ProBio Automatic Report
Accessibility level: Public. Report issued: 2024 September, 18. Data cut-off date: 2024 September, 17
This report contains summary information of the enrollment and follow-up of patients in ProBio. All the data are anonymized and blinded on both the subjects’ biomarker profile and randomized therapy
This is a computer-generated document. Contact the author Alessio Crippa for any question.
Overall information on study design, enrollment, and follow-up is reported in the Home. Separate information for metastatic Hormone-Sensitive Prostate Cancer (mHSPC) and metastatic Castration-Resistant Prostate Cancer (mCRPC) patients are reported in dedicated tabs.
The results are presented in separated tabs:
- Study information:
- Report summary;
- Protocol synopsis;
- Protocol amendment history;
- Stopping rules.
- Report summary;
- Enrollment information:
- indicators of enrolled and randomized patients, and enrolling centers;
- maps of recruiting centers;
- enrolled patients over time (by center);
- info centers.
- indicators of enrolled and randomized patients, and enrolling centers;
- Follow-up variable:
- flowchart;
- classification patients (randomized, incomplete, excluded);
- flowchart;
- Data Manager:
- info on incomplete patients;
- info on excluded patients;
- info on randomized patients.
- info on incomplete patients;
Report summary
| PROTOCOL TITLE: | An outcome-adaptive and randomised multi-arm biomarker driven study in patients with metastatic prostate cancer |
| EUDRACT NUMBER: | 2018-002350-78 |
| CLINICALTRIALS.GOV NUMBER: | NCT03903835 |
| PROTOCOL VERSION: | v5.1 |
| PRINCIPAL INVESTIGATOR: | Henrik Grönberg, Professor, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden |
| DATE REPORT ISSUED: | 2024 September, 18 |
| DATA CUTOFF DATE: | 2024 September, 17 |
| PREPARED BY: | Alessio Crippa, PhD |
Protocol synopsis
| Protocol Title: | ProBio is an outcome-adaptive and randomised multi-arm biomarker driven study in patients with metastatic prostate cancer |
| Principal Investigator: | Henrik Grönberg, Professor |
| Study activation date: | January 29th, 2019 |
| Planned Accrual Period: | Patients will be followed from time of consent through the study duration |
| Study design: | ProBio is an outcome-adaptive, multi-arm, open-label, multiple assignment randomized biomarker driven platform trial in patients with metastatic prostate cancer |
| Study objectives: | To determine whether therapy class choice based on a biomarker signature can improve Progression Free Survival (PFS) compared to standard of care in patients with metastatic prostate cancer |
| Treatment Description: | Patients can be randomized to either the control group (i.e. standard-of-care) or to the experimental arm consisting of one of the following therapy classes: AR signalling inhibitors (ARSi), Taxane-based chemotherapy, Platinum-based chemotherapy, and PARP Inhibitor (PARPi) |
| Inclusion criteria: | Male patients, aged above 18 years, with histologically confirmed prostate adenocarcinoma, initiating systemic therapy for metastatic disease, encompassing - Newly diagnosed (i.e. de novo) metastatic hormone-sensitive prostate cancer (mHSPC) or - First-line mCRPC, i.e. first evidence of progressive metastatic prostate cancer under castrate levels (<50 ng/dL) of serum testosterone, as defined by the EAU guidelines, encompassing biochemical and/or radiologic progression criteria |
| Exclusion criteria: | Upon entering the mHSPC phase of the trial, prior systemic therapy (including ADT) is not allowed. Patients with mCRPC may not enter the trial when they have already received prior systemic therapy (with the exception of standard ADT) for mCRPC. Patients with mCRPC can enter the mCRPC phase of the trial regardless which prior therapy they received in the hormone-sensitive or non-metastatic CRPC phase |
| Study outcomes (mHSPC): | PFS is defined as the time to development of castration-resistance, as defined by EAU guidelines (Cornford et al. 2017), i.e. whilst having castration levels of serum testosterone (<50ng/dL or 1.7 nmol/L) the time from randomisation to biochemical and/or radiologic progression |
| Study outcomes (mCRPC): | PFS is defined as the time to no longer clinical benefit (NLCB), as defined by Prostate Cancer Working Group (PCWG) 3, i.e. the date and the specific reason(s) a therapy was ultimately discontinued, by evaluating biochemical, radiologic, and clinical progression criteria |
Protocol amendment history
Major changes going from v4.1 to v5.1:
Major changes going from v3.0 to v4.1:
- Introduction of a structured clinical protocol, according to the guidelines of the Clinical Trials Facilitation and Coordination Group (CTFG), a working group of the Heads of Medicines Agencies (HMA) on clinical studies
- Expansion of the patient population into the disease stage before metastatic castration-resistant prostate cancer (i.e. current study), i.e. de novo metastatic hormone-sensitive prostate cancer (mHSPC)
- Addition of a new treatment arm with a PARP inhibitor: Niraparib + Abiraterone acetate. This can be done as single agents or as a fixed dose combination
- Addition of a new IMP Apalutamide (Erleada)
- Addition of new centers in Belgium, Sweden and Norway
- Addition of an extra PROM: BPI-SF
Stopping rules
| Graduation: | \(n \ge 25\) for the evaluated treatment-signature combination \(\pi_s \ge 85\%\), \(\pi_s\) being the probability of superiority for the evaluated treatment vs the control within the biomarker signature \(\pi_j \ge 70\%\), \(\pi_j\) being the probability of superiority for the evaluated treatment vs the control within all the biomarker subgroup combinations belonging to the evaluated signature |
| Futility: | \(n \ge 25\) for the evaluated treatment-signature combination \(\pi_s \le 30\%\), \(\pi_s\) being the probability of superiority for the evaluated treatment vs the control within the biomarker signature \(\pi_j \le 50\%\), \(\pi_j\) being the probability of superiority for the evaluated treatment vs the control within all the biomarker subgroup combinations belonging to the evaluated signature |
| Max patients: | \(n \ge 150\) |
More information on the aims, study design and statistical aspects are available at http://rpubs.com/alecri/useR2019.
NB At least 5 patients are required in each biomarker subgroup combination.
Have a look at slide 20 for an intuition of the definition of a probability of superiority.
Visual indicators for progressive number of enrolling centers, enrolled patients (who signed the informed consent form), randomized patients.
Center maps
Interactive map with summary numbers of enrollment, randomization status, and progression for the recruiting centers.
Accrual plot
Cumulative number of enrolled patients over time (consent date). Solid line includes men enrolled in the study (also not randomized), dashed line includes only randomized patients.
Info centers
| Center | City | Total | ||||
|---|---|---|---|---|---|---|
| Enrolled | Randomized | Excluded | Incomplete | Days from last enrollment | ||
| Sweden | ||||||
| Capio S:t Görans Sjukhus | Stockholm | 88 | 58 | 30 | 0 | 37 |
| Länssjukhuset I Sundsvall | Sundsvall | 47 | 30 | 17 | 0 | 117 |
| Akademiska Sjukhuset | Uppsala | 44 | 27 | 17 | 0 | 153 |
| Karolinska Universitetssjukhuset | Stockholm | 43 | 27 | 16 | 0 | 26 |
| Länssjukhuset I Ryhov | Jönköping | 39 | 25 | 13 | 1 | 6 |
| Centralsjukhuset Karlstad | Karlstad | 23 | 13 | 10 | 0 | 92 |
| Centralsjukhuset Karlstad | Sweden | 23 | 13 | 10 | 0 | 92 |
| Norrlands Universitetssjukhus | Umeå | 22 | 16 | 6 | 0 | 916 |
| Norrlands Universitetssjukhus | Sweden | 22 | 16 | 6 | 0 | 916 |
| Växjö Lasarett | Sweden | 19 | 12 | 7 | 0 | 34 |
| Länssjukhuset I Kalmar | Kalmar | 16 | 9 | 7 | 0 | 127 |
| Falu Lasarett | Falun | 9 | 5 | 4 | 0 | 404 |
| Södra Älvsborgs Sjukhus | Borås | 7 | 5 | 1 | 1 | 23 |
| Universitetssjukhuset Örebro | Örebro | 2 | 1 | 1 | 0 | 127 |
| Norway | ||||||
| Stavanger Universitetssjukehus | Stavanger | 53 | 29 | 24 | 0 | 37 |
| Stavanger Universitetssjukehus | Norway | 53 | 29 | 24 | 0 | 37 |
| Akershus Universitetssykehus | Akershus University Hospital | 40 | 18 | 20 | 2 | 6 |
| Akershus Universitetssykehus | Oslo | 40 | 18 | 20 | 2 | 6 |
| Ålesund Sjukehus | Ålesund | 12 | 3 | 9 | 0 | 30 |
| Universitetssykehuset Nord-Norge Tromsö | Tromsø | 11 | 7 | 4 | 0 | 34 |
| Sörlandet Sykehus Kristiansand | Kristiansand | 10 | 8 | 1 | 1 | 27 |
| Sykehuset Östfold Kalnes | Norway | 7 | 4 | 3 | 0 | 120 |
| Belgium | ||||||
| Gza Sint-Augustinus | Antwerp | 52 | 32 | 20 | 0 | 27 |
| Uz Gent | Ghent | 42 | 23 | 19 | 0 | 40 |
| Az St-Jan Brugge | Bruges | 35 | 19 | 15 | 1 | 19 |
| Chu Liège | Liège | 30 | 22 | 7 | 1 | 13 |
| Az Groeninge | Kortrijk | 28 | 16 | 11 | 1 | 63 |
| Olv Aalst | Aalst | 23 | 7 | 16 | 0 | 106 |
| Az Nikolaas | Sint-Niklaas | 23 | 15 | 8 | 0 | 91 |
| Ziekenhuis Oost-Limburg | Ziekenhuis Oost-Limburg | 19 | 15 | 4 | 0 | 42 |
| Az Damiaan | Ostend | 12 | 7 | 5 | 0 | 147 |
| Az St-Lucas Brugge | AZ Sint-Lucas | 9 | 3 | 6 | 0 | 279 |
| Az St-Lucas Brugge | Bruges | 9 | 3 | 6 | 0 | 279 |
| Jessa Ziekenhuis | Hasselt | 2 | 2 | 0 | 0 | 608 |
| Switzerland | ||||||
| University Hospital Basel | Basel | 29 | 20 | 9 | 0 | 68 |
| St. Claraspital | Basel | 8 | 3 | 2 | 3 | 15 |
Flowchart
Patient enrolled flowchart. Patients may enter ProBio a metastatic hormone-sensitive (mHS) or first line metastatic castration-resistant (mCR). Patients having progressive disease may be re-randomized up to two treatment lines for mCR prostate cancer. Patients in the control arm remain as control. Patients signing consent may not be randomized because of low circulated tumour DNA or techincal failure in liquid biospy test, MSI+ dection, or becaue of exclusion criteria.
Pie chart
Pie chart for randomization status of enrolled patients. Incomplete patients has not yet been randomized because of pending ctDNA analysis.
This panel is available only for data manager.
The results are presented in separated tabs:
- Enrollment information:
- indicators of enrolled and randomized patients, and enrolling centers;
- maps of recruiting centers;
- enrolled patients over time (by center);
- inclusion rate;
- info centers.
- indicators of enrolled and randomized patients, and enrolling centers;
- Follow-up variable:
- classification patients (randomized, incomplete, excluded);
- flowchart;
- swimmer plot.
- classification patients (randomized, incomplete, excluded);
- Baseline variables (tables 1 for):
- clinical characteristics;
- metastatic burden profile;
- routine blood diagnostics.
- clinical characteristics;
- Biomarkers:
- prevalence of signatures and subgroup combinations (by treatment).
- prevalence of signatures and subgroup combinations (by treatment).
- Therapies:
- prevalence of therapies in the control group;
- overlap of biomarker signatures by therapies.
- prevalence of therapies in the control group;
- Number of Progressions:
- flowchart;
- type of progressions (upset and alluvial plot);
- response evaluation.
- flowchart;
- Evaluation of therapies:
- results by therapy classes;
- posterior STR/HR distributions;
- PFS curves (Kaplan Meier and posterior).
- results by therapy classes;
- Serious adverse events.
Visual indicators for progressive number of enrolling centers, enrolled patients (who signed the informed consent form), randomized and re-randomized (2nd randomization) patients.
Center maps
Interactive map with summary numbers of enrollment, randomization status, and progression for the recruiting centers.
Accrual plot
Cumulative number of enrolled patients over time (consent date). Solid line includes men enrolled in the study (also not randomized), dashed line includes only randomized patients.
Inclusion rate
Randomization rate by quarters of year (randomized/signed ICF) over time overall (dashed lines) and by country (solid coloured lines).
Info centers
| Center | City | Enrolled | Randomized | Excluded | Incomplete | days from last enrollment |
|---|---|---|---|---|---|---|
| Belgium | ||||||
| Az St-Jan Brugge | Bruges | 15 | 9 | 6 | 0 | 65 |
| Uz Gent | Ghent | 5 | 4 | 1 | 0 | 40 |
| Az Groeninge | Kortrijk | 18 | 11 | 6 | 1 | 63 |
| Olv Aalst | Aalst | 2 | 0 | 2 | 0 | 184 |
| Az Damiaan | Ostend | 9 | 6 | 3 | 0 | 147 |
| Ziekenhuis Oost-Limburg | Ziekenhuis Oost-Limburg | 11 | 9 | 2 | 0 | 42 |
| Az St-Lucas Brugge | Bruges | 3 | 0 | 3 | 0 | 279 |
| Chu Liège | Liège | 19 | 15 | 3 | 1 | 13 |
| Az Nikolaas | Sint-Niklaas | 13 | 9 | 4 | 0 | 91 |
| Gza Sint-Augustinus | Antwerp | 29 | 19 | 10 | 0 | 27 |
| Norway | ||||||
| Akershus Universitetssykehus | Oslo | 14 | 9 | 4 | 1 | 9 |
| Stavanger Universitetssjukehus | Norway | 14 | 8 | 6 | 0 | 37 |
| Ålesund Sjukehus | Ålesund | 2 | 0 | 2 | 0 | 79 |
| Sörlandet Sykehus Kristiansand | Kristiansand | 6 | 4 | 1 | 1 | 28 |
| Sykehuset Östfold Kalnes | Norway | 6 | 3 | 3 | 0 | 120 |
| Sweden | ||||||
| Capio S:t Görans Sjukhus | Stockholm | 31 | 22 | 9 | 0 | 37 |
| Karolinska Universitetssjukhuset | Stockholm | 5 | 3 | 2 | 0 | 26 |
| Akademiska Sjukhuset | Uppsala | 11 | 6 | 5 | 0 | 153 |
| Länssjukhuset I Sundsvall | Sundsvall | 21 | 14 | 7 | 0 | 117 |
| Växjö Lasarett | Sweden | 2 | 1 | 1 | 0 | 176 |
| Länssjukhuset I Kalmar | Kalmar | 7 | 4 | 3 | 0 | 127 |
| Switzerland | ||||||
| University Hospital Basel | Basel | 24 | 17 | 7 | 0 | 68 |
| St. Claraspital | Basel | 4 | 3 | 0 | 1 | 20 |
Flowchart
Patient enrolled flowchart. Patients signing consent may not be randomized because of low circulated tumour DNA or techincal failure in liquid biospy test, MSI+ dection, or becaue of exclusion criteria. After first progression, patients in the experimental arms can be re-randomized to a second experimental treatment, while progressive patients in the control arm remain as control.
Pie chart
Pie chart for randomization status of enrolled patients. Incomplete patients has not yet been randomized because of pending ctDNA analysis.
Swimmer plot
This panel is available only for ProBio investigators or members in the DMSB.
Clinical characteristics by study arm of randomized participants
Metastatic burden profile by study arm of randomized participants
Routine blood diagnostics by study arm of randomized participants
This panel is available only for ProBio investigators or members in the DMSB.
Prevalence of biomarker signatures
Prevalence of biomarker subgroup combinations
Pie chart subgroup combinations
Prevalence of biomarker signatures across therapy classes
This panel is available only for ProBio investigators or members in the DMSB.
Prevalence of therapies in the control group
Overlap of biomarker signatures by therapies.
This panel is available only for ProBio investigators or members in the DMSB.
This panel is available only for members in the DMSB.
This panel is available only for ProBio investigators or members in the DMSB.
The results are presented in separated tabs:
- Enrollment information:
- indicators of enrolled and randomized patients, and enrolling centers;
- maps of recruiting centers;
- enrolled patients over time (by center);
- inclusion rate;
- info centers.
- indicators of enrolled and randomized patients, and enrolling centers;
- Follow-up variable:
- therapies timeline;
- classification patients (randomized, incomplete, excluded);
- flowchart;
- swimmer plot.
- therapies timeline;
- Baseline variables (tables 1 for):
- clinical characteristics;
- metastatic burden profile;
- routine blood diagnostics;
- baseline variables by randomization status.
- clinical characteristics;
- Biomarkers (first randomization):
- prevalence of signatures and subgroup combinations (by treatment);
- changes after progression.
- prevalence of signatures and subgroup combinations (by treatment);
- Therapies:
- prevalence of therapies in the control group;
- overlap of biomarker signatures by therapies.
- prevalence of therapies in the control group;
- Number of Progressions:
- flowchart;
- type of progressions (upset and alluvial plot);
- response evaluation.
- flowchart;
- Evaluation of therapies:
- results by therapy classes;
- posterior STR/HR distributions;
- PFS curves (Kaplan Meier and posterior).
- results by therapy classes;
- Serious adverse events.
Visual indicators for progressive number of enrolling centers, enrolled patients (who signed the informed consent form), randomized and re-randomized (2nd randomization) patients.
Center maps
Interactive map with summary numbers of enrollment, randomization status, and progression for the recruiting centers.
Accrual plot
Cumulative number of enrolled patients over time (consent date). Solid line includes men enrolled in the study (also not randomized), dashed line includes only randomized patients.
Inclusion rate
Randomization rate by quarters of year (randomized/signed ICF) over time overall (dashed lines) and by country (solid coloured lines).
Info centers
| Center | City | Enrolled | Randomized | Re-randomized | Excluded | Incomplete | days from last enrollment |
|---|---|---|---|---|---|---|---|
| Belgium | |||||||
| Az St-Jan Brugge | Bruges | 20 | 10 | 4 | 9 | 1 | 19 |
| Uz Gent | Ghent | 37 | 19 | 10 | 18 | 0 | 50 |
| Az Groeninge | Kortrijk | 10 | 5 | 3 | 5 | 0 | 194 |
| Olv Aalst | Aalst | 21 | 7 | 1 | 14 | 0 | 106 |
| Az Damiaan | Ostend | 3 | 1 | 0 | 2 | 0 | 638 |
