NCT02258464

Study of Radium-223 Dichloride Versus Placebo and Hormonal Treatment as Background Therapy in Subjects With Bone Predominant HER2 (Human Epidermal Growth Factor Receptor 2) Negative Hormone Receptor Positive Metastatic Breast Cancer

Terminated Phase 2 Results posted Last updated 10 August 2020

What this trial tests

Phase 2 trial testing Radium-223 dichloride (Xofigo, BAY88-8223) in Breast Neoplasms in 99 participants. Terminated before completion.

Timeline

2 March 2015

Primary endpoint
13 August 2019

13 August 2019

Quick facts

Lead sponsor	Bayer
Phase	Phase 2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	99
Start date	2 March 2015
Primary completion	13 August 2019
Estimated completion	13 August 2019
Sites	71 locations across Hong Kong, Finland, Taiwan, Ireland, Poland, South Korea, Denmark, Netherlands

Drugs / interventions tested

• Radium-223 dichloride (Xofigo, BAY88-8223) — full drug profile →
• Placebo (saline)
• Background hormonal therapy

Conditions studied

• Breast Neoplasms — all drugs for Breast Neoplasms →

Sponsor

Bayer — full company profile →

Who can join

18 and older, female only, with Breast Neoplasms. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Symptomatic Skeletal Event Free Survival (SSE-FS) Primary · Up to approximately 51 months

Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause

Group	Value	95% CI
Radium 223 Dichloride	30.1	21.8 – 43.0
Placebo	18.4	9.1 – 28.2

Overall Survival Secondary · Up to approximately 51 months

Time from randomization to death from any cause

Group	Value	95% CI
Radium 223 Dichloride	43.0	22.9 – NA
Placebo	32.4	23.7 – NA

Time to Opiate Use for Cancer Pain Secondary · Up to approximately 51 months

Interval from the date of randomization to the date of opiate use

Group	Value	95% CI
Radium 223 Dichloride	21.3	8.3 – NA
Placebo	20.2	8.8 – NA

Time to Pain Progression Secondary · Up to approximately 51 months

Time from randomization to the first date a participants (only in participants with baseline WPS ≤8) experiences pain progression based on worst pain score (WPS) ranging from 0 to 10 and analgesic use. Pain progression is 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 an increase in pain management (IPM) with respect to baseline, whichever occurs first

Group	Value	95% CI
Radium 223 Dichloride	14.8	5.9 – 21.3
Placebo	8.8	3.7 – 14.3

Pain Improvement Rate Secondary · Up to approximately 51 months

The percentage of participants (baseline WPS\>=2) with confirmed pain improvement at any time point. Confirmed pain improvement is defined as a 2 point decrease in worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart

Group	Value	95% CI
Radium 223 Dichloride	37.5	25.9 – 50.4
Placebo	25.7	16.2 – 37.5

Time to Cytotoxic Chemotherapy Secondary · Up to approximately 51 months

Time from the date of randomization to the date of the first cytotoxic chemotherapy

Group	Value	95% CI
Radium 223 Dichloride	16.0	14.1 – 22.4
Placebo	17.3	10.9 – 27.6

Radiological Progression-free Survival (rPFS) Secondary · Up to approximately 51 months

Time from the date of randomization to the date of first radiological progression or death (if death occurs before progression)

Group	Value	95% CI
Radium 223 Dichloride	8.1	5.7 – 10.6
Placebo	5.8	5.1 – 7.9

Number of Participants With Treatment-emergent Adverse Events Secondary · Up to approximately 7 months

Any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake

Any TEAE

Group	Value	95% CI
Radium 223 Dichloride	46
Placebo	46

Radium 223/Placebo related TEAEs

Group	Value	95% CI
Radium 223 Dichloride	21
Placebo	16

Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Secondary · From 30 days after the last dose of study treatment until the end of study, assessed up to approximately 44 months

AEs related to the study drug, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events (regardless of severity and relationship to study drug), and some symptoms needed for the characterization of an symptomatic skeletal event

Any post-treatment AE

Group	Value	95% CI
Radium 223 Dichloride	15
Placebo	16

Anaemia

Group	Value	95% CI
Radium 223 Dichloride	1
Placebo	0

Febrile neutropenia

Group	Value	95% CI
Radium 223 Dichloride	0
Placebo	1

Chest pain

Group	Value	95% CI
Radium 223 Dichloride	0
Placebo	1

Fibula fracture

Group	Value	95% CI
Radium 223 Dichloride	0
Placebo	1

Rib fracture

Group	Value	95% CI
Radium 223 Dichloride	0
Placebo	1

Tibia fracture

Group	Value	95% CI
Radium 223 Dichloride	0
Placebo	1

Traumatic fracture

Group	Value	95% CI
Radium 223 Dichloride	2
Placebo	4

Adverse events — posted to ClinicalTrials.gov

Time frame: From the start of study drug administration until the end of study, assessed up to approximately 51 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Radium 223 Dichloride

