Bicalutamide with or without Metformin Hydrochloride in Lowering PSA Levels in Patients with Prostate Cancer

Status: Active

Description

This randomized phase II trial studies bicalutamide with or without metformin hydrochloride in lowering prostate-specific antigen (PSA) levels in patients with prostate cancer. Androgen receptors are proteins that attach to male hormones (androgens) causing prostate cancer cells to grow. Bicalutamide blocks these proteins and may keep cancer cells from growing. Metformin hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether bicalutamide with or without metformin hydrochloride is a better treatment for prostate cancer biochemical recurrence.

Eligibility Criteria

Inclusion Criteria

  • Ability to understand and the willingness to sign a written informed consent
  • Histologically or cytologically confirmed diagnosis of prostate cancer
  • Patient must have had previous treatment with definitive surgery or radiation therapy or cryoablation
  • Patient may have prior salvage therapy (surgery, radiation or other local ablative procedures) within 6 months prior to randomization if the intent was for cure; prophylactic radiotherapy to prevent gynecomastia within 4 weeks prior to randomization is allowed
  • Body mass index (BMI) > 25 at study entry
  • Patient may have had prior neoadjuvant and/or adjuvant therapy (chemotherapy, vaccines or experimental agents) within 4 weeks prior to randomization, if the PSA rise and PSADT were documented after the testosterone level was > 150 ng/dL
  • Patient may not have had therapy modulating testosterone levels (such as luteinizing hormone, releasing-hormone agonists/antagonists and antiandrogens) within 6 months prior to randomization; agents such as 5 alpha reductase inhibitors, ketoconazole, abiraterone, systemic steroids, or herbal supplements known to decrease PSA levels including any dose of megestrol acetate, finasteride (e.g., saw palmetto and prostate cancer [PC]-SPES, African pygeum extract, lycopene, alanine, glutamic acid and glycine, beta-sitosterol, lycopene, nettle root extract, quercetin, Belizian Man Vine extract, muira puama extract and epimedium extract campesterol, stigmasterol, sitostanol and brassicasterol) are not permitted at any time during the period that the PSA values are being collected
  • Patient must have hormone-sensitive prostate cancer as evident by a serum total testosterone level > 150 ng/dL within 12 weeks prior to randomization
  • PSA must be < 30 ng/mL at study entry
  • Patient must have evidence of biochemical failure after primary therapy and subsequent progression; biochemical failure is declared when the PSA reaches a threshold value after primary treatment and it differs for radical prostatectomy or radiation therapy * For radical prostatectomy the threshold for this study is PSA >= 0.2 ng/mL * For radiation therapy the threshold is a PSA rise of 2 ng/mL above the nadir PSA achieved post radiation with or without hormone therapy (2006 Radiation Therapy Oncology Group [RTOG]-American Society for Radiation Oncology [ASTRO] Consensus definition) * PSA progression requires a PSA rise above the threshold measured at any time point since the threshold was reached
  • PSA doubling time between 3 and 9 months; PSA calculation requires at least two consecutive PSA rises (PSA2 and PSA3) above the threshold PSA (at least 3 PSA values); PSA2 and PSA3 must be obtained within 12 months of study entry; all baseline PSAs should be obtained at the same reference laboratory (lab); patient's PSA doubling time must be calculated
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
  • Ability to swallow the study drugs
  • Absolute neutrophil count >= 1,000/mL
  • Hemoglobin >= 10 g/dL
  • Platelets >= 100,000/mL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 X institutional upper limit of normal (ULN)
  • Creatinine clearance >= 60 mL/min/1.73 m^2
  • Glycosylated hemoglobin (Hgb A1c) =< 6.5%

Exclusion Criteria

  • Evidence of metastatic disease on imaging studies (computed tomography [CT] and/or bone scan)
  • Diagnosis of diabetes mellitus defined as * Fasting blood glucose > 126 mg/dl or * Random blood glucose > 200 mg/dl * Hemoglobin A1C > 6.5%
  • 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)
  • Treatment with any investigational drug 30 days prior to randomization
  • Radiation therapy within prior 6 months (prophylactic radiotherapy to prevent gynecomastia within 4 weeks prior to randomization is allowed)
  • Known hypersensitivity to metformin
  • Prior history of lactic acidosis
  • Any history of myocardial infarction in the past 12 months
  • 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)
  • Patient with previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions: basal cell or squamous cell carcinoma of the skin or prior malignancy that has been adequately treated and patient has been continuously disease free for >= 2 years
  • Subjects currently treated with metformin and/or bicalutamide or who have been treated with metformin and/or bicalutamide in the past 6 months
  • Subjects who have taken 5a-reductase inhibitors (finasteride or dutasteride), saw palmetto, or PC-SPES within the last 6 weeks are ineligible; subjects will be eligible for the study after the wash out period of 6 weeks

Locations & Contacts

Maryland

Bethesda
National Institutes of Health Clinical Center
Status: Active
Contact: Marijo Bilusic
Phone: 301-402-0576
Email: marijo.bilusic@nih.gov

Pennsylvania

Philadelphia
Fox Chase Cancer Center
Status: Active
Contact: Daniel M. Geynisman
Phone: 215-728-3889
Email: Daniel.Geynisman@fccc.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. The proportion of patients with undetectable PSA (< 0.2 ng/mL) at 32 weeks with metformin (metformin hydrochloride) plus bicalutamide compared to bicalutamide monotherapy.

SECONDARY OBJECTIVES:

I. The proportion of patients with PSA decline > 85% at 32 weeks with metformin plus bicalutamide compared to bicalutamide monotherapy.

II. The time to PSA progression with metformin plus bicalutamide compared to bicalutamide monotherapy.

III. To evaluate the time to onset of radiographic evidence of metastatic disease (radiographic progression-free survival [rPFS]) with metformin plus bicalutamide compared to bicalutamide monotherapy.

IV. To characterize the PSA doubling time (PSADT) changes pre-study, during treatment, and off treatment.

V. To evaluate the safety and tolerability of metformin in this patient population.

VI. To evaluate quality of life (QOL) with metformin plus bicalutamide compared to bicalutamide monotherapy.

VII. To evaluate the time to next therapy (i.e. antiandrogen or gonadotropin-releasing hormone [GnRH] antagonist/agonist).

TERTIARY OBJECTIVES:

I. Immunogenicity of bicalutamide +/- metformin by flow cytometric analysis of T-cell frequency, activation status, cytokine profiles, antibody levels and analysis of sCD27 and sCD40L.

II. Evaluate circulating PSA levels and correlations with immunogenicity and/or efficacy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients undergo observation for 8 weeks (courses 1-2). Beginning in week 9, patients receive bicalutamide orally (PO) once daily (QD) on days 1-28 (courses 3-8).

ARM B: Patients receive metformin hydrochloride PO twice daily (BID) on days 1-28 (courses 1-8). Beginning in week 9, patients also receive bicalutamide PO QD on days 1-28 (courses 3-8).

In both arms, treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 months for up to 5 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Fox Chase Cancer Center

Principal Investigator
Daniel M. Geynisman

Trial IDs

Primary ID GU-079
Secondary IDs NCI-2015-02227, 15-1015
Clinicaltrials.gov ID NCT02614859