Trial Outcomes & Findings for 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 (NCT NCT02258464)

NCT ID: NCT02258464

Last Updated: 2020-08-10

Results Overview

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

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

99 participants

Primary outcome timeframe

Up to approximately 51 months

Results posted on

2020-08-10

Participant Flow

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

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

Participant milestones

Participant milestones
Measure	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	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
Overall Study STARTED	49	50
Overall Study COMPLETED	32	25
Overall Study NOT COMPLETED	17	25

Reasons for withdrawal

Reasons for withdrawal
Measure	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	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
Overall Study Progressive disease (PD)	9	17
Overall Study Study drug never administered	1	1
Overall Study AE not related to clinical PD	1	3
Overall Study Withdrawal by Subject	5	4
Overall Study AE related to clinical PD	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Radium 223 Dichloride n=49 Participants 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	Placebo n=50 Participants 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	Total n=99 Participants Total of all reporting groups
Age, Continuous	57.08 years STANDARD_DEVIATION 11.51 • n=99 Participants	58.74 years STANDARD_DEVIATION 11.97 • n=107 Participants	57.92 years STANDARD_DEVIATION 11.72 • n=206 Participants
Sex: Female, Male Female	49 Participants n=99 Participants	50 Participants n=107 Participants	99 Participants n=206 Participants
Sex: Female, Male Male	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	47 Participants n=99 Participants	47 Participants n=107 Participants	94 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=99 Participants	3 Participants n=107 Participants	5 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	9 Participants n=99 Participants	9 Participants n=107 Participants	18 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race (NIH/OMB) White	35 Participants n=99 Participants	40 Participants n=107 Participants	75 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=99 Participants	1 Participants n=107 Participants	5 Participants n=206 Participants

PRIMARY outcome

Timeframe: Up to approximately 51 months

Population: Intent to treat analysis set: all randomized participants

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

Outcome measures

Outcome measures
Measure	Radium 223 Dichloride n=49 Participants 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	Placebo n=50 Participants 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
Symptomatic Skeletal Event Free Survival (SSE-FS)	30.1 months 80% Confidence Interval 21.8 • Interval 21.8 to 43.0	18.4 months 80% Confidence Interval 9.1 • Interval 9.1 to 28.2

SECONDARY outcome

Timeframe: Up to approximately 51 months

Population: Intent to treat analysis set: all randomized participants

Time from randomization to death from any cause

Outcome measures

Outcome measures
Measure	Radium 223 Dichloride n=49 Participants 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	Placebo n=50 Participants 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
Overall Survival	43.0 months Interval 22.9 to NA: Value not estimated due to censored data	32.4 months Interval 23.7 to NA: Value not estimated due to censored data

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Radium 223 Dichloride n=48 Participants 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	Placebo n=49 Participants 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
Time to Opiate Use for Cancer Pain	21.3 months Interval 8.3 to NA: Value not estimated due to censored data	20.2 months Interval 8.8 to NA: Value not estimated due to censored data

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Radium 223 Dichloride n=48 Participants 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	Placebo n=49 Participants 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
Time to Pain Progression	14.8 months Interval 5.9 to 21.3	8.8 months Interval 3.7 to 14.3

SECONDARY outcome

Timeframe: Up to approximately 51 months

Population: Participants in safety analysis set taken into account for this endpoint analysis

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

Outcome measures

Outcome measures
Measure	Radium 223 Dichloride n=32 Participants 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	Placebo n=35 Participants 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
Pain Improvement Rate	37.5 percentage of participants analyzed 80% Confidence Interval 25.9 • Interval 25.9 to 50.4	25.7 percentage of participants analyzed 80% Confidence Interval 16.2 • Interval 16.2 to 37.5

SECONDARY outcome

Timeframe: Up to approximately 51 months

Population: Intent to treat analysis set: all randomized participants

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

Outcome measures

Outcome measures
Measure	Radium 223 Dichloride n=49 Participants 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	Placebo n=50 Participants 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
Time to Cytotoxic Chemotherapy	16.0 months 80% Confidence Interval 14.1 • Interval 14.1 to 22.4	17.3 months 80% Confidence Interval 10.9 • Interval 10.9 to 27.6

SECONDARY outcome

Timeframe: Up to approximately 51 months

Population: Intent to treat analysis set: all randomized participants

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

Outcome measures

Outcome measures
Measure	Radium 223 Dichloride n=49 Participants 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	Placebo n=50 Participants 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
Radiological Progression-free Survival (rPFS)	8.1 months 80% Confidence Interval 5.7 • Interval 5.7 to 10.6	5.8 months 80% Confidence Interval 5.1 • Interval 5.1 to 7.9

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Radium 223 Dichloride n=48 Participants 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	Placebo n=49 Participants 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
Number of Participants With Treatment-emergent Adverse Events Any TEAE	46 Participants	46 Participants
Number of Participants With Treatment-emergent Adverse Events Radium 223/Placebo related TEAEs	21 Participants	16 Participants

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Radium 223 Dichloride n=48 Participants 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	Placebo n=49 Participants 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
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Osteonecrosis of jaw	1 Participants	0 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Pain in extremity	1 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Pathological fracture	5 Participants	4 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Spinal pain	0 Participants	3 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Cauda equina syndrome	0 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Paraesthesia	0 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Spinal cord compression	1 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Acute kidney injury	0 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Any post-treatment AE	15 Participants	16 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Anaemia	1 Participants	0 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Febrile neutropenia	0 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Chest pain	0 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Fibula fracture	0 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Rib fracture	0 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Tibia fracture	0 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Traumatic fracture	2 Participants	4 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Weight decreased	0 Participants	1 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Arthralgia	1 Participants	0 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Back pain	4 Participants	0 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Bone pain	2 Participants	3 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Muscle spasms	1 Participants	0 Participants
Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events Musculoskeletal chest pain	1 Participants	0 Participants

Adverse Events

Radium 223 Dichloride

Serious events: 4 serious events

Other events: 43 other events

Deaths: 18 deaths

Placebo

Serious events: 14 serious events

Other events: 44 other events

Deaths: 18 deaths

Serious adverse events

Serious adverse events
Measure	Radium 223 Dichloride n=48 participants at risk 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	Placebo n=49 participants at risk 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
Blood and lymphatic system disorders Anaemia	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Gastrointestinal disorders Oesophagitis	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 2 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
General disorders Chest pain	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Infections and infestations Bacteraemia	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Infections and infestations Infection	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 2 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Infections and infestations Sinusitis	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Infections and infestations Urosepsis	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 2 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Injury, poisoning and procedural complications Fibula fracture	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Injury, poisoning and procedural complications Tibia fracture	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Investigations Platelet count decreased	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Bone pain	2.1% 1/48 • Number of events 2 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	6.1% 3/49 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Pathological fracture	2.1% 1/48 • Number of events 2 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Nervous system disorders Nerve compression	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Nervous system disorders Seizure	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Nervous system disorders Syncope	2.1% 1/48 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	0.00% 0/49 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Psychiatric disorders Psychotic disorder	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Renal and urinary disorders Acute kidney injury	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Respiratory, thoracic and mediastinal disorders Respiratory failure	2.1% 1/48 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	0.00% 0/49 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event

Other adverse events

Other adverse events
Measure	Radium 223 Dichloride n=48 participants at risk 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	Placebo n=49 participants at risk 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
Blood and lymphatic system disorders Anaemia	6.2% 3/48 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	6.1% 3/49 • Number of events 7 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Blood and lymphatic system disorders Leukopenia	6.2% 3/48 • Number of events 6 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	0.00% 0/49 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Blood and lymphatic system disorders Neutropenia	10.4% 5/48 • Number of events 12 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	0.00% 0/49 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Gastrointestinal disorders Abdominal pain	10.4% 5/48 • Number of events 6 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	4.1% 2/49 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Gastrointestinal disorders Constipation	8.3% 4/48 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	8.2% 4/49 • Number of events 4 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Gastrointestinal disorders Diarrhoea	20.8% 10/48 • Number of events 15 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	14.3% 7/49 • Number of events 10 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Gastrointestinal disorders Nausea	25.0% 12/48 • Number of events 18 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	18.4% 9/49 • Number of events 13 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Gastrointestinal disorders Vomiting	14.6% 7/48 • Number of events 7 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	14.3% 7/49 • Number of events 11 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
General disorders Fatigue	25.0% 12/48 • Number of events 15 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	18.4% 9/49 • Number of events 10 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
General disorders Influenza like illness	6.2% 3/48 • Number of events 4 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
General disorders Oedema peripheral	6.2% 3/48 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
General disorders Pain	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	6.1% 3/49 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Infections and infestations Nasopharyngitis	6.2% 3/48 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	6.1% 3/49 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Infections and infestations Urinary tract infection	4.2% 2/48 • Number of events 2 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	8.2% 4/49 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Injury, poisoning and procedural complications Traumatic fracture	4.2% 2/48 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	8.2% 4/49 • Number of events 6 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Investigations Weight decreased	6.2% 3/48 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	6.1% 3/49 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Metabolism and nutrition disorders Decreased appetite	6.2% 3/48 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	10.2% 5/49 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Arthralgia	20.8% 10/48 • Number of events 14 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	22.4% 11/49 • Number of events 17 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Back pain	29.2% 14/48 • Number of events 18 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	14.3% 7/49 • Number of events 10 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Bone pain	22.9% 11/48 • Number of events 12 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	18.4% 9/49 • Number of events 15 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Musculoskeletal pain	12.5% 6/48 • Number of events 10 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	8.2% 4/49 • Number of events 4 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Myalgia	8.3% 4/48 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	4.1% 2/49 • Number of events 2 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Neck pain	8.3% 4/48 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	2.0% 1/49 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Pain in extremity	12.5% 6/48 • Number of events 8 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	14.3% 7/49 • Number of events 9 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Pathological fracture	12.5% 6/48 • Number of events 8 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	14.3% 7/49 • Number of events 8 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	8.3% 4/48 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	4.1% 2/49 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Musculoskeletal and connective tissue disorders Spinal pain	2.1% 1/48 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	8.2% 4/49 • Number of events 7 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Nervous system disorders Dizziness	4.2% 2/48 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	6.1% 3/49 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Nervous system disorders Headache	27.1% 13/48 • Number of events 19 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	8.2% 4/49 • Number of events 4 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Nervous system disorders Paraesthesia	2.1% 1/48 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	8.2% 4/49 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Respiratory, thoracic and mediastinal disorders Cough	2.1% 1/48 • Number of events 1 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	8.2% 4/49 • Number of events 4 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.2% 3/48 • Number of events 4 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	0.00% 0/49 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Vascular disorders Hypertension	6.2% 3/48 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	6.1% 3/49 • Number of events 5 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event
Vascular disorders Hot flush	0.00% 0/48 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event	6.1% 3/49 • Number of events 3 • From the start of study drug administration until the end of study, assessed up to approximately 51 months Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event

Additional Information

Therapeutic Area Head

Bayer AG

Phone: (+) 1-888-8422937

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60