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Prostate CarcinomaPhase 2NCT01561482

Study of Metformin With Simvastatin for Men With Prostate Carcinoma

A Phase 2 study testing Metformin and Simvastatin in people with Prostate Carcinoma, run by Nicholas Mitsiades at 3 sites in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

The purpose of this study is to find out whether the two drugs used in the study, metformin and simvastatin, can slow down the speed of rise of prostate specific antigen (PSA) or stop its rise or even bring the level down. Read more about this study

Who is it for?
Ages 18 years and older, men only
Conditions the study is for
Prostate Carcinoma
What is being tested?
Metformin and Simvastatin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
3 sitesUnited States
Study dates
Jan 2012to Jul 2014
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Men only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • The study population will consist of subjects who have undergone primary therapy (prostatectomy or primary radiation) for biopsy-proven adenocarcinoma of the prostate and now have biochemical-only recurrence.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Male 18 years or older.
  • Histologically or cytologically confirmed diagnosis of prostate cancer.
  • Biochemical recurrence following prostatectomy or radiation to the prostate, defined as at least 3 PSA rises, with each PSA determination at least 4 weeks apart, and each PSA value greater than or equal to 0.2 ng/mL.
  • PSA must be less than 50 ng/mL at study entry.
Show all 15Show fewer
  • Screening PSA greater than or equal to 0.5 ng/mL for men who had a prostatectomy. Prior treatment with neoadjuvant, adjuvant, or salvage radiation therapy is allowed, again, with screening PSA greater than or equal to 0.5 ng/mL required for eligibility.
  • Screening PSA greater than or equal to 1.0 ng/mL above their postradiation nadir for men who were treated with primary radiation therapy (external beam and/or brachytherapy). Men who had primary radiation therapy followed by salvage prostatectomy are eligible if screening PSA is greater than or equal to 0.5 ng/mL.
  • PSA doubling time between 3 and 36 months.
  • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
  • Subjects must have normal organ and marrow function as defined below:
  • Leukocytes greater than or equal to 3,000/mcL * Absolute neutrophil count greater than or equal to 1,500/mcL * Hemoglobin greater than or equal to 10 g/dL * Platelets greater than or equal to 100,000/mcL * Total bilirubin within normal institutional limits * AST(SGOT)/ALT(SGPT) less than or equal to 1.5 X institutional upper limit of normal * Creatinine within normal institutional limits OR creatinine clearance or calculated greater than or equal to 60 mL/min/1.73 m2 for subjects with creatinine clearance or estimated creatinine levels above institutional glomerular filtration rate (eGFR) normal * Creatine phosphokinase (CPK) less than or equal to the institutional upper limit of normal
  • Ability to swallow the study drugs.
  • Life expectancy of at least 12 months.
  • Subjects should agree to avoid grapefruit juice which is a major inhibitor of CYP3A4.

Who cannot join

  • Evidence of metastatic disease on imaging studies.
  • Need for treatment with any conventional modality for prostate cancer (surgery, radiation therapy, and hormonal therapy).
  • Prior hormonal therapy for recurrent prostate cancer (hormonal therapy given in a neoadjuvant or adjuvant setting and greater than 6 months before entry is acceptable).
  • Prior chemotherapy for prostate cancer.
  • Treatment within the last 30 days with any investigational drug.
  • Radiation therapy within prior 6 months.
Show all 19Show fewer
  • Known hypersensitivity to metformin or statins.
  • Subjects who need to take CYP3A4 inhibitors, such as cyclosporin, sirolimus, tacrolimus, verapamil,danazol, gemfibrozil, ketoconazole, or macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)will be excluded. Prior use of these agents is acceptable, as long as they are stopped at least a week prior to study entry.
  • Subjects who need to take CYP3A4 inducers, such as phenobarbital, dexamethasone, carbamazepine,phenytoin, rifampicin, or non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine,etravirine) will be excluded. Prior use of these agents is acceptable, as long as they are stopped at least a week prior to study entry.
  • Prior history of rhabdomyolysis.
  • Prior history of lactic acidosis.
  • Any history of myocardial infarction in the past 12 months.
  • HIV-positive status.
  • Subjects who consume more than 3 alcoholic beverages per day.
  • Subjects with serious intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or other nonmalignant medical or psychiatric illness that is uncontrolled or whose control may be jeopardized by the complications of this therapy or may limit compliance with the study requirements (at the discretion of the investigator).
  • Subjects diagnosed with or treated for another malignancy within 2 years prior to study enrollment or previously diagnosed with another malignancy and still having any evidence of residual disease. Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
  • Subjects currently treated with metformin or a statin or who have been treated with metformin or a statin in the past 6 months are ineligible for this study.
  • Subjects who have taken 5a-reductase inhibitors (finasteride or dutasteride), saw palmetto, or PC-SPES within the last 6 weeks are ineligible for this study. Subjects taking other herbal supplements, vitamins, or other alternative medications are eligible for this study as long as they were started more than 2 months prior to study entry, have remained on a stable regimen, and will remain on a stable regimen for the duration of participation on this study.
  • Men of all races and ethnic groups are eligible for this trial.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Baylor College of Medicine

    Houston, Texas, 77030

  • Ben Taub General Hospital

    Houston, Texas, 77030

  • Michael E. Debakey Veterans Affairs Medical Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: Open-Label Study Of Metformin In Combination With Simvastatin For Men With Prostate Carcinoma And A Rising Serum Prostate-Specific Antigen Level After Radical Prostatectomy And/Or Radiation Therapy

The purpose of this study is to find out whether the two drugs used in the study, metformin and simvastatin, can slow down the speed of rise of prostate specific antigen (PSA) or stop its rise or even bring the level down.

Recently, scientists noticed that men who take metformin to treat their high blood sugar or simvastatin to treat their high cholesterol are less likely to develop prostate cancer. Also, scientists found that, when these drugs are used in preclinical studies, they can slow down the growth of the prostate cancer cells. This study will try to find out whether these drugs can actually slow down the growth of prostate cancer in men.

Read the detailed description

Men who participate in this study will take both metformin and simvastatin every day. Both drugs are pills and can be taken at home.

Subjects will be asked to take metformin and simvastatin until metastasis from their prostate cancer appears or until their PSA has doubled from what it was before they started the study.

Primary Objective:

To define the efficacy, as measured by an improvement in PSA doubling time (PSADT) at 6 months, of the combination of metformin plus simvastatin in patients with recurrent prostate cancer following definitive treatment.

Secondary Objectives:

  1. To define the time to protocol-specified event for men treated with the combination of metformin plus simvastatin.
  2. To describe the pattern of change in log PSA levels and PSA velocity over time during treatment with metformin plus simvastatin.
  3. To describe the associations between changes in metabolic parameters (fasting glucose/insulin/lipid panel/leptin/adiponectin and others) with the pattern of change in log PSA levels.
Being tested
Metformin, Simvastatin
Keywords
Prostate carcinoma, Prostate cancer, Prostate Specific Antigen, PSA, Metformin, Simvastatin, Radiation therapy, Prostatectomy
Medical subject headings
Prostatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MetforminDrug

    Also called Glucophage

    Metformin treatment will be started at 500 mg twice daily (dose level -2), in order to minimize gastrointestinal discomfort and, if no gastrointestinal toxicity grade greater than 1, will be increased to 500 mg with breakfast/1000 mg at bedtime (dose level -1) 4 days later (+/- 1 day allowed). If no gastrointestinal toxicity grade greater than 1, it will be increased to 1000 mg twice daily (dose level 0) 10 days later (+/- 2 days allowed), which is the target dose for the remainder of the study. If gastrointestinal toxicity grade greater than 1 occurs during these first 4 weeks, the subject will be evaluated every 2 weeks until resolution of toxicity to grade less than or equal to 1 and, then, the metformin dose will be increased to the next dose level.

  • SimvastatinDrug

    Also called Zocor

    The simvastatin dose at treatment initiation will be 20 mg once daily (dose level -1), taken at bedtime for 2 weeks. After these 2 weeks, the subject will have blood work and, if no AST/ALT/CPK elevation grade greater than 1, will be escalated to 40 mg once daily (dose level 0), taken at bedtime. If AST or ALT or CPK elevation grade greater than 1 during the first 2 weeks, the subject will be evaluated every 2 weeks until resolution of toxicity to grade less than or equal to 1, and then the simvastatin dose will be increased to dose level 0.

Study groups in NCT01561482
Study groupRoleWhat they receive
Metformin, SimvastatinExperimentalBoth metformin and simvastatin will be taken every day. Metformin will be taken as 1 pill in the morning and 1 pill before going to bed. Simvastatin will be taken as 1 pill before going to bed. They will be taken until metastasis from the prostate cancer appears or until the subjects PSA has doubled from what it was before they started the study.
Receives: Drug: Metformin; Drug: Simvastatin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Efficacy, as measured by an improvement in PSA doubling time (PSADT) between baseline and 6 months, of the combination of metformin plus simvastatin in patients with recurrent prostate cancer following definitive treatment.

    Measured: 6 months after subject start of study

Secondary outcomes (3)

  1. Time to protocol-specified event for men treated with the combination of metformin plus simvastatin.

    Measured: From treatment initiation till disease progression (assessed up to 5 years)

  2. Pattern of change in log PSA levels and PSA velocity over time during treatment with metformin plus simvastatin.

    Measured: From treatment initiation till disease progression (assessed up to 5 years)

  3. Associations between changes in metabolic parameters (fasting glucose/insulin/lipid panel/leptin/adiponectin and others) with the pattern of change in log PSA levels.

    Measured: From treatment initiation till disease progression (assessed up to 5 years)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Mar 2012 (estimated)
  2. Study startJan 2012
  3. Primary completionJul 2014
  4. Study completionJul 2014

Why it stopped: Study closed due to slow/low enrollment; no subjects were enrolled.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01561482
Sponsor's protocol ID
H-28936
Status last verified
Jul 2015
First submitted
20 Mar 2012
Last updated
22 Jul 2015
Results posted
No
Data monitoring committee
Yes

Publications

  • Bonorden MJ, Rogozina OP, Kluczny CM, Grossmann ME, Grambsch PL, Grande JP, Perkins S, Lokshin A, Cleary MP. Intermittent calorie restriction delays prostate tumor detection and increases survival time in TRAMP mice. Nutr Cancer. 2009;61(2):265-75. doi: 10.1080/01635580802419798.

    PubMed 19235043

  • Giovanella BC, Shepard RC, Stehlin JS, Venditti JM, Abbott BJ. Calorie restriction: effect on growth of human tumors heterotransplanted in nude mice. J Natl Cancer Inst. 1982 Feb;68(2):249-57.

    PubMed 6278189

  • Hermann LS. Metformin: a review of its pharmacological properties and therapeutic use. Diabete Metab. 1979 Sep;5(3):233-45.

    PubMed 387488

  • Sarkar NH, Fernandes G, Telang NT, Kourides IA, Good RA. Low-calorie diet prevents the development of mammary tumors in C3H mice and reduces circulating prolactin level, murine mammary tumor virus expression, and proliferation of mammary alveolar cells. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7758-62. doi: 10.1073/pnas.79.24.7758.

    PubMed 6296850

  • Albanes D. Caloric intake, body weight, and cancer: a review. Nutr Cancer. 1987;9(4):199-217. doi: 10.1080/01635588709513929.

    PubMed 3299283

  • Bailey CJ. Biguanides and NIDDM. Diabetes Care. 1992 Jun;15(6):755-72. doi: 10.2337/diacare.15.6.755.

    PubMed 1600835

  • Hursting SD, Switzer BR, French JE, Kari FW. The growth hormone: insulin-like growth factor 1 axis is a mediator of diet restriction-induced inhibition of mononuclear cell leukemia in Fischer rats. Cancer Res. 1993 Jun 15;53(12):2750-7.

    PubMed 8389243

  • Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1995 Dec;1(12):1311-4. doi: 10.1038/nm1295-1311.

    PubMed 7489415

  • Frederich RC, Lollmann B, Hamann A, Napolitano-Rosen A, Kahn BB, Lowell BB, Flier JS. Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest. 1995 Sep;96(3):1658-63. doi: 10.1172/JCI118206.

    PubMed 7657836

  • Frystyk J, Vestbo E, Skjaerbaek C, Mogensen CE, Orskov H. Free insulin-like growth factors in human obesity. Metabolism. 1995 Oct;44(10 Suppl 4):37-44. doi: 10.1016/0026-0495(95)90219-8.

    PubMed 7476310

  • Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995 Jul 28;269(5223):543-6. doi: 10.1126/science.7624777.

    PubMed 7624777

  • Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995 Nov 10;270(45):26746-9. doi: 10.1074/jbc.270.45.26746.

    PubMed 7592907

  • Burfeind P, Chernicky CL, Rininsland F, Ilan J, Ilan J. Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7263-8. doi: 10.1073/pnas.93.14.7263.

    PubMed 8692980

  • Cioffi JA, Shafer AW, Zupancic TJ, Smith-Gbur J, Mikhail A, Platika D, Snodgrass HR. Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nat Med. 1996 May;2(5):585-9. doi: 10.1038/nm0596-585.

    PubMed 8616721

  • Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996 Feb 1;334(5):292-5. doi: 10.1056/NEJM199602013340503.

    PubMed 8532024

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Metformin and Simvastatin in people with Prostate Carcinoma, run by Nicholas Mitsiades at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 22 Jul 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Efficacy, as measured by an improvement in PSA doubling time (PSADT) between baseline and 6 months, of the combination of metformin plus simvastatin in patients with recurrent prostate cancer following definitive treatment. (time frame: 6 months after subject start of study). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01561482, which also lists 36 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jul 2015.

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