HSV-tk + Valacyclovir Therapy in Combination With Brachytherapy for Recurrent Prostate Cancer

This investigational new drug application describes a proposed phase I/II study designed to
assess the safety and efficacy of AdV-tk gene therapy in combination with standard
brachytherapy for patients with locally recurrent prostate cancer after having failed
radiation as a primary treatment with or without minimal metastasis. These patients do not
have any standard treatment that has been demonstrated to have a high degree of efficacy in
eradicating the tumor with a reasonable degree of safety. Thus, the potential risks
associated with the use of gene therapy in this group would appear reasonable. This
application is for use of a replication defective adenovirus vector (ADV/RSV-tk) delivering
the HSV-tk gene as a biologic vector for gene therapy.

Direct introduction of therapeutic genes into malignant cells in vivo may provide an
effective treatment of solid tumors such as prostate cancer. The herpes simplex virus
thymidine kinase (HSV-tk) gene codes for an enzyme which phosphorylates the nucleoside
analog ganciclovir (GCV) into an intermediate that is incorporated into newly synthesized
DNA and terminates further replication, leading to cell death. Since normal mammalian cells
do not possess this enzyme, cytotoxicity depends on the successful introduction and
expression of the HSV-tk gene, phosphorylation of ganciclovir and synthesis of DNA.
Non-dividing cells may express HSV-tk and phosphorylate ganciclovir but are not harmed since
they do not synthesize DNA. This approach is especially suitable for the treatment of tumors
where rapidly dividing tumor cells are adjacent to tissues made up largely of
non-proliferating cells. Using human and animal models for prostate cancer we have
demonstrated that adenovirus-mediated transfer of the HSV-tk gene resulted in sensitivity to
ganciclovir in vitro and growth suppression of mouse prostate cancer in vivo.

INCLUSION CRITERIA:

- biopsy-proven local recurrence of prostate cancer without metastatic disease after
the hormone therapy at least 2 year after the completion of definitive radiation
therapy

- Zubrod performance status 0-1

- WBC ≥ 4,000/μl, platelets ≥ 100,000/μl

- hemoglobin ≥ 8.5 mg/dl

- normal partial thromboplastin time and prothrombin time

- bilirubin < 1.5 mg/dl, and AST and alanine aminotransferase < 2.5 times the upper
limit of normal

- Serum creatinine ≤ 1.6 mg/dl

- Must undergo pre-treatment evaluation of tumor extent and tumor measurement

- Nutritional and general physical condition must be considered compatible with the
proposed radio-therapeutic treatment

- Not on any other experimental therapeutic cancer treatment

- No active untreated infection

- No major medical or psychiatric illness

- International Prostate Symptom Score (IPSS) less than 15

- Signed study-specific consent form prior to study entry

- Prostate volume less than 50 cc

- PSA > 10ng/ml within the past 3 months may enter study

EXCLUSION CRITERIA:

- Symptomatic metastasis disease

- Patients with a life expectancy < 10 years

- Patients on corticosteroids or any immunosuppressive drugs.

- HIV + patients

- Patients with acute infections (viral, bacterial, or fungal infections requiring
therapy)

- Patients with cirrhosis.

- Patients with collagen vascular diseases

- International Prostate Symptom Score (IPSS) greater than 15

- Prostate volume greater than 50 cc

- Second active cancer except cutaneous cancer

- Patients with history of allergies to valacyclovir, acyclovier or who cannot take
oral pills