Metformin Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery

Phase 2

Completed

• Conditions: Stage IIB Prostate Cancer; Stage I Prostate Cancer; Adenocarcinoma of the Prostate; Recurrent Prostate Cancer; Stage IIA Prostate Cancer
• Interventions: Other: placebo; Drug: metformin hydrochloride; Other: laboratory biomarker analysis

• Registration Number: NCT01433913
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

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.

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2011-09-09
• Study First Submitted QC: 2011-09-13
• Study First Posted: 2011-09-14
• Study Start: 2011-11
• Primary Completion: 2014-04
• Study Completion: 2014-04
• Results First Submitted: 2015-04-29
• Results First Submitted QC: 2015-04-29
• Results First Posted: 2015-05-15
• Status Verified: 2017-12
• Last Update Submitted: 2017-12-12
• Last Update Posted: 2018-01-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 20

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (metformin hydrochloride)	laboratory biomarker analysis	Patients receive extended-release metformin hydrochloride PO QD for 4-12 weeks.
Arm II (placebo)	placebo	Patients receive placebo PO QD for 4-12 weeks.
Arm II (placebo)	laboratory biomarker analysis	Patients receive placebo PO QD for 4-12 weeks.
Arm I (metformin hydrochloride)	metformin hydrochloride	Patients receive extended-release metformin hydrochloride PO QD for 4-12 weeks.

Primary Outcome Measures

Name	Time	Method
Cell Proliferation in the Prostatectomy Tissue as Assessed by Ki67 Expression Using Immunohistochemistry (IHC)	12 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Changes in Serum PSA	Baseline and 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 Fasting Insulin	Baseline and 12 weeks
Prostate Tissue Metformin Concentration Levels as Assessed by Liquid Chromatography Tandem Mass Spectrometry	12 weeks
Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1	12 weeks
Angiogenesis in the Prostatectomy Tissue as Assessed by IHC of CD34	12 weeks
Apoptosis Levels in the Prostatectomy Tissue as Assessed by IHC of Cleaved Caspase 3	12 weeks	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
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
mTOR Regulation in the Prostatectomy Tissue as Assessed by IHC of Phospho-p70 S6 Kinase (p-p70S6K)	12 weeks
Changes in Serum IGF-1/IGFBP-3	Baseline and 12 weeks

Trial Locations

Locations (3)

Arizona Cancer Center - Tucson; 🇺🇸 Tucson, Arizona, United States

University of Arizona Health Sciences Center; 🇺🇸 Tucson, Arizona, United States

University of Southern California/Norris Cancer Center; 🇺🇸 Los Angeles, California, United States