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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Recurrent Prostate Carcinoma; Stage I Prostate Cancer; Stage III Prostate Cancer; Stage IIA Prostate Cancer; Stage IIB Prostate Cancer
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Aspirin; Drug: Metformin Hydrochloride; Other: Placebo; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm I (metformin hydrochloride, aspirin); Patients receive metformin hydrochloride PO BID and aspirin PO QD for 6 months in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Aspirin; Given PO; Other Names: Acetylsalicylic Acid; ASA; Aspergum; Ecotrin; Empirin; Entericin; Extren; Measurin; Drug: Metformin Hydrochloride; Given PO; Other Names: Glucophage; Metformin HCl
PLACEBO_COMPARATOR: Arm II (metformin hydrochloride placebo, aspirin placebo); 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; Correlative studies; Other: Placebo; Given metformin hydrochloride placebo PO; Other Names: placebo therapy; PLCB; sham therapy; Other: Placebo; Given aspirin placebo PO; Other Names: placebo therapy; PLCB; sham therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: National Cancer Institute (NCI); Rutgers Cancer Institute of New Jersey

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 23, 2015
• Primary Completion (ACTUAL): December 1, 2019
• Study Completion (ACTUAL): December 1, 2019

Study Registration Dates

• First Submitted: April 15, 2015
• First Submitted That Met QC Criteria: April 15, 2015
• First Posted (ESTIMATE): April 20, 2015

Study Record Updates

• Last Update Posted (ACTUAL): February 8, 2023
• Last Update Submitted That Met QC Criteria: February 6, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin; Metformin
• Other Study ID Numbers: 081501 (Rutgers Cancer Institute of New Jersey); P30CA072720 (U.S. NIH Grant/Contract); NCI-2015-00397 (REGISTRY: CTRP (Clinical Trial Reporting Program)); Pro20150001378 (OTHER: Rutgers Cancer Institute of New Jersey)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO