Clinical trial NCT03137186: Repurposing Metformin as Anticancer Drug: in Advanced Prostate Cancer
Official title: Mansmed Trial : Repurposing Metformin as Anticancer Drug, RCT in Advanced Prostate Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: Metformin, prostate cancer
Lead sponsor: Mansoura University
Sponsor class: OTHER
First posted: 2017-05-02
Enrollment: 120
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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)
2. OR newly diagnosed metastatic or node-positive disease at least one of:

   * Stage T any N+ M0
   * Stage T any Nany M+
3. 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+)
4. 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:

1. Age \< 18 years
2. Excessive alcohol intake, acute or chronic
3. Patients already treated with Metformin or an analoge
4. Known hypersensitivity or allergy to Metformin or any of the excipients.
5. Patients with a history of lactic acidosis
6. Patient treated for a cancer other than prostate cancer, with the exception of basal cell carcinoma
7. Acute or chronic metabolic acidosis.
8. Patients suffering from severe dehydration.
9. Patients with chronic heart failure.
10. Patients with hepatic impairment.
11. Patients with severe renal disease.

Primary outcomes:
measure: duration in months from beginning of treatment till development of CRPC
timeFrame: 2 years
Secondary outcomes:
measure: CRPC free survival
timeFrame: 4 years
measure: Overall patients' survival
timeFrame: 4 years
Other outcomes:
Locations:
city: Mansourah
country: Egypt
facility: Mansoura university
Study officials:
affiliation: Mansoura University
name: Reham Alghandour
role: PRINCIPAL_INVESTIGATOR
References:
citation: Colquhoun AJ, Venier NA, Vandersluis AD, Besla R, Sugar LM, Kiss A, Fleshner NE, Pollak M, Klotz LH, Venkateswaran V. Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer. Prostate Cancer Prostatic Dis. 2012 Dec;15(4):346-52. doi: 10.1038/pcan.2012.16. Epub 2012 May 22.
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citation: Spratt DE, Zhang Z, Zelefsky MJ. Reply to Leah Bensimon, Samy Suissa, and Laurent Azoulay's letter to the editor re: Daniel E. Spratt, Chi Zhang, Zachary S. Zumsteg, Xin Pei, Zhigang Zhang, Michael J. Zelefsky. metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. Eur Urol 2013;63:709-16. Eur Urol. 2013 Aug;64(2):e29-30. doi: 10.1016/j.eururo.2013.04.015. Epub 2013 Apr 19. No abstract available.
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