Investigation of Radium-223 dichloride (Xofigo), a treatment that gives off radiation that helps kill cancer cells, compared to a treatment that inactivates hormones (new antihormonal therapy, NAH) in patients with prostate cancer that has spread to the bone getting worse on or after earlier NAH

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bayer Consumer Care AG, Bayer AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Aug 2020 → ongoing

Decision date (initial)

2024-02-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Bayer Consumer Care AG

External identifiers

EU CT number

2023-505830-89-00

EudraCT number

2019-000476-42

ClinicalTrials.gov

NCT04597125

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Efficacy

To assess the overall survival of radium-223 dichloride compared to second NAH

Secondary objectives 3

1. To assess the efficacy of radium-223 dichloride compared to second NAH
2. To evaluate the safety of radium-223 dichloride compared to second NAH
3. Patient reported outcome (PRO)(FACT-P)

Conditions and MedDRA coding

metastatic castrate resistant prostate cancer (mCRPC)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

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 an approved NAH (eg. abiraterone, enzalutamide, apalutamide, or darolutamide, after being treated for at least 3 months) in an authorized prostate cancer indication.
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. Skin cancer or low-grade superficial bladder cancer)
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. Magnetic resonance imaging (MRI). Participants with history of spinal cord compression should have completely recovered.
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 10^9/L b. Platelet count ≥ 100 x 10^9/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 m^2 as calculated using the Cockcroft-Gault equation g. International normalized ratio (INR) of prothrombin time (PT; PTINR) 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 (or whose partner is pregnant at study start) must use a condom during intercourse or sexual activity while receiving 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. For a non-pregnant partner of childbearing potential, additional contraception recommendations should also be considered. Suitable contraception could be, for example, the use of an oral contraceptive by the partner. Note: Conservation of sperm: There are no human data on the effect of radium-223 dichloride on fertility; however, based on studies in animals, there is a potential risk that radiation from radium-223 dichloride could cause adverse effects on fertility. Participants should seek advice on conservation of sperm prior to treatment. 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

Exclusion criteria 21

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 10 mg prednisone / prednisolone equivalent daily for more than 2 months.
3. Pathological finding consistent with tumors with predominant neuroendocrine features or small cell carcinoma of the prostate (ie. tumors documented as having a small cell carcinoma histology and those having predominant neuroendocrine features [if mixed histology]).
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 nonmelanoma 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 antihypertensive 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 orunstable angina, or New York Heart Association (NYHA) Class II to IV heart disease or cardiac ejection fraction measurement of <50% at baseline. c. Current clinical evidence of any uncontrolled cardiac arrhythmia. 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 therapeutic systemic radiation with any radiopharmaceutical medication for the treatment of prostate cancer, including but o tlimited to lutetium-177, strontium-89, samarium-153, iodine-131, rhenium-186, rhenium-188, or radium-223. Radiopharmaceutical compounds used for diagnosis purposes only are allowed.
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 investigationa lstudy drug administration.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival (OS)

Secondary endpoints 6

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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bayer Consumer Care AG

Sponsor organisation

Bayer Consumer Care AG

Address

Peter Merian-Strasse 84

City

Basel

Postcode

4052

Country

Switzerland

Scientific contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Public contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Third parties 2

Bayer AG

Sponsor organisation

Bayer AG

Address

-

City

Leverkusen

Postcode

51368

Country

Germany

Scientific contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Public contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Sponsor responsibilities

Article 77 compliance

Bayer Consumer Care AG

Article 77 implementation

Bayer Consumer Care AG

Locations

10 EU/EEA countries · 63 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 25 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications