Castration Compared to Castration Plus Metformin as First Line Treatment for Patients With Advanced Prostate Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by The University of Texas Health Science Center at San Antonio
Sponsor:
Information provided by (Responsible Party):
Devalingam Mahalingam, The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier:
NCT01620593
First received: May 31, 2012
Last updated: September 13, 2013
Last verified: September 2013
  Purpose

Prostate cancer is the most common non-cutaneous cancer in men. Patients with recurrent or metastatic prostate cancer are treated with androgen-deprivation therapy, often termed castration therapy. While the short and medium term benefits of castration are clear in relation to therapeutic efficacy in patients with prostate cancer, it is now appreciated that the resulting hypogonadism associated with castration is responsible for adverse consequences or metabolic syndrome that include increase in body mass index (BMI) and fat mass, hyperinsulinemia and insulin resistance, hyperlipidemia, reduced lean body mass (LBM) and muscle strength, osteoporosis, sexual dysfunction, poor quality of life and higher cardiovascular mortality. Lower testosterone levels in men independently predict the development of metabolic syndrome. Low testosterone levels in men are associated with insulin resistance and diabetes. Metformin is commonly prescribed for the treatment of type II diabetes because it lowers both glucose and insulin levels. Studies show preliminary evidence that metformin might have both antineoplastic and chemopreventative activity. Castration therapy decreases insulin sensitivity, adversely alters lipid profiles and results in weight gain, and it may be associated with a greater incidence of diabetes and cardiovascular disease. Little is known about the optimal strategy to mitigate the adverse metabolic effects of castration in men with prostate cancer. The rationale for using metformin in castrated men with advanced prostate cancer stems from the observation that castration therapy is associated with the metabolic syndrome, hyperinsulinemia and insulin resistance. Furthermore, reports that hyperinsulinemia stimulates insulin receptor expression on prostate cancer leading to tumor growth and development of castrate resistant prostate cancer suggest metformin through its activation of the AMPK-LKBI pathway reduces liver gluconeogenesis secondarily decreasing insulin levels may circumvent tumor growth and resistance to castration therapy. More importantly, evidence that metformin inhibits the mTOR pathway implicates an added therapeutic benefit as an anti-cancer agent.


Condition Intervention Phase
Prostate Cancer
Drug: Placebo and Castration
Drug: Metformin and Castration
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase II, Randomized, Placebo Controlled, Double Blind, Prospective Study of Castration Compared to Castration Plus Metformin as First Line Treatment for Patients With Advanced Prostate Cancer.

Resource links provided by NLM:


Further study details as provided by The University of Texas Health Science Center at San Antonio:

Primary Outcome Measures:
  • Metabolic Syndrome [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    Compare both cohorts of castrated men (metformin vs. placebo) with regard to metabolic consequences of castration therapy.


Secondary Outcome Measures:
  • PSA response [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    PSA response, defined as a PSA less than or equal to 4 ng/ml or undetectable value at 7 months.

  • Treatment failure [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Progression time from randomization to the earliest disease progression defined as an increase of 20% or more as per RECIST criteria. Patients will not be removed from protocol treatment for PSA progression alone in the first 12 weeks on this study. Further rise in PSA even in the absence of deterioration of pre-existing lesions will constitute treatment failure. Adverse event leading to withdrawal related to metformin or placebo or castration treatment. Death from any cause. Patients unwillingness to continue. Patient's non-compliance with taking the study intervention - 50% or higher.

  • Pathway Inhibition [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Inhibition of the downstream targets of the mTOR pathway, 4E-BPI and p70S6K1 observed on peripheral blood mononuclear cells (PBMCs).

  • Safety and Efficacy [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    The safety and tolerability of metformin with castration therapy as compared to castration therapy alone as measured by CTCAE version 4 criteria.


Estimated Enrollment: 94
Study Start Date: April 2011
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo and Castration
Metabolic consequences including development of hyperinsulinemia and insulin resistance using metformin compared to placebo in men on castration therapy.
Drug: Placebo and Castration
All eligible subjects will be randomized in a 1:l manner to receive a bottle containing sufficient 500mg tablets of metformin or placebo, blinded to the patient and the study team.
Active Comparator: Metformin and Castration
Metabolic consequences including development of hyperinsulinemia and insulin resistance using metformin compared to placebo in men on castration therapy. In the rare case where a patient may not tolerate 500 mg three times a day, he may remain on the study taking only 500 mg twice a day.
Drug: Metformin and Castration
All eligible subjects will be randomized in a 1:l manner to receive a bottle containing sufficient500mg tablets of metformin or placebo, blinded to the patient and the study team.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

(Eligible subjects must meet one of the inclusion criteria 1-3 and all of items 4-6)

  1. Men with metastatic prostate cancer that require castration therapy with either using an LHRH analogue or surgical castration are eligible. Complete androgen blockade using anti-androgen therapy prior to castration or up to 4 weeks following castration therapy is permitted to prevent disease flare. Thereafter anti-androgen therapy may continue or be discontinued based on treating physicians preference.

    OR

  2. Any men with prostate cancer who are candidates for castration therapy despite no evidence of definite metastatic disease including patient with biochemical failure or 'rising PSA' are also permitted to enter study provided castration therapy is planned for a minimum of a year. Patients with biochemical failure prior to enrolment should have also have already received appropriate salvage therapy. Men with prostate cancer who have already started castration therapy are also permitted to enter study provided castration therapy was initiated within one month of study entry.

    OR

  3. Men with prostate cancer previously treated with castration therapy for management of localized prostate cancer in the adjuvant setting or in combination with radiation therapy are permitted to enter study provided they currently have known metastatic disease and have non-castrate testosterone levels (Testosterone > 50 ng1dL).
  4. An ECOG performance status of 0-2.
  5. Patients will need to have documentation of metastatic disease in bone and/or soft tissue, and a baseline PSA of 35 nglml. Patients with biochemical failures, with rising PSA (baseline PSA does not need to be 2 5 nglml to be eligible), without metastatic disease are also eligible if castration therapy is indicated for a minimum of a year.
  6. Patients must have provided informed consent, be willing to have blood specimens taken, and exhibit no severe other medical or psychiatric problems.

Exclusion Criteria:

  1. Patients with severe medical or psychiatric diseases are INELIGIBLE. (Patients with stable chronic diseases such as high cholesterol or hypertension ARE eligible.) Examples of problems that would make patients INELIGIBLE include severe heart failure, or hypoxia due to severe lung disease.
  2. Patients with clinical or biochemical evidence of renal failure or liver failure are INELIGIBLE. Creatinine and bilirubin needs to be less than or equal to 1.3~up per limit of normal (ULN), and ASTIALT less than or equal to 2.5 x ULN unless liver metastasis is present then up to 5 X ULN permitted).
  3. Patients already receiving metformin or anti-diabetic medications are INELIGIBLE.
  4. If any patient develops symptomatic diabetes requiring drug therapy, he must receive such a therapy, which may include metformin. This must be documented, and the patient will not continue on the study.
  5. Patients with important infections requiring antibiotics are INELIGIBLE, but patients who acquire minor infections while on the study may remain on the study.
  6. Alcohol abuse problems make patients INELIGIBLE. Patients need to be consuming less than or equal to 14 units of alcohol weekly.
  7. Patients with history or evidence of lactic acidosis or metabolic acidosis will be excluded.
  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: NCT01620593

Contacts
Contact: Epp Goodwin 210-450-5798 onctrial@idd.org

Locations
United States, Texas
Cancer Therapy and Research Center University of Texas Health Science Center San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Epp Goodwin    210-450-5798    onctrial@idd.org   
Principal Investigator: Devalingam Mahalingam, MD, PhD         
Sponsors and Collaborators
Devalingam Mahalingam
Investigators
Principal Investigator: Devalingam Mahalingam, MD, PhD University of Texas Health Science Center San Antonio
  More Information

No publications provided

Responsible Party: Devalingam Mahalingam, Principal Investigator, The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT01620593     History of Changes
Other Study ID Numbers: CTRC 10-21, HSC20110273H
Study First Received: May 31, 2012
Last Updated: September 13, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by The University of Texas Health Science Center at San Antonio:
Prostate Cancer
Metformin
Castration therapy

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 16, 2014