Metformin Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery

Phase II Study of Metformin in a Pre-prostatectomy Prostate Cancer Cohort

This randomized phase II trial studies how well metformin hydrochloride works compared to placebo in treating patients with prostate cancer undergoing surgery. Metformin hydrochloride may make some enzymes active. These enzymes may block other enzymes needed for cell growth and stop the growth of tumor cells.

Study Overview

• Status: Completed
• Conditions: Recurrent Prostate Cancer; Stage I Prostate Cancer; Adenocarcinoma of the Prostate; Stage IIA Prostate Cancer; Stage IIB Prostate Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: metformin hydrochloride; Other: placebo

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the effect of 4-12 weeks of metformin (metformin hydrochloride) intervention on cell proliferation in the prostatectomy tissue.

SECONDARY OBJECTIVES:

I. To determine the effect of metformin intervention on prostate tissue bioavailability of metformin.

II. To determine the effect of metformin intervention on apoptosis and angiogenesis in the prostatectomy tissue.

III. To determine the effect of metformin intervention on potential molecular targets of metformin including activated protein kinase (AMPK) activation, mammalian target of rapamycin (mTOR) regulation, and cell cycle regulation in the prostatectomy tissue.

IV. To determine the effect of metformin intervention on changes in systemic hormones and growth factors that have been shown to be modulated by metformin in other patient populations including fasting glucose, fasting insulin, insulin-like growth factor axis, testosterone, and sex hormone binding globulin (SHBG).

V. To determine the effect of metformin intervention on changes in prostate-specific antigen (PSA) levels.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive extended-release metformin hydrochloride orally (PO) once daily (QD) for 4-12 weeks.

ARM II: Patients receive placebo PO QD for 4-12 weeks.

Patients in both arms undergo surgery one day after completion of treatment.

After completion of study treatment, patients are followed up within 30 days of surgery.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Health Sciences Center
    • Tucson, Arizona, United States, 85724-5024
      • Arizona Cancer Center - Tucson
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California/Norris Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Men will be eligible to this study if they are diagnosed with a histologically confirmed organ-confined adenocarcinoma of the prostate (PCa) treatable by prostatectomy and have a current PSA less than 50 ng/ml
• Have not received chemotherapy and/or radiation for any malignancy (excluding non-melanoma skin cancer and cancers confined to organs with removal as only treatment) in the past 5 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 70%)
• Leukocytes >= 3,000/uL
• Absolute neutrophil count >= 1,500/uL
• Platelets >= 100,000/uL
• Total bilirubin =< 1.5 times institutional upper limits of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 times institutional ULN
• Creatinine within normal institutional limits
• Willing to use adequate contraception (barrier method, abstinence, subject has had a vasectomy or partner is using effective birth control or is postmenopausal) for the duration of study participation
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Type I or type II diabetic patients on treatment with any drug for diabetes or participants with fasting glucose >= 126 mg/dL
• History of impaired liver or kidney function
• Participants with a current history of high alcohol consumption (> 3 standard drinks/day) or binge drinking (5 or more drinks) in one session of 1-3 hours
• History of lactic acidosis or at increased risk for lactic acidosis such as patients with unstable or acute congestive heart failure who are at risk of hypoperfusion with hypoxemia
• Participants may not be receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical composition to metformin
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• History of acute or chronic metabolic acidosis
• Concurrent use of cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin)
• Concurrent use of non-study metformin or other biguanides

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (metformin hydrochloride); Patients receive extended-release metformin hydrochloride PO QD for 4-12 weeks.	Other: laboratory biomarker analysis; Correlative studies; Drug: metformin hydrochloride; Given PO; Other Names: Glucophage
Placebo Comparator: Arm II (placebo); Patients receive placebo PO QD for 4-12 weeks.	Other: laboratory biomarker analysis; Correlative studies; Other: placebo; Given PO; Other Names: PLCB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cell Proliferation in the Prostatectomy Tissue as Assessed by Ki67 Expression Using Immunohistochemistry (IHC)	Data between the two study groups will be compared using a two-group t-test at a two-sided 0.05 level of significance. If the data are not normally distributed, a non-parametric rank-sum test will be utilized.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prostate Tissue Metformin Concentration Levels as Assessed by Liquid Chromatography Tandem Mass Spectrometry		12 weeks
Apoptosis Levels in the Prostatectomy Tissue as Assessed by IHC of Cleaved Caspase 3	Average number of positively stained cells that exhibited nuclear fragmentation from five randomly selected high-power fields (40x) in the tumor region was calculated for each participant	12 weeks
Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1		12 weeks
mTOR Regulation in the Prostatectomy Tissue as Assessed by IHC of Phospho-p70 S6 Kinase (p-p70S6K)		12 weeks
Angiogenesis in the Prostatectomy Tissue as Assessed by IHC of CD34		12 weeks
AMPK Activation in the Prostatectomy Tissue as Assessed by IHC of p-AMPK		12 weeks
Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Retinoblastoma Protein Phosphorylation (p-pRb)		12 weeks
Changes in Serum PSA		Baseline and 12 weeks
Changes in Serum Fasting Insulin		Baseline and 12 weeks
Changes in Serum IGF-1/IGFBP-3		Baseline and 12 weeks
Changes in Serum Testosterone		Baseline and 12 weeks
Changes in Serum SHBG		Baseline and 12 weeks
Changes in Serum Fasting Glucose		Baseline and 12 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Robert Krouse, Arizona Cancer Center - Tucson

Publications and helpful links

General Publications

• Roy S, Malone S, Grimes S, Morgan SC. Impact of Concomitant Medications on Biochemical Outcome in Localised Prostate Cancer Treated with Radiotherapy and Androgen Deprivation Therapy. Clin Oncol (R Coll Radiol). 2021 Mar;33(3):181-190. doi: 10.1016/j.clon.2020.09.005. Epub 2020 Sep 29.
• Nguyen MM, Martinez JA, Hsu CH, Sokoloff M, Krouse RS, Gibson BA, Nagle RB, Parnes HL, Cordova C, Chow HS. Bioactivity and prostate tissue distribution of metformin in a preprostatectomy prostate cancer cohort. Eur J Cancer Prev. 2018 Nov;27(6):557-562. doi: 10.1097/CEJ.0000000000000394.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: September 9, 2011
• First Submitted That Met QC Criteria: September 13, 2011
• First Posted (Estimate): September 14, 2011

Study Record Updates

• Last Update Posted (Actual): January 10, 2018
• Last Update Submitted That Met QC Criteria: December 12, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: NCI-2012-00243 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA023074 (U.S. NIH Grant/Contract); N01CN35158 (U.S. NIH Grant/Contract); CDR0000712087; UARIZ-UAZ10-16-01; 11-0211-04 (Other Identifier: Arizona Cancer Center - Tucson); UAZ10-16-01 (Other Identifier: DCP)