Metformin Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01433913
First received: September 9, 2011
Last updated: July 11, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Adenocarcinoma of the Prostate
Recurrent Prostate Cancer
Stage I Prostate Cancer
Stage IIA Prostate Cancer
Stage IIB Prostate Cancer
Drug: metformin hydrochloride
Other: placebo
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Phase II Study of Metformin in a Pre-prostatectomy Prostate Cancer Cohort

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Cell proliferation in the prostatectomy tissue as assessed by Ki67 expression using immunohistochemistry (IHC) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Descriptive statistics will be performed on prostate tissue metformin concentrations within each intervention group. Little if any metformin is expected in the placebo group. Data between the two study groups will be compared using a two-group t-test at a two-sided 0.05 level of significance. The means (and 95% confidence intervals) and distribution of actual values will be reported. Linear regression will be performed to the post-intervention metformin concentration levels to adjust for demographics and duration on intervention. Logistic regression will also be performed.

  • Comparison of apoptosis (cleaved caspase 3), angiogenesis (CD34), AMPK activation (p-AMPK), mTOR regulation (p-p70S6K), cell cycle regulation (cyclin D1and p-pRb) in the prostatectomy tissue between study groups as assessed by IHC [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Changes in a serum biomarker (from baseline to post-intervention) and secondary tissue endpoints will be compared between intervention groups using a t-test. If the distributions are not normally distributed, a non-parametric rank-sum test will be utilized. Correlations among the biomarkers and between postintervention metformin levels and changes in biomarker levels, will be explored (using Pearson or Spearman Rank correlation coefficients). Plasma levels of metformin will also be compared between groups using a t-test and the correlation of plasma and prostate tissue levels will be examined.

  • Comparison of changes in serum PSA, fasting glucose, fasting insulin, IGF-1/IGFBP-3, testosterone, and SHBG between study groups as assessed by liquid chromatography-tandem mass spectrometry assay [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]
    Changes in a serum biomarker (from baseline to post-intervention) and secondary tissue endpoints will be compared between intervention groups using a t-test. If the distributions are not normally distributed, a non-parametric rank-sum test will be utilized. Correlations among the biomarkers and between postintervention metformin levels and changes in biomarker levels, will be explored (using Pearson or Spearman Rank correlation coefficients). Plasma levels of metformin will also be compared between groups using a t-test and the correlation of plasma and prostate tissue levels will be examined.


Enrollment: 21
Study Start Date: November 2011
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (metformin hydrochloride)
Patients receive extended-release metformin hydrochloride PO QD for 4-12 weeks.
Drug: metformin hydrochloride
Given PO
Other Name: Glucophage
Other: laboratory biomarker analysis
Correlative studies
Placebo Comparator: Arm II (placebo)
Patients receive placebo PO QD for 4-12 weeks.
Other: placebo
Given PO
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01433913

Locations
United States, Arizona
Arizona Cancer Center - Tucson
Tucson, Arizona, United States, 85724-5024
University of Arizona Health Sciences Center
Tucson, Arizona, United States, 85724
United States, California
University of Southern California/Norris Cancer Center
Los Angeles, California, United States, 90033
Sponsors and Collaborators
Investigators
Principal Investigator: Robert Krouse Arizona Cancer Center - Tucson
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01433913     History of Changes
Obsolete Identifiers: NCT01528527
Other Study ID Numbers: NCI-2012-00243, NCI-2012-00243, CDR0000712087, UARIZ-UAZ10-16-01, 11-0211-04, UAZ10-16-01, P30CA023074, N01CN35158
Study First Received: September 9, 2011
Last Updated: July 11, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma
Prostatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 24, 2014