Finasteride and Flutamide in Pre-surgical Trial in Prostate Cancer. (2F)

A Randomized, Phase IIB, Double Blind, Placebo Controlled, Multicenter, Pre-surgical, Window-of-opportunity Trial of Finasteride Vs. Low-dose Flutamide Vs. Placebo in Prostate Cancer (2F Trial)

Pre-surgical, window-of-opportunity trials provide a suitable model to assess the activity of preventive interventions in a cost-effective manner using tissue biomarkers as surrogate endpoints. Finasteride has been shown to reduce prostate cancer development in a large phase III trial, and flutamide has a well-known anticancer effect in advanced prostate cancer at the dose of 750 mg/day.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer; Prostatic Intraepithelial Neoplasia
• Intervention / Treatment: Drug: Flutamide; Drug: Finasteride; Other: Placebo

Detailed Description

In this randomized, phase IIB, double blind, placebo controlled, multicenter, pre-surgical, window-of-opportunity trial we compared the effects of finasteride (5 mg/day) versus low-dose flutamide (250 mg/day) or placebo on tissue biomarkers in patients with prostate cancer who were candidate to radical surgery. Specifically, the effects of both drugs on the change in epithelial cell nuclear area in prostate cancer tissue between pre- and post-treatment biopsies was evaluated (primary endpoint). Moreover, the changes of the proliferation marker Ki-67 and of karyometric parameters in benign, dysplastic (HG-PIN) and malignant tissues were evaluated (secondary endpoints). Additional endpoints include the changes of serum PSA and testosterone, assessment of toxicity, overall survival, recurrence-free survival and event-free (recurrence + death) survival. Patients with intracapsular biopsy proven prostate cancer were randomized to either flutamide, 250 mg/day, or finasteride, 5 mg/day, or placebo for 4-6 weeks before radical prostatectomy. Blood samples were taken before and after treatment. At surgery, end-of-study ex-vivo biopsies were obtained from the prostatectomy specimens to assess the treatment changes in nuclear area (primary endpoint), Ki-67, topoisomerase-II-α and a 20-feature karyometric discrimant function in normal, high-grade PIN and malignant tissue. After surgery patients were followed up for at least 15 years to assess recurrence and/or mortality. We also plan to follow-up patients by telephone interview to assess their vital status for up to 20 years.

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Italy
  • Genova, Italy, 16128
    • Medical Oncology Ente Ospedaliero Ospedali Galliera

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients aged > 18 years
• Patients with a biopsy proven, clinically intracapsular PCa who are candidates to radical retropubic prostatectomy
• ECOG performance status ≤ 2

• Satisfactory hematological and biochemical functions:

  • Platelets ≥100 x 10^9/L
  • AST and ALT in the normal range
• Able to understand and sign an informed consent

Exclusion Criteria:

• Previous hormone treatment during the 8 weeks before enrollment
• Neurologic and psychiatric diseases precluding patient participation in the study
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing or participating in the study and/or comply with the study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Flutamide; 1 tablet 250 mg daily until the day before surgery	Drug: Flutamide; 1 tablet daily until the day before surgery; Other Names: Arm A
Experimental: Finasteride; 1 tablet 5 mg daily until the day before surgery	Drug: Finasteride; 1 tablet daily until the day before surgery; Other Names: Arm B
Placebo Comparator: Placebo; 1 tablet daily until the day before surgery	Other: Placebo; 1 tablet daily until the day before surgery; Other Names: Arm C

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Nuclear area size	The study primary endpoint is the change of epithelial cell nuclear area in prostate cancer tissue and HG-PIN tissue between pre- and post-treatment measure in the two active treatment arms (Finasteride or Flutamide) compared with the placebo arm.	4-6 weeks (baseline and at the end of the study biopsy)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of ki-67 value	Changes of Ki-67 labeling index in normal, HG-PIN and prostate cancer cells in the three arms.	4-6 weeks (baseline and at the end of the study biopsy)
Change Kariometry value	Changes in karyometric features in normal HG-PIN and prostate cancer cells in the three arms.	4-6 weeks (baseline and at the end of the study biopsy)
Serum biomarkers values	Changes in total PSA, free PSA and testosterone concentrations after treatment in the three arms.	4-6 weeks (on blood samples at baseline and the day before surgery)
Adverse Events	Toxicity is assessed using the National Cancer Institute-Common Terminology Criteria for Adverse Events (version 3, 2003).	4-6 weeks (during the treatment)
Recurrence-free survival	Comparison of Recurrence-free survival among arms will be assessed by the Kaplan Meier actuarial survival curves and analyzed by the log-rank test and the Cox proportional hazard model for multivariate analyses. Vital status and medical condition will be assessed by telephone interview and clinical visit.	up to 20 years
Comparison of Event free survival	Comparison of Event free survival among arms will be assessed by the Kaplan Meier actuarial survival curves and analyzed by the log-rank test and the Cox proportional hazard model for multivariate analyses. Vital status and medical condition will be assessed by telephone interview and clinical visit.	up to 20 years
Comparison of Overall Survival	Comparison of Overall Survival among arms will be assessed by the Kaplan Meier actuarial survival curves and analyzed by the log-rank test and the Cox proportional hazard model for multivariate analyses. Vital status and medical condition will be assessed by telephone interview and clinical visit.	up to 20 years

Collaborators and Investigators

• Sponsor: Ente Ospedaliero Ospedali Galliera
• Collaborators: University of Arizona; Università Politecnica delle Marche; Universita degli Studi di Genova; European Institute of Oncology; Cliniche Humanitas Gavazzeni
• Investigators: Principal Investigator: Andrea De Censi, MD, E.O. Ospedali Galliera

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2004
• Primary Completion (Actual): March 20, 2008
• Study Completion (Actual): June 16, 2017

Study Registration Dates

• First Submitted: February 12, 2019
• First Submitted That Met QC Criteria: September 13, 2024
• First Posted (Estimated): September 19, 2024

Study Record Updates

• Last Update Posted (Estimated): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 13, 2024
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Prostate Cancer; Chemoprevention; Finasteride; Flutamide; Prostatic Intraepithelial Neoplasia; Biomarkers, drug response; Karyometry
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Male; Prostatic Diseases; Carcinoma in Situ; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Neoplasms; Prostatic Neoplasms; Prostatic Intraepithelial Neoplasia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Urological Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Steroid Synthesis Inhibitors; Androgen Antagonists; 5-alpha Reductase Inhibitors; Flutamide; Finasteride
• Other Study ID Numbers: 13CE20102003; Italian League against Cancer (Other Identifier: LILT (Lega Italiana contro i Tumori)); Berlucchi Foundation (Other Identifier: Fondazione Berlucchi)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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