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

  • STATUS
    Recruiting
  • End date
    Dec 18, 2026
  • participants needed
    750
  • sponsor
    Karolinska Institutet
Updated on 10 February 2022

Summary

Metastatic castrate resistant prostate cancer (mCRPC) is an advanced form of prostate cancer and it is estimated that around 20-30% of all prostate cancer diagnoses will develop mCRPC at some point in their disease trajectory. The last years, new drugs have been approved for treatment of mCRPC. Although the drugs are beneficial for many patients they carry three serious disadvantages: treatment costs are high, the response rates are low and there are no predictive treatment markers available in clinical care today. There are promising research that linked changes in the tumor's genome with better or worse response to drug treatment.The purpose of the ProBio study is to investigate whether profiling of the tumor's genome can be used to select a treatment that is highly likely to produce good effect. In order to investigate the tumor cells' genome we will use a biomarker in blood, so-called circulating tumor DNA.

Our hypothesis is that one can significantly prolong progression-free survival compared to current clinical practice by measuring free circulating tumor DNA in plasma and adapting the treatment accordingly.

In this way, treatment can be tailored, which leads to benefits for both patient and health care.

The hypothesis will be tested in a large clinical study with 750 patients diagnosed with CRPC. Recruitment to the clinical treatment study will take place at a number of Swedish and Belgian hospitals, and the study will be expanded to sites in Norway and Switzerland.

Description

ProBio is an outcome-adaptive, multi-arm, open-label, multiple assignment randomized biomarker driven platform trial in patients with metastatic castrate resistant 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. The biomarker signatures are defined as tumor 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 circulating tumor DNA (ctDNA) panel specifically designed for mCRPC.

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

signatures
  • Androgen receptor
  • DNA-repair deficiency
  • TP53
  • TMPRSS2-ERG gene fusion

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

  • Enzalutamide
  • Abiraterone
  • Cabazitaxel
  • Docetaxel
  • Carboplatin
  • Niraparib plus Abiraterone acetate plus Prednisone

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 two 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 150 patients 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.

Details
Condition Metastatic Castration-Resistant Prostatic Cancer
Treatment carboplatin, Enzalutamide Oral Capsule [Xtandi], Abiraterone Oral Tablet [Zytiga], Cabazitaxel 60 mg Solution for Injection, Docetaxel Injectable Solution, Radium Chloride Ra-223, Niraparib plus Abiraterone acetate plus Prednisone
Clinical Study IdentifierNCT03903835
SponsorKarolinska Institutet
Last Modified on10 February 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Man with metastatic castrate resistant prostate cancer (histologically confirmed prostate adenocarcinoma) and castrate levels < 50 ng/dl of serum
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 umol/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
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
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