Metformin Hydrochloride and Aspirin in Treating Patients With Hormone-Dependent Prostate Cancer That Has Progressed After Surgery or Radiation Therapy

Study Overview
=================
Brief Summary
-----------------
This randomized phase II trial studies how well metformin hydrochloride and aspirin work in treating patients with hormone-dependent prostate cancer that has progressed after surgery or radiation therapy. Metformin hydrochloride and aspirin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving metformin hydrochloride and aspirin together can slow the growth of prostate cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine the effect of metformin (metformin hydrochloride) and aspirin on the change in prostate-specific antigen (PSA) progression in men with rising PSA after definitive therapy for localized prostate cancer and stable disease during a run-in period with the study regimen. SECONDARY OBJECTIVES: I. To determine the feasibility and safety of administering metformin and aspirin. II. To determine the effect of metformin and aspirin on PSA levels and the serum obesity-related prostate cancer (PCa) biomarkers (insulin, insulin-like growth factor [IGF]-1, interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha). OUTLINE: RUN-IN STAGE: Patients receive metformin hydrochloride orally (PO) twice daily (BID) and aspirin PO once daily (QD) for 4 months. Patients with disease progression (PSA increase of > 50% and minimum of 2ng/ml rise in PSA) come off study. Patients achieving disease response (>25% decline in PSA) continue to receive study agents in the absence of disease progression or unacceptable disease. Patients with stable disease continue on to the randomized study regimen. RANDOMIZATION STAGE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive metformin hydrochloride PO BID and aspirin PO QD for 6 months in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive metformin hydrochloride placebo PO BID and aspirin placebo PO QD for 6 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 12-16 weeks for 1 year.

Official Title
-----------------
A Phase 2 Randomized Discontinuation Trial in Patients With Hormone-Dependent Rising Prostate-Specific Antigen Progression After Local Therapy for Prostate Cancer Evaluating the Synergy of Metformin Plus Aspirin (PRIMA Trial)

Conditions
-----------------
Stage IIB Prostate Cancer, Recurrent Prostate Carcinoma, Stage I Prostate Cancer, Stage IIA Prostate Cancer, Stage III Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Aspirin
* Other: Laboratory Biomarker Analysis
* Drug: Metformin Hydrochloride
* Other: Placebo
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with histologically proven prostate cancer treated with surgery, radiation, or the combination of surgery and radiation for prostate cancer (metastatic to regional lymph nodes) with resection of the nodes, who now has a rising PSA value after definitive local therapy, and no visible metastatic disease on conventional imaging studies Patients must have undergone local treatment via prostatectomy or radiation therapy Patients must have PSA progression after local treatment: PSA values for patients after surgery (or surgery and salvage/adjuvant radiation) must be greater than or equal to 0.2 ng/mL, determined by two measurements, at least 1 month apart and at least 6 months after prostatectomy PSA values for patients after radiation must be greater than or equal to 2.0 ng/ml greater than the nadir achieved after radiation, determined by two measurements at 1 month apart and at least 6 months after the radiation treatment is completed; (patients who received adjuvant or salvage radiation after prostatectomy must have PSA of greater than or equal to 0.2) The first two PSA values, along with a third (study baseline) value must all be rising (i.e., there must be an overall rising trajectory, such that the third value cannot be lower than the first value) PSA must be less than 50 ng/mL at study entry PSA doubling time using the mkscc.org PSA doubling time calculator must be greater than 4 months Baseline bone scan, chest x-ray and computed tomography (CT)/magnetic resonance imaging (MRI) of abdomen/pelvis demonstrating no metastatic disease Estimated life expectancy of at least 6 months Eastern Cooperative Oncology Group (ECOG) performance status =< 2 White blood cells (WBC) > 3500/ul Absolute neutrophil count (ANC) > 1500/ul Hemoglobin > 10 g/dl Platelet count > 100,000/ul Adequate renal function with estimated glomerular filtration rate (GFR) by Cockcroft Gault of greater than 40 ML per minute Total bilirubin must be within 1.5 X the normal institutional limits; if total bilirubin is outside the normal institutional limits, assess direct bilirubin The direct bilirubin must be within normal parameters Transaminases (serum glutamic oxaloacetic transaminase [SGOT] and/or serum glutamate pyruvate transaminase [SGPT]) must be less than 2.5 X the institutional upper limit of normal Patients must have a serum total testosterone level >= 150 ng/dL at the time of enrollment within 4 weeks prior to randomization Patients must sign informed consent Exclusion Criteria: Serious concomitant systemic disorder that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator Patients may have received prior androgen deprivation therapy (ADT) in the neoadjuvant, adjuvant and/or salvage setting, but must be off therapy for at least 3 months and have a testosterone level > 150 ng/dl Second primary malignancy except most situ carcinoma (e.g. adequately treated non-melanomatous carcinoma of the skin) or other malignancy treated at least 2 years previously with no evidence of recurrence Patients with type II diabetes currently already on metformin Patients taking aspirin for previously diagnosed cardiovascular disease Patients who received aspirin or metformin within the past 28 days Patients taking medications with known interactions with metformin or aspirin Patients taking warfarin or platelet inhibitors Patients requiring chronic use of nonsteroidal anti-inflammatory drugs (NSAIDS) Other concurrent experimental or investigational drugs Prior history of lactic acidosis or metabolic acidosis Patients with history of gastrointestinal (GI) bleeding and peptic ulcer disease Any unstable, serious co-existing medical conditions including but not limited to myocardial infarction, coronary bypass surgery, unstable angina, cardiac arrhythmias, clinically evident congestive heart failure, or cerebrovascular accident within 6 months prior to screening

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (metformin hydrochloride, aspirin)<br>Patients receive metformin hydrochloride PO BID and aspirin PO QD for 6 months in the absence of disease progression or unacceptable toxicity. | Drug: Aspirin<br>* Given PO<br>* Other names: Measurin;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Metformin Hydrochloride<br>* Given PO<br>* Other names: Metformin HCl;|
| Placebo Comparator: Arm II (metformin hydrochloride placebo, aspirin placebo)<br>Patients receive metformin hydrochloride placebo PO BID and aspirin placebo PO QD for 6 months in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo<br>* Given metformin hydrochloride placebo PO<br>* Other names: sham therapy;Other: Placebo<br>* Given aspirin placebo PO<br>* Other names: sham therapy;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of PSA ng/mL Rates After Six Months of Metformin Hydrochloride and Aspirin or Placebo Therapy in Patients Who Have Received Four Months of Open Label Treatment |  | 6 months |