Repurposing Metformin as Anticancer Drug: in Advanced Prostate Cancer

Study Overview
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Brief Summary
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This study evaluate the addition of metformin to standard of care in locally advanced and metastatic prostate cancer, half the patient will receive metformin in combination with standard treatment, and the other half will receive the standard of care only

Detailed Description
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Advanced-stage PCa is usually treated with androgen-deprivation therapy (ADT). Most patients with metastatic disease who were managed with ADT eventually progress to castration-resistant prostate cancer (CRPC) and die of the disease. CRPC can be treated with docetaxel, abiraterone plus prednisone, enzalutamide, and cabazitaxel, which provide limited survival benefits. Thus, there is still a need to improve the therapeutic options available for advanced-stage prostate cancer patients. Targeting therapy-resistant cancer stem cells (CSCs )in prostate cancer provides a unique opportunity for novel therapeutic interventions. Metformin, a common well-tolerated oral biguanide prescribed for type II diabetes, could be used to sensitize prostate CSCs to current conventional anticancer therapies and improve the efficacy of treatment. Some studies reported that Metformin could enhance the effectiveness of ADT. Metformin augmented the antiproliferative and apoptotic effects of ADT in prostate cancer. The combination of these two drugs significantly reduces prostate cancer cell growth compared to monotherapy with either drug. Also, metformin might reduce the development of CRPC. Many studies showed that obesity and DM were linked to aggressive prostate cancer phenotype, including biochemical failure after radical prostatectomy and external beam radiotherapy with higher incidence of complications of ADT. Interestingly, metformin reduces the incidence of diabetes and the adverse metabolic effects of ADT, including hyperinsulinaemia and dyslipidaemia, and decreases myocardial infarction risk and prolongs survival in diabetic patients. To the best of our knowledge, after extensive computer research, there is no published results from prospective randomized trials evaluating role of metformin among men with high risk locally advanced or metastatic prostate cancer patients who will start treatment with ADT.

Official Title
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Mansmed Trial : Repurposing Metformin as Anticancer Drug, RCT in Advanced Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: High-risk newly diagnosed non-metastatic node-negative disease at least two of: Stage T3/4, PSA≥40ng/ml or Gleason sum score 8-10 Intention to treat with radical radiotherapy (unless there is a contraindication) OR newly diagnosed metastatic or node-positive disease at least one of: Stage T any N+ M0 Stage T any Nany M+ OR previously treated with radical surgery and/or radiotherapy, now relapsing At least one of: (-PSA ≥4ng/ml and rising with doubling time less than 6 months,N+, M+) And for all patients Age > 18 years Histologically confirmed prostate adenocarcinoma Intention to treat with long-term androgen deprivation therapy Fit for all protocol treatment and follow-up, ECOG performance status 0-2 Diabetic and non-diabetic patients Patients with adequate organ function(AST - ALAT ≤ 2.5x ULN,Bilirubin ≤ 1.5 x ULN) Exclusion Criteria: Age < 18 years Excessive alcohol intake, acute or chronic Patients already treated with Metformin or an analoge Known hypersensitivity or allergy to Metformin or any of the excipients. Patients with a history of lactic acidosis Patient treated for a cancer other than prostate cancer, with the exception of basal cell carcinoma Acute or chronic metabolic acidosis. Patients suffering from severe dehydration. Patients with chronic heart failure. Patients with hepatic impairment. Patients with severe renal disease.

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Investigational arm<br>Metformin will be added to standard of care | Drug: Metformin<br>* Metformin will be added as a daily treatment to the standard treatment in both neoadjuvant and adjuvant settings of locally advanced cases and lifelong to metastatic cases. The starting daily dose of metformin is 850mg Once daily, to be increased to 850 mg if tolerated<br>* Other names: Cidophage;|
| No Intervention: Control arm<br>Patients will treated according to Standard of care only | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| duration in months from beginning of treatment till development of CRPC | time till development of CRPC [Castrate resistant prostate cancer], is defined by disease progression despite androgen depletion therapy (ADT) and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CRPC free survival | Number of survivors without CRPC at 4 years | 4 years | 
| Overall patients' survival | Number of overall survivors at 4 years regardless occurrence of CRPC or not | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metformin, prostate cancer