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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03903835
Recruitment Status : Recruiting
First Posted : April 4, 2019
Last Update Posted : January 17, 2024
Sponsor:
Collaborators:
The Swedish Research Council
Kom Op Tegen Kanker
Janssen Pharmaceutica N.V., Belgium
AstraZeneca
Cancerfonden
Information provided by (Responsible Party):
Henrik Grönberg, Karolinska Institutet

Tracking Information
First Submitted Date  ICMJE March 29, 2019
First Posted Date  ICMJE April 4, 2019
Last Update Posted Date January 17, 2024
Actual Study Start Date  ICMJE February 1, 2019
Estimated Primary Completion Date December 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 11, 2024)
  • 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).
  • 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)
Original Primary Outcome Measures  ICMJE
 (submitted: April 2, 2019)
Progression free survival (PFS) [ Time Frame: Until progressive disease or 36 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).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 11, 2024)
  • Treatment response rate in mCRPC [ Time Frame: 4 months after treatment start ]
    Treatment response is evaluated according to PCWG3 and RECIST 1.1
  • 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)
  • 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
  • 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.
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: April 2, 2019)
  • Treatment response rate [ Time Frame: 4 months after treatment start ]
    Treatment response is evaluated according to PCWG3 and RECIST 1.1
  • 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)
  • Patient Reported Outcome Measures (PROM) [ Time Frame: From enrolment to completion of study (60 months) ]
    QoL will be assessed using a modified EORTC QLQ-C30 instrument
  • 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.
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ProBio: A Biomarker Driven Study in Patients With Metastatic Prostate Cancer
Official Title  ICMJE ProBio: An Outcome-adaptive and Randomized Multi-arm Biomarker Driven Study in Patients With Metastatic Prostate Cancer
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
ProBio will use outcome-adaptive randomization, adapting the randomization based on the observed 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 analysed within a Bayesian framework, which allows for calculations of the probability for each treatment that 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Castration-resistant Prostate Cancer (mCRPC)
  • Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
Intervention  ICMJE
  • 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 Name: 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 Name: Zytiga
  • 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].
  • 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 Name: Xofigo
  • 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 Name: Akeega
  • 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.
  • 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 Name: Erleada
  • 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 Name: Nubeqa
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Enzalutamide Oral Capsule
    • Drug: Abiraterone Oral Tablet
    • Drug: Cabazitaxel 60 mg Solution for Injection
    • Drug: Docetaxel Injectable Solution
    • Drug: Radium Chloride Ra-223
    • Drug: Apalutamide
  • 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.
    Interventions:
    • Drug: Enzalutamide Oral Capsule
    • Drug: Abiraterone Oral Tablet
    • Drug: Apalutamide
  • 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.
    Interventions:
    • Drug: Abiraterone Oral Tablet
    • Drug: Docetaxel Injectable Solution
    • Drug: Darolutamide
  • 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.
    Intervention: Drug: Niraparib plus Abiraterone acetate plus Prednisone
  • 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.
    Interventions:
    • Drug: Enzalutamide Oral Capsule
    • Drug: Abiraterone Oral Tablet
  • 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.
    Intervention: Drug: Niraparib plus Abiraterone acetate plus Prednisone
  • 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.
    Intervention: Drug: Capivasertib plus Docetaxel
  • 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.
    Intervention: Drug: Carboplatin
Publications * Crippa A, De Laere B, Discacciati A, Larsson B, Connor JT, Gabriel EE, Thellenberg C, Janes E, Enblad G, Ullen A, Hjalm-Eriksson M, Oldenburg J, Ost P, Lindberg J, Eklund M, Gronberg H. The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer. Trials. 2020 Jun 26;21(1):579. doi: 10.1186/s13063-020-04515-8.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 2, 2019)
750
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2026
Estimated Primary Completion Date December 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Berit Larsson, MSc +46 8 52482576 berit.larsson@ki.se
Contact: Henrik Grönberg, Professor +46 70 3411356 Henrik.gronberg@ki.se
Listed Location Countries  ICMJE Belgium,   Norway,   Sweden,   Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03903835
Other Study ID Numbers  ICMJE EudraCT No 2018-002350-78
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Henrik Grönberg, Karolinska Institutet
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Karolinska Institutet
Original Study Sponsor  ICMJE Henrik Grönberg
Collaborators  ICMJE
  • The Swedish Research Council
  • Kom Op Tegen Kanker
  • Janssen Pharmaceutica N.V., Belgium
  • AstraZeneca
  • Cancerfonden
Investigators  ICMJE
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
PRS Account Karolinska Institutet
Verification Date January 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP