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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02194842
Recruitment Status : Recruiting
First Posted : July 18, 2014
Last Update Posted : April 25, 2018
Astellas Pharma Europe Ltd.
Academic and Community Cancer Research United
Cancer Trials Ireland
Canadian Urologic Oncology Group
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Brief Summary:
The objective of this randomized phase III open label trial is to assess if upfront combination of enzalutamide and Ra223 improves radiological progression-free survival compared to enzalutamide single agent in asymptomatic or mildly symptomatic castration resistant prostate cancer patients metastatic to bone.

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: Ra223 Drug: Enzalutamide Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 560 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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.
Study Start Date : October 2015
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : April 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Active Comparator: Enzalutamide
Enzalutamide will be given at a dose of 160 mg daily
Drug: Enzalutamide
Experimental: Enzalutamide and Ra223
Ra223 will be administered 50kBq/kg standard dose monthly for 6 months and given in combination with enzalutamide at a dose of 160 mg daily.
Drug: Ra223
Drug: Enzalutamide

Primary Outcome Measures :
  1. radiological progression-free survival [ Time Frame: 46 months after first patient entry ]

    Radiological progression free survival (rPFS1) is defined according to the recommendations of the "Prostate-Cancer clinical trials Working Group" version 2 and referred to as the "PCWG2"; for the setting "delay/prevent" progression.

    An event of progression according to their definition is either of:

    • Objective progression of the disease according to RECIST criteria for soft tissue lesions with the additional requirement that progression at the first follow-up assessment be confirmed by a second scan ≥ 6 weeks apart
    • Appearance of ≥ 2 new bone lesions (see chapter 6 for clinical examinations required) and for the first follow-up assessment only, a confirmatory scan performed ≥ 6 weeks later that shows a minimum of two or more additional new lesions

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 63 months after first patient entry ]
    number of participants

  2. prostate cancer specific survival [ Time Frame: 63 months after first patient entry ]
    number of participants

  3. First symptomatic skeletal event [ Time Frame: 46 and 63 months after first patient entry ]
    number of participants

  4. Time and incidence of first skeletal progression-free [ Time Frame: 46 and 63 months after first patient entry ]
    number of participants

  5. Time from entry to initiation of next systemic therapy [ Time Frame: 46 and 63 months after first patient entry ]
    number of participants

  6. Treatments elected after first disease progression [ Time Frame: 46 and 63 months after first patient entry ]
    number of participants

  7. Second progression-free survival in sequential regimen [ Time Frame: 46 and 63 months after first patient entry ]
    number of participants

  8. Pain [ Time Frame: 46 and 63 months after first patient entry ]
    Brief Pain Inventory questionnaire

  9. Time to pain progression [ Time Frame: 63 months after first patient entry ]
    number of participants

  10. Occurence of adverse events [ Time Frame: 63 months after first patient entry ]
    Adverse events will be graded according to the "Common Terminology Criteria for Adverse events" CTCAE, version 4.0

  11. Time to use of opioid analgesics [ Time Frame: 63 months after first patient entry ]
    number of participants

  12. Quality of Life [ Time Frame: 46 and 63 months after first patient entry ]
    EQ5D-5L questionnaire

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed diagnosis of prostate adenocarcinoma:

