Breast Neoplasms
Conditions
Keywords
Breast Cancer
Brief summary
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
Interventions
DRUGRadium-223 dichloride (Xofigo, BAY88-8223)
Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of National Institute of Standards and Technology \[NIST\] update)
DRUGPlacebo (saline)
Up to 6 cycles of saline injection
OTHERBackground hormonal therapy
Prescribed by PI and was provided as long as patient can tolerate treatment. It must be prescribed as per local label in country participating.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documentation of histological or cytological confirmation of estrogen receptor positive (ER+) and HER2 negative adenocarcinoma of the breast must be available. * Women (≥18 years of age) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy. * Documentation of menopausal status: post menopausal or premenopausal subjects are eligible. * Subjects with bone dominant disease with at least 2 skeletal metastases identified at baseline by bone scintigraphy and confirmed by CT/magnetic resonance imaging (MRI). Presence of metastases in soft tissue (skin, subcutaneous, muscle, fat, lymph nodes)and/or visceral metastases is allowed. * Measurable or non-measurable disease (but radiologically evaluable) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. * Subjects must have received at least one line of hormonal therapy in the metastatic setting * Subjects who are eligible for further standard of care endocrine treatment. * Subjects enrolled in the current study must start treatment with the single hormone agent either within 15 days prior to randomization or after randomization (before or simultaneously to the first injection of Ra-223/placebo). * Subjects must have experienced no more than two skeletal-related events (SREs) prior to study entry defined as: Need for external beam radiotherapy (EBRT) tor bone, pathological bone fracture (excluding major trauma), spinal cord compression and/or orthopedic surgical procedure. Subjects with no prior SREs are not permitted. * Subjects must be on therapy with bisphosphonate and denosumab. and are required to have been on such therapy for at least 1 month before start of study treatment. * Adequate hematological, liver and kidney function.
Exclusion criteria
* Subjects with Inflammatory breast cancer. * Subjects who have either received chemotherapy for metastatic disease or are considered by the treating investigator to be appropriate candidates for chemotherapy as current treatment for metastatic breast cancer are excluded. Chemotherapy administered for adjuvant/neo adjuvant disease is acceptable. * Subjects with known or history of brain metastases or leptomeningeal disease: subjects with neurological symptoms must undergo a contrast CT scan or MRI of the brain within 28 days prior to randomization to exclude active brain metastasis. Imaging of the central nervous system (CNS) is otherwise not required. * Known presence of osteonecrosis of jaw. * Patients with immediately life-threatening visceral disease, for whom chemotherapy is the preferred treatment option. * Lymphangitic carcinomatosis. * Patients with ascites requiring paracentesis within 2 weeks prior to study entry (signature of informed consent) and during the screening period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptomatic Skeletal Event Free Survival (SSE-FS) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Opiate Use for Cancer Pain | Up to approximately 51 months | Interval from the date of randomization to the date of opiate use |
| Time to Pain Progression | 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 |
| Pain Improvement Rate | 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 |
| Overall Survival | Up to approximately 51 months | Time from randomization to death from any cause |
| Radiological Progression-free Survival (rPFS) | 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) |
| Number of Participants With Treatment-emergent Adverse Events | 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 |
| Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | 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 |
| Time to Cytotoxic Chemotherapy | Up to approximately 51 months | Time from the date of randomization to the date of the first cytotoxic chemotherapy |
Countries
Austria, Canada, Czechia, Denmark, Finland, France, Germany, Hong Kong, Ireland, Israel, Netherlands, Norway, Poland, Singapore, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
151 participants were screened at 69 active centers in 20 countries, the first participant first visit was on 02 Mar 2015 and last participant last visit was on 13 Aug 2019
Pre-assignment details
Of the 151 screened participants, 99 participants (65.6%) completed screening and were assigned to treatment: 49 in the radium 223 dichloride and 50 in the placebo arm
Participants by arm
| Arm | Count |
|---|---|
| Radium 223 Dichloride Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology \[NIST\] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks | 49 |
| Placebo Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks | 50 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | AE not related to clinical PD | 1 | 3 |
| Overall Study | AE related to clinical PD | 1 | 0 |
| Overall Study | Progressive disease (PD) | 9 | 17 |
| Overall Study | Study drug never administered | 1 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | Radium 223 Dichloride |
|---|---|---|---|
| Age, Continuous | 58.74 years STANDARD_DEVIATION 11.97 | 57.92 years STANDARD_DEVIATION 11.72 | 57.08 years STANDARD_DEVIATION 11.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 94 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 18 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) White | 40 Participants | 75 Participants | 35 Participants |
| Sex: Female, Male Female | 50 Participants | 99 Participants | 49 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 18 / 48 | 18 / 49 |
| other Total, other adverse events | 43 / 48 | 44 / 49 |
| serious Total, serious adverse events | 4 / 48 | 14 / 49 |
Outcome results
Primary
Symptomatic Skeletal Event Free Survival (SSE-FS)
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
Time frame: Up to approximately 51 months
Population: Intent to treat analysis set: all randomized participants
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Radium 223 Dichloride | Symptomatic Skeletal Event Free Survival (SSE-FS) | 30.1 months | 80% Confidence Interval 21.8 |
| Placebo | Symptomatic Skeletal Event Free Survival (SSE-FS) | 18.4 months | 80% Confidence Interval 9.1 |
Comparison: The null hypothesis that both treatment groups have the same SSE-FS distribution will be tested against the alternative hypothesis that the distribution of SSE-FS time in radium-223 dichloride is different from the placebo groupp-value: 0.333980% CI: [0.504, 1.102]Log Rank
Secondary
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events
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
Time frame: From 30 days after the last dose of study treatment until the end of study, assessed up to approximately 44 months
Population: Safety analysis set: all randomized subjects who received at least one dose of study medication (radium 223 dichloride or placebo)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Fibula fracture | 0 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Bone pain | 2 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Any post-treatment AE | 15 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Muscle spasms | 1 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Rib fracture | 0 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Musculoskeletal chest pain | 1 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Febrile neutropenia | 0 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Osteonecrosis of jaw | 1 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Tibia fracture | 0 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Pain in extremity | 1 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Acute kidney injury | 0 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Pathological fracture | 5 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Traumatic fracture | 2 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Spinal pain | 0 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Chest pain | 0 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Cauda equina syndrome | 0 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Weight decreased | 0 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Paraesthesia | 0 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Arthralgia | 1 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Spinal cord compression | 1 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Anaemia | 1 Participants |
| Radium 223 Dichloride | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Back pain | 4 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Acute kidney injury | 1 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Any post-treatment AE | 16 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Anaemia | 0 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Febrile neutropenia | 1 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Chest pain | 1 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Fibula fracture | 1 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Rib fracture | 1 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Tibia fracture | 1 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Traumatic fracture | 4 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Arthralgia | 0 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Back pain | 0 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Bone pain | 3 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Muscle spasms | 0 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Musculoskeletal chest pain | 0 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Osteonecrosis of jaw | 0 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Pain in extremity | 1 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Pathological fracture | 4 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Spinal pain | 3 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Cauda equina syndrome | 1 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Paraesthesia | 1 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Spinal cord compression | 1 Participants |
| Placebo | Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | Weight decreased | 1 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events
Any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake
Time frame: Up to approximately 7 months
Population: Safety analysis set: all randomized subjects who received at least one dose of study medication (radium 223 dichloride or placebo)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium 223 Dichloride | Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 46 Participants |
| Radium 223 Dichloride | Number of Participants With Treatment-emergent Adverse Events | Radium 223/Placebo related TEAEs | 21 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 46 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Radium 223/Placebo related TEAEs | 16 Participants |
Secondary
Overall Survival
Time from randomization to death from any cause
Time frame: Up to approximately 51 months
Population: Intent to treat analysis set: all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium 223 Dichloride | Overall Survival | 43.0 months |
| Placebo | Overall Survival | 32.4 months |
p-value: 0.725980% CI: [0.576, 1.37]Log Rank
Secondary
Pain Improvement Rate
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
Time frame: Up to approximately 51 months
Population: Participants in safety analysis set taken into account for this endpoint analysis
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Radium 223 Dichloride | Pain Improvement Rate | 37.5 percentage of participants analyzed | 80% Confidence Interval 25.9 |
| Placebo | Pain Improvement Rate | 25.7 percentage of participants analyzed | 80% Confidence Interval 16.2 |
p-value: 0.34580% CI: [-2.7, 26.3]Cochran-Mantel-Haenszel
Secondary
Radiological Progression-free Survival (rPFS)
Time from the date of randomization to the date of first radiological progression or death (if death occurs before progression)
Time frame: Up to approximately 51 months
Population: Intent to treat analysis set: all randomized participants
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Radium 223 Dichloride | Radiological Progression-free Survival (rPFS) | 8.1 months | 80% Confidence Interval 5.7 |
| Placebo | Radiological Progression-free Survival (rPFS) | 5.8 months | 80% Confidence Interval 5.1 |
p-value: 0.922780% CI: [0.753, 1.391]Log Rank
Secondary
Time to Cytotoxic Chemotherapy
Time from the date of randomization to the date of the first cytotoxic chemotherapy
Time frame: Up to approximately 51 months
Population: Intent to treat analysis set: all randomized participants
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Radium 223 Dichloride | Time to Cytotoxic Chemotherapy | 16.0 months | 80% Confidence Interval 14.1 |
| Placebo | Time to Cytotoxic Chemotherapy | 17.3 months | 80% Confidence Interval 10.9 |
p-value: 0.912880% CI: [0.657, 1.425]Log Rank
Secondary
Time to Opiate Use for Cancer Pain
Interval from the date of randomization to the date of opiate use
Time frame: Up to approximately 51 months
Population: Safety analysis set: all randomized participants who received at least one study drug administration (radium 223 dichloride or placebo)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium 223 Dichloride | Time to Opiate Use for Cancer Pain | 21.3 months |
| Placebo | Time to Opiate Use for Cancer Pain | 20.2 months |
p-value: 0.878580% CI: [0.513, 1.693]Log Rank
Secondary
Time to Pain Progression
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
Time frame: Up to approximately 51 months
Population: Safety analysis set: all randomized participants who received at least one study drug administration (radium 223 dichloride or placebo)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium 223 Dichloride | Time to Pain Progression | 14.8 months |
| Placebo | Time to Pain Progression | 8.8 months |
p-value: 0.52480% CI: [0.556, 1.22]Log Rank