Trial Outcomes & Findings for A Randomized Phase IIa Efficacy and Safety Study of Radium-223 Dichloride With Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (CRPC) (NCT NCT02034552)

NCT ID: NCT02034552

Last Updated: 2019-07-23

Results Overview

Radiological bone scan response based on change from baseline of digitized technetium-99 bone scans using computer-aided detection software. Responder (R): 30% or greater resolution of the BSLA compared to baseline. Stable Disease (SD): Not meeting the criteria for R, PD, or UE. Progressive Disease (PD): Two or more new areas of radiotracer uptake attributable to metastatic disease in regions of bone that had not previously shown radiotracer uptake or greater than 30% increase from baseline in BSLA attributable to metastatic disease. Unable to Evaluate (UE): Assigned if bone scan results cannot be interpreted due to inconsistent image acquisition parameters compared to the reference scan, incomplete imaging, or other similar technical deficiencies.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

68 participants

Primary outcome timeframe

At 24 weeks

Results posted on

2019-07-23

Participant Flow

Study was conducted at 19 study centers in USA from 7-Mar-2014 (first subject's first visit) to 26-Jun-2018 (last subject's last visit).

Overall, 103 subjects were screened. Of them, 68 subjects were randomized, and 63 subjects were received study treatment.

Participant milestones

Participant milestones
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.
Overall Study STARTED	22	24	22
Overall Study Received Treatment	19	22	22
Overall Study COMPLETED	8	4	5
Overall Study NOT COMPLETED	14	20	17

Reasons for withdrawal

Reasons for withdrawal
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.
Overall Study Never treated	3	2	0
Overall Study Radiological progression	3	5	4
Overall Study AE not assoc. with disease progression	1	4	2
Overall Study AE associated with disease progression	0	1	0
Overall Study Withdrawal by Subject	2	1	1
Overall Study Non-compliance with study drug	0	0	1
Overall Study Clinical progression	5	7	9

Baseline Characteristics

A Randomized Phase IIa Efficacy and Safety Study of Radium-223 Dichloride With Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (CRPC)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision n=24 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Total n=68 Participants Total of all reporting groups
Age, Continuous	71.5 Years STANDARD_DEVIATION 10.2 • n=39 Participants	68.6 Years STANDARD_DEVIATION 8.6 • n=41 Participants	71.0 Years STANDARD_DEVIATION 8.7 • n=35 Participants	70.3 Years STANDARD_DEVIATION 9.1 • n=31 Participants
Sex: Female, Male Female	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants
Sex: Female, Male Male	22 Participants n=39 Participants	24 Participants n=41 Participants	22 Participants n=35 Participants	68 Participants n=31 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=39 Participants	1 Participants n=41 Participants	1 Participants n=35 Participants	3 Participants n=31 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	21 Participants n=39 Participants	23 Participants n=41 Participants	20 Participants n=35 Participants	64 Participants n=31 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=39 Participants	0 Participants n=41 Participants	1 Participants n=35 Participants	1 Participants n=31 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants
Race (NIH/OMB) Asian	1 Participants n=39 Participants	2 Participants n=41 Participants	0 Participants n=35 Participants	3 Participants n=31 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants
Race (NIH/OMB) Black or African American	2 Participants n=39 Participants	5 Participants n=41 Participants	3 Participants n=35 Participants	10 Participants n=31 Participants
Race (NIH/OMB) White	18 Participants n=39 Participants	17 Participants n=41 Participants	17 Participants n=35 Participants	52 Participants n=31 Participants
Race (NIH/OMB) More than one race	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=39 Participants	0 Participants n=41 Participants	2 Participants n=35 Participants	3 Participants n=31 Participants
Eastern Cooperative Oncology Group Missing	3 Participants n=39 Participants	2 Participants n=41 Participants	0 Participants n=35 Participants	5 Participants n=31 Participants
Eastern Cooperative Oncology Group PS 0	10 Participants n=39 Participants	13 Participants n=41 Participants	11 Participants n=35 Participants	34 Participants n=31 Participants
Eastern Cooperative Oncology Group PS1	9 Participants n=39 Participants	9 Participants n=41 Participants	11 Participants n=35 Participants	29 Participants n=31 Participants

PRIMARY outcome

Timeframe: At 24 weeks

Population: Imaging endpt analysis set (IMG): consists of mITT subj. (ITT subj. who received at least one dose of each study drug as randomized) with evaluable imaging scan at baseline, eg. bl quantitated technetium-99 bone scan imaging of sufficient completeness and quality to be assessable and having a non-zero BSLA, as determ. by the central reviewer.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) n=18 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision n=19 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide n=16 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.
Patient Bone Scan Response Rate Missing	50.0 Percentage	15.8 Percentage	18.8 Percentage
Patient Bone Scan Response Rate Responder (R)	22.2 Percentage Interval 10.1 to 39.6	57.9 Percentage Interval 40.8 to 73.7	50.0 Percentage Interval 31.8 to 68.2
Patient Bone Scan Response Rate Stable Disease (SD)	0 Percentage	21.1 Percentage	18.8 Percentage
Patient Bone Scan Response Rate Progressive Disease (PD)	27.8 Percentage	5.3 Percentage	12.5 Percentage

