Metformin Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01433913

Enrollment

Registered

2011-09-14

Start date

2011-11-30

Completion date

2014-04-30

Last updated

2018-01-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

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.

Interventions

DRUGmetformin hydrochloride

Given PO

OTHERplacebo

Given PO

OTHERlaboratory biomarker analysis

Correlative studies

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

MALE

Age

18 Years to No maximum

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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	—
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	—
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
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	—
Prostate Tissue Metformin Concentration Levels as Assessed by Liquid Chromatography Tandem Mass Spectrometry	12 weeks	—

Countries

United States

Participant flow

Participants by arm

Arm	Count
Arm I (Metformin Hydrochloride) Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg metformin tablets until the day before surgery) for 4-12 weeks.	10
Arm II (Placebo) Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets until the day before surgery) for 4-12 weeks.	10
Total	20

Baseline characteristics

Characteristic	Arm II (Placebo)	Total	Arm I (Metformin Hydrochloride)
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	4 Participants	10 Participants	6 Participants
Age, Categorical Between 18 and 65 years	6 Participants	10 Participants	4 Participants
Age, Continuous	61 years STANDARD_DEVIATION 6	63 years STANDARD_DEVIATION 8	65 years STANDARD_DEVIATION 10
Region of Enrollment United States	10 participants	20 participants	10 participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	10 Participants	20 Participants	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	6 / 10	5 / 10
serious Total, serious adverse events	1 / 10	0 / 10

Outcome results

Primary

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.

Time frame: 12 weeks

Population: Participants with tissue sections available from prostatectomy

Arm	Measure	Value (MEDIAN)
Arm I (Metformin Hydrochloride)	Cell Proliferation in the Prostatectomy Tissue as Assessed by Ki67 Expression Using Immunohistochemistry (IHC)	6.5 % positively stained nuclei
Arm II (Placebo)	Cell Proliferation in the Prostatectomy Tissue as Assessed by Ki67 Expression Using Immunohistochemistry (IHC)	3.67 % positively stained nuclei

p-value: 0.23Wilcoxon (Mann-Whitney)

Secondary

AMPK Activation in the Prostatectomy Tissue as Assessed by IHC of p-AMPK

Time frame: 12 weeks

Population: Data were not collected due to budgetary constraints

Secondary

Angiogenesis in the Prostatectomy Tissue as Assessed by IHC of CD34

Time frame: 12 weeks

Population: Data were not collected due to budgetary constraints

Secondary

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

Time frame: 12 weeks

Population: Participants with tissue sections available from prostatectomy

Arm	Measure	Value (MEDIAN)
Arm I (Metformin Hydrochloride)	Apoptosis Levels in the Prostatectomy Tissue as Assessed by IHC of Cleaved Caspase 3	0.07 Number of positive cells
Arm II (Placebo)	Apoptosis Levels in the Prostatectomy Tissue as Assessed by IHC of Cleaved Caspase 3	0.1 Number of positive cells

p-value: 0.77Wilcoxon (Mann-Whitney)

Secondary

Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1

Time frame: 12 weeks

Population: Participants with tissue sections available from prostatectomy

Arm	Measure	Value (MEDIAN)
Arm I (Metformin Hydrochloride)	Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1	37.5 % positive cells
Arm II (Placebo)	Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1	13.3 % positive cells

p-value: 0.09Wilcoxon (Mann-Whitney)

Secondary

Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Retinoblastoma Protein Phosphorylation (p-pRb)

Time frame: 12 weeks

Population: Data were not collected due to budgetary constraints

Secondary