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    EudraCT Number:2018-002944-10
    Sponsor's Protocol Code Number:c16-174
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-20
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-002944-10
    A.3Full title of the trial
    Phase III Trial of Docetaxel vs. Docetaxel and Radium-223 for Metastatic Castration-Resistant Prostate Cancer (mCRPC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trial comparing subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC) treated with Docetaxel vs. subjects treated with a combination of Docetaxel and Radium-223
    A.3.2Name or abbreviated title of the trial where available
    Dora trial
    A.4.1Sponsor's protocol code numberc16-174
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03574571
    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 SponsorMemorial Sloan Kettering Cancer Center
    B.1.3.4CountryUnited States
    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 LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSiron bv
    B.5.2Functional name of contact pointCEO
    B.5.3 Address:
    B.5.3.1Street AddressBrugstraat 44a
    B.5.3.2Town/ cityRoosendaal
    B.5.3.3Post code4701LJ
    B.5.4Telephone number+31652511287
    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. name Xofigo
    D. 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.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Patients with histological or cytological proof of Metastatic Castration-Resistant Prostate Cancer (mCRPC)
    E.1.1.1Medical condition in easily understood language
    Advanced prostate cancer with bone metastases
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Compare overall survival for subjects treated with docetaxel versus subjects treated with docetaxel plus raduim-223
    E.2.2Secondary objectives of the trial
    To compare:
    a. Radiographic progression free survival as defined in PCWG3 criteria;
    b. Symptomatic Skeletal event free survival;
    c. Time to total alkaline phosphatase (ALP) progression;
    d.On-treatment alterations in quality of life as assessed by FACT-P, BPI, and BFI measures between subjects who receive docetaxel with those who receive docetaxel and radium-223.
    To determine if there is excessive:
    e. Febrile neutropenia in subjects treated with docetaxel plus radium-223;
    f. Treatment discontinuation in subjects who are on their fourth line of therapy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria:
    •Willing and able to provide, or have a legally authorized representative provide, written informed consent (ICF) and HIPAA authorization for the release of personal health information. A signed informed consent must be obtained before screening procedures are performed.

    NOTE: HIPAA authorization may be either included in the informed consent or obtained separately.
    •Males 18 years of age and above
    •Histological or cytological proof of prostate cancer

    •Documented progressive mCRPC based on at least one of the following criteria:
    1.a) PSA progression defined as a minimum of 2 rising PSA levels with a minimum of a 1 week interval between each determination. A minimum PSA of 1.0 ng/mL is required for study entry.
    2.Soft-tissue progression defined as an increase ≥ 20% in the sum of the LD of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions.
    3.Progression of bone disease (evaluable disease) or two or more new bone lesions by bone scan.

    •Two or more bone lesions defined by nuclear bone scan
    •ECOG 0- 1

    •Normal organ function with acceptable initial laboratory values within 14 days of randomization:
    ◦Albumin > 30 g/L
    ◦ANC ≥ 1.5 x 10^9/L
    ◦Hemoglobin ≥ 10 g/dL
    ◦Platelet count ≥ 100 x 10^9/L
    ◦Creatinine ≤ 1.5 x the institutional upper limit of normal (ULN)
    ◦Bilirubin ≤ ULN (unless documented Gilbert's disease)
    ◦SGOT (AST) ≤ 1.5 x ULN
    ◦SGPT (ALT) ≤ 1.5 x ULN
    ◦WBC count ≥ 3 x 10^9/L

    •3.1.8 Subjects must agree to use a medically acceptable method of birth control (e.g., spermicide in conjunction with a barrier such as a condom) or sexual abstinence for the duration of the study, including 6 months after the last dose of study drug. Sperm donation is prohibited during the study and for 6 months after the last dose of study drug. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent.
    •Serum testosterone < 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy.
    •All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less.
    •Willing and able to comply with the protocol, including follow-up visits and examinations.
    E.4Principal exclusion criteria
    Exclusion Criteria:
    •3.2.1 Received any other investigational therapeutic agents or other anticancer therapies within 2 weeks or 5 half-lives, whichever is shorter, prior to randomization.
    •Received external beam radiotherapy within the 2 weeks prior to randomization.
    •Has an immediate need for external beam radiotherapy.
    •Has received any other systemic investigational or anti-cancer radiopharmaceutical in the past.
    •Has received any prostate cancer directed chemotherapy in the castration resistant setting.
    •Has received > 6 prior doses of docetaxel in the castration sensitive setting. Subjects who have received up to 6 prior doses of docetaxel in the castration sensitive setting are permitted if they have not experienced disease progression within 36 weeks of last treatment with docetaxel.
    •Has received four or more systemic anticancer regimens for mCRPC.
    ◦Treatment with docetaxel or abiraterone for non-castrate metastatic disease is permissible and does not count towards the lines of therapy for mCRPC
    ◦A 'line' is a regimen. Combinations of hormones and other types of therapies count as single lines.

    •Has known Grade ≥3 non-hematological docetaxel related toxicities or docetaxel toxicity related dose interruption or discontinuation.
    •Has received blood transfusions or growth factors within the last 4 weeks prior to randomization.
    •Symptomatic nodal disease (i.e., scrotal, penile, or leg edema).
    •Has visceral metastases with ≥ 3 lung and/or liver metastases or individual lesion ≥2 cm, as assessed by CT scan or MRI of the chest/abdomen/pelvis within the last 8 weeks prior to randomization.
    •Symptomatic loco-regional disease that causes ongoing Grade 3 or Grade 4 urinary or rectal symptoms.
    •Subjects with a second malignancy with a risk of recurrence >30% within the next 3 years. Non-melanoma skin cancers, non-invasive bladder cancers, and other in-situ or non-invasive malignancies are permitted while on study.
    •Has imminent or established cord compression based on clinical findings and/or MRI.
    •Known bone marrow dysplasia
    •Has received any of the following in the 4 weeks prior to randomization: 5-alpha-reductase inhibitors, herbal medications, natural hormonally active foods (e.g., phytoestrogens) or other food supplements known to alter PSA in humans
    •Is receiving ongoing treatment with herbal medications that are known in humans to alter PSA or the natural history of prostate cancer. Subjects must discontinue any such herbal medications prior to the first dose of study drug
    •Any other serious illness or medical condition that would, in the opinion of the investigator, make this protocol unreasonably hazardous, including but not limited to:
    ◦Uncontrolled infection
    ◦NYHA III or IV heart failure
    ◦Crohn's disease or those with ulcerative colitis who have not undergone a colectomy
    ◦Known active infection with HIV, Hepatitis B or Hepatitis C
    E.5 End points
    E.5.1Primary end point(s)
    primary endpoint
    The overall survival comparison between treatments will be evaluated at each interim analysis and the final analysis using the stratified logrank test. The stratification factors are:
    1. Prior docetaxel for castrationsensitive disease (Yes or No)
    2. Visceral disease (presence or absence)
    E.5.1.1Timepoint(s) of evaluation of this end point
    At each interim analysis and the final analysis
    E.5.2Secondary end point(s)
    secondary and correlative endpoints
    · • Time to event endpoints will be analyzed using a stratified log-rank test with the same stratification factors. Kaplan-Meier estimates of symptomatic skeletal event-free survival and radiographic PFS will be computed. The cumulative incidence function will be used to compute probabilities for the time to first skeletal related event and the time to ALP progression. All time to event probability estimates will be calculated within treatment.
    · tALP response will be compared between the treatment groups using a CMH test adjusting for the randomization strata.
    · Time to maximum % post-therapy decrease in PSA will be summarized using descriptive statistics
    · Maximum % decrease in PSA will be summarized using descriptive statistics (e.g., mean, standard deviation, median, minimum, and maximum)
    · Longitudinal kernel smoothing methods will be used to estimate the PSA, bone marker, BSI, CTC, and ctDNA trajectories over time. Joint modeling will used to evaluate these trajectories with respect to overall survival.
    · • PROs will include scores from the QOL questionnaires: FACT-P, BPI, and BFI. The QOLs will be administered at baseline, week 19, safety follow up, and follow up visits every 3 months for 1 year from last dose of either study drug. The score-specific area under the curve (with respect to time) will be derived for each subject and these area-under-curve (AUCs) will be compared between treatments. To account for potential subject withdrawal, the Mann-Whitney U-statistic will be used for the comparison; where for each pair of subjects (one from each treatment) the AUCs are based on the minimum follow-up time. In addition, a linear mixed effects model will be employed to evaluate the effect of treatment on QOL scores after adjusting for potential confounding factors.
    · The number and percentage of febrile neutropenia in subjects treated with docetaxel plus radium-223
    · The percentage of treatment discontinuation in subjects who are on their fourth line of therapy will be calculated by treatment arm and total.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All time to event probability estimates will be calculated within 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 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. 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E. description
    no treatment (Docetaxel plus Radium is compared to Docetaxel alone)
    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
    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
    The last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 148
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 590
    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 state200
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 250
    F.4.2.2In the whole clinical trial 738
    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)
    Not different from the expected normal treatment of that condition
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Stichting DUOS
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-11-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-27
    P. End of Trial
    P.End of Trial StatusOngoing
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