Castration resistant prostate cancer patients metastatic to bone. MedDRA version: 21.1 Level: PT Classification code 10036909 Term: Prostate cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
European Organisation for Research and Treatment of Cancer (EORTC)
Eligibility
Sex/Gender
Male
Inclusion 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 25 g/L ? Normal cardiac function according to local standard by 12-lead ECG (complete, standardized 12-lead recording). ? 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
Exclusion criteria
Exclusion criteria: ? Known central nervous system metastases or leptomeningeal tumor spread. ? 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 treatment with enzalutamide, apalutamide, darolutamide or Ra223. ? Concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel) and ketoconazole. ? 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. ? Prior therapy with other radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188). ? Involvement in another therapeutic trial involving an experimental drug. ? Anticancer therapy (except ADT) or treatment with another investigational agent within the last 4 weeks prior to randomization. ? Known hypersensitivity to compounds related to enzalutamide or Ra223 . ? 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. ? 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). ? Major surgery within 4 weeks prior to treatment. ? Drug or alcohol abuse. ? 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. -An
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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.;Secondary Objective: To assess if upfront combination of enzalutamide with Ra223 (experimental arm) offers further benefits over enzalutamide alone in terms of the secondary efficacy endpoints listed below, to compare the safety profile of the approaches and to document their impact on patient reported outcomes (pain and quality of life (QoL).;Primary end point(s): Radiological Progression free survival (rPFS1);Timepoint(s) of evaluation of this end point: Radiological Progression free survival (rPFS1) counted from randomization to the first progression defined as per the Prostate Cancer clinical trials Working Group version 3 and referred to as the "PCWG3" for the setting "delay/prevent" progression or to death from any cause. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall survival; 2. Prostate-cancer specific survival; 3. First symptomatic skeletal event (SSE); 4. Time and incidence of first skeletal progression-free survival; 5. Rate of skeletal fractures 6. Time to next systemic anti-neoplastic therapy; 7. Treatments elected after first disease progression; 8. Second progression-free survival 9. Safety according to Common Terminology Criteria for Adverse Events. 10. Pain: Brief Pain Inventory (BPI). In this study only pain related to prostate cancer is considered. 11. 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) 12. Time to opiate use for cancer-related pain 13. Quality of Life (EQ-5D-5L);Timepoint(s) of evaluation of this end point: 1.Randomization until death (any cause) 2.Randomization until death prostate cancer 3.Randomization until day 1st SSE recorded 4.Between randomization and day 1st skeletal radiological progression 5.Treatment+F-up 6.Between randomization and 1st day next systemic anti-neoplastic therapy 7.Every 12w from first PD until 2nd PD 8.Randomization to 1st clinical PD on 2nd line treatment,or to death 9.From 21d prior to randomization,at the end of every cycle,every 12w after PD,at discontinuation of treatment in absence of progression 10&13.Screening,every 3 cycles,at treatment discontinuation in absence of PD,every 12w during f/up until PD. 11.Randomization to 1st report of pain progression. 12.Interval between randomiz and the 1st report of intake of opioids for cancer-related pain. | — |
Countries
Belgium, Brazil, Canada, Denmark, France, Ireland, Italy, Netherlands, Norway, Poland, Spain, Switzerland, United Kingdom, United States
Contacts
Public ContactRegulatory Affairs Department
European Organisation for Research and Treatment of Cancer (EORTC)
Outcome results
None listed