Conditions: Prostate Cancer Prostate Cancer Recurrent
Keywords: Prostate Cancer Prostate Cancer Recurrent
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 59
Healthy volunteers: no

Brief summary:
This is a Phase II clinical study to determine if Metformin can increase Prostate Specific Antigen (PSA) doubling time for patients with Prostate Cancer who have failed primary treatment with radiation, or surgical patients that are at high risk for recurrence based on surgical pathology. Men with confirmed prostate cancer and rising serum PSA levels will receive Metformin and will be monitored for PSA response and disease progression.

Detailed description:
Prostate cancer patients who have received treatment with radiation therapy or surgery, who have indicators of high-risk disease will be administered 750mg Metformin Extended Release twice per day for a period of 9 months. Metformin is an FDA-approved drug that is prescribed to treat high blood sugar levels in patients with Type 2 Diabetes. To track prostate cancer response in study participants, investigators will obtain prostate specific antigen (PSA) levels every three months for the duration of the trial.

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Metformin Hydrochloride Extended Release 750mg
Intervention descriptions: intervention 1: Metformin Hydrochloride Extended Release 750mg twice per day for 9 months.

Protocol document:
Prot_SAP_000.pdf: 
Metformin Prostate Cancer Adjuvant Trial Protocol v.8 06/22/2018 
Page 1 
 
Title: Metformin Prostate Cancer Adjuvant Trial  
Principal Investigator: Aaron E. Katz, MD 
Sub-Investigators: Jonathan Haas, MD, Jeffrey Schiff, MD, Cindy Bredefeld, MD, Seth 
Blacksburg, MD,  James Lewis, PA-C, Anthony T. Corcoran, MD 
Clinical Research Coordinator:  Amanda Le Sueur, Ph.D. 
Research Analyst: Ardenne Martin 
Biostatistician: Melissa J. Fazzari, Ph.D. 
 
PURPOSE OF STUDY AND BACKGROUND 
Purpose  
This is a Phase II clinical study to determine if Metformin can increase Prostate Specific 
Antigen (PSA) doubling time for patients with Prostate Cancer who have failed primary 
treatment with radiation, or surgical patients that are at high risk for recurrence based on 
surgical pathology.  Men with confirmed prostate cancer and rising serum PSA levels will 
receive Metformin and will be monitored for PSA response and disease progression. 
Background 
Recent population studies have identified Metformin as a drug which could potentially 
halt the progression of several cancers, including Prostate Cancer1.   The specific effect of 
Metformin on cancer cells is still unclear, but several studies have shown that its mechanism of 
action may be related to regulation of cellular metabolism.    In vitro studies have demonstrated 
that Metformin reduces cell viability and causes cell cycle arrest in prostate cancer cells2, 
reduces proliferation of breast cancer cells3, and induces programmed cell death in p53 
deficient colon cancer cells4.   
A large scale population study of 3,837 patients showed that cumulative Metformin use 
among men with diabetes was associated with a significant decrease in the risk of Prostate 
Cancer related death in a dose-dependent fashion.  For every additional 6 months of treatment 
with Metformin, the risk of prostate cancer specific mortality decreased by 24%.5    The study 
 
1 (Margel, et al., 2013) 
2 (Sahra, et al., 2010) 
3 (Zakikhani, Dowling, Fantus, Sonenberg, & Pollack, 2006) 
4 (Buzzai, et al., 2007) 
5 (Margel, et al., 2013) 
NCT02176161


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also demonstrated that Metformin treatment produced this survival benefit independent of 
any other cancer treatment.  A Phase II trial of Metformin in men with progressive castration-
resistant Prostate cancer observed a prolongation of PSA Doubling Time in 52.3% of patients, 
and two patients had a confirmed >50% PSA decline after 12 weeks of Metformin treatment.6 
Works Cited 
Buzzai, M., Jones, R. G., Amaravadi, R. K., Lum, J. J., DeBerardinis, R. J., Zhao, F., et al. (2007). Systemic 
Treatment with the Antidiabetic Drug Metformin Selectively Impairs p53-Deficient Tumor Cell Growth. 
Cancer Research , 6745-6752. 
Margel, D., Urbach, D. R., Lipscombe, L. L., Bell, C. M., Kulkarni, G., Austin, P. C., et al. (2013). Metformin 
Use and All-Cause and Prostate Cancer-Specific Mortality Among Men with Diabetes. Journal of Clinical 
Oncology , 3069-3075. 
Rothermundt, C., Hayoz, S., Templeton, A. J., Winterhalder, R., Strebel, R. T., Bartschi, D., et al. (2014). 
Metformin in Chemotherapy-naive Castration-resistant Prostate Cancer: A Multicenter Phase 2 Trial 
(SAKK 08/09). European Urology . 
Sahra, I. B., Laurent, K., Giuliano, S., Larbret, F., Ponzio, G., Gounon, P., et al. (2010). Targeting Cancer 
Cell Metabolism: The Combination of Metformin and 2-Deoxyglucose Induces p53-Dependent Apoptosis 
in Prostate Cancer Cells. Cancer Research , 2465-2475. 
Zakikhani, M., Dowling, R., Fantus, I. G., Sonenberg, N., & Pollack, M. (2006). Metformin is an AMP 
Kinase-Dependent Growth Inhibitor for Breast Cancer Cells. Cancer Research , 10269-10273. 
 
Study Design 
 
This study will have three arms:   
1. High Risk Surgical Cohort: Radical prostatectomy patients with high risk surgical 
pathology (>Gleason 8, positive surgical margins, evidence of extra capsular extension or 
seminal vesicle invasion) and undetectable PSA 
2. Rising PSA Surgical Cohort: Radical prostatectomy patients with rising PSA defined as 
any rise in PSA over three successive PSA serum tests at least one month apart  
3. Radiation Cohort: Radiation patients with rising PSA meeting Phoenix criteria for 
Biochemical Recurrence (nadir PSA level plus 2ng/mL, occurring at least 2 years since 
the last radiation treatment)  
After receiving informed consent but prior to beginning the treatment, patients will be asked to 
complete the Memorial Anxiety Scale for Prostate Cancer (MAX-PC) to determine baseline of 
 
6 (Rothermundt, et al., 2014) 


Metformin Prostate Cancer Adjuvant Trial Protocol v.8 06/22/2018 
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disease-related patient anxiety, and the Expanded Prostate Cancer Index Composite (EPIC) to 
determine baseline disease-related quality of life.  Participants will be asked to complete these 
questionnaires every 3 months while enrolled in the study.   
Statistical methods (rising PSA surgical and radiation cohorts):  At least three PSA data points 
(pre and post treatment initiation) will be collected for each patient.  Prior to enrollment, a 
minimum of three PSA measurements at least 1 month apart within 1 year of enrollment will be 
obtained.  Post-enrollment, PSA will be measured every 3 months until month 9, for a total of 3 
measurements.   
PSA kinetics:  The relationship between the log of PSA and time of PSA measurement will be 
estimated from a piecewise linear regression model:  log(PSA) = α1+ α2(POST) + β1(Time) + 
β2(Time x POST),  where POST=1 if post treatment initiation, and 0 if pre-enrollment.  Pre- and 
Post-treatment PSA slope will be estimated for each patient (β1 and β1+ β2, respectively).   PSA-
DT will be computed as the natural log of 2 divided by the estimated slope.   
Response:  The primary end point is changes in PSA doubling time (PSA-DT) computed at 9 
months compared to pre-treatment PSA-DT.  Response to treatment will be defined as the 
lengthening of PSA-DT at 9 months from pre-treatment PSA-DT by > 3 months.  Secondary 
outcomes include safety and other measures of response such as the proportion of patients 
achieving a PSA decline of ≥ 50% in the highest measured pre-treatment PSA.   
Statistical methods (High Risk surgical cohort):   
PSA kinetics:  The patients in the surgical cohort all have non-detectable pre-treatment PSA 
levels however are considered at a higher risk for relapse based on surgical parameters such as 
surgical margins, age, and Gleason scores.   
Response:  The primary end point is the maintenance of undetectable PSA levels achieved post-
surgery for a minimum of 9 months.  Response to treatment will be defined as a PSA of < 0.20 
at 9 months.  Secondary outcomes include safety and PSA slope (if rising PSA levels observed).   
Trial Design and sample size considerations:  For each patient group (surgical, rising PSA 
surgical, radiation), a single arm Phase II trial of the same treatment regimen will be conducted 
in parallel.  For each, Simon’s two-stage optimal design will be used with the following 
assumptions:  an ineffectiveness cutoff of 10%; a clinically relevant response rate of at least 
30%; type I error rate of 0.05; type II error rate of 0.10.  Given these parameters, a total of 18 
patients will be enrolled at the first stage of the trial.  Based response defined as a PSA-DT 
change > 3 months, if 2 or fewer responses are observed, the study will be terminated at the 
first stage.  However if at least 3 responses are observed in the set of 18 patients, an additional 
17 patients will be enrolled in the second stage, for a total of 35 patients enrolled.  At the end 


Metformin Prostate Cancer Adjuvant Trial Protocol v.8 06/22/2018 
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of the second stage, if 6 or fewer responses are observed then the treatment will be declared 
ineffective.  Otherwise, the study is considered to have achieved the targeted response rate.  
Under this optimal design, the probability of early stopping given an ineffective treatment is 
0.73.    
Primary Endpoints 
• 
Increase PSA Doubling Time 
• 
Decrease PSA Levels (% PSA decline) 
Secondary Endpoints:  
• 
Determine time to secondary therapy for prostate cancer upon PSA recurrence 
• 
Time to Cancer Progression 
• 
Salvage therapy outcomes after treatment with Metformin 
• 
Determine the safety and incidence of serious adverse events from the administration 
of 9 months of metformin to men with high risk prostate cancer and prostate cancer 
with rising PSA post-treatment. 
Number of Subjects 
 
Stage 1: 18 High Risk Surgical patients, 18 Rising PSA Surgical Patients, 18 Radiation 
patients 
 
Stage 2 (if Stage 1 deemed successful): 17 High Risk Surgical Patients, 17 Rising PSA 
Surgical patients, 17 Radiation patients 
Gender of Subjects 
 
All subjects included in this study will be male. 


Metformin Prostate Cancer Adjuvant Trial Protocol v.8 06/22/2018 
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Age of Subjects 
 
Subjects will be at least 18 years or older. 
Racial and Ethnic Origin 
 
 
Subjects will be recruited from all racial and ethnic groups. 
Inclusion/Exclusion Criteria 
Inclusion Criteria: 
1) Must be male > 18 years of age  
2) Biopsy confirmed adenocarcinoma of the prostate. 
3) Radiation Patients: Rising serum PSA for on >3 time points at least 1 month apart, after 
Nadir has been reached.  Must be at least 18 months since last radiation treatment. PSA-DT 
must be >6 months. 
4) High Risk Surgical Patients: patients who have had radical prostatectomy and: 
a) High Risk based on Surgical Pathology (Patients have any of the following: ≥Gleason 8 or 
higher, Extra-capsular extension, positive surgical margins, or seminal vesicle invasion) 
b) Undetectable PSA 
5) Rising PSA Surgical Patients: Patients who have had radical prostatectomy and: 
a) Rising serum PSA for >3 time points at least 1 month apart 
b) Unwilling or medically unfit for salvage Radiation Therapy 
6) Able to swallow and retain oral medication  
7) Hemoglobin A1c < 7.0%  
8) Able and willing to participate in the full 12 months of the study  
9) Able to understand instructions related to study procedures  
10) Able to read and write (health outcome questionnaires are self-administered), understand 
instructions related to study procedures and give written informed consent  
Exclusion Criteria: 
1. Metastatic Disease 


