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JOURNAL ONKOLOGIE – STUDIE
ProBio

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

Rekrutierend

NCT-Nummer:
NCT03903835

Studienbeginn:
Februar 2019

Letztes Update:
17.01.2024

Wirkstoff:
Carboplatin, Cabazitaxel 60 mg Solution for Injection, Docetaxel Injectable Solution, Radium Chloride Ra-223, Niraparib plus Abiraterone acetate plus Prednisone, Enzalutamide Oral Capsule, Abiraterone Oral Tablet, Capivasertib plus Docetaxel, Apalutamide, darolutamide

Indikation (Clinical Trials):
Prostatic Neoplasms

Geschlecht:
Männer

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Karolinska Institutet

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

Studienleiter

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

Kontakt

Studienlocations
(3 von 32)

Capio St.Görans Hospital
Stockholm
SwedenRekrutierend» Google-Maps
Ansprechpartner:
Henrik Grönberg, Professor
E-Mail: henrik.gronberg@capiostgoran.se

Berit Larsson, MSc
E-Mail: berit.larsson@ki.se» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. 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).

2. 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)

Secondary outcome:

1. Treatment response rate in mCRPC (Time Frame - 4 months after treatment start):
Treatment response is evaluated according to PCWG3 and RECIST 1.1

2. 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)

3. 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

4. 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.

5. 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

6. 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

Studien-Arme

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

Geprüfte Regime

  • Enzalutamide Oral Capsule (Xtandi):
    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).
  • Abiraterone Oral Tablet (Zytiga):
    Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
  • 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].
  • 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.
  • 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.
  • Radium Chloride Ra-223 (Xofigo):
    Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
  • Niraparib plus Abiraterone acetate plus Prednisone (Akeega):
    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.
  • 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.
  • Apalutamide (Erleada):
    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).
  • Darolutamide (Nubeqa):
    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).

Quelle: ClinicalTrials.gov


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