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    Summary
    EudraCT Number:2013-004055-20
    Sponsor's Protocol Code Number:ICR-CTSU/2013/10040
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2014-09-08
    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 ConcernedUK - MHRA
    A.2EudraCT number2013-004055-20
    A.3Full title of the trial
    A phase II randomised trial of biomarkers to assess (dose-) response in patients with metastatic castration resistant prostate cancer treated with radium-223.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase II study assessing whether biological markers can be used to determine response to treatment with radium-223 in patients with metastatic castration resistant prostate cancer (CRPC).
    A.3.2Name or abbreviated title of the trial where available
    REASURE (Radium-223: Evaluation of Activity and SUrrogate REsponse)
    A.4.1Sponsor's protocol code numberICR-CTSU/2013/10040
    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 SponsorThe Royal Marsden NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    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 Healthcare Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe Institute of Cancer Research
    B.5.2Functional name of contact pointSophie Perry
    B.5.3 Address:
    B.5.3.1Street AddressICR-CTSU, 15 Cotswold Road
    B.5.3.2Town/ citySutton
    B.5.3.3Post codeSM2 5NG
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02087224614
    B.5.6E-mailreasure-icrctsu@icr.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorThe Institute of Cancer Research
    B.1.3.4CountryUnited Kingdom
    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 Healthcare Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe Institute of Cancer Research
    B.5.2Functional name of contact pointSophie Perry
    B.5.3 Address:
    B.5.3.1Street AddressICR-CTSU, 15 Cotswold Road
    B.5.3.2Town/ citySutton
    B.5.3.3Post codeSM2 5NG
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02087224614
    B.5.6E-mailreasure-icrctsu@icr.ac.uk
    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 Information not present in EudraCT
    D.2.1.1.1Trade name Xofigo 1000 kBq/mL solution for injection
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma 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 nameRadium-223 dichloride solution for injection
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRadium-223 chloride
    D.3.9.1CAS number 44811-40-9
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit Bq/kg becquerel(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number55Bq/kg to 88Bq/kg
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Castrate resistant prostate cancer with bone metastases.
    E.1.1.1Medical condition in easily understood language
    Prostate cancer that has spread to the 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 10062904
    E.1.2Term Hormone-refractory prostate cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10005993
    E.1.2Term Bone metastases
    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
    The principal research question is: can response to radium-223, in patients with CRPC and bone metastases, be measured reliably by functional imaging and/or circulating biomarkers? The primary objective is to evaluate patients' response to treatment using a type of imaging technique called whole body diffusion-weighted MRI (DW-MRI).
    E.2.2Secondary objectives of the trial
    1) To evaluate treatment response to radium-223 using 18F fluoride and 18F choline PET/CT scans.
    2) To evaluate treatment response using circulating biomarkers in blood (serum) and urine (including alkaline phosphatase (ALP), n-telopeptide, PSA, CTCs, plasma tumour DNA).
    3) To evaluate the safety of treatment with radium-223, in terms of what dose is given.

    EXPLORATORY OBJECTIVES
    1) To explore how radium-223 works by evaluating measures of cell proliferation, cell death, DNA damage and DNA repair including Ki67, caspase cleaved cytokeratin, γH2AX and RAD51 foci formation in bone marrow.
    2) To explore the relationship between radium-223 dose and response in terms of functional imaging, tumour molecular characterisation and circulating biomarkers.
    3) To explore the predictive value of ALP as a predictive biomarker for response to radium-223 using DW-MRI.
    4) To compare the abilty of evaluating treatment response to radium-223 using changes in regional bone plasma clearance (K i) a
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional sub-study: 18F-Fluoride PET/CT quantitative assessment of treatment response using regional bone plasma clearance (K i).

    This sub-study forms part of the main REASURE protocol. The objective is to compare the ability of evaluating treatment response to radium-223 using changes in regional bone plasma clearance (K i) and conventional SUV parameters.
    E.3Principal inclusion criteria
    1) Histologically or cytologically confirmed adenocarcinoma of the prostate.
    2) Known castration resistant disease defined as:
    - Castrate serum testosterone level: ≤ 50 ng/dL (2.0nM) and;
    - Bilateral orchidectomy or on maintenance androgen ablation therapy with LHRH agonist or polyestradiol phosphate throughout the study and;
    - Serum PSA progression defined by PCWG II criteria (i.e. two consecutive increases in PSA over a previous reference value, each measurement taken at least 1 week apart)
    3) Serum PSA value ≥ 2 ng/mL.
    4) Available ALP result from a blood sample taken within previous 8 weeks.
    5) Multiple skeletal metastases (≥ 2 hot spots) on bone scintigraphy within previous 12 weeks.
    6) Age ≥18 years.
    7) ECOG performance status 0-2.
    8) Life expectancy ≥ 6 months.
    9) No prior chemotherapy for CRPC (adjuvant chemotherapy for hormone naïve disease is permissible).
    10) Adequate laboratory requirements:
    a. Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L
    b. Platelet count greater than or equal to 100 x109/L
    c. Haemoglobin greater than or equal to 10.0 g/dL (100 g/L; 6.2 mmol/L)
    d. Total bilirubin level less than or equal to 1.5 institutional upper limit of normal (ULN)
    e. ASAT and ALAT less than or equal to 2.5 x ULN
    f. Creatinine less than or equal to 1.5 x ULN
    g. Albumin greater than 30 g/L
    11) Willing and able to comply with the protocol, including all assessments, scans, procedures, follow-up visits and examinations.
    12) Must be fully informed about the study and has signed the informed consent form.
    E.4Principal exclusion criteria
    1) Any prior radioisotope therapy.
    2) Surgery, radiation, chemotherapy, or other anti-cancer therapy within four weeks prior to randomisation into the study with the exception of LHRH agonists.
    3) Intention to commence cytotoxic chemotherapy within six months.
    4) Prior other malignancy within three years. Adequately treated basal cell or squamous cell skin or superficial (pTis, pTa, and pT1) bladder cancer are allowed.
    5) Treatment with any investigational drug within 30 days prior to randomisation into the study.
    6) History of visceral metastasis, or visceral metastases, as assessed by chest/abdominal/pelvic CT within previous 8 weeks.
    7) Malignant lymphadenopathy exceeding 1.5 cm in short-axis diameter.
    8) Known brain or leptomeningeal involvement.
    9) Imminent/established spinal cord compression based on clinical findings/MRI (can be re-screened following appropriate treatment).
    10) Blood transfusion or erythropoietin stimulating agents within the four weeks prior to randomisation.
    11) Faecal incontinence.
    12) Unsuitable for MRI (patient refusal or clinical contra-indication).
    13) Inadequate organ or bone marrow function.
    14) Any other serious illness or medical condition.
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients showing bone metastases response on diffusion weighted MRI (DW-MRI).
    E.5.2Secondary end point(s)
    - Quantitative and qualitative assessment of treatment response using DW-MRI
    - Quantitative and qualitative assessment of treatment response using PET imaging
    - Quantitative response in circulating/urinary biomarkers (ALP, n-telopeptide, PSA, CTCs)
    - Time to PSA progression
    - Time to total-ALP progression
    - Time to first new bone fracture
    - Incidence and severity of adverse events and laboratory abnormalities
    - Incidence of treatment discontinuations due to adverse events
    - Incidence of fractures occurring during and after radium-223 treatment

    EXPLORATORY
    - Bone marrow samples: evidence and degree of anti-tumour activity and tumour cell DNA damage using measures of proliferation, apoptosis, DNA damage and DNA repair including Ki67, caspase cleaved cytokeratin, γH2AX and RAD51 foci formation in bone marrow
    - Molecular characterisation of CRPC cells, associating subtype with anti-tumour activity
    - Quantitative and qualitative assessment of treatment response depending on dose cohort (50kBq/kg or 80kBq/kg radium-223) and individual administered dose
    - Changes in PSA
    - Changes in total ALP
    - Quantitative and qualitative assessment of treatment response to radium-223 using DW-MRI according to ALP level.
    - Difference in treatment response changes as measured by quantitative regional bone plasma clearance (K i) and conventional semi-quantitative SUV parameters.
    - Association of mean density of lesions on baseline CT scan with response determined by WB DW-MRI
    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 No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Identification of biomarkers of response
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Radium-223 (comparison of two different doses)
    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 concerned4
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    The trial end date is deemed to be the date of last data capture.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days4
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 19
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 19
    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 state38
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 38
    F.4.2.2In the whole clinical trial 38
    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)
    Radium-223 was licensed in the EU in November 2013. In January 2016, NICE recommended radium-223 be made available to NHS patients with CRPC and bone metastases who have previously received treatment with docetaxel.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-09-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-09-23
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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