T-reg Function Changes: a Novel Immune Regulatory Effect Underlying Benefit of Statin Use on Lethal Prostate Cancer

Trial Title: T-reg Function Changes: a Novel Immune Regulatory Effect Underlying Benefit of Statin Use on Lethal Prostate Cancer

NCT ID: NCT05586360

Condition: Prostate Cancer

Conditions: Official terms:
Prostatic Neoplasms
Simvastatin

Conditions: Keywords:
Prostate cancer
Neoadjuvant
Statin

Study type: Interventional

Study phase: Phase 2

Overall status: Recruiting

Study design:

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Intervention:

Intervention type: Drug
Intervention name: Simvastatin 40mg
Description: Simvastatin 40mg taken orally daily for 8 weeks
Arm group label: Simvastatin

Summary: This study will evaluate whether simvastatin reduces intraprostatic immunosuppressive microenvironment through YAP-mediated T-reg dysfunction, and increases intraprostatic anti-tumor immune response in men recently diagnosed with localized prostate cancer electing to receive prostatectomy for their care. Half the men will be randomized to receive statins for 8 weeks prior to their surgery, while the other half will receive standard of care.

Detailed description: Prior research has demonstrated a consistently strong inverse association between statin drug use and risk of developing lethal prostate cancer, and a stronger protective effect with a longer duration of use. Further, in men with clinically localized prostate cancer, statins are associated with a reduced risk of progression to metastasis and dying from prostate cancer. For statins to have clinical utility as chemo-preventive and therapeutic (adjuvant) agents, additional characterization of the mechanisms through which statins interact with the tumor microenvironment are needed. Statin drugs have been shown to inhibit Yes-associated protein (YAP) nuclear translocation and transcriptional activation (via YAP phosphorylation) required for T regulatory cell (T-reg) immunosuppressive function. YAP is a critical regulator of the immunosuppressive microenvironment contributing to T-reg differentiation and immunosuppressive function and antitumor T cell response. Simvastatin is a moderate intensity statin regimen recommended for cholesterol reduction, and was previously shown to have a strong cytoplasmic YAP sequestration activity. This trial is designed to investigate the effect of 40 mg oral simvastatin daily on YAP-mediate T-reg disfunction and antitumor immune response. Eligible patients include men newly diagnosed with pathologically-confirmed localized prostate cancer determined to be intermediate (stage T2b, or Gleason 7 or PSA 10-20ng/mL) or high risk (stage T2c or PSA >/= 20 ng/mL, or Gleason >/= 8) of biochemical recurrence at the time of biopsy; not currently taking a statin who are scheduled for prostatectomy. For the trial, 52 patients will be randomized in a 1:1 ratio to the statin group or the control group. Randomization sequence will be computer generated using random blocks with concealed allocation of the random treatment assignment (e.g., statin or control) and will be stratified by race (Black vs non-Hispanic White) and BMI (<30 vs ≥30). Patients randomized to the statin group will receive moderate intensity simvastatin (40mg, day) for eight weeks until the date of prostatectomy. Patients randomized to the control group will not receive any intervention, this is not a placebo-controlled trial and participants, and investigators will not be masked. Patients in both groups will receive standard clinical laboratory assessments at baseline and at the end of the study after eight weeks to evaluated adherence based on the change in cholesterol and inflammation biomarkers from baseline to the end of follow-up at eight weeks. Multiplex immunofluorescence will be used to assess intra-prostatic YAP-mediate T-reg dysfunction (the number FOXP3+ T-regs with phosphorylated YAP), and intra-prostatic anti-tumor immune response (the count and density of CD4+ and CD8+ T cells) in whole tumor sections obtained from the tumor block containing the index tumor (i.e., largest and/or highest Gleason sum).

Criteria for eligibility:
Criteria:
Inclusion Criteria: 1. Men with pathologically-confirmed localized prostate cancer determined to be intermediate (stage T2b, or Gleason 7, or PSA 10-20 ng/mL) or high risk (stage T2c, or PSA >/=20 ng/mL, or Gleason >/=8) of biochemical recurrence at the time of biopsy 2. Electing to undergo prostatectomy; 3. Ability to provide written informed consent and willing to complete study procedures. Exclusion Criteria: 1. Current statin use or use of non-statin lipid-lowering drug (fibrates, bile acid sequestrants, or niacin); 2. Current use of medications contraindicated for concomitant use with 40mg simvastatin: - Gemfibrozil - Cyclosporine - Danazol - CYP3A4 inhibitors: itraconazole; ketoconazole; posaconazole; erythromycin; clarithromycin; telithromycin; HIV protease inhibitors; boceprevir; telaprevir; nefazodone 3. Current use of medications requiring lower dose of simvastatin not already listed as exclusions criteria: - Verapamil - Diltiazem - Amiodarone - Ranolazine - Calcium channel blockers: verapamil; diltiazem; amlodipine 4. Men with low-density lipoprotein cholesterol <50mg/dL 5. Statin use in the previous 12 months; 6. Discontinued statin use because of statin-related adverse event; 7. Evidence or suspicion of metastases; 8. Prior neoadjuvant or adjuvant chemotherapy, hormone therapy, or radiation therapy; 9. History of non-prostate cancer other than non-melanoma skin cancer in the last 24 months; 10. Diagnosed diabetes or currently taking diabetes medications 11. Prior myocardial infarction or stroke 12. Chronic liver disease (hepatitis or cirrhosis) or abnormal liver function (>1.5x clinical laboratory's upper limit of normal alanine aminotransferase); 13. Stage 4 or 5 chronic kidney disease (Creatinine clearance / estimated glomerular filtration rate < 30 mL/min calculated by Cockgroft-Gault formula); 14. History of myopathy or inflammatory muscle disease (>3x clinical laboratory's upper limit of normal creatine kinase).

Gender: Male

Gender based: Yes

Gender description: This trial is focused on prostate cancer, a cancer of a male organ, and is applicable to men only. Men from all racial and ethnic groups are eligible to participate in this trial.

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Locations:

Facility:
Name: Hollings Cancer Center at Medical University of South Carolina

Address:
City: Charleston
Zip: 29425
Country: United States

Status: Recruiting

Contact:
Last name: Alan Brisendine, CCRP

Phone: 843-792-9007
Email: brisend@musc.edu

Contact backup:
Last name: Jasmin Brooks
Email: brooksjm@musc.edu

Investigator:
Last name: Michael Marrone, PhD
Email: Principal Investigator

Investigator:
Last name: Stephen Savage, MD
Email: Sub-Investigator

Start date: March 11, 2024

Completion date: August 1, 2026

Lead sponsor:
Agency: Medical University of South Carolina
Agency class: Other

Source: Medical University of South Carolina

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT05586360