| Ziekenhuis Oost-Limburg | Ziekenhuis Oost-Limburg | 9 | 7 | 4 | 2 | 0 | 355 |
| Az St-Lucas Brugge | AZ Sint-Lucas | 6 | 3 | 0 | 3 | 0 | 534 |
| Chu Liège | Liège | 17 | 13 | 6 | 4 | 0 | 125 |
| Jessa Ziekenhuis | Hasselt | 2 | 2 | 1 | 0 | 0 | 608 |
| Az Nikolaas | Sint-Niklaas | 10 | 6 | 1 | 4 | 0 | 97 |
| Gza Sint-Augustinus | Antwerp | 24 | 14 | 2 | 10 | 0 | 99 |
| Norway | |||||||
| Akershus Universitetssykehus | Akershus University Hospital | 27 | 9 | 5 | 16 | 2 | 6 |
| Stavanger Universitetssjukehus | Stavanger | 39 | 21 | 9 | 18 | 0 | 56 |
| Universitetssykehuset Nord-Norge Tromsö | Tromsø | 11 | 7 | 0 | 4 | 0 | 34 |
| Ålesund Sjukehus | Ålesund | 10 | 3 | 1 | 7 | 0 | 30 |
| Sörlandet Sykehus Kristiansand | Kristiansand | 5 | 5 | 0 | 0 | 0 | 27 |
| Sykehuset Östfold Kalnes | Norway | 1 | 1 | 0 | 0 | 0 | 190 |
| Sweden | |||||||
| Capio S:t Görans Sjukhus | Stockholm | 58 | 37 | 13 | 21 | 0 | 162 |
| Karolinska Universitetssjukhuset | Stockholm | 38 | 24 | 12 | 14 | 0 | 161 |
| Akademiska Sjukhuset | Uppsala | 34 | 22 | 9 | 12 | 0 | 175 |
| Norrlands Universitetssjukhus | Umeå | 22 | 16 | 7 | 6 | 0 | 916 |
| Länssjukhuset I Sundsvall | Sundsvall | 29 | 18 | 7 | 10 | 1 | 84 |
| Länssjukhuset I Ryhov | Jönköping | 39 | 25 | 14 | 13 | 1 | 6 |
| Växjö Lasarett | Sweden | 17 | 11 | 4 | 6 | 0 | 34 |
| Centralsjukhuset Karlstad | Karlstad | 23 | 13 | 8 | 10 | 0 | 92 |
| Länssjukhuset I Kalmar | Kalmar | 9 | 5 | 2 | 4 | 0 | 218 |
| Falu Lasarett | Falun | 9 | 5 | 1 | 4 | 0 | 404 |
| Södra Älvsborgs Sjukhus | Borås | 7 | 5 | 0 | 1 | 1 | 23 |
| Universitetssjukhuset Örebro | Örebro | 2 | 1 | 0 | 1 | 0 | 127 |
| Switzerland | |||||||
| University Hospital Basel | Basel | 6 | 4 | 1 | 2 | 0 | 217 |
| St. Claraspital | Basel | 5 | 1 | 1 | 2 | 2 | 15 |
Flowchart
Patient enrolled flowchart. Patients signing consent may not be randomized because of low circulated tumour DNA or techincal failure in liquid biospy test, MSI+ dection, or becaue of exclusion criteria. After first progression, patients in the experimental arms can be re-randomized to a second experimental treatment, while progressive patients in the control arm remain as control.
Pie chart
Pie chart for randomization status of enrolled patients. Incomplete patients has not yet been randomized because of pending ctDNA analysis.
Swimmer plot
This panel is available only for ProBio investigators or members in the DMSB.
Clinical characteristics by study arm of randomized participants
Metastatic burden profile by study arm of randomized participants
Routine blood diagnostics by study arm of randomized participants
Treatment history by study arm of randomized participants
Baseline variables by randomization status
This panel is available only for ProBio investigators or members in the DMSB.
Prevalence of biomarker signatures
Prevalence of biomarker subgroup combinations
Pie chart subgroup combinations
Prevalence of biomarker signatures across therapy classes. Only first randomizations are included.
Change in subgroup combination
This panel is available only for ProBio investigators or members in the DMSB.
Prevalence of therapies in the control group
Overlap of biomarker signatures by therapies.
This panel is available only for ProBio investigators or members in the DMSB.
Flowchart
Type of progressions
Alluvial plot
Swimmer plot for response evaluation
This panel is available only for members in the DMSB.
This panel is available only for ProBio investigators or members in the DMSB.