Study of Metformin With Simvastatin for Men With Prostate Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to find out whether the two drugs used in the study, metformin and simvastatin, can slow down the speed of rise of prostate specific antigen (PSA) or stop its rise or even bring the level down. Recently, scientists noticed that men who take metformin to treat their high blood sugar or simvastatin to treat their high cholesterol are less likely to develop prostate cancer. Also, scientists found that, when these drugs are used in preclinical studies, they can slow down the growth of the prostate cancer cells. This study will try to find out whether these drugs can actually slow down the growth of prostate cancer in men.

Detailed Description
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Men who participate in this study will take both metformin and simvastatin every day. Both drugs are pills and can be taken at home. Subjects will be asked to take metformin and simvastatin until metastasis from their prostate cancer appears or until their PSA has doubled from what it was before they started the study. Primary Objective: To define the efficacy, as measured by an improvement in PSA doubling time (PSADT) at 6 months, of the combination of metformin plus simvastatin in patients with recurrent prostate cancer following definitive treatment. Secondary Objectives: To define the time to protocol-specified event for men treated with the combination of metformin plus simvastatin. To describe the pattern of change in log PSA levels and PSA velocity over time during treatment with metformin plus simvastatin. To describe the associations between changes in metabolic parameters (fasting glucose/insulin/lipid panel/leptin/adiponectin and others) with the pattern of change in log PSA levels.

Official Title
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Open-Label Study Of Metformin In Combination With Simvastatin For Men With Prostate Carcinoma And A Rising Serum Prostate-Specific Antigen Level After Radical Prostatectomy And/Or Radiation Therapy

Conditions
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Prostate Carcinoma

Intervention / Treatment
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* Drug: Metformin
* Drug: Simvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The study population will consist of subjects who have undergone primary therapy (prostatectomy or primary radiation) for biopsy-proven adenocarcinoma of the prostate and now have biochemical-only recurrence. Ability to understand and the willingness to sign a written informed consent document. Male 18 years or older. Histologically or cytologically confirmed diagnosis of prostate cancer. Biochemical recurrence following prostatectomy or radiation to the prostate, defined as at least 3 PSA rises, with each PSA determination at least 4 weeks apart, and each PSA value greater than or equal to 0.2 ng/mL. PSA must be less than 50 ng/mL at study entry. Screening PSA greater than or equal to 0.5 ng/mL for men who had a prostatectomy. Prior treatment with neoadjuvant, adjuvant, or salvage radiation therapy is allowed, again, with screening PSA greater than or equal to 0.5 ng/mL required for eligibility. Screening PSA greater than or equal to 1.0 ng/mL above their postradiation nadir for men who were treated with primary radiation therapy (external beam and/or brachytherapy). Men who had primary radiation therapy followed by salvage prostatectomy are eligible if screening PSA is greater than or equal to 0.5 ng/mL. PSA doubling time between 3 and 36 months. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%). Subjects must have normal organ and marrow function as defined below: * Leukocytes greater than or equal to 3,000/mcL * Absolute neutrophil count greater than or equal to 1,500/mcL * Hemoglobin greater than or equal to 10 g/dL * Platelets greater than or equal to 100,000/mcL * Total bilirubin within normal institutional limits * AST(SGOT)/ALT(SGPT) less than or equal to 1.5 X institutional upper limit of normal * Creatinine within normal institutional limits OR creatinine clearance or calculated greater than or equal to 60 mL/min/1.73 m2 for subjects with creatinine clearance or estimated creatinine levels above institutional glomerular filtration rate (eGFR) normal * Creatine phosphokinase (CPK) less than or equal to the institutional upper limit of normal Ability to swallow the study drugs. Life expectancy of at least 12 months. Subjects should agree to avoid grapefruit juice which is a major inhibitor of CYP3A4. Exclusion Criteria: Evidence of metastatic disease on imaging studies. Need for treatment with any conventional modality for prostate cancer (surgery, radiation therapy, and hormonal therapy). Prior hormonal therapy for recurrent prostate cancer (hormonal therapy given in a neoadjuvant or adjuvant setting and greater than 6 months before entry is acceptable). Prior chemotherapy for prostate cancer. Treatment within the last 30 days with any investigational drug. Radiation therapy within prior 6 months. Known hypersensitivity to metformin or statins. Subjects who need to take CYP3A4 inhibitors, such as cyclosporin, sirolimus, tacrolimus, verapamil,danazol, gemfibrozil, ketoconazole, or macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)will be excluded. Prior use of these agents is acceptable, as long as they are stopped at least a week prior to study entry. Subjects who need to take CYP3A4 inducers, such as phenobarbital, dexamethasone, carbamazepine,phenytoin, rifampicin, or non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine,etravirine) will be excluded. Prior use of these agents is acceptable, as long as they are stopped at least a week prior to study entry. Prior history of rhabdomyolysis. Prior history of lactic acidosis. Any history of myocardial infarction in the past 12 months. HIV-positive status. Subjects who consume more than 3 alcoholic beverages per day. Subjects with serious intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or other nonmalignant medical or psychiatric illness that is uncontrolled or whose control may be jeopardized by the complications of this therapy or may limit compliance with the study requirements (at the discretion of the investigator). Subjects diagnosed with or treated for another malignancy within 2 years prior to study enrollment or previously diagnosed with another malignancy and still having any evidence of residual disease. Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. Subjects currently treated with metformin or a statin or who have been treated with metformin or a statin in the past 6 months are ineligible for this study. Subjects who have taken 5a-reductase inhibitors (finasteride or dutasteride), saw palmetto, or PC-SPES within the last 6 weeks are ineligible for this study. Subjects taking other herbal supplements, vitamins, or other alternative medications are eligible for this study as long as they were started more than 2 months prior to study entry, have remained on a stable regimen, and will remain on a stable regimen for the duration of participation on this study. Men 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin, Simvastatin<br>Both metformin and simvastatin will be taken every day. Metformin will be taken as 1 pill in the morning and 1 pill before going to bed. Simvastatin will be taken as 1 pill before going to bed. They will be taken until metastasis from the prostate cancer appears or until the subjects PSA has doubled from what it was before they started the study. | Drug: Metformin<br>* Metformin treatment will be started at 500 mg twice daily (dose level -2), in order to minimize gastrointestinal discomfort and, if no gastrointestinal toxicity grade greater than 1, will be increased to 500 mg with breakfast/1000 mg at bedtime (dose level -1) 4 days later (+/- 1 day allowed). If no gastrointestinal toxicity grade greater than 1, it will be increased to 1000 mg twice daily (dose level 0) 10 days later (+/- 2 days allowed), which is the target dose for the remainder of the study. If gastrointestinal toxicity grade greater than 1 occurs during these first 4 weeks, the subject will be evaluated every 2 weeks until resolution of toxicity to grade less than or equal to 1 and, then, the metformin dose will be increased to the next dose level.<br>* Other names: Glucophage;Drug: Simvastatin<br>* The simvastatin dose at treatment initiation will be 20 mg once daily (dose level -1), taken at bedtime for 2 weeks. After these 2 weeks, the subject will have blood work and, if no AST/ALT/CPK elevation grade greater than 1, will be escalated to 40 mg once daily (dose level 0), taken at bedtime. If AST or ALT or CPK elevation grade greater than 1 during the first 2 weeks, the subject will be evaluated every 2 weeks until resolution of toxicity to grade less than or equal to 1, and then the simvastatin dose will be increased to dose level 0.<br>* Other names: Zocor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy, as measured by an improvement in PSA doubling time (PSADT) between baseline and 6 months, of the combination of metformin plus simvastatin in patients with recurrent prostate cancer following definitive treatment. |  | 6 months after subject start of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to protocol-specified event for men treated with the combination of metformin plus simvastatin. |  | From treatment initiation till disease progression (assessed up to 5 years) | 
| Pattern of change in log PSA levels and PSA velocity over time during treatment with metformin plus simvastatin. |  | From treatment initiation till disease progression (assessed up to 5 years) | 
| Associations between changes in metabolic parameters (fasting glucose/insulin/lipid panel/leptin/adiponectin and others) with the pattern of change in log PSA levels. |  | From treatment initiation till disease progression (assessed up to 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostatectomy, Prostate carcinoma, Prostate cancer, Prostate Specific Antigen, PSA, Metformin, Simvastatin, Radiation therapy