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    Summary
    EudraCT Number:2019-004818-34
    Sponsor's Protocol Code Number:CTRIAL-IE-19-32
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-05-05
    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 ConcernedIreland - HPRA
    A.2EudraCT number2019-004818-34
    A.3Full title of the trial
    DASL-HiCaP: Darolutamide Augments Standard Therapy for Localised Very High-Risk Cancer of the Prostate (ANZUP1801). A randomised phase 3 double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation in very high risk, clinically localised prostate cancer.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical research study to investigate whether the addition of a new medication (darolutamide) to standard treatment is better for improving the outcomes for men with localised prostate cancer compared to standard treatment.
    A.4.1Sponsor's protocol code numberCTRIAL-IE-19-32
    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 SponsorCancer Trials Ireland
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBayer
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportNHMRC Clinical Trials Centre (CTC), University of Sydney
    B.4.2CountryAustralia
    B.4.1Name of organisation providing supportAustralian and New Zealand Urogenital and Prostate Cancer (ANZUP)
    B.4.2CountryAustralia
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCancer Trials Ireland
    B.5.2Functional name of contact pointHead of Clinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressRCSI House, 121 St. Stephen's Green
    B.5.3.2Town/ cityDublin
    B.5.3.3Post codeD02 H903
    B.5.3.4CountryIreland
    B.5.4Telephone number+35316677211
    B.5.6E-mailinfo@cancertrials.ie
    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 nameDarolutamide
    D.3.2Product code BAY 1841788 (darolutamide, ODM-201)
    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 INNDAROLUTAMIDE
    D.3.9.3Other descriptive nameBAY 1841788 (darolutamide, ODM-201)
    D.3.9.4EV Substance CodeSUB185326
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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
    Clinically localised prostate cancer defined as very high risk, or with very high risk features.
    E.1.1.1Medical condition in easily understood language
    Clinically localised prostate cancer defined as very high risk, or with very high risk features.
    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
    Primary objective:

    1. Metastasis-free survival (MFS) (metastasis or death from any cause)
    E.2.2Secondary objectives of the trial
    Secondary objectives:

    2. Overall survival (OS) (death from any cause)
    3. Prostate cancer-specific survival
    4. PSA-progression free survival
    5. Time to subsequent hormonal therapy (restart or change to treat recurrence/progression)
    6. Time to castration-resistance (PCWG3 criteria)
    7. Frequency and severity of adverse events (CTCAE v5.0, RTOG/EORTC acute/late radiation morbidity criteria)
    8. Health related quality of life (EORTC QLQ-C30, QLQ-PR25, EQ-5D-5L)
    9. Fear of cancer recurrence (FCR) (FCRI)

    Tertiary objectives:

    10. Incremental cost-effectiveness

    Also to:

    11. Identify biomarkers that are prognostic, and/or predictive of response to treatment, safety and resistance to study treatment (associations of biomarkers with clinical outcomes).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men aged 18 years and older, with pathological diagnosis of adenocarcinoma of the prostate.

    2. EITHER planned for primary RT and judged to be at very high risk for recurrence based on any of the following:
    - Grade Group 5, OR
    - Grade Group 4 AND one or more of the following: clinical T2b-4 OR MRI with seminal vesicle invasion OR extracapsular extension OR PSA* > 20ng/mL, OR
    - Pelvic nodal involvement (involvement of lymph nodes (LNs) at or below the bifurcation of the aorta into the common iliac arteries) defined radiologically as greater than 10mm on short axis using standard CT or MRI, or pathologically confirmed (PSMA PET alone is not considered enough if ≤ 10mm)
    OR
    Post-radical prostatectomy ≤ 365 days prior to randomisation and planned for RT with PSA ≥ 0.1 ng/mL that has risen or remained stable (within ≤ 0.05 ng/mL) since a previous level at least 1 week earlier, judged to be at very high risk for recurrence based on any of the following:

    - Grade Group 5, OR
    - Grade Group 4 AND pT3a or higher, OR
    - Pelvic nodal involvement (involvement of LNs at or below the bifurcation of the aorta into the common iliac arteries) defined radiologically as greater than 10mm on short axis using standard CT or MRI, or pathologically confirmed (PSMA PET alone is not considered enough if ≤ 10mm)

    * Screening PSA levels are those measured within 240 days prior to randomisation.

    3. Adequate bone marrow function: Haemoglobin ≥ 100g/L, white cell count (WCC) ≥ 4.0x10^9/L, absolute neutrophil count (ANC) ≥ 1.5x10^9/L and platelets > 100 x 10^9/L

    4. Adequate liver function: alanine aminotransferase (ALT) < 2 x upper limit of normal (ULN) and total bilirubin < 1.5 x ULN, (or if total bilirubin is between 1.5 - 2 x ULN, they must have a normal conjugated bilirubin)

    5. Adequate renal function: calculated creatinine clearance > 30 mL/min (Cockroft-Gault)

    6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.

    7. Study treatment both planned and able to start within 7 days after randomisation

    8. Willing to complete health-related quality of life (HRQL) questionnaires UNLESS is unable to complete because of literacy or limited vision

    9. Willing and able to comply with all study requirements, including standard of care treatment such as EBRT, timing and/or nature of required assessments

    10. Signed, written informed consent

    Additional:
    Conventional imaging must be used to confirm eligibility and disease progression, PSMA PET alone is not considered enough.
    E.4Principal exclusion criteria
    11. Prostate cancer with predominant non-adenocarcinoma features(sarcomatoid/spindle cell/neuroendocrine small cell/squamous cell components/other non-adenocarcinoma)

    12. Involvement of LNs by conventional CT imaging superior to the common iliac artery bifurcation,and/or outside the pelvis(distant LNs).LN involvement is defined by histopathological confirmation,or by a short axis measurement > 10mm on standard imaging(CT or MRI,but not PET).

    13. Evidence of metastatic disease. Minimum imaging requirements to exclude metastatic disease are defined in the trial protocol.
    • If endocrine therapy (ET)had not started,imaging must be within 60 days prior to randomisation.
    • If ET has been started,radiographic imaging (CT/MRI/CXR)must have been performed no more than 60 days prior to starting ET&no more than 30 days after starting ET &prior to randomisation. Refer to protocol for further detail.

    14. PSA >100 ng/mL at any time.

    15. Any prior use of new generation potent AR inhibition(abiraterone,enzalutamide,apalutamide,darolutamide or similar agents).

    16. Prior endocrine therapy for prostate cancer except for the following,which are allowed:

    • (i)LHRHA and/or(ii)a first-generation nonsteroidal antiandrogen(NSAA)are allowed if commenced no more than 90 days before randomisation.If an NSAA has been used,it must be stopped before starting study treatment with darolutamide/placebo; and
    • Prior use of 5-alpha reductase inhibitor is allowed&if used,it must be stopped before starting study treatment with darolutamide/placebo.

    17. Bilateral orchidectomy

    18. Prior pelvic brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields that would preclude the required RT

    19. History of
    • Loss of consciousness or transient ischemic attack or stroke within 6 months prior to randomisation,or
    • Significant cardiovascular disease within 6 months prior to randomisation:including myocardial infarction,unstable angina,congestive heart failure(NYHA grade II or greater),ongoing arrhythmias of Grade >2(CTCAE v5.0),thromboembolic events,coronary artery bypass graft.Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.

    20. Known gastrointestinal disease/procedure that could interfere with the oral absorption or tolerance of darolutamide,including difficulty swallowing tablets

    21. History of another malignancy within 5 years prior to randomisation except for those malignancies treated with curative intent with a predicted risk of relapse of less than 10% including but not limited to non-melanoma carcinoma of the skin;or adequately treated,non-muscle-invasive urothelial carcinoma of the bladder(i.e.Tis, Ta &low grade T1 tumours).
    All such cases with a history of malignancy within the last 5 years are to be discussed with study team before randomisation. Melanoma in-situ&other adequately treated in-situ neoplasms are not considered malignancies for the purposes of eligibility assessment.

    22. Concurrent illness,including severe infection that might jeopardise the ability of the participant to undergo the procedures outlined in the protocol with reasonable safety(HIV infection is not an exclusion criterion if it is controlled with anti-retroviral drugs that are unaffected by concomitant darolutamide)

    23. Presence of any psychological,familial,sociological or geographical condition potentially hampering compliance with the study protocol &follow-up schedule,including alcohol dependence or drug abuse

    24. Patients who are sexually active with women of child-bearing potential and not willing/able to use medically acceptable&highly effective forms of contraception during study treatment&for at least 4 weeks after completion of study treatment.Contraception must include:
    - Condom use (also required if sexual partner is pregnant),and
    - Additional birth control with low failure rate (less than 1% per year)when used consistently and correctly. E.g. combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, true sexual abstinence.

    True sexual abstinence will only be an acceptable form of contraception when this is in line with the preferred &usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to study treatment, and withdrawal are not acceptable methods of contraception.

    25. Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases

    26. Major surgery within 21 days prior to randomisation

    27. Patients with history of hypersensitivity to the study treatment.
    E.5 End points
    E.5.1Primary end point(s)
    Metastasis-free survival (MFS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    1,100 participants followed until 130 MFS events are recorded (e.g. given a 3 year accrual period plus at least 4 years of follow-up, and an 85% 5-year MFS in control arm).

    An unblinded interim analysis on MFS is planned once 67% of the 130 required events have been recorded.

    Final analysis will be performed after the study has been completed, the data cleaned, and the database closed out, according to the trial
    Statistical Analysis Plan.
    E.5.2Secondary end point(s)
    - Overall survival
    - Prostate cancer-specific survival
    - PSA-progression free survival
    - Time to subsequent hormonal therapy
    - Time to castration-resistance
    - Frequency and severity of adverse events
    - Health-related quality of life
    - Fear of cancer recurrence
    - Incremental cost-effectiveness
    - Prognostic/predictive biomarkers
    E.5.2.1Timepoint(s) of evaluation of this end point
    1,100 participants followed until 130 MFS events are recorded (e.g. given a 3 year accrual period plus at least 4 years of follow-up, and an 85% 5-year MFS in control arm).

    An unblinded interim analysis on MFS is planned once 67% of the 130 required events have been recorded.

    Final analysis will be performed after the study has been completed, the data cleaned, and the database closed out, according to the trial
    Statistical Analysis Plan.
    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 No
    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 No
    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 No
    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 concerned9
    E.8.5The trial involves multiple Member States No
    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
    New Zealand
    Australia
    Canada
    United Kingdom
    United States
    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
    End of trial occurs when all of the following criteria have been satisfied:

    1. All study participants have completed/stopped study treatment and study follow-up.

    2. The trial is mature for the analysis of the primary end point. Primary end point of 130 Metastasis-free Survival (MFS) events has been reached.

    3. The Database has been fully cleaned and frozen for this analysis.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days0
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state80
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 1100
    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)
    Patients will receive standard after care according to institutional guidelines.
    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 Decision2020-07-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-23
    P. End of Trial
    P.End of Trial StatusOngoing
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