PRIMARY outcome

Timeframe: At 24 weeks

Bone scan lesion area was defined as the sum of the pixel areas (cm2) of the set of the whole body technetium-99 bone scan imaging pixels identified as bone lesion.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) n=18 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision n=19 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide n=16 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.
Bone Scan Lesion Area	30227.13 cm^2 Standard Deviation 64912.24	10185.58 cm^2 Standard Deviation 12407.65	17321.45 cm^2 Standard Deviation 22577.59

SECONDARY outcome

Timeframe: From randomization to radiological disease progression or death from any cause (about 30.82 months )

Population: MITT analysis set: Included all ITT subjects who received at least one dose of each study drug as randomized.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) n=19 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.
Radiological Progression Free Survival	4.40 Months Interval 3.75 to 11.5	NA Months Interval 18.5 to NA = Value cannot be estimated due to censored data.	NA Months Interval 10.15 to NA = Value cannot be estimated due to censored data.

SECONDARY outcome

Timeframe: From the randomization date to the date of radiological disease progression (about 30.82months)

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) n=19 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.
Time to Radiological Progression	4.40 Months Interval 3.75 to 11.5	NA Months Interval 18.5 to NA = Value cannot be estimated due to censored data	NA Months Interval 10.15 to NA = Value cannot be estimated due to censored data

SECONDARY outcome

Timeframe: From the randomization date to the date of radiological bone progression (about 30.82 months)

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) n=19 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.
Time to Radiological Bone Progression	11.5 Months Interval 4.4 to 11.5	NA Months NA = Value cannot be estimated due to censored data	NA Months NA = Value cannot be estimated due to censored data

SECONDARY outcome

Timeframe: From the randomization date to the first SSE on or following the randomization date (about 30.82 months)

Population: MITT analysis set: Included all ITT subjects who received at least one dose of each study drug as randomized.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) n=19 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.
Time to First Symptomatic Skeletal Event	NA Months Interval 12.78 to NA = Value cannot be estimated due to censored data	NA Months Interval 17.28 to NA = Value cannot be estimated due to censored data	NA Months Interval 19.91 to NA = Value cannot be estimated due to censored data

SECONDARY outcome

Timeframe: From the randomization date to the first SSE on or following the randomization date or death, whichever occurred first (about 32.39 months)

Population: MITT analysis set: Included all ITT subjects who received at least one dose of each study drug as randomized.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) n=19 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.
Symptomatic Skeletal Event-free Survival	11.93 Months Interval 10.05 to 24.61	NA Months Interval 17.28 to NA = Value cannot be estimated due to censored data	19.91 Months Interval 12.22 to 28.09

SECONDARY outcome

Timeframe: From the randomization date to the date of death due to any cause (about 42.94 months)

Population: MITT analysis set: Included all ITT subjects who received at least one dose of each study drug as randomized.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride (Xofigo, BAY88-8223) n=19 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus).	Radium-223 With Abiraterone & Prednision n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.	Radium-223 With Enzalutamide n=22 Participants Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection.
Overall Survival	35.81 Months Interval 21.26 to 41.4	37.55 Months Interval 35.88 to NA = Value cannot be estimated due to censored data	29.86 Months Interval 26.58 to NA = Value cannot be estimated due to censored data

Adverse Events

Radium-223

Serious events: 2 serious events

Other events: 18 other events

Deaths: 0 deaths

Radium-223 + Abiraterone Acetate + Prednisone

Serious events: 10 serious events

Other events: 22 other events

Deaths: 0 deaths

Radium-223 + Enzalutamide

Serious events: 8 serious events

Other events: 22 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Therapeutic Area Head

Bayer

Phone: (+)1-888-84 22937

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Radium-223 n=19 participants at risk Radium-223	Radium-223 + Abiraterone Acetate + Prednisone n=22 participants at risk Radium-223 + Abiraterone Acetate + Prednisone	Radium-223 + Enzalutamide n=22 participants at risk Radium-223 + Enzalutamide
Cardiac disorders Cardiac failure congestive	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 2 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Gastrointestinal disorders Nausea	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
General disorders General physical health deterioration	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Infections and infestations Pneumonia	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Injury, poisoning and procedural complications Fall	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Metabolism and nutrition disorders Dehydration	10.5% 2/19 • Number of events 3 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Metabolism and nutrition disorders Hypocalcaemia	5.3% 1/19 • Number of events 8 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	9.1% 2/22 • Number of events 2 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Nervous system disorders Dizziness	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Nervous system disorders Syncope	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	13.6% 3/22 • Number of events 3 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Renal and urinary disorders Haematuria	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Renal and urinary disorders Acute kidney injury	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
General disorders Chest pain	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Infections and infestations Tooth abscess	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/19 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	4.5% 1/22 • Number of events 1 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).	0.00% 0/22 • All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of any study medication (about 18 months).