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Metformin Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery

Primary Purpose

Adenocarcinoma of the Prostate, Recurrent Prostate Cancer, Stage I Prostate Cancer

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
metformin hydrochloride
placebo
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adenocarcinoma of the Prostate

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • Arizona Cancer Center - Tucson
  • University of Arizona Health Sciences Center
  • University of Southern California/Norris Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm I (metformin hydrochloride)

Arm II (placebo)

Arm Description

Patients receive extended-release metformin hydrochloride PO QD for 4-12 weeks.

Patients receive placebo PO QD for 4-12 weeks.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Prostate Tissue Metformin Concentration Levels as Assessed by Liquid Chromatography Tandem Mass Spectrometry
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
Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1
mTOR Regulation in the Prostatectomy Tissue as Assessed by IHC of Phospho-p70 S6 Kinase (p-p70S6K)
Angiogenesis in the Prostatectomy Tissue as Assessed by IHC of CD34
AMPK Activation in the Prostatectomy Tissue as Assessed by IHC of p-AMPK
Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Retinoblastoma Protein Phosphorylation (p-pRb)
Changes in Serum PSA
Changes in Serum Fasting Insulin
Changes in Serum IGF-1/IGFBP-3
Changes in Serum Testosterone
Changes in Serum SHBG
Changes in Serum Fasting Glucose

Full Information

First Posted
September 9, 2011
Last Updated
December 12, 2017
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01433913
Brief Title
Metformin Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery
Official Title
Phase II Study of Metformin in a Pre-prostatectomy Prostate Cancer Cohort
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
November 2011 (undefined)
Primary Completion Date
April 2014 (Actual)
Study Completion Date
April 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adenocarcinoma of the Prostate, Recurrent Prostate Cancer, Stage I Prostate Cancer, Stage IIA Prostate Cancer, Stage IIB Prostate Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (metformin hydrochloride)
Arm Type
Experimental
Arm Description
Patients receive extended-release metformin hydrochloride PO QD for 4-12 weeks.
Arm Title
Arm II (placebo)
Arm Type
Placebo Comparator
Arm Description
Patients receive placebo PO QD for 4-12 weeks.
Intervention Type
Drug
Intervention Name(s)
metformin hydrochloride
Other Intervention Name(s)
Glucophage
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
placebo
Other Intervention Name(s)
PLCB
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Cell Proliferation in the Prostatectomy Tissue as Assessed by Ki67 Expression Using Immunohistochemistry (IHC)
Description
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.
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Prostate Tissue Metformin Concentration Levels as Assessed by Liquid Chromatography Tandem Mass Spectrometry
Time Frame
12 weeks
Title
Apoptosis Levels in the Prostatectomy Tissue as Assessed by IHC of Cleaved Caspase 3
Description
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
Time Frame
12 weeks
Title
Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1
Time Frame
12 weeks
Title
mTOR Regulation in the Prostatectomy Tissue as Assessed by IHC of Phospho-p70 S6 Kinase (p-p70S6K)
Time Frame
12 weeks
Title
Angiogenesis in the Prostatectomy Tissue as Assessed by IHC of CD34
Time Frame
12 weeks
Title
AMPK Activation in the Prostatectomy Tissue as Assessed by IHC of p-AMPK
Time Frame
12 weeks
Title
Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Retinoblastoma Protein Phosphorylation (p-pRb)
Time Frame
12 weeks
Title
Changes in Serum PSA
Time Frame
Baseline and 12 weeks
Title
Changes in Serum Fasting Insulin
Time Frame
Baseline and 12 weeks
Title
Changes in Serum IGF-1/IGFBP-3
Time Frame
Baseline and 12 weeks
Title
Changes in Serum Testosterone
Time Frame
Baseline and 12 weeks
Title
Changes in Serum SHBG
Time Frame
Baseline and 12 weeks
Title
Changes in Serum Fasting Glucose
Time Frame
Baseline and 12 weeks

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Krouse
Organizational Affiliation
Arizona Cancer Center - Tucson
Official's Role
Principal Investigator
Facility Information:
Facility Name
Arizona Cancer Center - Tucson
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724-5024
Country
United States
Facility Name
University of Arizona Health Sciences Center
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
University of Southern California/Norris Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
32994091
Citation
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.
Results Reference
derived
PubMed Identifier
28692586
Citation
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.
Results Reference
derived

Learn more about this trial

Metformin Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery

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