Cellular Effect of Cholesterol-Lowering Prior to Prostate Removal

Phase 0 Trial of Presurgical Cholesterol-lowering on Prostate Cancer Cell Growth

There is evidence in human studies as well as animal studies that treatments to lower cholesterol can reduce the risk of dying from prostate cancer.To decide if cholesterol-lowering therapy can slow the growth of prostate cancer, the investigators would like to lower cholesterol prior to surgery and then measure the growth of prostate cancers cells when the prostate has been removed. The investigators will use the combination of two drugs that is approved by the U.S. Food and Drug Administration to lower cholesterol. The drug combination is commercially available with a doctor's prescription and sold as Vytorin®. It is known that maximal cholesterol-lower effects are seen after 2 weeks of treatment with Vytorin®. Therefore, study patients receive at least 2 weeks, but no more than 6 weeks of Vytorin® prior to surgery.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: ezetimibe 10mg-simvastatin 40mg

Detailed Description

BACKGROUND AND RATIONALE

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among men in North America. In the US, there are more than 200,000 newly diagnosed cases and nearly 40,000 deaths from prostate cancer (CaP) annually. Although elevated lipid levels are understood to increase risk of coronary heart disease, their importance for CaP is not understood. Epidemiologic studies consistently show an association between lipid lowering interventions and decreased risk of advanced CaP. There are no reports of prospective studies of lipid-lowering interventions directed at CaP.

Epidemiologic studies and preclinical observations suggest that interventions to lower cholesterol will decrease the risk of developing lethal CaP. However, a definitive, phase III study of cholesterol-lowering effects on advanced CaP development is needed prior to clinical implementation of this intervention. Such a trial will require a massive commitment of resources for the large number of patients needing long follow-up. A rational intermediate step is to conduct a presurgical intervention study to lower cholesterol in men undergoing radical prostatectomy. Molecular evidence of treatment effect will provide a sound rationale for definitive clinical trials, and may provide predictive biomarkers that can be validated in these future trials.

The investigators propose a prospective trial to assess the effects on the human prostate of a maximal cholesterol lowering strategy using dual agents in men already scheduled to undergo radical prostatectomy for prostate cancer.

Simvastatin is a cholesterol-lowering drug approved by the FDA in 1991 and is now commercially available as Zocor (Merck) or as a generic agent. After ingestion, it is converted from an inactive lactone to the corresponding β-hydroxyacid, which inhibits HMG-CoA reductase and the conversion of HMG-CoA to mevalonate. Ezetimibe is a cholesterol-lowering agent that operates by a distinct mechanism from HMG-CoA reductase inhibitors. It was FDA approved in 2002 and is commonly administered alone or in combination with a statin. It specifically inhibits a cholesterol transporter in the small intestines and selectively inhibits the absorption of cholesterol and related sterols.

A single pill that combines simvastatin and ezetimibe is available from Merck (Vytorin). This commercially available agent at its standard dose is used in this trial. This study uses the combination of simvastatin and ezetimibe to achieve maximal cholesterol lowering prior to prostatectomy.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center

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:

• Biopsy containing ≥ 10 tissue cores sampled
• Biopsy positive for adenocarcinoma of the prostate containing any quantity of Gleason 3 component (e.g. Gleason score 3+3, 3+4, 4+3)
• Scheduled to undergo robotic radical prostatectomy
• Serum Prostate-Specific Antigen (PSA) <20 ng/ml
• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

• Pharmacologic therapy (e.g. statins or ezetimibe) to lower cholesterol within 30 days prior to registration.
• Prior treatment for CaP by surgery, irradiation, local ablative (e.g. cryosurgery or high intensity focused ultrasound) or androgen deprivation therapy.
• 5-alpha reductase inhibitors (e.g. finasteride or dutasteride) within 180 days prior to registration.
• Hypersensitivity to simvastatin or ezetimibe.
• Pharmacologic therapy with agents reported to produce adverse drug-drug interactions. (Table 2)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Vytorin (ezetimibe 10mg-simvastatin 40mg)	Drug: ezetimibe 10mg-simvastatin 40mg; Vytorin (ezetimibe 10mg-simvastatin 40mg) will be given on an outpatient basis. The drug will be taken orally each day until the subject undergoes radical prostatectomy. The start of Vytorin is timed so that patients get the last dose the day before surgery. Subjects receive a two to four weeks of Vytorin.; Other Names: Vytorin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Growth of Gleason grade 3 prostate cancer	Prostate tissue removed at the time of surgery will be examined to measure cellular growth using molecular assays.	following 2-6 weeks of cholesterol lowering intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Growth of benign prostate glands	Prostate tissue removed at the time of surgery will be examined to measure cellular growth using molecular assays.	following 2-6 weeks of cholesterol lowering intervention.
Growth of high grade prostate cancer (e.g. Gleason grade 4/5)	Prostate tissue removed at the time of surgery will be examined to measure cellular growth using molecular assays.	following 2-6 weeks of cholesterol lowering intervention.

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: Roswell Park Cancer Institute
• Investigators: Principal Investigator: Hyung L Kim, MD, Cedars-Sinai Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2015
• Primary Completion (Actual): February 28, 2019
• Study Completion (Actual): February 28, 2019

Study Registration Dates

• First Submitted: August 25, 2015
• First Submitted That Met QC Criteria: August 26, 2015
• First Posted (Estimate): August 27, 2015

Study Record Updates

• Last Update Posted (Estimate): February 22, 2023
• Last Update Submitted That Met QC Criteria: February 20, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: prostatectomy, cholesterol, statin
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin; Ezetimibe
• Other Study ID Numbers: Pro00040945

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes