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    Summary
    EudraCT Number:2018-001746-34
    Sponsor's Protocol Code Number:56021927PCR3011
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-02-21
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2018-001746-34
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Apalutamide in Subjects with High-risk, Localized or Locally Advanced Prostate Cancer Who are Candidates for Radical Prostatectomy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of androgen deprivation therapy (ADT) plus apalutamide (with or without abiraterone acetate with prednisone/prednisolone [AAP]) in patients with prostate cancer
    A.3.2Name or abbreviated title of the trial where available
    PeRiOperative Treatment with Erleada United with Surgery (PROTEUS)
    A.4.1Sponsor's protocol code number56021927PCR3011
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorJanssen-Cilag International NV
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International NV
    B.5.2Functional name of contact pointClinical Registry Group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg, 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333
    B.5.3.4CountryNetherlands
    B.5.6E-mailClinicalTrialsEU@its.jnj.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameApalutamide
    D.3.2Product code JNJ-56021927
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApalutamide
    D.3.9.1CAS number 956104-40-8
    D.3.9.2Current sponsor codeJNJ-56021927-AAA
    D.3.9.3Other descriptive nameAPALUTAMIDE
    D.3.9.4EV Substance CodeSUB127215
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    High-risk localized or locally advanced prostate cancer
    E.1.1.1Medical condition in easily understood language
    Prostate cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10060862
    E.1.2Term Prostate cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine if treatment with apalutamide plus ADT before and after RP with pLND in subjects with high-risk localized or locally advanced prostate cancer results in an improvement in pCR rate and MFS based on conventional or prostate specific membrane antigen (PSMA) positron emission tomography (PET) imaging, as compared to placebo plus ADT
    E.2.2Secondary objectives of the trial
    with pLND in subjects with high risk localized or locally advanced prostate cancer results in:
    - improvement of PSA-free survival
    - an improvement in EFS as compared with standard of care (SoC)
    - a prolongation of time to first subsequent local or systemic treatment (TTST1)
    - longer time to distant metastasis (TTDM) on conventional or PSMA PET imaging
    - an improvement of MFS based on conventional imaging

    To characterize the safety profile of treatment with apalutamide plus ADT before and after RP with pLND in subjects with high risk localized or locally advanced prostate cancer
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    This is an open-label substudy to compare the current standard of care (SoC) with perioperative apalutamide plus androgen deprivation therapy
    (ADT).
    The above referenced substudy is described with details on study design, hypothesis, objectives, and endpoints in Attachment 9
    (Open-label Substudy) of Protocol Amendment 6 dated 04 November 2021.
    The primary objective of this substudy is to determine if treatment with apalutamide plus ADT before and after RP with pLND in subjects with
    high-risk localized or locally advanced prostate cancer results in an improvement in event-free survival (EFS) as compared with SoC.
    Key secondary objectives are to determine if this treatment results in improvement of other efficacy endpoints and to characterize the safety
    profile.
    E.3Principal inclusion criteria
    1. Must be ≥18 years of age
    2. Signed an informed consent form (ICF) indicating that the subject understands the purpose of and procedures required for the study and is willing to participate in the study; subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol (Section 4.3)
    3. Histologically confirmed adenocarcinoma of the prostate
    4. Criterion modified per Amendment 1
    4.1. Criterion modified per Amendment 2
    4.2 High risk disease defined by a total Gleason Sum Score ≥4+3 (=Grade Groups [GG] 3 5) and ≥1 of the following 4 criteria:
    • Any combination of Gleason Score 4+3 (=GG 3) and Gleason Score 8 (4+4 or 5+3) in ≥6 systematic cores (with ≥1 core Gleason Score 8 [4+4 or 5+3] included);
    • Any combination of Gleason Score 4+3 (=GG 3) and Gleason Score 8 (4+4 or 5+3) in ≥3 systematic cores and PSA ≥20 ng/mL (with ≥1 core Gleason Score 8 [4+4 or 5+3] included);
    • Gleason Score ≥9 (=GG 5) in at least 1 systematic or targeted core; or
    • At least 2 systematic or targeted cores with continuous Gleason Score ≥8 (=GG 4), each with ≥80% involvement
    5. Criterion modified per Amendment 1
    5.1. Candidate for RP with pLND as per the investigator
    6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
    7. Criterion modified per Amendment 1
    7.1. Criterion modified per Amendment 2
    7.2. Adequate organ function determined by the following central laboratory values:
    a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin within normal limits, ie, ≤ the upper limit of normal ([ULN]; note that in subjects with Gilbert's syndrome, if total bilirubin is >1.5 X ULN, measure direct and indirect bilirubin. If direct bilirubin is ≤ 1.5 X ULN, the subject may be eligible);
    b. Serum creatinine <1.8 mg/dL;
    c. Platelets ≥75,000/microliter, without transfusion and/or growth factors within 1 month prior to randomization;
    d. Hemoglobin ≥12.0 g/dL (7.4 mmol), without transfusion and/or growth factors within 1 month prior to randomization
    8. Criterion modified per Amendment 4
    8.1 Able to receive ADT for at least 13 months, based on cardiovascular risk assessment and the investigator's assessment
    9. Criterion modified per Amendment 1
    9.1. Be able to swallow whole study drug tablets
    10. Criterion modified per Amendment 1
    10.1. Criterion modified per Amendment 2
    10.2. Criterion modified per Amendment 7
    10.3. Contraceptive use by male subjects (and female partners of male subjects enrolled in the study who are of childbearing potential or are pregnant) should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.
    E.4Principal exclusion criteria
    1. Distant metastasis based on conventional imaging (clinical stage M1).
    Nodal disease below the iliac bifurcation (clinical stage N1) is not an
    exclusion. Diagnosis of distant metastasis (clinical M stage; M0 versus
    M1a, M1b, M1c) and pelvic nodal disease (clinical N stage; N1 versus N0)
    will be assessed by central radiological review. Patients are considered
    eligible only if the central radiological review confirms clinical stage M0
    2. 2. Criterion modified per Amendment 2
    2.1. (a) Prior treatment with androgen receptor antagonists.
    (b) Treatment with GnRHa analogs prior to ICF signature.
    4. Criterion deleted per Amendment 1
    5. Bilateral orchiectomy
    6. Criterion modified per Amendment 1
    6.1. Criterion modified per Amendment 2
    6.2. History of prior systemic or local therapy for prostate cancer,
    including pelvic radiation for prostate cancer
    7. Criterion modified per Amendment 1
    7.1. Use of any investigational agent ≤4 weeks prior to randomization or any therapeutic procedure for prostate cancer at any time
    8. Major surgery ≤4 weeks prior to randomization
    9. Criterion modified per Amendment 4
    9.1. Any of the following within 12 months prior to first dose of study drug: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias or New York Heart Association Class II to IV heart disease; uncomplicated deep vein thrombosis is not considered exclusionary
    10. Human immunodeficiency virus-positive subjects with 1 or more of the following:
    a. Not receiving highly active antiretroviral therapy
    b. Had a change in antiretroviral therapy within 6 months of the start of screening
    c. Receiving antiretroviral therapy that may interfere with study drug (consult sponsor for review of medication prior to enrollment)
    d. CD4 count <350 at screening
    e. AIDS-defining opportunistic infection within 6 months of start of screening
    11. Active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction
    12. Criterion modified per Amendment 2
    12.1. History of seizure; any condition that may predispose to seizure
    (including, but not limited to, prior stroke, transient ischemic attack, or
    loss of consciousness ≤1 year prior to randomization); presence of brain
    arteriovenous malformation; or intracranial masses such as
    schwannomas and meningiomas that are causing edema or mass effect
    13. Treatment with drugs known to lower the seizure threshold within 4
    weeks prior to randomization
    14. Gastrointestinal conditions affecting absorption
    15. Criterion modified per Amendment 1
    15.1. Known or suspected contraindications or hypersensitivity to
    apalutamide, GnRHa or any of the components of the
    formulations
    16. Any condition for which, in the opinion of the investigator,
    participation would not be in the best interest of the subject
    17. Criterion modified per Amendment 2
    17.1. Active malignancies (ie, progressing or requiring treatment or
    treatment change in the last 24 months) other than prostate cancer. The
    only allowed exceptions are: non-muscle invasive bladder cancer
    (NMIBC); skin cancer (non-melanoma or melanoma) treated within the
    last 24 months that is considered completely cured; breast cancer
    (adequately treated lobular carcinoma in situ or ductal carcinoma in situ,
    or history of localized breast cancer and receiving antihormonal agents
    and considered to have a very low risk of recurrence); malignancy that is
    considered cured with minimal risk of recurrence.
    E.5 End points
    E.5.1Primary end point(s)
    - pCR rate (as defined in the pathology charter and assessed by a pathology blinded independent central review [BICR])
    - MFS based on conventional or PSMA PET imaging (defined as the time from randomization to the date of the first
    occurrence of radiographic distant metastasis on conventional imaging [ie, computed tomography (CT)/magnetic resonance imaging (MRI) and bone scan] or PSMA PET imaging evaluated by radiology BICR, pathologic finding of distant metastasis, or death from any cause, whichever occurs first).
    E.5.1.1Timepoint(s) of evaluation of this end point
    - at radical prostatectomy
    - until documented distant metastasis, death, lost to follow-up, withdrawal of consent, or termination of the study by the sponsor, whichever occurs first
    E.5.2Secondary end point(s)
    - Prostate-specific antigen (PSA)-free survival
    - EFS defined as time from randomization to any of the following events: biochemical failure (BCF); or local or regional recurrence on PSMA PET or conventional imaging by BICR; or histopathological assessment; or Distant metastasis on PSMA PET or conventional imaging by BICR or histopathological assessment; or Death
    - TTST1
    - TTDM on conventional or PSMA PET imaging
    - MFS based on conventional imaging, defined as the time from
    randomization to the date of the first occurrence of radiographic distant metastasis on CT/MRI and bone scan by radiology BICR, pathologic finding of distant metastasis, or death from any cause, whichever occurs first
    - Adverse events (AEs), vital signs measurements, physical
    examinations, clinical laboratory tests, and treatment compliance.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. the time from randomization to the first detectable serum PSA level with recovered testosterone levels after undetectable PSA post-radical prostatectomy with lymph node dissection (RPLND) or death, whichever occurs first
    2. time from randomization to first documentation of BICR-confirmed radiographic progressive disease or death due to any cause (whichever occurs first) + 1 day
    3. from signing of consent until 30 days after last dose of study drug. Clinical Labs & compliance per T&E on treatment
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarkers and tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA71
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Israel
    Japan
    Korea, Republic of
    Taiwan
    United States
    France
    Poland
    Netherlands
    Spain
    Czechia
    Germany
    Italy
    Russian Federation
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days9
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 950
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1550
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1176
    F.4.2.2In the whole clinical trial 2500
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    subsequent treatment is at investigator discretion
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-03-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-10
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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