Randomized Trial of Suicide Gene Therapy and Prostate Cancer

OBJECTIVES

This is a randomized, controlled trial that will test the hypothesis that
replication-competent adenovirus-mediated suicide gene therapy in combination with 80 Gy
intensity modulated radiotherapy (IRMT)will improve freedom from failure (FFF) relative to
80 Gy IMRT alone in patients with newly-diagnosed prostate cancer with an intermediate-risk
profile.

The trial contains two treatment arms:

Arm 1- Gene Therapy + IMRT Arm 2- IMRT

The study will be stratified by clinical site and pre-treatment risk factors (e.g., %
positive biopsy cores, Gleason score.

- Gleason score 5/6 AND PSA <10 ng/mL; AND >=50% positive biopsy cores

- (Gleason score 5/6 and PSA 10-20 ng/mL) OR (Gleason score 7 and PSA 0 - 20 ng/mL); AND
<50% positive biopsy cores

- Gleason score 5/6 and PSA 10-20 ng/mL) OR (Gleason score 7 and PSA 0-20 ng/mL) AND
>=50% positive biopsy cores.

An interim safety analysis (Interim Analysis 1) will be conducted after the first 21
patients in the investigational therapy arm, and a total of 42 subjects in both arms, have
completed the 90 day toxicity assessment following randomization (phase 2 component). If, at
this point, there are no safety concerns as determined by the Data and Safety Monitoring
Board (DSMB), the trial will continue as a phase 3 study with two additional interim
analyses (Interim Analyses 2 & 3). The primary analysis for treatment efficacy will be based
on all randomized subjects.

Primary

To assess the relative efficacy of replication-competent adenovirus-mediated suicide gene
therapy in combination with 80 Gy intensity modulated radiotherapy (IMRT) versus 80 Gy IMRT
alone in patients with newly-diagnosed prostate cancer with an intermediate-risk profile.
The primary endpoint is freedom from failure (FFF) (biochemical or clinical).

Secondary

To assess the difference between the two treatment arms for:

- Acute (<= 90 days) and long-term (> 90 days) toxicity.

- Prostate biopsy status (12 cores) at 2 years.

- Freedom from distant metastases.

- Disease-specific and overall survival.

- Quality of life.

Exploratory

To examine:

- Possible effect of gene therapy on PSA doubling time (PSADT) after PSA failure.

- Possible association between the primary and secondary outcomes and
Ad5-yCD/mutTKSR39rep-ADP adenovirus persistence (as measured by adenoviral DNA in
blood).

- Possible association between the primary and secondary outcomes and specific
immunological endpoints including levels of circulating CD4+ and CD8+ T lymphocytes,
T-cell proliferation response, cytotoxic T lymphocyte (CTL) response, and development
of antibodies to prostate-specific antigens.

Inclusion Criteria:

- Men with histologically-confirmed adenocarcinoma of the prostate within 180 days
prior to registration. To be eligible, the subjects must have one of the following
conditions:

- Stage T1 or T2, Gleason Score 7, PSA <= 20 ng/mL, Any number positive biopsy
cores

- Stage T1 or T2, Gleason Score 5 or 6, PSA >=10 ng/mL and <20 ng/mL, Any number
positive biopsy cores

- Stage T1 or T2, Gleason Score 5 or 6, PSA <10 ng/mL and >=50% positive biopsy
cores

- Negative lymph nodes as established by imaging, nodal sampling, or dissection within
90 days prior to registration.

- No evidence of metastatic disease as evaluated by bone scan and CT scan of the
abdomen and pelvis within 90 days prior to registration

- Karnofsky performance status >=70

- Subjects must have adequate baseline organ function, as assessed by the following
laboratory values, within 30 days before initiating the study

- Adequate renal function with serum creatinine <=1.5 mg/dL or creatinine clearance
>=45 mL/min/m2.

- Platelet count > 100,000/μL.

- Absolute neutrophil count > 1,000/μL.

- Hemoglobin > 10.0 g/dL.

- Normal partial thromboplastin time (PTT) and prothrombin (PT).

- Bilirubin < 1.5 mg/dL; SGOT and SGPT < 2.5 times upper limit of normal (ULN).

- Men of child-producing potential must be willing to consent to use effective
contraception while on treatment and for at least 3 months afterwards.

- Subjects must possess the ability to give informed consent and express a willingness
to meet all of the expected requirements of the protocol for the duration of the
study.

Exclusion Criteria:

Subjects with the following conditions will be excluded from the study:

- Stage >= T3.

- Prostate specific antigen (PSA) > 20 ng/mL.

- Gleason score >= 8.

- Prostate volume >120cc.

- Pathologically positive lymph nodes or nodes > 1.5 cm on imaging. Note: nodes > 1.5
cm but biopsy negative are allowed.

- Evidence of M1 metastatic disease.

- Prior invasive malignancy except for non-melanoma skin cancer within 5 years of
enrollment.

- Prognosis for survival of < 5 years.

- Prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral
orchiectomy for any reason.

- Prior radiotherapy, including brachytherapy, to the region of the study cancer that
would result in overlap of radiation fields.

- Prior or planned androgen suppression therapy or prior systemic chemotherapy for the
study cancer. Note that prior chemotherapy for a different cancer is allowed;
however, patients must be >2 years post-completion of chemotherapy at time of
registration. Patients on Proscar therapy must stop to be eligible.

- Severe, active co-morbidity defined as:

- Unstable angina and/or congestive heart failure requiring hospitalization within the
last 6 months.

- Transmural myocardial infarction within the last 6 months.

- Acute infection. Acute infection is defined by any viral, bacterial, or fungal
infection that requires specific therapy within 72 hours of initiation of the study
therapy.

- Positive serological test for HIV at baseline.

- Previous history of liver disease including hepatitis.

- Immunosuppressive therapy including systemic corticosteroids. Use of inhaled and
topical corticosteroids is permitted.

- Impaired immunity or susceptibility to serious viral infections.

- Allergy to any product used in the protocol. (If the subject has an allergy to
Ciprofloxacin, another antibiotic can be substituted at the discretion of the
treating physician.

- Serious medical or psychiatric illness or concomitant medication, which, in the
judgment of the principal investigator, might interfere with the subject's ability to
respond to or tolerate the treatment or complete the trial.