk Prostate Cancer Trial Using Gene & Androgen Deprivation Therapies, Radiotherapy, & Surgery

This phase II study plans to assess efficacy and toxicity of HSV-tk+ valacyclovir gene
therapy in combination with androgen deprivation therapy, brachytherapy, external beam
radiotherapy, and prostatectomy in previously untreated high-risk prostate cancer patients.

Clinical response as evaluated by changes in serum PSA level and digital rectal examination
as well as by histological alterations on re-biopsy and prostatectomy such as the presence of
apoptosis, necrosis, tumor proliferation and immunologic response, will be assessed following
HSV-tk + valacyclovir treatment. Blood samples will be taken for systemic immunological
response, blood counts and liver functions tests. Toxicity will be graded by the Common
Terminology Criteria for Adverse Events (CTCAE) and Radiation Therapy Oncology Group (RTOG)
neuro-toxicity scores (See Appendices). Additionally, patients will be followed closely to
assess nadir PSA, freedom from PSA-progression, and freedom from local and distant
progression and overall survival.

Inclusion Criteria:

- All patients must have biopsy proven adenocarcinoma of the prostate

- Patients in should have at least one or more of the following characteristics PSA>20,
Gleason score 8-10, Primary Gleason pattern 5, >4 cores with Gleason 8-10, and
Clinical stage T3a-T4.

- No prior surgical, hormonal, or radiotherapy prostate treatment.

- ECOG performance status 0-1

- No evidence of metastatic disease or other malignancy (except squamous or basal cell
skin cancers.

- Patients must have PSA within 3 months of entry.

- Signed informed consent to participate in the study must be obtained from patients
after they have been fully informed of the nature and potential risks of the study by
the investigator (or his/her designee) with the aid of written information.

- Willing to provide biopsies as required by the study.

- Patients must have adequate baseline organ function as assessed by the following
laboratory values before initiating the protocol:

- serum creatinine < 1.5 mg%

- T. bilirubin < 2.5 mg%, ALT and AST < 2x normal

- Pts > 100,000/mm3 , ANC> 1500 mm , Hgb> 10gm%

- Normal partial thromboplastin time (PTT) and Pro-Thrombin Time (PT)

Exclusion Criteria:

- Prior treatment with immunomodulatory therapy, immunotherapy, and/or gene vector
therapy in the past 3 months.

- Any cytotoxic chemotherapy, RT, or immunotherapy or any investigational drug within 3
weeks of study treatment start.

- Evidence of metastatic disease

- Prostate volume >50cc

- Prior prostate surgery (hyperthermia, cryotherapy, etc.)

- Prior pelvic radiotherapy

- Prior androgen ablation hormonal therapy (except finasteride if discontinued > 3 mo.
prior to enrollment)

- Patients on corticosteroids or any immunosuppressive drugs.

- History of liver disease, such as cirrhosis or active/chronic hepatitis B or C.

- History of or current alcohol misuse/abuse within the past 12 months.

- Known or suspected allergy or hypersensitivity to any component of the proposed
regimen (gene vector/Valacyclovir).

- Inability to swallow food or any condition of the upper gastrointestinal tract that
precludes administration of oral medications (Valacyclovir).

- No active malignancy except for non-melanoma skin cancer or in situ cervical cancer or
treated cancer from which the patient has been continuously disease free for more than
5 years.

- Presence of active or suspected acute or chronic uncontrolled infection or history of
immunocompromise, including a positive HIV test result.

- Patients < 18 years of age

- Unwilling or unable to comply with the study protocol.