Repurposing Metformin as Anticancer Drug: in Advanced Prostate Cancer

Prostate Cancer Clinical Trial

— Mansmed  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03137186
• Other study ID #: Mansmed trial I
• Status: Recruiting
• Phase: Phase 2
• First received: April 9, 2017
• Last updated: April 29, 2017
• Start date: January 2017
• Est. completion date: January 2020

Study information

• Verified date: April 2017
• Source: Mansoura University
• Contact: Reham Alghandour
• Phone: 01002682875
• Email: Rehamalghandour[@]mans.edu.eg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: January 2020
• Est. primary completion date: January 2018
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Metformin
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

Locations

Country	Name	City	State
Egypt	Mansoura university	Mansourah

Sponsors (1)

Lead Sponsor	Collaborator
Mansoura University

Country where clinical trial is conducted

Egypt, 

References & Publications (12)

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 — View Citation

Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 2011 Apr 6;9:33. doi: 10.1186/1741-7015-9-33. Review. — View Citation

Eriksson A, Attvall S, Bonnier M, Eriksson JW, Rosander B, Karlsson FA. Short-term effects of metformin in type 2 diabetes. Diabetes Obes Metab. 2007 Jul;9(4):483-9. — View Citation

Hamilton RJ. Metformin for castrate-resistant prostate cancer: learning more about an old dog's new tricks. Eur Urol. 2014 Sep;66(3):475-7; discussion 477-8. doi: 10.1016/j.eururo.2014.01.013. Epub 2014 Jan 23. — View Citation

Hankinson SJ, Fam M, Patel NN. A review for clinicians: Prostate cancer and the antineoplastic properties of metformin. Urol Oncol. 2017 Jan;35(1):21-29. doi: 10.1016/j.urolonc.2016.10.009. Epub 2016 Nov 9. Review. — View Citation

Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, Mason M, Matveev V, Wiegel T, Zattoni F, Mottet N; European Association of Urology.. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-re — View Citation

Mayer MJ, Klotz LH, Venkateswaran V. Metformin and prostate cancer stem cells: a novel therapeutic target. Prostate Cancer Prostatic Dis. 2015 Dec;18(4):303-9. doi: 10.1038/pcan.2015.35. Epub 2015 Jul 28. Review. — View Citation

Ranasinghe WK, Sengupta S, Williams S, Chang M, Shulkes A, Bolton DM, Baldwin G, Patel O. The effects of nonspecific HIF1a inhibitors on development of castrate resistance and metastases in prostate cancer. Cancer Med. 2014 Apr;3(2):245-51. doi: 10.1002/c — View Citation

Rothermundt C, Hayoz S, Templeton AJ, Winterhalder R, Strebel RT, Bärtschi D, Pollak M, Lui L, Endt K, Schiess R, Rüschoff JH, Cathomas R, Gillessen S. Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK — View Citation

Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol. 2009 May;181(5):1998-2006; discussion 2007-8. doi: 10.1016/j.juro.2009.01.047. Epub 2009 Mar 14. Review. — View Citation

Song CW, Lee H, Dings RP, Williams B, Powers J, Santos TD, Choi BH, Park HJ. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep. 2012;2:362. doi: 10.1038/srep00362. Epub 2012 Apr 12. — View 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 devel — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	CRPC free survival	Number of survivors without CRPC at 4 years	4 years
Secondary	Overall patients` survival	Number of overall survivors at 4 years regardless occurrence of CRPC or not	4 years