ProBio: A Biomarker Driven Study in Patients With Metastatic Prostate Cancer (ProBio)

January 11, 2024 updated by: Henrik Grönberg, Karolinska Institutet

ProBio: An Outcome-adaptive and Randomized Multi-arm Biomarker Driven Study in Patients With Metastatic Prostate Cancer

ProBio is an international, outcome-adaptive, multi-arm, open-label, multiple assignment randomized biomarker driven platform trial in patients with metastatic prostate cancer. Patients will be randomized to control or experimental treatment arms. Patients in the control arm will receive standard of care following national guidelines. Patients in the experimental arm will be randomized to treatments based on a biomarker signature inferred from diagnostic tissue or liquid biopsy profiling. The predefined biomarker signatures are tumor properties or mutations in genes/pathways with previously demonstrated clinical validity (e.g. prognostic value or association with treatment response). The biomarker signatures are identified using a hybridisation capture gene panel specifically designed for prostate cancer.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

ProBio is an outcome-adaptive, multi-arm, open-label, multiple assignment randomised biomarker driven platform trial in patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

Patients will be randomised to control or experimental treatment class arms. Patients in the control arm will receive standard of care following national guidelines and will remain within the control arm throughout the course of the trial. Patients in the experimental arm will be randomised to a treatment class (consisting of one or multiple drugs) based on a biomarker signature. The biomarker signatures are defined as tumour properties or mutations in certain genes/pathways identified in the scientific literature as important in prostate cancer treatment response. The biomarker signatures are identified using a gene panel specifically designed for advanced prostate cancer.

Alterations in the following genes/pathways or combinations thereof constitute the biomarker signatures:

  • Androgen receptor
  • DNA-repair deficiency
  • TP53
  • TMPRSS2-ERG gene fusion
  • PI3K pathway alterations

Patients in the experimental arm can be randomized to the following treatments classes:

for mHSPC

  • AR signalling inhibitors (Abiraterone acetate, Enzalutamide, Apalutamide)
  • Taxane-based chemotherapy in combination with ARSi (Docetaxel plus Abiraterone acetate, or Darolutamide)
  • PolyADP Ribose Polymerase Inhibitors (Niraparib plus Abiraterone Acetate)

for mCRPC

  • AR signalling inhibitors (Enzalutamide, Abiraterone acetate)
  • Poly ADP Ribose Polymerase Inhibitors (Niraparib plus Abiraterone acetate)
  • Selective AKT Inhibitor (Capivasertib plus Docetaxel)

ProBio will use outcome-adaptive randomization, adapting the randomization based on the observed progression free survival (PFS) within biomarker signatures. Treatments will initially be assigned to patients based on the biomarker signatures for which that treatment is most likely to be effective. The trial will be analyzed within a Bayesian framework, which allows for calculations of the probability for each treatment that it is superior to standard of care within a given signature. Each experimental arm will be evaluated for efficacy relative to the control arm with the same biomarker signatures.

Participants and treating physicians will be blinded to ctDNA profile of each patient. The biomarker signatures will thus not influence treatment choice among controls (reflecting today's standard of care).

Further, ProBio will use the sequential multiple assignments trial (SMART) concept, where each patient who progresses within the trial will re-enter the trial and be re-assigned to another treatment based on the patient's current ctDNA profile. Patients will be withdrawn after in total maximal three randomized consecutive treatments after inclusion into the study.

The randomization probabilities within the experimental arm are defined in proportion to the probability that each treatment is superior to standard of care within a given biomarker signature, and therefore change as data accumulates in the trial and knowledge accumulates for what biomarker signatures and specific treatments that are more probable to be effective.

Trial results will be evaluated regularly by an independent data and safety monitoring board (DSMB). The DSMB will evaluate treatment-signature combinations with respect to:

  • Graduation for superiority: A treatment-biomarker signature combination will be graduated from the trial if it has a Bayesian predictive probability of success in a future confirmatory phase III trial exceeding a pre-specified threshold (85%).
  • Termination for futility: Treatment-biomarker signature combinations will be dropped from the trial for futility when success probabilities drop sufficiently low (less than 10% using a minimum of 20 patients assigned to the specific treatment-biomarker signature combination).
  • Alternatively, if the maximum sample size of 300 and 150 patients (for mHSPC and mCRPC, respectively) assigned to a treatment biomarker signature is reached without graduation for superiority, assignments to that combination will end.

ProBio is a platform study. This means that new treatments and biomarker signatures can be added to the experimental arm in the future. This will be done after protocol amendments.

Study Type

Interventional

Enrollment (Estimated)

750

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Belgium
      • Aalst, Belgium
        • Recruiting
        • OLV Ziekenhuis Aalst
        • Contact:
        • Principal Investigator:
          • Peter Schatterman, MD
      • Antwerp, Belgium
        • Recruiting
        • GZA Sint-Augustinus
        • Contact:
        • Principal Investigator:
          • Michiel Strijbos, MD, PhD
      • Brugge, Belgium, B-8000
        • Recruiting
        • AZ Sint-Jan AV
        • Contact:
        • Principal Investigator:
          • Christophe Ghysel, MD
      • Brugge, Belgium
        • Recruiting
        • AZ Sint-Lucas
        • Contact:
        • Principal Investigator:
          • Daan De Maeseneer
      • Genk, Belgium
        • Recruiting
        • Ziekenhuis Oost-Limburg
        • Contact:
        • Principal Investigator:
          • Wendy De Roock, MD
      • Gent, Belgium
        • Not yet recruiting
        • AZ Jan Palfijn Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Caroline Verbaeys, MD, PhD
      • Ghent, Belgium, B-9000
        • Recruiting
        • University Hospital Ghent
        • Contact:
        • Principal Investigator:
          • Piet Ost, Prof. dr.
      • Hasselt, Belgium
        • Recruiting
        • Jessa Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Daisy Luyten, MD
      • Kortrijk, Belgium
        • Recruiting
        • Az Groeninge
        • Principal Investigator:
          • Siska Van Bruwaene
        • Contact:
      • Liège, Belgium
        • Recruiting
        • University Hospital Luik
        • Contact:
        • Principal Investigator:
          • Brieuc Sautois, MD
      • Oostende, Belgium
        • Recruiting
        • AZ Damiaan
        • Contact:
        • Principal Investigator:
          • Jochen Darras, MD
      • Sint-Niklaas, Belgium
        • Recruiting
        • VITAZ
        • Contact:
        • Principal Investigator:
          • Els Everaert, MD, PhD
  • Norway
      • Kristiansand, Norway
        • Recruiting
        • Kreftsenter Kristiansand
        • Contact:
        • Principal Investigator:
          • Christoph Müller, MD, PhD
      • Lørenskog, Norway
        • Recruiting
        • Akershus universitetssykehus
        • Contact:
          • Berit Larsson, MSc
        • Principal Investigator:
          • Jan Oldenburg, Prof. dr
      • Stavanger, Norway
        • Recruiting
        • Stavanger Universitetssjukehus
        • Contact:
          • Berit Larsson, MSc
        • Principal Investigator:
          • Maria N Vigmostad, MD, PhD
      • Tromsø, Norway
        • Not yet recruiting
        • Universitetssykehuset Nord-Norge Tromsö
        • Contact:
        • Principal Investigator:
          • Hege S Haugnes, Prof, dr
      • Ålesund, Norway
        • Not yet recruiting
        • Ålesund sjukehus
        • Contact:
        • Principal Investigator:
          • Bjorg Y Aksnessaether, MD PhD
  • Sweden
      • Borås, Sweden
        • Recruiting
        • Södra Älvsborgs Sjukhus
        • Contact:
        • Principal Investigator:
          • Christine Jaredsson, MD, PhD
      • Jönköping, Sweden, 551 11
        • Recruiting
        • Länssjukhuset Ryhov - Onkologiska kliniken
        • Contact:
        • Principal Investigator:
          • Linn Pettersson, MD, PhD
      • Kalmar, Sweden, 392 44
        • Recruiting
        • Länssjukhuset
        • Contact:
        • Principal Investigator:
          • Mats Andén, MD, PhD
      • Karlstad, Sweden, 651 85
        • Recruiting
        • Centralsjukhuset Region Värmland
        • Contact:
        • Principal Investigator:
          • Johan Sandzen, MD, PhD
      • Stockholm, Sweden, 17176
        • Recruiting
        • Karolinska University Hospital
        • Contact:
        • Principal Investigator:
          • Anders Ullén, MD, PhD
      • Stockholm, Sweden
      • Sundsvall, Sweden, 851 86
        • Recruiting
        • Länssjukhuset Sundsvall Härnösand
        • Contact:
        • Principal Investigator:
          • Elin Jänes, MD PhD
      • Umeå, Sweden, 90185
        • Recruiting
        • Norrlands universitetssjukhus
        • Contact:
        • Principal Investigator:
          • Camilla Thellenberg Karlsson, MD PhD
      • Uppsala, Sweden, 75185
        • Recruiting
        • Akademiska Sjukhuset
        • Contact:
        • Principal Investigator:
          • Gunilla Enblad, Professor
      • Varberg, Sweden
        • Recruiting
        • Hallands Sjukhus Varberg
        • Contact:
        • Principal Investigator:
          • Ingela Franck Lissbrant, MD, PhD
      • Växjö, Sweden, 351 85
        • Recruiting
        • Centrallasarettet Onkologkliniken
        • Contact:
        • Principal Investigator:
          • Martha Olsson, MD, PhD
      • Örebro, Sweden
        • Recruiting
        • Universitetssjukhuset Örebro
        • Contact:
        • Principal Investigator:
          • Jenny Kahlmeter Brandell, MD, PhD
    • Region Dalarna
      • Falun, Region Dalarna, Sweden, 79182
        • Recruiting
        • Falu Lasarett
        • Contact:
          • Berit Larsson, MSc
        • Contact:
        • Principal Investigator:
          • Ingrida Verbiéne, MD, PhD
  • Switzerland
      • Basel, Switzerland
        • Recruiting
        • Universitätsspital Basel
        • Contact:
        • Principal Investigator:
          • Ashkan Mortezavi, MD PhD
      • Basel, Switzerland
        • Recruiting
        • St. Claraspital
        • Contact:
        • Principal Investigator:
          • Arnoud Templeton, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Man with histologically confirmed prostate adenocarcinoma, initiating systemic therapy for metastatic disease, encompassing newly diagnosed (i.e. de novo) hormone sensitive prostate cancer (mHSPC) or first-line castration resistant prostate cancer (mCRPC)
  • Distant metastatic disease documented by positive bone scan or metastatic lesions on CT or MRI
  • Adequate health as assessed by the investigator to receive all available treatments in the trial
  • ECOG/WHO (Eastern Cooperative Oncology Group/ World Health Organization) performance score 0-2
  • Adequate organ and bone marrow function
  • Albumin greater than or equal to 28 g/L
  • Able to understand the patient information and sign written informed consent

Exclusion Criteria:

  • Other malignancies within 5 years except non-melanoma skin cancer
  • Within 6 months of randomization: myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke, TIA (transient ischemic attack), or congestive heart failure NYHA (New York Heart Association) class III or IV
  • Uncontrolled hypertension
  • Uncontrolled hypotension
  • Received systemic therapy (with the exception of standard ADT) prior to study inclusion, for the CRPC indication
  • Any severe acute or chronic medical condition that places the patient at increased risk of serious toxicity or interferes with the interpretation of study results
  • Unable to comply with study procedures
  • Current participation in another clinical trial that will be in conflict with the present study, administration of an investigational therapeutic or invasive surgical procedure within 28 days prior to study enrolment
  • Patients who are unlikely to comply with the protocol
  • Any condition or situation which, in the opinion of the investigator, would put the subject at risk, may confound study results, or interfere with the subjects participation in this study.
  • Any medical condition that would make use of the study treatments contraindicated, according to the SmPC, e.g. significant heart or liver disease.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Control: Standard Care
Randomization between assignment to the control arm or the biomarker driven arm will be stratified on biomarker signatures, previous treatment, and fraction of ctDNA and will therefore occur after the results from the ctDNA profiling is obtained. Patients in the control arm will receive standard of care following national guidelines.
Drug: Cabazitaxel 60 mg Solution for Injection
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Drug: Docetaxel Injectable Solution
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Drug: Radium Chloride Ra-223
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Other Names:
  • Xofigo
Drug: Enzalutamide Oral Capsule
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Other Names:
  • Xtandi
Drug: Abiraterone Oral Tablet
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Other Names:
  • Zytiga
Drug: Apalutamide
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Other Names:
  • Erleada
Experimental: Treatment 1 in mHSPC: AR signalling inhibitors (ARSi)
Assignments to therapy in the biomarker driven arms will be done on the basis of the biomarker signature using the current information about the efficacy of the various regimens for that signature. Information from previous studies may be incorporated in the randomization at study onset if such reliable data exists. Specifically, patients with an intact androgen receptor (AR) and without TP53 mutations will have increased chance of being randomized to treatment with ARSi.
Drug: Enzalutamide Oral Capsule
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Other Names:
  • Xtandi
Drug: Abiraterone Oral Tablet
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Other Names:
  • Zytiga
Drug: Apalutamide
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Other Names:
  • Erleada
Experimental: Treatment 2 in mHSPC: taxane-based chemotherapy in combination with ARSi
Patients with TP53 mutations and TMPRSS2-ERG gene fusions will have an increased chance of being randomised to treatment with chemotherapy plus an ARSi.
Drug: Docetaxel Injectable Solution
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Drug: Abiraterone Oral Tablet
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Other Names:
  • Zytiga
Drug: Darolutamide
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Other Names:
  • Nubeqa
Experimental: Treatment 3 in mHSPC: Poly ADP Ribose Polymerase (PARP) inhibitor
DNA-repair deficient patients will have an increased chance of receiving PARP inhibitors at study onset.
Drug: Niraparib plus Abiraterone acetate plus Prednisone
Niraparib and Abiraterone acetate will be provided by Janssen and will be provided either as a fixed dose combination or as single agents. Detailed use of the study treatment including dose and dosages are described in the Investigator's brochures and SmPC.
Other Names:
  • Akeega
Experimental: Treatment 1 in mCRPC: AR signalling inhibitors (ARSi)
Specifically, patients with an intact androgen receptor (AR) and without TP53 mutations will have increased chance of being randomized to treatment with ARSi.
Drug: Enzalutamide Oral Capsule
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Other Names:
  • Xtandi
Drug: Abiraterone Oral Tablet
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Other Names:
  • Zytiga
Experimental: Treatment 2 in mCRPC: Poly ADP Ribose Polymerase (PARP) inhibitor
DNA-repair deficient patients will have an increased chance of receiving PARP inhibitors at study onset.
Drug: Niraparib plus Abiraterone acetate plus Prednisone
Niraparib and Abiraterone acetate will be provided by Janssen and will be provided either as a fixed dose combination or as single agents. Detailed use of the study treatment including dose and dosages are described in the Investigator's brochures and SmPC.
Other Names:
  • Akeega
Experimental: Treatment 3 in mCRPC: selective AKT Inhibitor
Patients with alterations in the PI3K pathway will have an increased chance of receiving the combination treatment with Capivasertib plus Docetaxel.
Drug: Capivasertib plus Docetaxel
Capivasertib is provided by AstraZeneca and will be given in combination with Docetaxel. All subjects will be given up to ten 21-day docetaxel cycles. All subjects will receive Capivasertib, which will be administered as tablets taken twice a day orally, on a 4 days on/3 days off continuous schedule, commencing cycle one, day 2, until disease progression.
Experimental: Treatment 4 in mCRPC: Carboplatin
Only patients with DNA-repair deficiency will be treated with Carboplatin as second line treatment in the castration-resistant phase of ProBio.
Drug: Carboplatin
Carboplatin will be administered every 3rd week with an AUC (area under curve) = 5 with a dose calculated according to the Carboplatin AUC Dose calculation (Calvert formula):Dose (mg) = TargetAUC (mg/ml x min) x [GFR ml/min + 25].

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression free survival (PFS) in mCRPC
Time Frame: Until progressive disease or 60 months from start of treatment, whatever occurs first.
Progression will be evaluated by the established international standards of the Prostate Cancer Working Group version 3 (PCWG3) and for soft tissue metastases (e.g. lung, liver and lymph nodes) according to the Response Evaluation Criteria in Solid Tumors (RECIST v. 1.1).
Until progressive disease or 60 months from start of treatment, whatever occurs first.
Progression free survival (PFS) in mHSPC
Time Frame: From date of treatment start until the date of first documentation of progression, assessed up to 60 months
Time to development of castration-resistance, as defined by EAU guidelines (biochemical progression or radiologic progression)
From date of treatment start until the date of first documentation of progression, assessed up to 60 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival (OS)
Time Frame: From enrolment to completion of study (60 months)
OS is defined as time to death from any cause (overall and prostate cancer specific)
From enrolment to completion of study (60 months)
Patient Reported Outcome Measures (PROM)
Time Frame: From enrolment to completion of study (60 months)
QoL will be assessed using the EORTC QLQ-C30 instrument
From enrolment to completion of study (60 months)
Cost-effectiveness
Time Frame: From enrolment to completion of study (60 months)
Cost effectiveness will be assessed by using the EQ-5D-5L instrument to estimate health utilities. Treatment costs will be based on drug costs and reimbursement data.
From enrolment to completion of study (60 months)
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Time Frame: From enrolment to completion of study (60 months)
Common Terminology Criteria for Adverse Events (CTCAE) developed and maintained by the US National Cancer Institute will be used to record adverse events
From enrolment to completion of study (60 months)
Treatment response rate in mCRPC
Time Frame: 4 months after treatment start
Treatment response is evaluated according to PCWG3 and RECIST 1.1
4 months after treatment start
Treatment response rate in mHSPC
Time Frame: 6 months after treatment start
Response rates at 6 months on therapy will be evaluated by the established standards of EAU Guidelines
6 months after treatment start

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Karolinska Institutet

Collaborators

The Swedish Research Council
AstraZeneca
Janssen Pharmaceutica N.V., Belgium
Kom Op Tegen Kanker
Cancerfonden

Investigators

  • Principal Investigator: Henrik Grönberg, Professor, Karolinska Institutet
  • Study Director: Martin Eklund, Professor, Karolinska Institutet
  • Study Director: Johan Lindberg, PhD, Karolinska Institutet
  • Principal Investigator: Piet Ost, Professor, University Hospital Ghent, Belgium
  • Principal Investigator: Jan Oldenburg, Professor, Akershus University Hospital, Norway
  • Principal Investigator: Ashkan Mortezavi, MD, PhD, University Hospital, Basel, Switzerland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2019

Primary Completion (Estimated)

December 1, 2026

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

March 29, 2019

First Submitted That Met QC Criteria

April 2, 2019

First Posted (Actual)

April 4, 2019

Study Record Updates

Last Update Posted (Actual)

January 17, 2024

Last Update Submitted That Met QC Criteria

January 11, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EudraCT No 2018-002350-78

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Metastatic Castration-resistant Prostate Cancer (mCRPC)

Clinical Trials on Cabazitaxel 60 mg Solution for Injection

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in South Africa

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe