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    Summary
    EudraCT Number:2014-001787-36
    Sponsor's Protocol Code Number:1333-GUCG
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-11-11
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2014-001787-36
    A.3Full title of the trial
    A Randomized multicenter phase III trial comparing enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer patients metastatic to bone.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized multicenter phase III trial comparing enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer patients metastatic to bone.
    A.3.2Name or abbreviated title of the trial where available
    PEACE III
    A.4.1Sponsor's protocol code number1333-GUCG
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02194842
    A.5.4Other Identifiers
    Name:NANumber:NA
    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 SponsorEuropean Organisation for Research and Treatment of Cancer (EORTC)
    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 supportBayer HealthCare Pharmaceuticals Inc
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportEORTC
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportAstellas Pharma
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEuropean Organisation for Research and Treatment of Cancer (EORTC)
    B.5.2Functional name of contact pointRegulatory Affairs Unit
    B.5.3 Address:
    B.5.3.1Street AddressAvenue E. Mounier 83/11
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1200
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3227741542
    B.5.5Fax number+3227727063
    B.5.6E-mailregulatory@eortc.org
    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 Yes
    D.2.1.1.1Trade name Xofigo
    D.2.1.1.2Name of the Marketing Authorisation holderBayer AG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameXofigo
    D.3.2Product code BAY88-8223
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRadium-223 dichloride
    D.3.9.3Other descriptive nameRADIUM RA 223 DICHLORIDE
    D.3.9.4EV Substance CodeSUB129907
    D.3.10 Strength
    D.3.10.1Concentration unit kBq/ml kilobecquerel(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1100
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Castration resistant prostate cancer patients metastatic to bone.
    E.1.1.1Medical condition in easily understood language
    Castration resistant prostate cancer patients metastatic to bone.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10036909
    E.1.2Term Prostate cancer metastatic
    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 assess if upfront combination of enzalutamide and Ra223 improves radiological progression-free survival (rPFS1) compared to enzalutamide single agent in CRPC patients metastatic to bone.
    E.2.2Secondary objectives of the trial
    To assess if upfront combination of enzalutamide with Ra223 (experimental arm) offers further benefits over enzalutamide alone in terms of the secondary efficacy endpoints listed below, to compare the safety profile of the approaches and to document their impact on patient reported outcomes (pain and quality of life (QoL).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ♦ Histologically confirmed diagnosis of prostate adenocarcinoma
    ♦ Asymptomatic or mildly symptomatic (defined as short form question #3 in Brief Pain Inventory worst pain must be < 4.
    ♦ Metastatic to bone with ≥ 4 bone metastases (ambiguous areas of increased uptake on 99mTC Bone Scan (BS) should be confirmed by CT or MRI) with or without additional lymph node metastases. Patients with visceral metastases are not allowed. Patients with multifocal bone lesions are allowed, while patients with diffuse confluent bone lesions (superscan) are not allowed in the trial.
    Note: Patients must start treatment with a bone protecting agent (at doses used to reduce the incidence of skeletal related events) ideally before or at the time of randomization, if patient is not already on one. A minimum of two doses is recommended before the first administration of Ra223 in the experimental arm. The first administration of Ra223 should be scheduled at least 6 weeks after the first administration of bone protecting agent.
    Note: For French sites only, patients must not have undergone a PET/CT scan for restaging prostate cancer using radiopharmaceuticals such as 18F-FDG, 18F-fluoride, 18F-Fluorocholine or a PSMA (prostate-specific membrane antigen) ligand or any other tracer.
    ♦ Progressive CRPC according to Prostate Cancer Working Group 3 (PCWG3) i.e. either:
    -For patients who manifest disease progression solely as a rising PSA level, PCWG3 criteria require documentation of a sequence of rising PSA values at a minimum of 1-week intervals with the last value ≥ 2 ng/mL.
    -For patients with disease progression manifest in the bone, irrespective of progression by rising PSA, PCWG3 guidelines require appearance of 2 or more new lesions. Ambiguous results should be confirmed by other imaging modalities than bone scan (e.g.: CT-scan or MRI).
    -For patients with disease progression manifest at nodal sites, irrespective of progression by rising PSA, PCWG3 requires progression according to RECIST 1.1.
    ♦ Ongoing androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy.
    Patients must be at least 18 years old
    ♦ WHO Performance status 0-1
    ♦ Charlson score ≤ 3
    ♦ T-score ≥ -2.5 on a DXA scan done in the past 12 months
    ♦ Castrate serum levels of testosterone < 50 ng/dL
    ♦ Biochemistry and hematology
    -Adequate bone marrow function (absolute neutrophil count (ANC) ≥ 1.5 109/L; platelets ≥ 100 109/L, and hemoglobin ≥ 10.0 g/dl.).
    -Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN), except for patient with Gilbert’s disease where ≤ 5.0 × ULN applies.
    -Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN.
    -Creatinine ≤ 1.5 x ULN
    -Albumin > 25 g/L
    ♦ Normal cardiac function according to local standard by 12-lead ECG (complete, standardized 12-lead recording).
    ♦ Able to swallow the study drug and comply with study requirements
    ♦ Prior or concomitant therapy.
    -Prior docetaxel is permitted if given in the castration sensitive state and if it was started within 4 months of ADT initiation.
    Note: patients having received docetaxel for CRPC are excluded.
    ♦ Prior use of abiraterone is permitted if the patient had a response or stable disease on abiraterone for a minimum of 1 year for metastatic castration sensitive prostate cancer
    Note: patients having received abiraterone for CRPC are excluded.
    ♦ Prior treatment with abiraterone is allowed if it was stopped at least 4 weeks prior to randomization.
    ♦ Previous treatment with bicalutamide, or flutamide is allowed if it was stopped at least 48 hours prior to randomization.
    ♦ Corticosteroids are allowed only at a dose ≤ 10 mg of prednisone (or equivalent) no matter the indication.
    ♦ Drugs known to lower the seizure threshold or prolong QT interval are not permitted.
    ♦ Participants who have pregnant partners must use a condom and those with partners of childbearing potential must use a condom and another adequate birth control measures if engaging in sexual activities during the study treatment period and for at least 3 months after last dose of enzalutamide and 6 months after the last dose of Ra223. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
    ♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
    ♦ Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
    ♦ For participation in translational research, specific consent must be given.
    E.4Principal exclusion criteria
    ♦ Known central nervous system metastases or leptomeningeal tumor spread.
    ♦ Significant cardiovascular disease including:
    -Myocardial infarction within 6 months prior to screening.
    -Uncontrolled angina within 3 months prior to screening.
    -Congestive heart failure New York Heart Association (NYHA) class III or IV, or patients with history of congestive heart failure NYHA class III or IV in the past, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%
    -History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes).
    -History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
    -Uncontrolled hypertension as indicated by a resting systolic blood pressure > 140 millimeters of mercury (mm Hg) or diastolic blood pressure > 90 mm Hg at screening.
    Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to randomization. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour. The mean SBP / DBP values from all blood pressure assessment timepoints must be ≤ 140/90 mm Hg in order for a patient to be eligible for the study.
    -Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening.
    -Uncontrolled hyperglycemia as indicated by a fasting glucose ≥ 7 mmol/L.
    -Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening ECG and on physical examination.
    ♦ Prior treatment with enzalutamide, apalutamide, darolutamide or Ra223.
    ♦ Concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel) and ketoconazole.
    ♦ Prior hemibody external radiotherapy. Patients who received other types of prior external radiotherapy are allowed provided that the bone marrow function is assessed and meets the protocol requirements for hemoglobin, absolute neutrophil count and platelets.
    ♦ Prior therapy with other radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188).
    ♦ Involvement in another therapeutic trial involving an experimental drug.
    ♦ Anticancer therapy (except ADT) or treatment with another investigational agent within the last 4 weeks prior to randomization.
    ♦ Known hypersensitivity to compounds related to enzalutamide or Ra223 .
    ♦ Prior history of malignancies other than prostate adenocarcinoma (except patients with basal cell, squamous cell carcinoma of the skin, in-situ carcinoma or low-grade superficial bladder cancer), or the patient has been free of malignancy for a period of 3 years prior to randomization date.
    ♦ History of seizure, including any febrile seizure, loss of consciousness, or transient ischemic attack within 12 months of randomization, OR any condition that may pre-dispose to seizure (e.g., prior stroke, brain arterio-venous malformation, head trauma with loss of consciousness requiring hospitalization).
    ♦ Major surgery within 4 weeks prior to treatment.
    ♦ Drug or alcohol abuse.
    ♦ Other serious illness or medical condition, such as but not limited to:
    -Any infection ≥ Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.
    -No gastrointestinal disorder affecting absorption (e.g., gastrectomy or active peptic ulcer disease).
    -Crohn’s disease or ulcerative colitis.
    -Osteonecrosis of the jaw.
    -Any bone disease with an osteoblastic activity.
    -Bone marrow dysplasia.
    -Fecal incontinence.
    -Life-threatening illness unrelated to cancer.
    ♦ Condition which, in the investigator’s opinion, makes the patient unsuitable for trial participation.
    E.5 End points
    E.5.1Primary end point(s)
    Radiological Progression free survival (rPFS1)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Radiological Progression free survival (rPFS1) counted from randomization to the first progression defined as per the Prostate Cancer clinical trials Working Group version 3 and referred to as the "PCWG3" for the setting "delay/prevent" progression or to death from any cause.
    E.5.2Secondary end point(s)
    1. Overall survival;
    2. Prostate-cancer specific survival;
    3. First symptomatic skeletal event (SSE);
    4. Time and incidence of first skeletal progression-free survival;
    5. Rate of skeletal fractures
    6. Time to next systemic anti-neoplastic therapy;
    7. Treatments elected after first disease progression;
    8. Second progression-free survival
    9. Safety according to Common Terminology Criteria for Adverse Events.
    10. Pain: Brief Pain Inventory (BPI). In this study only pain related to prostate cancer is considered.
    11. Time to pain progression (defined as an increase of 2 or more points in the “worst pain in 24 hours” score from baseline observed at 2 consecutive evaluations ≥ 4 weeks apart OR initiation of short or long-acting opioid use for pain)
    12. Time to opiate use for cancer-related pain
    13. Quality of Life (EQ-5D-5L)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.Randomization until death (any cause)
    2.Randomization until death prostate cancer
    3.Randomization until day 1st SSE recorded
    4.Between randomization and day 1st skeletal radiological progression
    5.Treatment+F-up
    6.Between randomization and 1st day next systemic anti-neoplastic therapy
    7.Every 12w from first PD until 2nd PD
    8.Randomization to 1st clinical PD on 2nd line treatment,or to death
    9.From 21d prior to randomization,at the end of every cycle,every 12w after PD,at discontinuation of treatment in absence of progression
    10&13.Screening,every 3 cycles,at treatment discontinuation in absence of PD,every 12w during f/up until PD.
    11.Randomization to 1st report of pain progression.
    12.Interval between randomiz and the 1st report of intake of opioids for cancer-related pain.
    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 No
    E.6.4Safety No
    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 No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    E.8.2.2Placebo No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    Switzerland
    Ireland
    Belgium
    Brazil
    Canada
    Denmark
    France
    Italy
    Netherlands
    Norway
    Poland
    Spain
    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 study occurs when all of the following criteria have been satisfied:
    1. Thirty days after all patients have stopped protocol treatment
    2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
    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 years9
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years9
    E.8.9.2In all countries concerned by the trial months6
    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: 23
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 423
    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 state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 320
    F.4.2.2In the whole clinical trial 446
    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)
    Treatment should be given as per the protocol until disease progression, unacceptable toxicity or patient refusal. After progression, treatment is at the discretion of the treating physician.
    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 Decision2016-01-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-18
    P. End of Trial
    P.End of Trial StatusOngoing
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