| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic castration resistant prostate cancer (mCRPC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| - To assess the overall survival of radium-223 dichloride compared to second NAH |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of radium-223 dichloride compared to second NAH
- To evaluate the safety of radium-223 dichloride compared to second NAH
- Patient reported outcome (PRO)(FACT-P) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be ≥18 years of age inclusive, at the time of signing the informed consent. The lower limit may be higher if legally required in the participating country.
2. Participants who have histologically confirmed adenocarcinoma of the prostate.
3. Participants with mCRPC progressing on/after one line of NAH (after being treated for at least 3 months) for metastatic prostate cancer (mHSPC and mCRPC).
4. One prior taxane treatment regimen (at least 2 cycles) for metastatic prostate cancer (mHSPC and mCRPC) or refusal or ineligibility of such a regimen.
5. Prostate cancer progression documented by PSA according to the Prostate Cancer Working Group 3 (PCWG3) criteria or radiological progression according to RECIST, version 1.1.
6. At least 2 bone metastases on bone scan within 4 weeks prior to randomization with no current or history of lung, liver, other visceral, and / or brain metastasis.
7. Symptomatic prostate cancer. A worst pain score (WPS) of at least 1 on the Brief Pain Inventory-Short Form (BPI-SF) Question #3 (worst pain in last 24 hours). This is to be assessed once during the Screening period.
8. Maintenance of medical castration or surgical castration with testosterone less than 50 ng/dL (1.7 nmol/L). If the participant is being treated with luteinizing hormone-releasing hormone (LHRH) agonists or antagonists (participant who has not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to randomization and must be continued throughout the study.
9. Participants must be on a BHA treatment, such as bisphosphonates or denosumab treatment unless such treatment is contraindicated or not recommended per investigator’s judgement and inclusion is agreed to by the medical monitor.
10. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
11. Life expectancy ≥ 6 months.
12. Able to swallow abiraterone and prednisone / prednisolone or enzalutamide as whole tablets/capsules.
13. Laboratory requirements:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
b. Platelet count ≥ 100 x 109/L
c. Hemoglobin (Hb) ≥ 9.0 g/dL (90 g/L; 5.6 mmol/L)
d. Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) (except for participants with documented Gilbert’s disease)
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
f. Creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate (eGFR)
≥ 30 mL/min/1.73 m2 as calculated using the Cockcroft-Gault equation
g. International normalized ratio (INR) of prothrombin time (PT; PT-INR) and partial thromboplastin time (PTT) ≤ 1.5 times the ULN. Participants treated with warfarin or heparin will be allowed to participate in the study if no underlying abnormality in coagulation parameters exists per prior history; weekly evaluation of PT-INR / PTT will be required until stability is achieved (as defined by local standard of care and based on pre-study PT-INR / PTT values)
h. Serum albumin > 30 g/L
I. Serum potassium ≥ 3.5 mmol/L.
14. Male. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
a. Male participants who have partners of childbearing potential must be willing to use a method of effective birth control during treatment and for 6 months following completion of treatment with radium-223 dichloride, 13 weeks after the last administration of abiraterone and 3 months after the last administration of enzalutamide. The contraception measures must be discussed with the participant. Suitable contraception could be, for example, an oral contraceptive of the partner combined with the use of condoms.
b. Female participants: not applicable
15. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol |
|
| E.4 | Principal exclusion criteria |
1. Active infection or other medical condition that would make prednisone / prednisolone (corticosteroid) use contraindicated.
2. Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg prednisone / prednisolone twice daily.
3. Pathological finding consistent with tumors with neuroendocrine features or small cell carcinoma of the prostate.
4. History of osteoporotic fracture
5. History of visceral metastasis, or presence of visceral metastasis detected by screening imaging examinations.
6. History of or known brain metastasis.
7. Malignant lymphadenopathy exceeding 3 cm in short-axis diameter.
8. Other malignancy treated within the last 3 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)
9. Imminent spinal cord compression based on clinical findings and / or magnetic resonance imaging (MRI). Participants with history of spinal cord compression should have completely recovered.
10. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg). Participants with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment.
11. Active or symptomatic viral hepatitis.
12. History of pituitary or adrenal dysfunction.
13. Any other serious illness or medical condition such as, but not limited to:
a. Any infection ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 Grade 2.
b. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II to IV heart disease or cardiac ejection fraction measurement of <50% at baseline.
c. Atrial fibrillation, or other cardiac arrhythmia requiring therapy.
d. Crohn’s disease or ulcerative colitis.
e. Bone marrow dysplasia.
f. Moderate and severe hepatic impairment (Child-Pugh Classes B and C).
g. Unmanageable fecal incontinence.
14. Any condition, which in the opinion of the investigator would preclude participation in this trial (eg, history of seizure).
15. Hypersensitivity to the active substances or to any excipients of radium-223 dichloride, or abiraterone acetate or enzalutamide.
16. Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, rhenium-188, or radium-223.
17. Prior hemibody external radiotherapy is excluded. Participants who received other types of prior external radiotherapy are allowed provided that the bone marrow function is assessed and meets the protocol requirements for Hb, ANC, and platelet count.
18. Blood transfusion or erythropoietin stimulating agents 4 weeks prior to Screening and during the whole Screening period before randomization.
19. Excessive intake of biotin above the recommended daily dose of 30 μg. Biotin is found in multivitamins, including prenatal multivitamins, biotin supplements, and dietary supplements for hair, skin, and nail growth at levels that may interfere with laboratory tests.
20. Prior administration of an investigational therapeutic for CRPC.
21. Previous (within the last 4 weeks of randomization) or concurrent participation in any interventional clinical study with investigational study drug administration. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At D1 and D15 of Cycle 1 - 6, at D1 of Cycle 7, at EOT, every 3 months during active follow up, and every months during long-term follow-up |
|
| E.5.2 | Secondary end point(s) |
1. Time to first symptomatic skeletal event (SSE)
2. Radiological Progression-free survival (rPFS)
3. Time to pain progression (BPI-SF)
4. Adverse events assessments using NCI CTCAE (V5.0)
5. Incidence of fractures
6. Time to deterioration of FACT-P total score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Before first dose, at D1 and D15 of Cycle 1 - 6, at D1 of Cycle 7, at EOT and every 3 months during active follow-up.
2. Before first dose, then every 8 weeks for first 24 weeks, then every 12 weeks up to 2 years, after 2 years every 3 months
3. At D1 of each cycle, at EOT and every 3 months during active follow-up.
4. Before first dose, at D1 and D15 of Cycle 1 - 6, at D1 of Cycle 7, at EOT, every 3 months during active follow-up, and every 6 months during long-term follow-up
5. Before first dose, at D1 and D15 of Cycle 1 - 6, at D1 of Cycle 7, at EOT, every 3 months during active follow-up, and every 6 months during long-term follow-up
6. Before first dose, at D1 of each cycle, at EOT and every 3 months during active follow-up |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 82 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Czech Republic |
| Finland |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Lithuania |
| Poland |
| Russian Federation |
| Singapore |
| Spain |
| Taiwan |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LPLV is defined as the date of the last survival follow-up visit or death or withdrawal of consent for follow-up for the last participant as shown in the Schedule of Activities. However, LPLV date can also be reached based on the last participant stopping study medication or switching to a roll-over-study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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