    1. Asymptomatic or mildly symptomatic (defined as no opioids and Brief Pain Inventory score)
    2. Metastatic to bone with ≥ 2 bone metastases (area of increase uptake on 99mTC BS (Technetium-99m bone scintigraphy) confirmed by standard X-Ray, Computed tomography (CT), or Magnetic resonance imaging (MRI)) with or without additional lymph node metastases. Visceral metastases are not allowed
    3. Progressive Castration-resistant prostate cancer (CRPC) according to Prostate Cancer Working Group 2 (PCWG2) i.e. either of:
  • For patients who manifest disease progression solely as a rising Prostate-specific antigen (PSA) level. PCWG2 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, PCWG2 guidelines require appearance of 2 or more new lesions. Ambiguous results should be confirmed by other imaging modalities than bone scan and x-ray (e.g.: CT-scan or MRI).
  • For patients with disease progression manifest at nodal sites, irrespective of progression by rising PSA, PCWG2 requires progression according to RECIST 1.1.
  • Ongoing androgen deprivation therapy with LHRH (Human luteinizing hormone-releasing hormone) agonist or antagonist or bilateral orchiectomy
  • Patients must be at least 18 years old
  • WHO Performance status 0-1
  • Charlson score ≤ 3
  • Castrate serum levels of testosterone (< 50 ng/dL)
  • Biochemistry and hematology:

    1. Adequate bone marrow function (absolute neutrophil count 1.5109/L; platelets 100 109/L, and hemoglobin > or = 10.0 g/dl.).
    2. Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN), except for patient with Gilbert's disease 5.0 ULN
    3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < or = 2.5 x ULN
    4. Creatinine < or= 1.5 x ULN
    5. Albumin > 25 g/L
  • Normal cardiac function according to local standard by 12-lead Electrocardiogram (ECG) (complete, standardized 12-lead recording)
  • Able to swallow the study drug and comply with study requirements
  • Prior or concomitant therapy

    1. Prior docetaxel is permitted under the following conditions: start within 2 months of Androgen deprivation therapy (ADT) initiation, given for a maximum of 6 cycles and progression within 6 months of the last dose of docetaxel.
    2. Previous treatment with bicalutamide, flutamide, prednisone, or dexamethasone is allowed if it was stopped at least 4 weeks prior to entry in the study
    3. Patients taking bisphosphonates or denosumab are eligible if they have received a stable dose for 4 weeks or more prior to randomization. (These treatments may then be continued on study)
  • use of adequate birth control measures 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.
  • 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

Exclusion Criteria:

  • No known history of central nervous system metastases or leptomeningeal tumor spread.
  • No significant cardiovascular disease including:

    1. Myocardial infarction within 6 months prior to screening
    2. Uncontrolled angina within 3 months prior to screening
    3. 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%
    4. History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
    5. History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
    6. Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at screening
    7. Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mm Hg) at screening
    8. Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening ECG and on physical examination
  • patients having received docetaxel for CRPC are excluded.
  • No prior treatment with enzalutamide or Ra223
  • No prior and concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel) and ketoconazole
  • No 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
  • No prior therapy with other radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188)
  • No involvement in another therapeutic trial involving an experimental drug
  • No anticancer therapy or treatment with another investigational agent within the last 4 weeks prior to randomization
  • No known hypersensitivity to compounds related to enzalutamide or Ra223
  • No 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
  • No history of seizure, including any febrile seizure, loss of consciousness, or transient ischemic attack within 12 months of enrollment (registration date), 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)
  • No major surgery within 4 weeks prior to treatment
  • No intake of narcotic analgesia for bone pain
  • No drug or alcohol abuse
  • No other serious illness or medical condition, such as but not limited to:

    1. Any infection ≥ Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4
    2. No gastrointestinal disorder affecting absorption (e.g., gastrectomy or active peptic ulcer disease)
    3. Crohn's disease or ulcerative colitis
    4. Bone marrow dysplasia
    5. Fecal incontinence
    6. Life-threatening illness unrelated to cancer
  • No condition which, in the investigator's opinion, makes the patient unsuitable for trial participation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02194842

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Contact: Evelien Nollet, PhD +3227741571
Contact: EORTC +3227741611

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Hopital Universitaire Brugmann Recruiting
Brussels, Belgium, 1020
Contact: Anne-Sophie Hambye         
Hopitaux Universitaires Bordet-Erasme - Hopital Universitaire Erasme Recruiting
Brussels, Belgium, 1070
Contact: Thierry Roumeguere         
Cliniques Universitaires Saint-Luc Recruiting
Brussels, Belgium, 1200
Contact: Bertrand Tombal         
Universitair Ziekenhuis Antwerpen Recruiting
Edegem, Belgium, 2650
Contact: Jan Van Den Brande         
AZ Groeninge Kortrijk Recruiting
Kortrijk, Belgium
Contact: Ignace Billiet         
CHU UCL Namur - Site Sainte-Elisabeth Recruiting
Namur, Belgium, 5000
Contact: Samuel Palumbo         
AZ Turnhout Recruiting
Turnhout, Belgium
Contact: Gino Pelgrims         
CHU Dinant Godinne - UCL Namur Recruiting
Yvoir, Belgium, 5530
Contact: Lionel D'Hondt         
Rigshospitalet Recruiting
Copenhagen, Denmark
Contact: Gedske Daugaard         
Institut J. Paoli & I. Calmettes Recruiting
Marseille, France, 13273
Contact: Gwenelle Gravis, Pr         
Institut régional du Cancer Montpellier Recruiting
Montpellier, France, 34298
Contact: Emmanuel Deshayes         
Gustave Roussy Recruiting
Villejuif, France, 94805
Contact: Yohann Loriot, Pr         
The Adelaide and Meath Hospital Recruiting
Dublin, Ireland
Contact: Ray McDermott, Pr         
Ospedale B.Ramazzini Recruiting
Carpi, Italy, 41012
Contact: Claudia Mucciarini         
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Recruiting
Meldola, Italy
Contact: Ugo De Giorgi         
Istituto Europeo di Oncologia Recruiting
Milano, Italy
Contact: Nole Franco         
Medical University Of Gdansk Recruiting
Gdańsk, Poland, 80211
Contact: Elzbieta Senkus-Koneftka         
Maria Sklodowska-Curie Memorial Cancer Centre Recruiting
Warsaw, Poland
Contact: Iwona Lugowska         
Hospital Del Mar Recruiting
Barcelona, Spain, 08003
Contact: Alejo Rodriguez-Vida         
Hospital De La Santa Creu I Sant Pau Recruiting
Barcelona, Spain, 08041
Contact: Pablo Maroto         
Hospital Universitario de Gran Canaria Doctor Negrin Recruiting
Las Palmas de Gran Canaria, Spain
Contact: Lara Pedro         
Corporacio Sanitaria Parc Tauli Recruiting
Sabadell, Spain
Contact: Enrique Gallardo         
Hospital Universitario de Salamanca Recruiting
Salamanca, Spain, 37007
Contact: Francisco Gomez Veiga         
Inselspital Recruiting
Bern, Switzerland
Contact: Martin Spahn         
Kantonsspital St Gallen Recruiting
St Gallen, Switzerland
Contact: Silke Gillessen         
UniversitaetsSpital Zurich Recruiting
Zurich, Switzerland, 8091
Contact: Thomas Hermanns, Pr         
United Kingdom
The Christie NHS Foundation Trust Recruiting
Manchester, United Kingdom
Contact: Ananya Choudhury         
Nottingham University Hospitals NHS Trust - City Hospital Recruiting
Nottingham, United Kingdom
Contact: Sundar Santhanam         
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Astellas Pharma Europe Ltd.
Academic and Community Cancer Research United
Cancer Trials Ireland
Canadian Urologic Oncology Group
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Study Chair: Bertrand Tombal, Pr Cliniques Universitaires de Saint Luc
Principal Investigator: Silke Gillessen, MD Cantonal Hospital of St. Gallen

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Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC Identifier: NCT02194842     History of Changes
Other Study ID Numbers: EORTC-1333-GUCG
2014-001787-36 ( EudraCT Number )
First Posted: July 18, 2014    Key Record Dates
Last Update Posted: April 25, 2018
Last Verified: April 2018
Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
prostate cancer
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases