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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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).
• Препарат 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.
• Препарат 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 \[GFR ml/min + 25\].
• Препарат 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.
• Препарат 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.
• Препарат 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.
• Препарат 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.
• Препарат 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.
• Препарат 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).
• Препарат 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).

Первичные конечные точки

• Progression free survival (PFS) in mCRPC [Срок оценки: Until progressive disease or 60 months from start of treatment, whatever occurs first.]
• Progression free survival (PFS) in mHSPC [Срок оценки: From date of treatment start until the date of first documentation of progression, assessed up to 60 months]

Вторичные конечные точки (6)

• Treatment response rate in mCRPC [Срок оценки: 4 months after treatment start]
• Overall survival (OS) [Срок оценки: From enrolment to completion of study (60 months)]
• Patient Reported Outcome Measures (PROM) [Срок оценки: From enrolment to completion of study (60 months)]
• Cost-effectiveness [Срок оценки: From enrolment to completion of study (60 months)]
• Number of Participants With Adverse Events as a Measure of Safety and Tolerability [Срок оценки: From enrolment to completion of study (60 months)]
• Treatment response rate in mHSPC [Срок оценки: 6 months after treatment start]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Швеция · 13 центров

• Falu lasarett — Falun
• Södra Alvsborgs sjukhus — Borås
• Länssjukhuset Ryhov - Onkologiska kliniken — Jönköping
• Länssjukhuset — Kalmar
• Centralsjukhuset Region Värmland — Karlstad
• Universitetssjukhuset Örebro — Örebro
• Karolinska University Hospital — Stockholm
• Capio St.Görans Hospital — Stockholm
• … и ещё 5 центров

Бельгия · 12 центров

• OLV Ziekenhuis Aalst — Aalst
• GZA Sint-Augustinus — Antwerp
• AZ Sint-Jan AV — Bruges
• AZ Sint-Lucas — Bruges
• Ziekenhuis Oost-Limburg — Genk
• University Hospital Ghent — Ghent
• AZ Jan Palfijn Ziekenhuis — Ghent
• Jessa ziekenhuis — Hasselt
• … и ещё 4 центра

Норвегия · 5 центров

• Ålesund Sjukehus — Ålesund
• Kreftsenter Kristiansand — Kristiansand
• Akershus Universitetssykehus — Lørenskog
• Stavanger Universitetssjukehus — Stavanger
• Universitetssykehuset Nord-Norge Tromsö — Tromsø

Швейцария · 2 центра

• St. Claraspital — Basel
• Universitätsspital Basel — Basel

Публикации

• Crippa A, Laere B, Discacciati A, Larsson B, Persson M, Johansson S, D'hondt S, Hjalm-Eriksson M, Pettersson L, Enblad G, Ullen A, Lumen N, Karlsson CT, Sandzen J, Janes E, Ghysel C, Olsson M, Sautois B, Schatteman P, Roock W, Bruwaene SV, Verbiene I, Darras J, Everaert E, Maeseneer D, Anden M, Strijbos M, Luyten D, Mortezavi A, Oldenburg J, Ost P, Lindberg J, Gronberg H, Eklund M; ProBio Investig PMID 40263079
• De Laere B, Crippa A, Discacciati A, Larsson B, Persson M, Johansson S, D'hondt S, Bergstrom R, Chellappa V, Mayrhofer M, Banijamali M, Kotsalaynen A, Schelstraete C, Vanwelkenhuyzen JP, Hjalm-Eriksson M, Pettersson L, Ullen A, Lumen N, Enblad G, Thellenberg Karlsson C, Janes E, Sandzen J, Schatteman P, Nyre Vigmostad M, Olsson M, Ghysel C, Sautois B, De Roock W, Van Bruwaene S, Anden M, Verbiene PMID 39164518
• De Laere B, Crippa A, Discacciati A, Larsson B, Oldenburg J, Mortezavi A, Ost P, Eklund M, Lindberg J, Gronberg H; ProBio Investigators. Clinical Trial Protocol for ProBio: An Outcome-adaptive and Randomised Multiarm Biomarker-driven Study in Patients with Metastatic Prostate Cancer. Eur Urol Focus. 2022 Nov;8(6):1617-1621. doi: 10.1016/j.euf.2022.03.005. Epub 2022 Mar 19. PMID 35317973
• 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. PMID 32586393

Идентификаторы

NCT: NCT03903835 · EudraCT No 2018-002350-78

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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