Biomarker Study of Neoadjuvant Vitamin E in Patients With Locally Treatable Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to find out if vitamin E can help treat prostate cancer. Vitamin E acts primarily as an anti-oxidant. By decreasing the oxidation in the cancer cell, the tumor cells may die. Vitamin E is a commonly used vitamin that has not been approved by the Food and Drug Administration for use in this type of cancer or for any known cancer. This study will test the hypothesis that vitamin E, in the setting of an oxidative stress such as smoking, can reduce prostate cancer related biomarkers in patients with localized prostate cancer in the neoadjuvant setting.

Detailed Description
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- Prostate Cancer Prostate cancer is the most common malignancy in American men. It was estimated that nearly 235,000 men in the United States would be diagnosed with prostate cancer and nearly 27,000 men would die. The treatment of localized prostate cancer includes surgery, radiation therapy, or watchful waiting. The relative benefits of these approaches is unclear and treatment choices are individualized and often patient driven. There is currently no proven benefit to receiving preoperative hormonal therapy for patients undergoing radical prostatectomy. As opposed to patients undergoing external beam radiation therapy, for patients undergoing brachytherapy pre treatment hormonal therapy is used in approximately 40% of patients. Thus, these patients offer a unique opportunity to test novel agents in the neoadjuvant setting. - Vitamin E The term vitamin E was introduced by Evans and Bishop to describe a dietary factor important for reproduction in rats. Natural vitamin E includes two groups of closely related fat-soluble compounds, the tocopherols and tocotrienols. Eight analogous compounds are widely distributed in nature. Rich, natural sources of vitamin E are edible plant oils. Distinct biological effects of different forms of vitamin E can be distinguished at a molecular level. Vitamin E is the major hydrophobic chain-breaking antioxidant that prevents the propagation of free radical reactions in the lipid components of membranes, vacuoles and plasma lipoproteins. As an antioxidant, vitamin E acts in cell membranes where it prevents the propagation of free radical reactions. Non-radical oxidation products are formed by the reaction between alpha-tocopheryl radical and other free radicals, which are conjugated to glucuronic acid and excreted through the bile or urine. Vitamin E is transported in plasma lipoproteins. Most studies of the safety of vitamin E supplementation have lasted for several months or less, so there is little evidence for the long-term safety of vitamin E supplementation. The Food and Nutrition Board of the Institute of Medicine has set an upper tolerable intake level (UL) for vitamin E at 1,000 mg (1,500 IU) for any form of supplementary alpha-tocopherol per day. Based for the most part on the result of animal studies, the Food and Nutrition Board decided that because vitamin E can act as an anticoagulant and may increase the risk of bleeding problems this is the highest dose unlikely to result in bleeding problems (http://dietary-supplements.info.nih.gov/factsheets/vitamin.asp). The dose of vitamin E used in the Selenium and vitamin E prostate cancer prevention trial (the SELECT trial) was 400 IU per day and thus this is the dose chosen for this study.

Official Title
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A Phase III Biomarker Study of Neoadjuvant Vitamin E in Patients With Locally Treatable Prostate Cancer Prior to Prostatectomy or Brachytherapy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Vitamin E


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed prostate cancer. Patients must have localized prostate cancer and have decided to undergo a prostatectomy or brachytherapy. Patient must not be taking supplemental vitamin E. Age >18 years. Life expectancy of greater than 6 months. ECOG performance status =< 2. Patients must have normal organ and marrow function as defined below: leukocytes >= 3,000/mcL absolute neutrophil count >=1,500/mcL platelets >=100,000/mcL total bilirubin within normal institutional limits AST/ALT =< 2.5 X institutional upper limit of normal creatinine =< 1.5 X normal institutional upper limit of normal INR =<1.4 PTT =<1.4 X institutional upper limit of normal Patients must have the ability to understand, and the willingness to sign a written informed consent document. Exclusion Criteria: Patients who have metastatic prostate cancer. Patients may not be receiving any other investigational agents. Patients with a known bleeding diathesis or patients on therapeutic anticoagulation. (This does not include the use of aspirin but refers to warfarin, heparin, or low molecular weight heparins). History of allergic reactions attributed to compounds of similar chemical or biologic composition to vitamin E. The patient may not receive a gonadotrophin release agonist (such as goserelin, or leuprolide), or an antiandrogen (such as bicalutamide, flutamide, or nilutamide) during the study. Uncontrolled intercurrent illness that would limit compliance with study requirements. Inclusion of Women and Minorities Only men are eligible for this trial. Members of all races and ethnic groups are eligible for this trial.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (Vitamin E)<br>Vitamin E | Drug: Vitamin E<br>* Patients will take one 400 IU tablet of vitamin E or a placebo daily. Patients will continue on this treatment from the time of randomization to the day before surgery or the brachytherapy procedure. This is expected to be between 4 to 6 weeks. The patient will continue with his regular medications. The vitamin E will be supplied by the clinical trial through the UNM CRTC pharmacy.<br>* Other names: Alpha-tocopherol (α-tocopherol);|
| Placebo Comparator: Arm 2<br>Placebo (same vehicle as used for vitamin E) | Drug: Vitamin E<br>* Patients will take one 400 IU tablet of vitamin E or a placebo daily. Patients will continue on this treatment from the time of randomization to the day before surgery or the brachytherapy procedure. This is expected to be between 4 to 6 weeks. The patient will continue with his regular medications. The vitamin E will be supplied by the clinical trial through the UNM CRTC pharmacy.<br>* Other names: Alpha-tocopherol (α-tocopherol);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduce Biomarkers of Prostate Cancer (PSA Blood Level) | PSA levels will be measured as a sensitive marker of anti-androgenic activity that is a critical endpoint to be measured in this study. PSA blood levels will be determined at the initiation and completion of Vitamin E supplementation from blood obtained at these time points. A clinical reference laboratory will perform blood PSA analysis and will be compared with plasma cholesterol levels as a relative control. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the Tolerability/Toxicity of a Short Course of Vitamin E in the Neoadjuvant Setting. | Cardiovascular Effects/ Thrombophlebitis Dermatologic Effects Gastrointestinal Effects (Gingival bleeding, and gastrointestinal irritations including: diarrhea, nausea, flatulence and stomach cramps) Hematologic Effects (Increased bleeding tendencies in vitamin K deficient patients; inhibition of prothrombin production Hepatic Effects (Vasculopathic hepatotoxicity and cholestasis) Neurologic Effects (Dizziness, headache, fatigue or weakness Ophthalmic Effects ( Blurred vision) Respiratory Effects (Pulmonary embolism) | 3 years | 
| Determine Concordance of the Biomarkers in This Setting | The correlation between the ATQ level and the androgen receptor will be explored. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin E, Prostate Cancer, Alpha-tocopherol (α-tocopherol)