Trials / Recruiting

RecruitingNCT03903835

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

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

Status: Recruiting
Phase: Phase 3
Study type: Interventional
Enrollment: 750 (estimated)

Sponsor: Karolinska Institutet · Academic / Other
Sex: Male
Age: 18 Years
Healthy volunteers: Not accepted

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.

Conditions

Interventions

Type	Name	Description
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).
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.
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.
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.
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).
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).

Timeline

Start date: 2019-02-01
Primary completion: 2026-12-01
Completion: 2026-12-01
First posted: 2019-04-04
Last updated: 2025-04-09

Locations

32 sites across 4 countries: Belgium, Norway, Sweden, Switzerland

Source: ClinicalTrials.gov record NCT03903835. Inclusion in this directory is not an endorsement.