ProBio: An outcome-adaptive and randomised multi-arm biomarker driven study in patients with metastatic prostate cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Karolinska Institutet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

8 Jan 2019 → ongoing

Decision date (initial)

2024-06-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Prostatacancerförbundet, Sweden. · Bayer Consumer Care AG, Switzerland. · Janssen Pharmaceutical NV, Sweden. · Kom op tegen Kanker, Belgium. · Vetenskapsrådet, Sweden. · Astra Zeneca, Sweden.

External identifiers

EU CT number

2023-506857-40-00

EudraCT number

2018-002350-78

ClinicalTrials.gov

NCT03903835

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacogenomic, Efficacy

To determine whether a therapy class choice or de-escalating treatment regimen based on a biomarker signature or ctDNA detectability can improve PFS compared to a control arm in patients with mHSPC and mCRPC.

Secondary objectives 1

1. 1. Evaluating whether treatment class selection based on biomarker signatures can, compared to standard of care, improve the time from the initial study randomisation to death from any cause. 2. Evaluating whether treatment class selection based on biomarker signatures can, compared to standard of care, improve quality of life. 3. Evaluating whether treatment class selection based on biomarker signatures can, compared to standard of care, improve health economy. 4. Evaluating whether treatment class selection based on biomarker signatures, compared to control, does not increase toxicity (i.e drug safety). 5. To identify additional predictive and prognostic biomarkers. 6. Identify superior treatment sequencing regimens (i.e. is treatment A followed by treatment B superior to treatment B followed by treatment A given a biomarker signature).

Conditions and MedDRA coding

Prostate Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. ● 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 ○ Recurrent (i.e. metachronous) mHSPC ■ Patients that have had prior local treatment with curative intent (e.g. primary radiotherapy or radical prostatectomy) and subsequently develop metachronous metastatic disease. These metachronous or recurring mHSPC patients are those observed in the setting of rising PSA until metastasis develops. Patients are not required to be ADT-naïve, but must have normal levels of testosterone (>50 ng/dL or 1.7 nmol/L) at ProBio screening and liquid biopsy collection 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 progression: Three consecutive rises in PSA 1 wk apart, resulting in two 50% increases over the nadir, and PSA >2 ng/ml and/or ■ Radiologic progression: The appearance of new lesions: either two or more new bone lesions on bone scan or a soft tissue lesion using the Response Evaluation Criteria in Solid Tumours. ● For the initial identification of patients with metastatic disease, distant metastases can either be identified by conventional imaging (i.e. bone scan or metastatic lesions on CT or MRI), or molecular imaging (i.e. miM1 disease on prostate-specific membrane antigen (PSMA) targeting positron emission tomography (PET)). Radiology taken within 6 weeks of screening may be used, if older a new scan needs to be taken. It is important to note that PSMA PET/CT can be used for initial identification and enrollment of patients with metastatic disease, but that it may not be used for response assessment or to infer disease progression. Radiographic follow-up and assessment of progression need to be performed with conventional imaging. ● Adequate health, hematologic, hepatic, and renal function, as assessed by the investigator, to receive all available treatments in the trial in each disease state (mHSPC and mCRPC) (i.e. haemoglobin ≥ 100 g/L (blood transfusion not less than 21 days prior to screening), absolute neutrophil count ≥ 1.5 x 10^9/L, platelets ≥100 x 10^9/L and Total bilirubin < 1.5 ULN (patients with Gilberts Syndrome bilirubin < 40 µg/L) and AST and ALT ≤ 1.5 ULN (or ≤ 3 ULN in the presence of liver metastases) and serum creatinine not greater than 1 ULN (if serum creatinine is between 1 and 1.5 ULN, patients may be eligible provided that the calculated GFR is at least 50 ml/min measured directly by 24-hour urine sampling OR using Cockcroft-Gault method) ● Albumin greater than or equal to 28 g/L ● ECOG/WHO performance status 0-2 ● Agrees to use an effective contraceptive method during and up to 6 months after study drug treatment and should not donate sperm during this period. ● Able to understand the patient information and sign written informed consent.

Exclusion criteria 1

1. ● Other malignancies within 5 years except non-melanoma skin cancer ● Within 6 months of randomisation: myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke, TIA, or congestive heart failure NYHA class III or IV ● Uncontrolled hypertension: SBP > 160 mmHg and or DBP > 95 mmHg. Subjects with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment ● Uncontrolled hypotension: SBP < 90 mmHg and/or DBP < 50 mmHg ● 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. ● 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. This includes a medical history significant for arrhythmia (e.g. multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study based on the Investigators judgement with cardiologist consultation recommended. ● Unable to comply with study procedures ● Current participation in another clinical trial that will be in conflict with the present study, e.g. administration of an investigational therapeutic or invasive surgical procedure within 28 days prior to study enrolment. Imaging-based interventional trials are allowed as long as the conventional imaging intervals within ProBio are preserved. ● Patients who are unlikely to comply with the protocol (e.g. uncooperative attitude, inability to return for subsequent visits) and/or otherwise considered by the Investigator to be unlikely to complete the study ● 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 subject’s participation in this study. This includes a history of QT prolongation associated with other medications that required discontinuation of that medication; and other factors that increase the risk of OTc prolongation or risk of arrhythmic events, hypokalemia of grade >1, potential for Torsade de Pointes, congenital long QT syndrome. ● Any medical condition that would make use of the study treatments contraindicated, according to the SmPC, e.g. significant heart or liver disease. The investigator should check the SmPC and/or IB for the assigned study treatments. This includes a family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives. ● The determination of a biomarker signature is necessary to randomise patients during ProBio mCRPC. Patients with detectable ctDNA and having a microsatellite unstable (MSI) or hypermutated tumor will be excluded from the trial since the plethora of mutations obscures a proper assessment of the disease-driving biomarker signature. Patients will therefore be excluded in case of: a. For patients in mCRPC: undetectable levels of ctDNA. b. For patients in mHSPC and mCRPC: microsatellite unstable (MSI+) or hypermutated tumor.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival, where progression is defined according to disease stage at trial entry: ● For mHSPC: Time to development of castration-resistance (European Association of Urology [EAU] guidelines) or death ● For mCRPC: Time to no longer clinical benefiting (NLCB) (Prostate Cancer Working Group [PCWG3] guidelines)

Secondary endpoints 1

1. 1.Overall survival (OS). 2. Quality of life assessed by In all patients enrolled in ProBio: ● EORTC-QLQ-C30 ● EQ-5D-5L ● BPI-SF In patients enrolled in ProBio with ctDNA-undetectable mHSPC: EORTC QLQ-PR25 (hormonal and sexual subdomains). 3. 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. 4. Frequency and severity of adverse events (AE).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 12

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Karolinska Institutet

Sponsor organisation

Karolinska Institutet

Address

Nobels Vag 6

City

Solna

Postcode

171 65

Country

Sweden

Scientific contact point

Organisation

Karolinska Institutet

Contact name

Henrik Grönberg

Public contact point

Organisation

Karolinska Institutet

Contact name

Henrik Grönberg

Locations

3 EU/EEA countries · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 86 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications