Clinical trial NCT02194842: Phase III Radium 223 mCRPC-PEACE III
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 type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Prostate Cancer
Keywords: metastatic
prostate cancer
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Bayer
name: Astellas Pharma Europe Ltd.
name: UNICANCER
name: Canadian Urologic Oncology Group
name: Latin American Cooperative Oncology Group
name: Cancer Trials Ireland
First posted: 2014-07-18
Enrollment: 446
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of the trial is 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


Eligibility criteria: 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, see Appendix E)
* 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) (Ref. 22) 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
* No known central nervous system metastases or leptomeningeal tumor spread.
* Patients must be at least 18 years old
* WHO Performance status 0-1(see Appendix C)
* Charlson score ≤ 3 (see Appendix G)
* T-score ≥ -2.5 on a DXA scan done in the past 12 months Note: For French sites only, DXA scan done within 6 weeks of randomization
* 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)
* No 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
* Bradycardia as indicated by a heart rate of \< 45 beats per minute on the screening ECG and on physical examination
* Uncontrolled hyperglycemia as indicated by a fasting glucose ≥ 7 mmol/L
* 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
* No prior treatment with enzalutamide, apalutamide, darolutamide or Ra223
* No concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel) and ketoconazole
* 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
* 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 (except ADT) or treatment with another investigational agent within the last 4 weeks prior to randomization
* No known hypersensitivity to compounds related to enzalutamide or Ra223 (refer to Investigator's brochures)
* 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 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)
* Drugs known to lower the seizure threshold or prolong QT interval are not permitted (refer to section 5.9.3.2)
* No major surgery within 4 weeks prior to treatment
* No drug or alcohol abuse
* No 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
* No condition which, in the investigator's opinion, makes the patient unsuitable for trial participation
* 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 measure 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. Important note: All eligibility criteria must be adhered to, in case of deviation discussion with EORTC Headquarters and study coordinator is mandatory

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

Primary outcomes:
measure: radiological progression-free survival
timeFrame: 46 months after first patient entry
Secondary outcomes:
measure: Overall survival
timeFrame: 63 months after first patient entry
measure: prostate cancer specific survival
timeFrame: 63 months after first patient entry
measure: First symptomatic skeletal event
timeFrame: 46 and 63 months after first patient entry
measure: Time and incidence of first skeletal progression-free survival
timeFrame: 46 and 63 months after first patient entry
measure: Time from entry to initiation of next systemic anti-neoplastic therapy
timeFrame: 46 and 63 months after first patient entry
measure: Treatments elected after first disease progression
timeFrame: 46 and 63 months after first patient entry
measure: Second progression-free survival in sequential regimen
timeFrame: 46 and 63 months after first patient entry
measure: Patient self-rate scale assessing the pain associated to prostate cancer
timeFrame: 46 and 63 months after first patient entry
measure: Time to pain progression
timeFrame: 63 months after first patient entry
measure: Occurence of adverse events
timeFrame: 63 months after first patient entry
measure: Time to opiate use for cancer-related pain
timeFrame: 63 months after first patient entry
measure: Patient self-rate scale assessing the Quality of Life
timeFrame: 46 and 63 months after first patient entry
measure: rate of skeletal fractures
timeFrame: 63 months after first patient entry
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Hopital Universitaire Brugmann
city: Brussels
country: Belgium
facility: Hopitaux Universitaires Bordet-Erasme - Hopital Universitaire Erasme
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Kortrijk
country: Belgium
facility: AZ Groeninge Kortrijk
city: Leuven
country: Belgium
facility: U.Z. Leuven - Campus Gasthuisberg
city: Turnhout
country: Belgium
facility: AZ Turnhout
city: Yvoir
country: Belgium
facility: CHU Dinant Godinne - UCL Namur
city: Barretos
country: Brazil
facility: Hospital de Amor
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner
city: Florianópolis
country: Brazil
facility: Centro Pesquisas Oncologicas
city: Fortaleza
country: Brazil
facility: Oncocentro
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
city: Porto Alegre
country: Brazil
facility: Centro de Pesquisas Clinicas em Oncologia - Hospital Sao Lucas
city: Recife
country: Brazil
facility: Instituto de Medicina Integral Professor Fernando Figueira - IMIP
city: Rio De Janeiro
country: Brazil
facility: Centro de Tratamentos de Tumores Botafogo
city: Salvador
country: Brazil
facility: Clínica Oncológica - CLION
city: Santo André
country: Brazil
facility: Centro de Estudos e Pesquisa Hematologia e Oncologia
city: São Paulo
country: Brazil
facility: Hospital Beneficencia Portuguesa
city: São Paulo
country: Brazil
facility: Hospital Paulistano
city: São Paulo
country: Brazil
facility: Sao Camilo Oncologia - Instituto Brasileiro de Controle do Cancer
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Hamilton
country: Canada
facility: Hamilton And District Urology Association
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Center
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre - Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Oci Princess Margaret Hospital
state: Ontario
city: Chicoutimi
country: Canada
facility: Centre de sante et de services sociaux de Chicoutimi
state: Quebec
city: Montréal
country: Canada
facility: CHUM - Centre Hospitalier de l'Université de Montreal - Pavillon Saint-Luc
state: Quebec
city: Québec
country: Canada
facility: Chuq-Pavillon Hotel-Dieu De Quebec
state: Quebec
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Angers
country: France
facility: Institut de Cancerologie de l'Ouest (ICO) - Centre Paul Papin
city: Caen
country: France
facility: Centre Francois Baclesse
city: Créteil
country: France
facility: Assistance Publique - Hopitaux de Paris - CHU Henri Mondor
city: Lyon
country: France
facility: Centre Leon Berard
city: Montpellier
country: France
facility: Institut régional du Cancer Montpellier
city: Saint-Herblain
country: France
facility: Institut de Cancerologie de l'Ouest (ICO) - Centre Rene Gauducheau
city: Strasbourg
country: France
facility: Hopitaux Universitaires de Strasbourg - Hôpitaux Universitaires de Strasbourg - Hôpital civil
city: Villejuif
country: France
facility: Gustave Roussy
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: St. Vincent's University Hospital
city: Dublin
country: Ireland
facility: Tallaght University Hospital
city: Carpi
country: Italy
facility: Ospedale B.Ramazzini
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Kristiansand
country: Norway
facility: Soerlandet Sykehus-Kristiansand
city: Tromsø
country: Norway
facility: University Hospital of North Norway
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Centre
city: Barcelona
country: Spain
facility: Hospital Del Mar
city: Barcelona
country: Spain
facility: Vall d'Hebron Institut d'Oncologia
city: Barcelona
country: Spain
facility: Hospital Clinic Universitari de Barcelona
city: Barcelona
country: Spain
facility: Hospital De La Santa Creu I Sant Pau
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario QuironSalud
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
city: Sabadell
country: Spain
facility: Corporacio Sanitaria Parc Tauli
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Bellinzona
country: Switzerland
facility: Oncology Institute of Southern Switzerland - Ospedale San Giovanni
city: St Gallen
country: Switzerland
facility: Kantonsspital St Gallen
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zurich
city: Lincoln
country: United Kingdom
facility: United Lincolnshire Hospitals NHS Trust - Lincoln County Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital - Chelsea, London
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust - City Hospital
Study officials:
affiliation: Cliniques Universitaires de Saint Luc
name: Bertrand Tombal, Prof
role: STUDY_CHAIR
affiliation: Oncology Institute of Southern Switzerland - Ospedale San Giovanni
name: Silke Gillessen, Prof
role: STUDY_CHAIR
References: