Castration Compared to Castration Plus Metformin as First Line Treatment for Patients With Advanced Prostate Cancer
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.
Drug: Placebo and Castration
Drug: Metformin and Castration
|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.|
- 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.
- 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.
|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)|
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01620593
|Contact: Epp Goodwinfirstname.lastname@example.org|
|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 email@example.com|
|Principal Investigator: Devalingam Mahalingam, MD, PhD|
|Principal Investigator:||Devalingam Mahalingam, MD, PhD||University of Texas Health Science Center San Antonio|