HCQ in Resectable Localized Prostate Cancer

A Randomized, Placebo Controlled Proof of Principle (Window of Opportunity) Study of Hydroxychloroquine (HCQ) in Prostate Cancer Patients Undergoing Radical Prostatectomy

This is randomized, double blind, placebo controlled proof of principle (window of opportunity) study of oral hydroxychloroquine in patients with resectable localized prostate cancer. To determine the effects of hydroxychloroquine (HCQ) on markers of autophagy, such as p62, LC3-II and NBR-1 in prostate cancer tissue of patients with resectable localized prostate cancer who undergo radical prostatectomy. To monitor/observe the safety and tolerability of daily oral hydroxychloroquine in the pre and perioperative period in patients who undergo radical prostatectomy. To evaluate the concentration of hydroxychloroquine in normal and prostate tumor tissue and to correlate prostate tissue concentrations with the plasma concentrations in these patients. To perform tumor genomic analysis (for common somatic mutations) and to correlate the molecular response to HCQ and presence/absence of such mutations.

Study Overview

• Status: Not yet recruiting
• Conditions: Resectable Localized Prostate Cancer
• Intervention / Treatment: Drug: Placebo; Drug: Hydroxychloroquine Sulfate 400Mg Tab

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Bridget M Labrie; Phone Number: 16036506227; Email: bridget.m.labrie@hitchcock.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• All patients must have pathological confirmation of adenocarcinoma of the prostate Gleason score 6 (grade Group 1) or greater.
• Patients must have resectable prostate cancer as defined by the AJCC (American Joint Committee on Cancer) TNM system and have planned radical prostatectomy.
• Patients must have sufficient tissue from the initial diagnostic prostate biopsy, as determined by the study pathologist, to perform the required study analyses without exhausting the tissue required for clinical purposes
• Age >18 years
• Adequate hematopoietic, hepatic and renal function documented prior to study entry to include: Hb. > 10g/dL, WBC > 3500/mm3, ANC > 1500/mm3 and platelets > 100,000/mm3; hepatic transaminases (AST or ALT) ≤ 2.0 times the upper limits of normal, total bilirubin ≤ 1.5 times the upper limits of normal, estimated creatinine clearance ≥ 60 mL/min or eGFR > 60 mL/min/1.73 m2 and normal serum cations (K+/Mg2+/Ca2+)
• All patients must be medically fit candidates for radical prostatectomy.
• A patient with any retinopathy will only be enrolled into the study with the approval of a board-certified ophthalmologist
• All patients must give informed consent indicating they are aware of the investigational nature of this study treatment prior to any study procedures being performed.

Exclusion Criteria:

• Patients may not have received radiation therapy for their prostate cancer.
• Patients may not have received chemotherapy for their prostate cancer.
• Patients with gastrointestinal abnormalities including: inability to take oral medication, requirement for intravenous alimentation, or prior major surgery or diseases which may cause malabsorption (e.g. bowel resection, ischemic bowel, Crohns or Ulcerative colitis)
• A serious uncontrolled medical disorder or active infection which would impair their ability to receive study treatment will be excluded.
• Patients with significant cardiac disease: including uncontrolled high blood pressure, unstable angina, congestive heart failure, myocardial infarction within the previous 3 months, or serious cardiac arrhythmias, including a QT interval corrected for heart rate using the Fridericia formula of ≥ 450 ms, or history of Torsade de pointes will be excluded.
• Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol will be excluded.
• Patients receiving any disease-modifying anti-rheumatic drugs (DMARDs) will be excluded.
• Patients with known or a history of G6PD deficiency will be excluded. Eligible patients will be based on clinician-investigator assessment, that the patient is not at an increased risk for G6PD deficiency (assessment should include information regarding self-reported race/ancestry), OR the patient has a negative screening test for G6PD deficiency.
• Patients taking other commercially available medications which may theoretically either stimulate or inhibit autophagy (calcitriol and chloroquine) will be excluded.
• Patients chronically taking drugs known to cause torsades de pointes will be excluded unless those agents can be discontinued for a period > 6 times their half-life before study enrollment
• Patients with poorly controlled diabetes mellitus will be excluded.
• Patients with a history of epilepsy will be excluded.
• Patients with a history of porphyria will be excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydroxychloroquine; Loading dose 400mg three times a day then 400mg twice daily for up to 28 days prior to surgical resection, taken orally	Drug: Hydroxychloroquine Sulfate 400Mg Tab; hydroxychloroquine sulfate tablet
Placebo Comparator: Placebo; Loading dose three times a day then twice daily for up to 28 days prior to surgical resection, taken orally	Drug: Placebo; Inactive tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in expression of markers of autophagy	To determine the effects of hydroxychloroquine (HCQ) on markers of autophagy, such as p62, LC3-II and NBR-1 in prostate cancer tissue of patients with resectable localized prostate cancer who undergo radical prostatectomy.	Day 1, Day 26/27, Day of surgery(approximately day 30)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	To monitor/observe the safety and tolerability of daily oral hydroxychloroquine in the pre and perioperative period in patients who undergo radical prostatectomy	Day 1 through post surgery visit(approximately day 60)
Evaluate the concentration of hydroxychloroquine	To evaluate the concentration of hydroxychloroquine in normal and prostate tumor tissue and to correlate prostate tissue concentrations with the plasma concentrations in these patients.	Day 1, Day 26/27, Day of surgery(approximately day 30)
Measure the tumor mutational burden	To perform tumor genomic analysis (for common somatic mutations)	Baseline and Day of Surgery(approximately Day 30)
Correlation between tumor mutations and HCQ responses	Correlate the molecular response to HCQ and presence/absence of such mutations.	Baseline and Day of Surgery(approximately Day 30)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory analyses of the effects of hydroxychloroquine on BNIP3 a marker of mitophagy	To perform exploratory analyses of the effects of HCQ on the induction of inflammation or necrosis(as measured by BNIP3 expression) in treated as compared to untreated tumors	Baseline and Day of Surgery(approximately Day 30)
Explore the effects of hydroxychloroquine on BNIP3	To explore the effects of hydroxychloroquine on BNIP3 expression in prostate cancer tissue	Baseline and Day of Surgery(approximately Day 30)

Collaborators and Investigators

• Sponsor: Lionel.D.Lewis, MD
• Collaborators: Dartmouth Cancer Center
• Investigators: Principal Investigator: Lionel Lewis, MB BCh., MD, Dartmouth-Hitchcock Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: February 26, 2024
• First Submitted That Met QC Criteria: May 6, 2024
• First Posted (Actual): May 10, 2024

Study Record Updates

• Last Update Posted (Actual): May 10, 2024
• Last Update Submitted That Met QC Criteria: May 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 23LEW054|STUDY02002054

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There are no plans at this time to share IPD

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No