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    Summary
    EudraCT Number:2014-002113-39
    Sponsor's Protocol Code Number:BAY88-8223/16298
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-04-13
    Trial results View 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 ConcernedGermany - BfArM
    A.2EudraCT number2014-002113-39
    A.3Full title of the trial
    A phase II randomized, double-blind, placebo-controlled trial of radium-223 dichloride versus placebo when administered to metastatic HER2 negative hormone receptor positive breast cancer subjects with bone metastases treated with hormonal treatment background therapy.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of radium-223 dichloride versus placebo and hormonal treatment as background therapy in subjects with bone predominant HER2 negative hormone receptor positive metastatic breast cancer.
    A.4.1Sponsor's protocol code numberBAY88-8223/16298
    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 SponsorBayer AG
    B.1.3.4CountryGermany
    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 AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street Address-
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.4Telephone number+49 30 300139003
    B.5.6E-mailclinical-trials-contact@bayer.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 Yes
    D.2.1.1.1Trade name Xofigo
    D.2.1.1.2Name of the Marketing Authorisation holderBayer AG (MAH)
    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 nameRadium-223 dichloride
    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.3.9.1CAS number 444811-40-9
    D.3.9.2Current sponsor codeBAY88-8223
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    HER2 negative hormone receptor positive metastatic breast cancer with bone metastases treated with standard of care hormonal treatment.
    E.1.1.1Medical condition in easily understood language
    Breast cancer that has spread to the bone treated with the standard of care hormonal treatment.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10055113
    E.1.2Term Breast 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 the efficacy and safety of radium-223 dichloride in subjects with HER2 negative, hormone receptor positive breast cancer with bone metastases treated with hormonal treatment background therapy.
    E.2.2Secondary objectives of the trial
    Not applicable.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Have provided written informed consent. Subjects must be able to understand and be willing to sign the written informed consent. A signed ICF must be appropriately obtained prior to the conduct of any study-specific procedure.
    2.Documentation of histological or cytological confirmation of ER+ and HER2 negative adenocarcinoma of the breast must be available. HER2 status should be determined by an accredited/Ministry of Health approved laboratory by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) or other validated in situ hybridization (ISH) assay for detection of HER2 gene expression.
    3.Tumors (from either primary or metastatic sites) must be ER+ defined as ≥10% positive tumor nuclei in the analyzed sample. ER+/ progesterone receptor positive (PR+), ER+/ progesterone receptor negative (PR-) subjects are eligible whereas estrogen receptor negative (ER )/PR+ and ER-/PR- disease will not be eligible.
    4.Women (≥18 years of age) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy. Women of reproductive potential and their male partners must agree to use adequate contraception during treatment and for 6 months following the completion of treatment with radium 223 dichloride/placebo.
    5.Documentation of menopausal status: post-menopausal or pre-menopausal subjects are eligible.
    o Pre-menopausal subjects with or without ovarian radiation or concomitant treatment with an LH-RH agonist/antagonist must have a negative pregnancy test at screening and agree to use an adequate method of contraception as recommended by their treating physicians.
    oPost-menopausal status is defined either by:
    oage ≥55 years and one year or more of amenorrhea
    oage <55 years and one year or more of amenorrhea with a plasma/serum estradiol assay within local laboratory postmenopausal range, performed within 7 days of randomization
    obilateral ovariectomy
    6.Subjects with bone dominant disease with at least 2 skeletal metastases identified at baseline by bone scintigraphy and confirmed by CT/magnetic resonance imaging (MRI). Presence of metastases in soft tissue (skin, subcutaneous, muscle, fat, lymph nodes) and/or visceral metastases is allowed.
    7.Measurable or non-measurable disease (but radiologically evaluable) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. All disease burden must be assessed at baseline by CT or MRI of chest, pelvis, and abdomen and any additional fields as needed.
    8.Subjects must have received at least one line of hormonal therapy in the metastatic setting.
    9.Subjects who are eligible for further standard of care endocrine treatment with any of the following administered as in second line or greater of hormone therapy in metastatic setting:
    oSERMs such as tamoxifen and toremifene
    oNSAIs such as anastrozole and letrozole
    oSteroidal AIs such as exemestane
    oER down-regulators such as fulvestrant
    10.Subjects must have experienced no more than 2 SREs prior to study entry defined as: Need for EBRT to bone, pathological bone fracture (excluding major trauma), spinal cord compression, and/or orthopedic surgical procedure. Subjects with no prior SREs are not permitted.
    11.Subjects must be on therapy with bisphosphonate or denosumab and are required to have been on such therapy for at least 1 month before the start of study treatment.
    12.Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
    13.Life expectancy ≥6 months
    14.Laboratory requirements:
    o Absolute neutrophil count (ANC) ≥1.5 x 109/L
    o Platelet count ≥100 x 109/L without platelet transfusion within 4 weeks prior to randomization
    o Hemoglobin ≥9.0 g/dL (90 g/L; 5.6 mmol/L) without transfusion or erythropoietin within 4 weeks prior to randomization
    o Total bilirubin level ≤1.5 x institutional upper limit of normal (ULN) (except for subjects with documented Gilbert’s disease)
    o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x institutional ULN.
    o Creatinine ≤1.5 x ULN
    o Estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula (Note: please refer to local labelling for administration of full dose of bisphosphonates)
    o International normalized ratio of prothrombin time (INR) and partial thromboplastin time (PTT) or activated PTT ≤1.5 x ULN at study entry. Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to participate in the study if no underlying abnormality in coagulation parameters exists per prior history; weekly evaluation of INR/PTT will be required until stability is achieved for anticoagulants that require their monitoring as per local label.
    o Serum albumin >30 g/L
    o Pulse oximetry O2 saturation >92% if lung metastases are present
    15.Able to swallow oral medication
    E.4Principal exclusion criteria
    1. HER2-positive breast cancer (IHC=3+, positive FISH/CISH/other ISH validated assay); equivocal or unknown HER2 status
    Note: Subjects with 3+ by IHC cannot be chosen regardless of their FISH/CISH/other ISH validated assay status and those with positive FISH/CISH/other ISH validated assay cannot be chosen either, regardless of the IHC findings. Subjects with 2+ by IHC will not be eligible if no negative FISH/CISH/other ISH validated assay for detection of HER2 gene expression is available.
    2. Subjects considered by the treating physician to be appropriate candidates for treatment with everolimus as current treatment for their metastatic breast cancer.
    3. Subjects with inflammatory breast cancer
    4. History and/or presence of confirmed visceral metastases
    5. Subjects who have either received chemotherapy for metastatic disease or are considered by the treating Investigator to be appropriate candidates for chemotherapy as current treatment for metastatic breast cancer are excluded. Chemotherapy administered for adjuvant/neoadjuvant disease is acceptable.
    6. Subjects with any previous untreated or concurrent cancer that is distinct in primary site or histology from the cancer under study, except treated basal cell carcinoma or superficial bladder tumor (Ta and Tis, American Joint Committee on Cancer, 7th edition). Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before enrollment are allowed. All cancer treatments must be completed at least 3 years prior to study entry (i.e., signature date of informed consent form).
    7. Subjects with known or history of brain metastases or leptomeningeal disease: subjects with neurological symptoms must undergo a contrast CT scan or MRI of the brain within 28 days prior to randomization to exclude active brain metastasis. Imaging of the central nervous system is otherwise not required.
    8. Imminent or established untreated spinal cord compression based on clinical findings and/or MRI. Following treatment of spinal cord compression, the subject may be eligible if all other eligibility criteria are fulfilled.
    9. Prior treatment with radium-223 dichloride
    10. Prior hemibody external radiotherapy. Subjects who received other types of prior external radiotherapy are allowed provided that bone marrow function is assessed and meets the protocol requirements for hemoglobin, absolute neutrophil count, and platelets.
    11. Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or rhenium-188
    12. ECOG Performance Status ≥2
    13. Blood transfusions, platelet transfusions or use of erythropoietin within 4 weeks prior to randomization.
    14. Use of biologic response modifiers, such as granulocyte macrophage-colony stimulating factor or granulocyte-colony stimulating factor, within 4 weeks prior to randomization.
    15. Treatment with an investigational drug or with any anti cancer treatments not permitted by the protocol, within 4 weeks prior to randomization
    16. Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget's disease of bone)
    17. Any other serious illness or medical condition such as, but not limited to:
    o Any uncontrolled infection
    o Cardiac failure New York Heart Association Class III or IV
    o Crohn's disease or ulcerative colitis
    o Bone marrow dysplasia
    18. Previous assignment to treatment in this study
    19. Breastfeeding women
    20. Known hypersensitivity to the active substance or to any of the excipients of radium-223 dichloride
    21. Known presence of osteonecrosis of jaw
    22. Patients with immediately life-threatening visceral disease, for whom chemotherapy is the preferred treatment option.
    23. Lymphangitic carcinomatosis.
    24. Patients with ascites requiring paracentesis within 2 weeks prior to study entry (signature of informed consent) and during the screening period.

    All local label specific criteria for the standard of care hormonal treatment as well as denosumab and bisphosphonates apply. Subjects must be treated according to the local standard of care requirements.
    E.5 End points
    E.5.1Primary end point(s)
    • Symptomatic skeletal event free survival(SSE-FS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    The time from randomization to the occurrence of one of the following:
    (1) An on-study SSE, which is defined as:
    a. the use of EBRT to relieve skeletal symptoms
    b. the occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral)
    c. the occurrence of spinal cord compression
    d. a tumor related orthopedic surgical intervention.
    (2) Death from any cause
    E.5.2Secondary end point(s)
    1. Overall survival (OS)
    2. Time to opiate use for cancer pain
    3. Time to pain progression (only in subjects with baseline worst pain score ≤8)
    4. Time to cytotoxic chemotherapy
    5. Radiological progression free survival (rPFS)
    6. Pain improvement rate
    7. Safety, acute and long term, including new primary malignancies and hematopoietic reserve for tolerability of subsequent chemotherapy
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. The time (days) from the date of randomization to the date of death due to any cause.
    2. The interval from the date of randomization to the date of opiate use.
    3. The interval from randomization to the first date a subject experiences pain progression based on WPS.
    4. The time (days) from the date of randomization to the date of the first cytotoxic chemotherapy.
    5. The time (days) from the date of randomization to the date of confirmed radiological progression in either soft tissue, viscera or bone, or death (if death occurs before progression).
    6. The interval from randomization to the first date a subject experiences pain improvement based on WPS.
    7. To be reviewed throughout the course of the study.
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA118
    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
    Austria
    Belgium
    Canada
    China
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Hong Kong
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Norway
    Poland
    Singapore
    Spain
    Sweden
    Switzerland
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    This study will end when all subjects have transitioned into the long-term follow-up study or discontinued from this study for another reason. Until the transition to the long-term follow-up study, subjects will continue to follow all the protocols required procedures and visits in the current protocol.

    For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last subject in any site has occurred.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days21
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    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: 91
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 136
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 132
    F.4.2.2In the whole clinical trial 227
    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)
    Following radium-223 dichloride/placebo treatment discontinuation, subjects will be treated and followed as per the institutional standard of care and/or according to the physician’s clinical judgment. If possible, cytotoxic chemotherapy, other systemic radioisotope, hemibody external radiotherapy, or other investigational drug should not be given before a 4-week washout period after last administration of radium-223 dichloride/placebo, provided the subject’s bone marrow is not compromised.
    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 Decision2015-06-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-13
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