Phase III Radium 223 mCRPC-PEACE III

Prostate Cancer Clinical Trial

— 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.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02194842
• Other study ID #: EORTC-1333-GUCG
• Secondary ID: 2014-001787-36
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 2015
• Est. completion date: December 2028

Study information

• Verified date: April 2024
• Source: European Organisation for Research and Treatment of Cancer - EORTC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 446
• Est. completion date: December 2028
• Est. primary completion date: February 19, 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Ra223

• Enzalutamide

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	Hopital Universitaire Brugmann	Brussels
Belgium	Hopitaux Universitaires Bordet-Erasme - Hopital Universitaire Erasme	Brussels
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Belgium	AZ Groeninge Kortrijk	Kortrijk
Belgium	U.Z. Leuven - Campus Gasthuisberg	Leuven
Belgium	AZ Turnhout	Turnhout
Belgium	CHU Dinant Godinne - UCL Namur	Yvoir
Brazil	Hospital de Amor	Barretos
Brazil	Hospital Erasto Gaertner	Curitiba
Brazil	Centro Pesquisas Oncologicas	Florianópolis
Brazil	Oncocentro	Fortaleza
Brazil	Centro de Pesquisas Clinicas em Oncologia - Hospital Sao Lucas	Porto Alegre
Brazil	Hospital Moinhos de Vento	Porto Alegre
Brazil	Instituto de Medicina Integral Professor Fernando Figueira - IMIP	Recife
Brazil	Centro de Tratamentos de Tumores Botafogo	Rio De Janeiro
Brazil	Clínica Oncológica - CLION	Salvador
Brazil	Centro de Estudos e Pesquisa Hematologia e Oncologia	Santo André
Brazil	Hospital Beneficencia Portuguesa	São Paulo
Brazil	Hospital Paulistano	São Paulo
Brazil	Sao Camilo Oncologia - Instituto Brasileiro de Controle do Cancer	São Paulo
Canada	Centre de sante et de services sociaux de Chicoutimi	Chicoutimi	Quebec
Canada	Hamilton And District Urology Association	Hamilton	Ontario
Canada	London Regional Cancer Center	London	Ontario
Canada	CHUM - Centre Hospitalier de l'Université de Montreal - Pavillon Saint-Luc	Montréal	Quebec
Canada	Chuq-Pavillon Hotel-Dieu De Quebec	Québec	Quebec
Canada	Saint John Regional Hospital	Saint John	New Brunswick
Canada	Odette Cancer Centre - Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	University Health Network - Oci Princess Margaret Hospital	Toronto	Ontario
Denmark	Rigshospitalet	Copenhagen
France	Institut de Cancerologie de l'Ouest (ICO) - Centre Paul Papin	Angers
France	Centre Francois Baclesse	Caen
France	Assistance Publique - Hopitaux de Paris - CHU Henri Mondor	Créteil
France	Centre Leon Berard	Lyon
France	Institut régional du Cancer Montpellier	Montpellier
France	Institut de Cancerologie de l'Ouest (ICO) - Centre Rene Gauducheau	Saint-Herblain
France	Hopitaux Universitaires de Strasbourg - Hôpitaux Universitaires de Strasbourg - Hôpital civil	Strasbourg
France	Gustave Roussy	Villejuif
Ireland	Cork University Hospital	Cork
Ireland	St. Vincent's University Hospital	Dublin
Ireland	Tallaght University Hospital	Dublin
Italy	Ospedale B.Ramazzini	Carpi
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	Istituto Europeo di Oncologia	Milano
Norway	Soerlandet Sykehus-Kristiansand	Kristiansand
Norway	University Hospital of North Norway	Tromsø
Poland	Maria Sklodowska-Curie Memorial Cancer Centre	Warsaw
Spain	Hospital Clinic Universitari de Barcelona	Barcelona
Spain	Hospital De La Santa Creu I Sant Pau	Barcelona
Spain	Hospital Del Mar	Barcelona
Spain	Vall d'Hebron Institut d'Oncologia	Barcelona
Spain	Hospital Universitario de La Princesa	Madrid
Spain	Hospital Universitario QuironSalud	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Complejo Hospitalario de Navarra	Pamplona
Spain	Corporacio Sanitaria Parc Tauli	Sabadell
Spain	Hospital Universitario de Salamanca	Salamanca
Switzerland	Oncology Institute of Southern Switzerland - Ospedale San Giovanni	Bellinzona
Switzerland	Kantonsspital St Gallen	St Gallen
Switzerland	UniversitaetsSpital Zurich	Zurich
United Kingdom	United Lincolnshire Hospitals NHS Trust - Lincoln County Hospital	Lincoln
United Kingdom	Royal Marsden Hospital - Chelsea, London	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Nottingham University Hospitals NHS Trust - City Hospital	Nottingham

Sponsors (7)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC	Astellas Pharma Europe Ltd., Bayer, Canadian Urologic Oncology Group, Cancer Trials Ireland, Latin American Cooperative Oncology Group, UNICANCER

Countries where clinical trial is conducted

Belgium,  Brazil,  Canada,  Denmark,  France,  Ireland,  Italy,  Norway,  Poland,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	radiological progression-free survival	Radiological progression free survival (rPFS1) is defined according to the recommendations of the "Prostate-Cancer clinical trials Working Group" version 3 and referred to as the "PCWG3"; 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 and for the first follow-up assessment only (i.e. within 12 weeks, during the flare period), a confirmatory scan performed = 6 weeks later that shows a minimum of two or more additional new lesions (2+2 criterion); In this protocol: • PSA progression is not considered disease progression and should NOT trigger a change of treatment.	46 months after first patient entry
Secondary	Overall survival	number of participants	63 months after first patient entry
Secondary	prostate cancer specific survival	number of participants	63 months after first patient entry
Secondary	First symptomatic skeletal event	number of participants	46 and 63 months after first patient entry
Secondary	Time and incidence of first skeletal progression-free survival	number of participants	46 and 63 months after first patient entry
Secondary	Time from entry to initiation of next systemic anti-neoplastic therapy	number of participants	46 and 63 months after first patient entry
Secondary	Treatments elected after first disease progression	number of participants	46 and 63 months after first patient entry
Secondary	Second progression-free survival in sequential regimen	number of participants	46 and 63 months after first patient entry
Secondary	Patient self-rate scale assessing the pain associated to prostate cancer	Brief Pain Inventory questionnaire: BPI questionnaire is a validated instrument that is a patient self-rated scale assessing level of pain, effect of the pain on activities of daily living, and analgesic use. The BPI also measures how much pain has interfered with seven daily activities, including general activity, walking, work, mood, enjoyment of life, relations with others, and sleep. The short form of the BPI is used in this study. It is intended to capture two dimensions of pain: severity and interference. This short version of the BPI contains four pain severity items and seven pain interference items rated on 0-10 scales and uses a 24-hour recall period.	46 and 63 months after first patient entry
Secondary	Time to pain progression	defined as an increase of 2 or more points in the "worst pain in 24 hours" score from baseline observed at 2 consecutive evaluations = 4 weeks apart OR initiation of short or long-acting opioid use for pain	63 months after first patient entry
Secondary	Occurence of adverse events	Adverse events will be graded according to the "Common Terminology Criteria for Adverse events" CTCAE, version 4.0	63 months after first patient entry
Secondary	Time to opiate use for cancer-related pain	number of participants	63 months after first patient entry
Secondary	Patient self-rate scale assessing the Quality of Life	EQ5D-5L questionnaire asks respondents to simply 'mark an X on the scale to indicate how your health is TODAY' and then to 'write the number you marked on the scale in the box below'. This information can be used as a quantitative measure of health outcome as judged by the individual respondents.; The respondent is asked to indicate his health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number expressing the level selected for that dimension. The digits for 5 dimensions can be combined in a 5-digit number describing the respondent's health state. It should be noted that the numerals 1-5 have no arithmetic properties and should not be used as a cardinal score.	46 and 63 months after first patient entry
Secondary	rate of skeletal fractures	The rate of skeletal fractures per patient/year of follow-up will be estimated in each treatment arm using recurrent-event analysis methods. Analyses by type of fracture (e.g. pathological fracture) will also be conducted as appropriate.	63 months after first patient entry