Prospective Evaluation of Mp-MRI, MR-guided Biopsy, and Molecular Markers for Active Surveillance of Prostate Cancer (PROMM-AS)

Prospective Phase II Trial Evaluating Multiparametric MRI, Radiomics, MR-guided Biopsy, and Molecular Markers for Active Surveillance of Patients With Low- and Intermediate-Risk Prostate Cancer

Active Surveillance (AS) is a treatment option in patients with favorable risk prostate cancer. According to the current guidelines patients are monitored by prostate specific antigen (PSA) testing (every 3 months) and regular re-biopsies. Due to histological reclassification and/or patient noncompliance a high number of patients discontinue AS. Nonetheless, because of an increasing number of diagnosed early stage tumors overdiagnosis and overtreatment of patients has become a major clinical problem. Therefore AS is a promising and important tool for patients with low and intermediate risk prostate cancer.

Multiparametric MRI (mp-MRI) in combination with radiomics analysis, MR-guided biopsies, and molecular markers are promising tools to optimize patient selection and observation during AS.

This prospective, single arm, multicenter phase II study evaluates mp-MRI, radiomics, MR-guided biopsies and molecular markers for AS with the primary endpoint of reducing discontinuation based on histologic reclassification.

At the end of this study the results may allow defining a MRI-based pathway to identify and monitor patients suitable for AS supported by radiomics. Thus, the high rate of discontinuation due to misclassification at initial diagnosis will be reduced.

Additionally, this strategy will allow reducing over-treatment of clinically insignificant PCA, and on the other hand, increasing early treatment of higher-risk disease. Monitoring by mp-MRI will reduce the number of prostate biopsies and cores per patient during AS, and thus increase the patient compliance. Finally, such a strategy will reduce the economic burden of treating insignificant prostate cancer.

Study Overview

• Status: Unknown
• Conditions: Prostate Cancer
• Intervention / Treatment: Diagnostic test: Multiparametric MRI; Diagnostic test: Radiomics; Diagnostic test: MR-guided Biopsy; Diagnostic test: Molecular Markers

Detailed Description

This prospective multicenter phase II study evaluates multiparametric MRI (mp-MRI), radiomics and MR-guided biopsies for Active Surveillance (AS) of men with low- and intermediate-risk prostate cancer (PCA) with the primary endpoint of reducing the rate of discontinuation of AS based on histologic reclassification in an observation period of 24 months.

Men with low- or intermediate-risk PCA diagnosed by mp-MRI followed by an MR/ultrasound fusion-guided biopsy (FUS-GB) plus systematic ultrasound-guided biopsy (SB) will be included in this study.

During the study observation period PSA values will be obtained every 3 months. After having obtained three values PSA doubling times (PSA-DT) will be calculated at every visit. In case of PSA-DT <3 years patients will get a repeat mp-MRI and in case of MRI progression a repeat targeted FUS-GB plus SB will be performed. In case of a Gleason score upgrading by the targeted biopsy the patient will discontinue AS and get treatment. In cases of stable MRI or stable Gleason score the patient will continue with PSA controls every 3 months.

In addition all patients with stable PSA values will undergo a mp-MRI after 12 months. If this MRI demonstrates progression the protocol proceeds as mentioned above for patients with PSA-increase. At the end of study (24 months after enrollment), all patients will receive another mp-MRI and FUS-GB+SB.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lars Schimmöller, MD; Phone Number: +49 211-81-08505; Email: Lars.Schimmoeller@med.uni-duesseldorf.de
• Study Contact Backup: Name: Christian Arsov, MD; Phone Number: +49 211-81-08607; Email: Christian.Arsov@med.uni-duesseldorf.de

Study Locations

• Germany
  • NRW
    • Dusseldorf, NRW, Germany, 40225
      • Recruiting
      • University Düsseldorf, Medical Faculty
      • Contact: Almut Diem; Phone Number: +49 211-8119353; Email: diem@med.uni-duesseldorf.de

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients with a Gleason score of 3+3=6 or 3+4=7a and ≤ 33% of positive biopsy cores verified by an at least 12 core systematic prostate biopsy (SB)
• Organ-confined disease (≤cT2a), note: tumor-positive biopsies in both lobes with non-palpable tumor are rated as cT1c
• PSA value ≤10 ng/ml

Exclusion Criteria:

• Gleason score ≥4+3=7b or a Gleason score 3+4=7a with positive biopsy cores >33% of all cores in SB
• PSA >10 ng/ml
• Patients not able to give informed consent
• Contraindication to mp-MRI
• Contraindication to prostate biopsy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Intervention Arm; PSA testing; Multiparametric MRI (mp-MRI); Radiomics; MR-guided biopsy (MR-guided and systematic US-guided); Molecular Markers (Histological analysis of biopsy cores)

Diagnostic test: Multiparametric MRI; Multiparametric prostate MRI (mp-MRI); Diagnostic test: Radiomics; Radiomics analyses will consist of image intensity normalization, image coregistration and resampling, radiomic feature extraction, combination with clinical and molecular parameters, feature extraction and machine learning, model testing on validation and test cohorts and comparison to existing clinical risk models.; Diagnostic test: MR-guided Biopsy; MR-guided targeted prostate biopsies as well as systematic TRUS-guided biopsies (at least 12 cores) will be performed on a fusion-guided biopsy system. The biopsy cores can either be obtained transrectal or transperineal.; Diagnostic test: Molecular Markers; Molecular markers will be analyzed on the initial and final targeted and systematic biopsy cores. The molecular panel consists of a methylation-specific PCR and a set of highly selected markers that can be detected by immunohistochemistry. The resulting data will be prospectively recorded to enable a retrospective analysis of the prognostic value.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of the discontinuation of Active Surveillance (AS)	Reduction of the discontinuation of AS from 25% to 15% of patients after 24 months based on re-biopsy Gleason score upgrading	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Value of MRI (ADC) regarding aggressiveness	Evaluation of ADC values in s/mm2	36 months
Detectionrates of targeted (FUS-GB) versus systematic (TRUS-GB) biopsies	Comparison of detection rates (in %)	36 months
Detectionrates of targeted (FUS-GB) versus systematic (TRUS-GB) biopsies	Comparison of Gleason score upgrades (in %) (Gleason score in units 6-10 )	36 months
Correlation of clinical parameters with Gleason score progression or MRI quantified progression	Correlation of PSA elevation in ng/ml	36 months
Correlation of clinical parameters with Gleason score progression or MRI quantified progression	Correlation of PSA density in ng/ml/ml	36 months
Correlation of clinical parameters with Gleason score progression or MRI quantified progression	Correlation of age in years	36 months
Patient compliance to recommended MRI-based observation	Number of patients drop outs	36 months
Patient compliance to recommended MRI-based observation	Patient discontinuation rate (in %)	36 months
Evaluation of Resolve DWI	Improvement of SNR (signal-to-noise ratio)	36 months
Evaluation of Resolve DWI	Subjective Image Quality (5-point scale; evaluated by 2 blinded radiologists; total score from 1=non diagnostic, 2=poor, 3=acceptable, 4=good, to 5=excellent)	36 months
Evaluation of Resolve DWI	Improvement of tumor detection rate (in %)	36 months
Evaluation of Resolve DWI	NPV (in %)	36 months

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf
• Investigators: Principal Investigator: Lars Schimmöller, MD, University Düsseldorf, Medical Faculty; Department of Diagnostic and Interventional Radiology; Principal Investigator: Christian Arsov, MD, University Düsseldorf, Medical Faculty; Department of Urology

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2017
• Primary Completion (Anticipated): September 30, 2020
• Study Completion (Anticipated): September 30, 2021

Study Registration Dates

• First Submitted: January 28, 2018
• First Submitted That Met QC Criteria: June 6, 2019
• First Posted (Actual): June 7, 2019

Study Record Updates

• Last Update Posted (Actual): June 7, 2019
• Last Update Submitted That Met QC Criteria: June 6, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Prostate Cancer; Multiparametric MRI; Active Surveillance; Radiomics; Prospective Study; Molecular Markers; MR-guided Biopsy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: 5941R

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

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