Placebo-Controlled Trial of Urolithin A Supplementation in Men With Prostate Cancer Undergoing Radical Prostatectomy, URO-PRO Trial

National Cancer Institute (NCI)

Status and phase: Enrolling; Phase 2

Conditions: Prostate Adenocarcinoma

Treatments: Drug: Placebo Administration; Procedure: Biopsy Procedure; Dietary Supplement: Urolithin A Supplement; Procedure: Biospecimen Collection

Study type: Interventional

Funder types: NIH

Identifiers

NCT06022822

NCI22-12-01 (Other Identifier)

NWU22-12-01 (Other Identifier)

UG1CA189828 (U.S. NIH Grant/Contract)

P30CA060553 (U.S. NIH Grant/Contract)

NCI-2023-03835 (Registry Identifier)

UG1CA242643 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This phase II randomized control trial assesses the effect of Urolithin A (Uro-A) supplementation compared to placebo in men with biopsy-confirmed prostate cancer undergoing radical prostatectomy (RP) progressive disease. A total of 90 men will be accrued and randomized 1:1 to receive a 1000 mg daily dose of Uro-A in two 250 mg capsules PO BID or two placebo capsules BID daily for 3 to 6 weeks prior to RP. The primary endpoint is to determine the effect of Uro-A on decreasing prostate tumor tissue oxidative stress (measured by 8-OHdG) compared to placebo.

Full description

PRIMARY OBJECTIVE:

I. To determine the effect of a 3-to-6-week intervention of urolithin A (Uro-A) supplements versus placebo on 8-OHdG percent positive change in prostate cancer tumor tissue obtained by core needle biopsy in participants who undergo radical prostatectomy after 3 to 6 weeks of therapy.

SECONDARY OBJECTIVES:

I. To determine prostate tissue and plasma concentrations of Uro-A, urolithin sulfate and urolithin A glucuronide, as measured by change from baseline to end-of-study, in comparison to changes from baseline to end-of-study in a control group receiving a placebo (except tissue levels, which will be compared between arms using end-of-study tissue only).

II. To compare the change in expression of cell cycle genes in prostate cancer tumor tissue from pre-study biopsy to radical prostatectomy in men receiving Uro-A supplements for 3 to 6 weeks and a control group of men receiving a placebo.

III. To determine the effect of Uro-A supplements on change in 8-OHdG expression in benign and tumor-adjacent prostatic tissue from pre-study biopsy to radical prostatectomy (RP) following 3-6 weeks of therapy in comparison to a control group of men receiving a placebo.

EXPLORATORY OBJECTIVES:

I. To determine the effect of Uro-A supplements on circulating levels of high sensitivity C-reactive protein (hsCRP), TNF-alpha, and IL-6, as measured by change from baseline to end-of-study compared with the men receiving a placebo.

II. To compare change in tumor gene expression patterns of Hallmark androgen signaling between study arms.

III. To determine the effect of a 3-to-6-week intervention of urolithin A (Uro-A) supplements versus placebo on 8-OHdG H-index (percent staining positive at each score in a 0-3 scale) change in prostate cancer tumor tissue obtained by core needle biopsy at baseline and at radical prostatectomy after 3 to 6 weeks of therapy.

IV. To collect stool samples for future analyses to determine the effect of Uro-A supplements on change in stool microbiome 16s ribosomal ribonucleic acid (rRNA) gene sequencing.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive urolithin A orally (PO) twice daily (BID) for 3-6 weeks prior to standard of care (SOC) RP. Patients also undergo biopsy at time of surgery and collection of blood samples during screening and on study.

ARM II: Patients receive placebo orally (PO) twice daily (BID) for 3-6 weeks prior to SOC RP. Patients also undergo biopsy at time of surgery and collection of blood samples during screening and on study.

Patients are followed up at 2 weeks after surgery.

Enrollment: 90 estimated patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Participants must have pathologically confirmed adenocarcinoma of the prostate with formalin-fixed paraffin embedded (FFPE) biopsy tissue available for analysis. Diagnosis can be any time in the six months prior to registration/randomization
• Participants >= 18 years will be enrolled. Because no dosing or adverse event (AE) data are currently available on the use of urolithin A in participants < 18 years of age, children and adolescents are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Absolute neutrophil count >= 1,000/microliter
• Platelets >= 100,000/microliter
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) Note: Higher total bilirubin levels (=< 3 mg/dL) can be allowed if due to known benign liver condition, i.e. Gilbert's
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal
• Creatinine =< 1.5 x institutional upper limit of normal
• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Participants on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
• Scheduled to undergo RP in the next 3-6 weeks
• Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

• Participants with prior primary treatment or hormonal therapy for prostate cancer (PC)
• Participants with documented active alcohol and illegal substance dependency
• Participants already receiving urolithin A (Mitopure, commercially available in the United States), or pomegranate supplements. Note: Other supplements are allowed but must be documented
• Participants receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to urolithin A
• Uncontrolled intercurrent illness, or psychiatric illness/social situations that would limit compliance with study requirements

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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90 participants in 2 patient groups, including a placebo group

Arm I (urolithin A)

Experimental group

Description:

Patients receive urolithin A PO BID for 3-6 weeks prior to SOC RP. Patients also undergo biopsy at time of surgery and collection of blood samples during screening and on study.

Treatment:

Procedure: Biospecimen Collection

Dietary Supplement: Urolithin A Supplement

Procedure: Biopsy Procedure

Arm II (placebo)

Placebo Comparator group

Description:

Patients receive placebo PO BID for 3-6 weeks prior to SOC RP. Patients also undergo biopsy at time of surgery and collection of blood samples during screening and on study.

Treatment:

Procedure: Biospecimen Collection

Procedure: Biopsy Procedure

Drug: Placebo Administration