Metformin Prostate Cancer Adjuvant Trial Protocol v.8 06/22/2018 
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2. PSADT < 6 months 
3. Subject that has ever been treated for prostate cancer with any of the following: 
• 
Chemotherapy  
• 
Hormonal therapy (e.g., megestrol, medoxyprogesterone, cyproterone)  
• 
Oral glucocorticoids  
• 
GnRH analogues (e.g., leuprolide, goserelin, degarelix)  
• Previous treatment with GnRH analogues is allowed after a wash out of 
at least one month and a return to normal serum Testosterone levels 
4. Current and/or previous use of the following medications: 
• 
Use of 5α-reductase inhibitors (eg. Finasteride, Dutasteride) within the past 6 
months of screening  
• 
Drugs with antiandrogenic properties (e.g., flutamide, bicalutamide, 
ketoconazole, progestational agents) within 6 months prior to screening  
• 
Diagnosis of Type 1 Diabetes Mellitus   
• 
Exposure to metformin within 12 months of screening  
• 
Planned or concurrent use of any oral or injectable diabetes drug 
• 
Known hypersensitivity or intolerance to metformin hydrochloride  
5. Any condition associated with increased risk of metformin hydrochloride-associated 
lactic acidosis  
6. Participation in any investigational or marketed drug trial within 30 days prior to 
screening or anytime during the study period. This includes any interventional or 
exercise trials. 
7. Any unstable serious co-existing medical condition(s) including, but not limited to, 
myocardial infarction, coronary bypass surgery, unstable angina, cardiac arrhythmias, 
clinically evident congestive heart failure, or cerebrovascular accident within 6 months 
prior to Screening visit. 
8. History of megaloblastic anemia. 
9. Abnormal liver function test: 
• Total bilirubin > institutional upper limit of normal (ULN)  
• Aspartate aminotransferase (AST) >  institutional ULN  
• Alanine aminotransferase (ALT) >  institutional ULN  
• Alkaline phosphatase (ALP) >  institutional ULN  


Metformin Prostate Cancer Adjuvant Trial Protocol v.8 06/22/2018 
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• Serum creatinine > institutional ULN  
10. History of other malignancies, with the exception of adequately treated nonmelanoma 
skin cancer, stage I melanoma, NMIBC or other solid tumors curatively treated with no 
evidence of disease for at least 5 years  
11. History or current evidence of substance abuse, as defined in DSM-IV, within 12 months 
of screening  
12. History of any illness (including psychiatric) that, in the opinion of the investigator, 
might confound the results of the study or pose additional risk to the subject  
Vulnerable Subjects 
 
No subjects from vulnerable populations (children, pregnant women, incarcerated 
persons) will be recruited for this study. 
METHODS AND PROCEDURES 
Pre-Enrollment Evaluation  
1. Personal Medical History, including medication history, alcohol and tobacco use 
2. Physical Examination including ECOG status, blood pressure, pulse, height, weight 
and BMI. 
3. Hematology and Serum Chemistry, Liver Panel, total and free PSA, Testosterone 
level, Hemoglobin A1C, Insulin levels. 
4. Tumor Characteristics, including Gleason score, tumor grade, MRI results (if 
available), biopsy results 
5. List of previous prostate cancer treatment, any previous radiation treatment (for any 
disease condition). 
6. PSA Kinetics: current PSA doubling time, record of all PSA tests in the year prior to 
enrollment 
7. Completion of two study questionnaires for baseline disease related anxiety and 
quality of life: MAX-PC and EPIC. 
Study Interventions 
1. Upon study initiation, patient will receive two weeks of 750mg Metformin Extended 
Release (ER) to assess any adverse reactions. 
2. After two weeks, patient will receive two doses of 750mg Metformin Extended Release 
(ER) per day for 8 months, two weeks.  
3. Patients will receive Metformin Extended Release (ER) from the Principal or Sub-
Investigators free of charge. 


Metformin Prostate Cancer Adjuvant Trial Protocol v.8 06/22/2018 
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4. The study drug, 750mg Metformin Extended Release (ER), will be stored in the Principal 
Investigator’s practice in a separate locked safe accessible only to research study 
personnel.   
Study Evaluations 
Patients will return to the Principal Investigator’s practice every three months for 
evaluation of study compliance, completion of study questionnaires, and blood draw. 
a) Study subjects will be required to bring the medication bottle with them on each study 
visit and will also be required to sign an attestation that they are taking the medication 
as per study protocol. 
b) Study subjects will also submit a blood sample for evaluation of hematology and serum 
chemistry, insulin levels, total and free PSA, and Hemoglobin A1C.   
c) Study subjects will complete two questionnaires, the Expanded Prostate Cancer Index 
Composite (EPIC) to evaluate Prostate Cancer specific symptoms, and the Memorial 
Anxiety Scale for Prostate Cancer (MAX-PC) for evaluation of disease and treatment 
related anxiety. 
d) At the end of the study, at approximately 9 months, subjects will also be tested for 
insulin and testosterone levels. 
Study Exit Procedures 
If study participants experience any of the following while receiving Metformin treatment, they 
will be removed from the study and referred for alternative treatment such as Androgen 
Deprivation Therapy, Salvage Cryotherapy for radiation patients, or Salvage Radiotherapy: 
• High Risk Surgical Patients: PSA level rises 0.6ng/mL from baseline 
• Rising PSA and Radiation Patients: PSA Doubling Time accelerates below 6 months 
These participants will be removed from the intervention arm of the study, but will continue to 
be followed for disease outcome and quality of life for three years following removal from the 
study.   
Data Analysis and Data Monitoring 
The Winthrop University Hospital Department of Biostatistics has been consulted during the 
development process of this protocol, and will be consulted for statistical analysis of PSA 
kinetics, adverse events, and overall outcome.   
The research coordinator will review study conduct including informed consent procedures, 
accrual, drop-outs, protocol deviations and AEs in aggregate on a monthly basis.  The principal 
and sub-investigators review serious adverse events (SAEs), and laboratory results monitoring 


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in real-time.  The research coordinator, research fellow and study investigators will review 
study subject compliance with study procedures on a three month basis. 
Study data are provided to the research coordinator and study investigators prior to each 
monthly review by the research fellow.  Data reports for end of phase analysis are prepared by 
the study statistician, Melissa J. Fazzari.  
The research coordinator provides a written report to the study team with recommendations 
for study modification, study continuation/discontinuation as relevant.  After the report is 
generated, the coordinator will meet with the study investigators to discuss relevant findings. 
The study team is responsible for forwarding the report to the IRB.  
Analysis of Adverse Events 
Adverse events will be monitored on an ongoing monthly basis throughout the duration of the 
study, and the rates will be formally analyzed at the end of the first stage of the study as 
outlined in the statistical methods section of the protocol.   
Analysis of Serious Adverse Events 
Serious adverse events will be monitored in real time, and the rate of subjects experiencing 
these events will be analyzed every month as needed as the study progresses.  
Analysis of Efficacy 
The primary end points for efficacy for each study cohort will be analyzed at the end of the first 
stage of the study (total accrual 18 patients, 9 months of treatment).   
• Efficacy in the Rising PSA Surgical and Radiation Cohorts: Response to treatment is 
defined as a lengthening of PSA doubling time from pre-treatment PSA doubling time by 
>3 months at the end of the 9 months of treatment. 
• Efficacy in the High Risk Surgical Cohort: Response to treatment is defined as PSA level 
of <0.20ng/mL at the end of the 9 months of treatment.  
• Secondary Efficacy in Rising PSA Surgical and Radiation Cohorts: The proportion of 
patients achieving a PSA decline of > 50% from the highest measured pre-treatment 
PSA.   
Data Storage and Confidentiality 
 
Data will be stored in our HIPAA-compliant case report form database.  Only the study 
investigators, research coordinator, research fellow, and biostatistician will be provided with 


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access information to the database.  A unique non-identifying code will be assigned to each 
study participant. 
 
RISK/BENEFIT ASSESSMENT 
Risk 
Expected AEs 
Expected AEs associated with Metformin include:   
• Hypoglycemia (10% of diabetic patients) 
• Diarrhea (9.6% of diabetic patients) 
• Nausea/Vomiting (6.5% of diabetic patients) 
• Constipation (Between 1-5% of diabetic patients) 
• Weight loss (14% of metastatic prostate cancer patients) 
• Fatigue (18% of metastatic prostate cancer patients) 
Rare but Serious AEs 
Rare but serious AEs that may be associated with Metformin include: 
• Lactic Acidosis: approximately 0.03 cases/1000 patient-years, with approximately 0.015 
fatal cases/1000 patient-years 
AE Management 
The rate of expected adverse events cannot be definitively predicted in this population of 
patients.  Adverse events will be recorded and monitored throughout the study, and the rates 
will be reported as part of the study end points.  Subjects who cannot tolerate adverse events 
will be removed from the study at the request of the subject or at the discretion of the 
investigators. 
Study subjects will be screened for known risk factors of Metformin associated lactic acidosis 
and will be excluded from enrollment in the study if any risk factors are found.  If lactic acidosis 
occurs in a study subject while on Metformin, the subject will be immediately removed from 
the study. 
 


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ADDENDUM: 
Subjects who cannot tolerate the 1500mg per day dose of Metformin will be kept on the study at a 
lower dosage.  They will receive Metformin 750mg, once daily dose for 8 months, 2 weeks. 
 
 
Protection against Risks 
 
Study subjects will be evaluated for adverse events at every study visit (every 3 months).  
In the case of unacceptable toxicity or side effects, patients may be removed from the study at 
the discretion of the Principal Investigator or Sub-Investigators.  Patients may also drop out of 
the study at any time if side effects become intolerable.   
 
Potential Benefits to Subjects 
 
The potential benefits to subjects include reduction of serum PSA levels, prolongation of 
PSA doubling time, and increased time to disease progression, however, the probability of 
these benefits are uncertain, and will be evaluated as part of this trial.  
 
INVESTIGATOR’S QUALIFICATIONS AND EXPERIENCE 
All research personnel are required to complete training in the protection of human subjects.  
In addition, all investigators will submit a copy of their CV through the IRB website.   
SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT 
Subject Identification and Recruitment 
 
Subjects meeting the inclusion criteria will be referred to the Principal Investigator or 
Sub-investigators by their treating physician.  IRB-approved posters will also be posted 
throughout the community to advertise and recruit patients. 
Process of Consent 


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Patients who have been identified as possible study subjects will meet with the Principal 
Investigator or one of the Sub-Investigators to review the study protocol details, and review 
and sign the informed consent form.   
Subject Capacity 
 
As this study includes self-administered questionnaires, and self reporting of symptoms, 
every subject must have full mental capacity, as judged by the Principal Investigator or Sub-
Investigators. 
Subject/Representative Comprehension  
 
No subjects with reduced mental capacity as judged by the investigators will be enrolled 
in this study. 
Early Withdrawal of Subjects 
 
Study subjects are permitted to leave the trial at any time for any reason.  Subjects 
electing to discontinue the study should contact the Principal Investigator or Research 
Coordinator.  Subjects may also be released from the study in the event of unacceptable 
adverse effects of the drug under the guidance of the Principal Investigator or Sub-
Investigators. 
 
Consent Forms and Documentation of Consent 
 
Consent forms will be reviewed with each study subject with the Principal Investigator 
or Sub-Investigator to ensure understanding the benefits, risks and all steps of the research 
study.  Consent forms will be signed and stored with the Research Coordinator in a locked file 
cabinet accessible only to study personnel.   
Costs to the Subject 
 
There are no anticipated extra costs for study subjects.  Research tests which are 
outside the standard of care will be paid for by the Department of Urology research fund.  
Prostate Specific Antigen testing is standard of care for Prostate Cancer patients and will not be 
included in research costs.  Hemoglobin A1C is not a standard of care and will be paid for by the 
Department of Urology. 
 


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Payment for Participation 
There will be no payment given to participants in this trial. 
 
STORAGE AND DISPENSING OF STUDY DRUG 
Study drug will be stored in the principal investigator’s practice at 1300 Franklin Ave Garden 
City, NY 11530, in a locked storage cabinet accessible only to necessary research personnel.  
Any unused study drug will be destroyed as per the Medical Waste and Tracking Act of 1989, 
EPA, New York DOH and New York DEC regulations and standards and WUH Regulated Medical 
Waste Policy and Procedures.