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

Study Overview
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Brief Summary
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This is a prospective phase II study to assess the 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.

Detailed Description
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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.

Official Title
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Phase II Study Evaluating HSV-tk + Valacyclovir Gene Therapy in Combination With Androgen Deprivation Therapy, Brachytherapy, External Beam Radiotherapy, and Prostatectomy for High-Risk Prostate Cancer

Conditions
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High-risk Prostate Cancer, Prostate Cancer

Intervention / Treatment
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* Drug: HSV-Tk
* Drug: Valacyclovir
* Drug: Bicalutamide
* Drug: Leuprolide Acetate
* Radiation: Brachytherapy, External beam radiotherapy
* Procedure: Radical prostatectomy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gene Therapy, ADT, RT, and Surgery<br>The investigational gene therapy, ADV/HSV-tk, will be administered by injection into the prostate at 5 x 10[11] virus particles (1.25 x 10[11] virus particles per tumor quadrant in 4 quadrants) on day 0 and day 30. The recommended dose of Valacyclovir for this trial is 2 g orally t.i.d. for 14 days (day 1 to day 15 and days 31 to 45). The recommended dose for Bicalutamide therapy in combination with an LHRH analogue is one 50 mg tablet once daily (morning or evening). Leuprolide acetate 7.5mg depot injection will be injected monthly for a total of 2 months. | Drug: HSV-Tk<br>* Injection of the HSV-tk gene therapy product in four quadrants of prostate to enhance the immune system via bystander effect in which cytotoxicity is conferred to non-transduced neighboring cells. In vivo bystander effects are likely due to a combination of host immunological responses and to gap junction-mediated transport of phosphorylated prodrug metabolites to surrounding cells.<br>* Other names: Herpes simplex virus thymidine kinase;Drug: Valacyclovir<br>* The recommended dose for this trial is 2 g orally t.i.d. for 14 days (day 1 to day 15 and days 31 to 45). This dose has been calculated to give a similar AUC as 10 mg/kg of intravenous acyclovir administered every 8 hours. This is the same dose regimen used in a previous phase I clinical trial of ADV/HSV-tk plus acyclovir and topotecan in patients with recurrent ovarian cancer.<br>* Other names: Valtrex;Drug: Bicalutamide<br>* The recommended dose for Bicalutamide therapy in combination with an LHRH analogue is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that Bicalutamide be taken at the same time each day. The use of an oral antiandrogen with medical castration for the treatment of prostate cancer is referred to as combined androgen blockade (CAB). Compared with LHRH-agonist monotherapy, CAB with bicalutamide did not reduce overall QoL but provided an early improvement in QoL related to lower urinary tract symptoms and pain.<br>* Other names: Casodex;Drug: Leuprolide Acetate<br>* Leuprolide acetate 7.5 mg depot injection will be injected monthly for a total of 2 months.<br>* Other names: Lupron;Radiation: Brachytherapy, External beam radiotherapy<br>* On day 60, patient will undergo high dose rate (HDR) Brachytherapy. The patient will have 8-14 needle catheters inserted under ultrasound guidance. CT simulation and radiation treatment planning will be performed. The needle catheters will be connected to an HDR afterloader containing an Iridium 192 source. A single dose of 1250cGy will be delivered.<br>* Other names: EBRT;Procedure: Radical prostatectomy<br>* approximately 2-3 weeks after radiotherapy completion, patient will undergo radical retropubic prostatectomy. Use of laparoscopy or robotic assistance will be at the urologist's discretion. Lymph node dissection will be performed.<br>* Other names: Prostatectomy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical control rate | measured by PSA | 5-year biochemical disease free survival rate | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate | Measured at the end of the study | 5-year overall survival rate | 
| Pathologic complete response rate | Measured by pathologic result of prostatectomy | After prostatectomy | 
| Safety based on questionnaire and clinical adverse event monitoring | Measured by the Sexual Health Inventory for Men (SHIM), the International Prostate Symptoms Score (IPSS), and the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) | 5-year post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gene therapy, untreated prostate cancer