Serious: 4/48 (8%)

Deaths: 18/48

Placebo

Serious: 14/49 (29%)

Deaths: 18/49

Serious adverse events (21 terms)

Reaction	System	Radium 223 Dichloride	Placebo
Bone pain	Musculoskeletal and connective tissue disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—
Oesophagitis	Gastrointestinal disorders	—	—
Chest pain	General disorders	—	—
Bacteraemia	Infections and infestations	—	—
Infection	Infections and infestations	—	—
Sinusitis	Infections and infestations	—	—
Urosepsis	Infections and infestations	—	—
Fibula fracture	Injury, poisoning and procedural complications	—	—
Tibia fracture	Injury, poisoning and procedural complications	—	—
Platelet count decreased	Investigations	—	—
Pathological fracture	Musculoskeletal and connective tissue disorders	—	—
Cancer pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Nerve compression	Nervous system disorders	—	—
Seizure	Nervous system disorders	—	—
Syncope	Nervous system disorders	—	—
Psychotic disorder	Psychiatric disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—

Other adverse events (34 terms — click to expand)

Reaction	System	Radium 223 Dichloride	Placebo
Back pain	Musculoskeletal and connective tissue disorders	—	—
Headache	Nervous system disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Bone pain	Musculoskeletal and connective tissue disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Pathological fracture	Musculoskeletal and connective tissue disorders	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Traumatic fracture	Injury, poisoning and procedural complications	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	—	—
Spinal pain	Musculoskeletal and connective tissue disorders	—	—
Paraesthesia	Nervous system disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Leukopenia	Blood and lymphatic system disorders	—	—
Influenza like illness	General disorders	—	—
Oedema peripheral	General disorders	—	—
Pain	General disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Weight decreased	Investigations	—	—
Dizziness	Nervous system disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Hypertension	Vascular disorders	—	—
Hot flush	Vascular disorders	—	—

Most-reported serious reactions: Bone pain, Anaemia, Gastrooesophageal reflux disease, Oesophagitis, Chest pain, Bacteraemia, Infection, Sinusitis.

Data from ClinicalTrials.gov NCT02258464 adverse events section.

Sponsor's own description

The objective of this study was to assess efficacy and safety of radium-223 dichloride in subjects with human epidermal growth factor receptor 2 negative (HER2 negative) hormone receptor positive breast cancer with bone metastases treated with hormonal treatment background therapy

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Metastatic bone disease: Pathogenesis and therapeutic options: Up-date on bone metastasis management.
   D'Oronzo S, Coleman R, Brown J, Silvestris F. · · 2019 · cited 201× · PMID 30937279 · DOI 10.1016/j.jbo.2018.10.004
2. Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials.
   Gdowski AS, Ranjan A, Vishwanatha JK. · · 2017 · cited 83× · PMID 28800754 · DOI 10.1186/s13046-017-0578-1
3. The evolution and understanding of skeletal complication endpoints in clinical trials of tumors with metastasis to the bone.
   Hussain A, Lee RJ, Graff JN, Halabi S. · · 2019 · cited 20× · PMID 31170574 · DOI 10.1016/j.critrevonc.2019.04.020
4. Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis.
   Kono M, Fujii T, Matsuda N, Harano K, et al · · 2018 · cited 17× · PMID 30310523 · DOI 10.7150/jca.26825
5. Radium-223 Therapy for Patients with Metastatic Castrate-Resistant Prostate Cancer: An Update on Literature with Case Presentation.
   Nguyen NC, Shah M, Appleman LJ, Parikh R, et al · · 2016 · cited 16× · PMID 27774318 · DOI 10.1155/2016/2568031
6. Radium-223 in combination with paclitaxel in cancer patients with bone metastases: safety results from an open-label, multicenter phase Ib study.
   Geva R, Lopez J, Danson S, Joensuu H, et al · · 2019 · cited 13× · PMID 30547207 · DOI 10.1007/s00259-018-4234-6
7. CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases (CARBON): study protocol for a phase IB/IIA randomised controlled trial.
   Coleman R, Brown J, Rathbone E, Flanagan L, et al · · 2020 · cited 12× · PMID 31941523 · DOI 10.1186/s13063-019-3643-6
8. Dual targeting with ²²⁴Ra/²¹²Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach.
   Juzeniene A, Stenberg VY, Bruland ØS, Revheim ME, et al · · 2022 · cited 8× · PMID 36733936 · DOI 10.3389/fmed.2022.1051825