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Liquid Biopsy-based Detection of Resistance to Targeted Therapy in Prostate Cancer Patients (PEARL)

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ClinicalTrials.gov Identifier: NCT03601143
Recruitment Status : Recruiting
First Posted : July 26, 2018
Last Update Posted : April 8, 2021
Sponsor:
Information provided by (Responsible Party):
Technische Universität München

Brief Summary:
This study will prospectively compare liquid-biopsy based methods for prediction of resistance under androgen-receptor signaling inhibitors. The main goal is to determine the optimal method to determine androgen-receptor variant 7 (AR-V7) status. In addition, the investigators will explore novel other, AR-V7 independent mechanisms of resistance and their predictive value for proper treatment. These are based on further AR splice variants, and on neuroendocrine differentiation of prostate cancer cells.

Condition or disease Intervention/treatment
Castration-resistant Prostate Cancer Other: Blood samples prior to a new line of AR-targeted therapy

Detailed Description:

Androgen receptor signaling inhibitors (ARSi) have become available in the past years for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and have significantly improved their survival. Despite this improvement, initial or emerging resistance to ARSi poses a major challenge in the treatment of these patients. There is therefore an urgent medical need for early detection of treatment resistance.

Liquid biopsies - blood samples containing circulating tumor cells (CTCs) and nucleic acids from the tumor - can provide information about such resistance. The investigators of this study and others have shown that liquid biopsies can be used to detect the messenger RNA (mRNA) of AR-V7, a splice variant of the androgen receptor (AR) that is insensitive to ARSi, in whole blood, and that high levels of AR-V7 mRNA in mCRPC patients are predictive to non-response to ARSi. Several liquid biopsy approaches involving different blood compartments such as CTCs, exosomes, and whole blood have been used so far to detect AR-V7. However, it is unclear which liquid biopsy approach or which combination of approaches is best to predict resistance under ARSi therapy in the clinical setting. In addition, current approaches explain only about half of resistant cases, suggesting that there are important non-AR-V7-mediated causes of resistance.

In this study, the investigators aim at determining the optimal liquid biopsy approach to detect AR-V7 and exploring novel ones for best possible prediction of resistance to ARSi. To this end, the investigators will systematically explore relevant blood compartments in a prospective cohort of mCRPC patients, quantify AR-V7 mRNA levels in each compartment, and determine the diagnostic value of compartment-specific AR-V7 mRNA levels for predicting response to subsequent ARSi therapy. The investigators will further explore the clinical relevance of AR-V7 protein subcellular localization in CTCs for prediction of ARSi resistance. In addition, novel other, AR-V7 independent mechanisms of resistance and their predictive value for proper treatment will be explored. These are based on further AR splice variants, and on neuroendocrine differentiation of prostate cancer cells.

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Study Type : Observational
Estimated Enrollment : 120 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Liquid Biopsy-based Detection of Resistance to Targeted Therapy in Prostate Cancer Patients
Actual Study Start Date : March 1, 2019
Estimated Primary Completion Date : November 1, 2022
Estimated Study Completion Date : November 1, 2024

Resource links provided by the National Library of Medicine



Intervention Details:
  • Other: Blood samples prior to a new line of AR-targeted therapy
    Blood will be drawn at baseline prior to a new line of AR-targeted therapy.


Primary Outcome Measures :
  1. Prostate-specific antigen (PSA) decline >=50% [ Time Frame: 24 months ]
    The optimal liquid biopsy-based test method to predict PSA response under AR-targeted therapy will be determined.


Secondary Outcome Measures :
  1. Clinical progression-free survival [ Time Frame: 24 months ]
    The optimal liquid biopsy-based test method to predict clinical progression-free survival under AR-targeted therapy will be determined.

  2. Overall survival [ Time Frame: 36 months ]
    The optimal liquid biopsy-based test method to predict overall survival under AR-targeted therapy will be determined.


Biospecimen Retention:   Samples With DNA
Blood


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
metastatic castration-resistant prostate cancer patients planned for a new line of therapy with androgen-receptor signaling inhibitors
Criteria

Inclusion Criteria:

  • Histologically confirmed prostate adenocarcinoma
  • Castrate serum testosterone <50ng/ml or <1.7nmol/l under continued androgen-deprivation therapy or surgical castration
  • Progressive disease at study entry in accordance with Prostate Cancer Working Group 3 criteria (PCWG3):

    • Biochemical progression: Three consecutive rises in PSA at least one week apart resulting in two 50% increases over the nadir, and a PSA >1.0 ng/ml as minimal starting value, or
    • Radiologic progression: either two or more new bone lesions on bone scan or a new soft tissue lesion using RECIST (Response evaluation criteria in solid tumors).
  • Metastatic disease confirmed on computed tomography (CT) or bone scan
  • Planned treatment with ARSi (androgen-receptor signaling receptors)
  • Written informed consent of the patient

Exclusion Criteria:

  • Persons who are in a dependency or employment relationship with the investigator or sponsor
  • Planned additional concurrent anticancer therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03601143


Contacts
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Contact: Matthias M Heck, MD +49894140 ext 2508 matthias.heck@tum.de
Contact: Christof Winter, MD PhD +49894140 ext 4765 christof.winter@tum.de

Locations
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Germany
Technical University of Munich, Klinikum rechts der Isar, Department of Urology and Institute of Clinical Chemistry Recruiting
Munich, Germany, 81675
Contact: Matthias M Heck, MD    +49894140 ext 2508    matthias.heck@tum.de   
Contact: Christof Winter, MD PhD    +49894140 ext 4765    christof.winter@tum.de   
Sponsors and Collaborators
Technische Universität München
Investigators
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Principal Investigator: Matthias M Heck, MD Technische Universität München
Principal Investigator: Christof Winter, MD PhD Technische Universität München
Publications:
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Responsible Party: Technische Universität München
ClinicalTrials.gov Identifier: NCT03601143    
Other Study ID Numbers: HE 7386/1-1
First Posted: July 26, 2018    Key Record Dates
Last Update Posted: April 8, 2021
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases