NCT02194842进行中（未招募）3 期
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.
European Organisation for Research and Treatment of Cancer - EORTC64 个研究点 分布在 10 个国家目标入组 446 人开始时间: 2015年10月1日最近更新:
适应症
干预措施
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 446
- 试验地点
- 64
- 主要终点
- radiological progression-free survival
研究概览
简要总结
The primary objective of the trial is to assess if upfront combination of enzalutamide and Ra223 improves radiological progression-free survival (rPFS1) by investigator assessment compared to enzalutamide single agent in castration resistant prostate cancer (CRPC) patients metastatic to bone
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
- 另有 19 项未显示
排除标准
- •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
- •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
- •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:
- •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
- •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
研究组 & 干预措施
Enzalutamide
Active Comparator
Enzalutamide will be given at a dose of 160 mg daily
干预措施: Enzalutamide (Drug)
Enzalutamide and Ra223
Experimental
Ra223 will be administered 55kBq/kg standard dose monthly for 6 months and given in combination with enzalutamide at a dose of 160 mg daily.
干预措施: Ra223 (Drug)
Enzalutamide and Ra223
Experimental
Ra223 will be administered 55kBq/kg standard dose monthly for 6 months and given in combination with enzalutamide at a dose of 160 mg daily.
干预措施: Enzalutamide (Drug)
结局指标
主要结局
radiological progression-free survival
时间窗: 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 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 1.1 criteria for soft tissue lesions * A skeletal radiological progression defined as the appearance of ≥ 2 new bone lesions and for the first follow-up assessment only (i.e., within 12 weeks ± 1 week, 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. The rPFS1 endpoint is subject to a retrospective Blinded Independent Central Review
progression-free survival per Blinded Independent Central Review (PFS1B)
时间窗: 96 months after first patient entry
PFS1 per BICR will be defined and analyzed in the same manner as the primary endpoint rPFS1 by investigator assessment. The central reviewers will provide timepoint assessments of skeletal and nonskeletal progression and determinations of respective progression dates from which PFS1 per BICR will be calculated.
次要结局
- Overall survival(63 months after first patient entry)
- prostate cancer specific survival(63 months after first patient entry)
- Time to First symptomatic skeletal event (TTSSE)(46 and 63 months after first patient entry)
- Time to first skeletal progression(46 and 63 months after first patient entry)
- Time from entry to initiation of next systemic anti-neoplastic therapy (TTNT)(46 and 63 months after first patient entry)
- Progression-free survival on second line of treatment (PFS2)(46 and 63 months after first patient entry)
- Patient self-rate scale assessing the pain associated to prostate cancer(46 and 63 months after first patient entry)
- Time to pain progression (TTPP)(63 months after first patient entry)
- Occurence of adverse events(63 months after first patient entry)
- Time to opiate use for cancer-related pain(63 months after first patient entry)
- Patient self-rate scale assessing the Quality of Life(46 and 63 months after first patient entry)
- rate of skeletal fractures(63 months after first patient entry)
研究者
研究点 (64)
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相关资讯
Radium-223 Plus Enzalutamide Extends Survival in Metastatic Castration-Resistant Prostate Cancer- The phase 3 PEACE-3 trial demonstrated that combining radium-223 with enzalutamide significantly improved radiological progression-free survival (rPFS) in mCRPC patients.
- Overall survival (OS) was also significantly extended with the combination therapy, showing a median OS of 42.3 months compared to 35.0 months with enzalutamide alone.
- The combination of radium-223 and enzalutamide showed a manageable safety profile, though with a higher incidence of adverse events compared to enzalutamide alone.
- The study supports the combination as a potential first-line treatment for mCRPC patients with bone metastases who have not received prior androgen-receptor pathway inhibitors, provided bone-protecting agents are also administered.2 years agoRadium-223 Plus Enzalutamide Improves Survival in mCRPC with Bone Metastases- The PEACE-3 trial demonstrated that adding Radium-223 to enzalutamide significantly improved radiographic progression-free survival (rPFS) in mCRPC patients with bone metastases.
- The combination therapy also led to a statistically significant improvement in overall survival (OS) compared to enzalutamide alone, with a manageable safety profile.
- Time to next systemic treatment was significantly prolonged with the combination, suggesting a potential new first-line treatment option.
- The study mandated bone-protecting agents, highlighting their importance in managing bone health in patients receiving this combination therapy.2 years ago