Clinical trial NCT01433913: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adenocarcinoma of the Prostate
Recurrent Prostate Cancer
Stage I Prostate Cancer
Stage IIA Prostate Cancer
Stage IIB Prostate Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2011-09-14
Enrollment: 20
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Cell Proliferation in the Prostatectomy Tissue as Assessed by Ki67 Expression Using Immunohistochemistry (IHC)
timeFrame: 12 weeks
Secondary outcomes:
measure: Prostate Tissue Metformin Concentration Levels as Assessed by Liquid Chromatography Tandem Mass Spectrometry
timeFrame: 12 weeks
measure: Apoptosis Levels in the Prostatectomy Tissue as Assessed by IHC of Cleaved Caspase 3
timeFrame: 12 weeks
measure: Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1
timeFrame: 12 weeks
measure: mTOR Regulation in the Prostatectomy Tissue as Assessed by IHC of Phospho-p70 S6 Kinase (p-p70S6K)
timeFrame: 12 weeks
measure: Angiogenesis in the Prostatectomy Tissue as Assessed by IHC of CD34
timeFrame: 12 weeks
measure: AMPK Activation in the Prostatectomy Tissue as Assessed by IHC of p-AMPK
timeFrame: 12 weeks
measure: Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Retinoblastoma Protein Phosphorylation (p-pRb)
timeFrame: 12 weeks
measure: Changes in Serum PSA
timeFrame: Baseline and 12 weeks
measure: Changes in Serum Fasting Insulin
timeFrame: Baseline and 12 weeks
measure: Changes in Serum IGF-1/IGFBP-3
timeFrame: Baseline and 12 weeks
measure: Changes in Serum Testosterone
timeFrame: Baseline and 12 weeks
measure: Changes in Serum SHBG
timeFrame: Baseline and 12 weeks
measure: Changes in Serum Fasting Glucose
timeFrame: Baseline and 12 weeks
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Cancer Center - Tucson
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Health Sciences Center
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California/Norris Cancer Center
state: California
Study officials:
affiliation: Arizona Cancer Center - Tucson
name: Robert Krouse
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.