Phase III Radium 223 mCRPC-PEACE III (PEACE III)

  • STATUS
    Recruiting
  • End date
    Dec 3, 2025
  • participants needed
    416
  • sponsor
    European Organisation for Research and Treatment of Cancer - EORTC
Updated on 3 July 2022
Investigator
EORTC
Primary Contact
Centre De Sante Et De Services Sociaux De Chicoutimi (6.5 mi away) Contact
+61 other location
gonadotropin
prednisone
androgens
dexamethasone
testosterone
metastasis
neutrophil count
docetaxel
antiandrogen therapy
androgen suppression
bone scan
bicalutamide
flutamide
orchiectomy
bone metastases
enzalutamide
luteinizing hormone
castration-resistant prostate cancer
adenocarcinoma
adenocarcinoma of prostate
gonadorelin
bilateral orchidectomy
diphosphonates

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

Details
Condition Prostate Cancer
Treatment Enzalutamide, Ra223
Clinical Study IdentifierNCT02194842
SponsorEuropean Organisation for Research and Treatment of Cancer - EORTC
Last Modified on3 July 2022

Eligibility

Yes No Not Sure

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
Patients must be at least 18 years old
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
Biochemistry and hematology
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
F-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
Albumin > 25 g/L
either
For patients who manifest disease progression solely as a rising PSA level, PCWG3
Able to swallow the study drug and comply with study requirements
criteria require documentation of a sequence of rising PSA values at a minimum of
Prior or concomitant therapy
-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
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
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
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
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](telnet://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
Myocardial infarction within 6 months prior to screening
Uncontrolled angina within 3 months prior to screening
patients having received docetaxel for CRPC are excluded
No prior treatment with enzalutamide or Ra223
No involvement in another therapeutic trial involving an experimental drug
No known hypersensitivity to compounds related to enzalutamide or Ra223
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
Crohn's disease or ulcerative colitis
Bone marrow dysplasia
Fecal incontinence
Life-threatening illness unrelated to cancer
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 > 170
mm Hg or diastolic blood pressure > 105 mm Hg at screening
Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury
(mm Hg) at screening
Bradycardia as indicated by a heart rate of < 45 beats per minute on the
screening ECG and on physical examination
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 anticancer therapy or treatment with another investigational agent within the last
weeks prior to randomization
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)
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)
No condition which, in the investigator's opinion, makes the patient unsuitable for
trial participation
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