Trial Outcomes & Findings for Carboplatin With or Without Atezolizumab in Treating Patients With Stage IV Triple Negative Breast Cancer (NCT NCT03206203)

NCT ID: NCT03206203

Last Updated: 2024-12-12

Results Overview

The PFS is defined as the time from the first day of treatment to the first observation of disease progression (RECIST V1.1) or death of any cause. Those without events were censored at the last follow up. The median PFS time will be estimated using the Kaplan-Meier method with 95% confidence intervals.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

106 participants

Primary outcome timeframe

Up to 3 years.

Results posted on

2024-12-12

Participant Flow

Participants were enrolled onto this study at 6 academic medical centers from August 2017 to October 2020.

Participant milestones

Participant milestones
Measure	Arm 1 (Atezolizumab, Carboplatin) Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Arm 2 (Carboplatin) Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression. Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Cross-Over Patients on Arm 2 have the option to cross-over to Arm 1 upon disease progression and receive atezolizumab by IV over 30-60 minutes
Treatment STARTED	56	50	0
Treatment COMPLETED	5	2	0
Treatment NOT COMPLETED	51	48	0
Optional Cross-Over STARTED	0	0	19
Optional Cross-Over COMPLETED	0	0	3
Optional Cross-Over NOT COMPLETED	0	0	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm 1 (Atezolizumab, Carboplatin) Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Arm 2 (Carboplatin) Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression. Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Cross-Over Patients on Arm 2 have the option to cross-over to Arm 1 upon disease progression and receive atezolizumab by IV over 30-60 minutes
Treatment Death	38	26	0
Treatment Withdrawal by Subject	1	0	0
Treatment Lost to Follow-up	4	0	0
Treatment N/A in Follow-Up	8	1	0
Treatment Disease progression	0	1	0
Treatment Refused follow-up	0	1	0
Treatment Cross over to Arm 1	0	19	0
Optional Cross-Over Death	0	0	14
Optional Cross-Over Refused follow-up	0	0	2

Baseline Characteristics

Carboplatin With or Without Atezolizumab in Treating Patients With Stage IV Triple Negative Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm 1 (Atezolizumab, Carboplatin) n=56 Participants Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Arm 2 (Carboplatin) n=31 Participants Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression. Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Cross-Over n=19 Participants Patients on Arm 2 have the option to cross-over to Arm 1 upon disease progression and receive atezolizumab by IV over 30-60 minutes	Total n=106 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	42 Participants n=5 Participants	22 Participants n=7 Participants	16 Participants n=5 Participants	80 Participants n=4 Participants
Age, Categorical >=65 years	14 Participants n=5 Participants	9 Participants n=7 Participants	3 Participants n=5 Participants	26 Participants n=4 Participants
Sex: Female, Male Female	56 Participants n=5 Participants	31 Participants n=7 Participants	19 Participants n=5 Participants	106 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	28 Participants n=5 Participants	18 Participants n=7 Participants	9 Participants n=5 Participants	55 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	27 Participants n=5 Participants	13 Participants n=7 Participants	10 Participants n=5 Participants	50 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	8 Participants n=5 Participants	9 Participants n=7 Participants	3 Participants n=5 Participants	20 Participants n=4 Participants
Race (NIH/OMB) White	42 Participants n=5 Participants	18 Participants n=7 Participants	13 Participants n=5 Participants	73 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	4 Participants n=7 Participants	3 Participants n=5 Participants	12 Participants n=4 Participants
Region of Enrollment United States	56 participants n=5 Participants	31 participants n=7 Participants	19 participants n=5 Participants	106 participants n=4 Participants

PRIMARY outcome

Timeframe: Up to 3 years.

Population: Randomized patients received treatments.

Outcome measures

Outcome measures
Measure	Arm 1 (Atezolizumab, Carboplatin) n=56 Participants Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Arm 2 (Carboplatin) n=50 Participants Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies
Progression Free Survival (PFS)	4.1 months Interval 2.4 to 7.0	2.2 months Interval 2.0 to 4.4

SECONDARY outcome

Timeframe: Up to 3 years

Population: Randomized patients who received treatments and evaluated for response with evaluanble result.

Patient response to treatment was evaluated by RECIST V1.1. The ORR (CR + PR) and corresponding 95% confidence intervals (exact) were estimated among evaluable patients.

Outcome measures

Outcome measures
Measure	Arm 1 (Atezolizumab, Carboplatin) n=54 Participants Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Arm 2 (Carboplatin) n=45 Participants Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies
Overall Response Rate (ORR)	31.5 percentage of participants Interval 21.0 to 45.0	8.9 percentage of participants Interval 4.0 to 21.0

SECONDARY outcome

Timeframe: Up to 3 years

Population: Randomized patients who received treatment and evaluated response with evaluable result.

Patient response to treatment was evaluated by RECIST 1.1. The CBR (CR + PR+stable disease ≥ 6 months) and corresponding 95% confidence intervals (exact) were estimated among evaluable patients.

Outcome measures

Outcome measures
Measure	Arm 1 (Atezolizumab, Carboplatin) n=54 Participants Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Arm 2 (Carboplatin) n=45 Participants Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies
Clinical Benefit Rate (CBR)	38.9 percentage of participants Interval 27.0 to 52.0	20.0 percentage of participants Interval 11.0 to 39.0

SECONDARY outcome

Timeframe: Up to 3 years

Population: Randomized patients who received treatment and had CR or PR.

DOR was defined as the time from CR or PR to progression using RECIST V1.1. The median DOR and corresponding 95% confidence intervals was estimated uisng Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Arm 1 (Atezolizumab, Carboplatin) n=17 Participants Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Arm 2 (Carboplatin) n=4 Participants Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies
Duration of Response (DOR)	11.6 months Interval 7.6 to 17.7	14.8 months Interval 8.2 to Too few number of patients to estimate.

SECONDARY outcome

Timeframe: Up to 3 years.

Population: Randomized patients who received treatment.

OS is defined as the time from first day of treatment to death. Those alive were censored at the last follow up. The median and OS time and corresponding 95% confidence intervals were estimated using Kaplan-meier method.

Outcome measures

Outcome measures
Measure	Arm 1 (Atezolizumab, Carboplatin) n=56 Participants Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Arm 2 (Carboplatin) n=50 Participants Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies
Overall Survival (OS)	12.6 months Interval 10.9 to 19.9	7.0 months Interval 3.2 to 10.1

Adverse Events

Arm 1 (Atezolizumab, Carboplatin)

Serious events: 23 serious events

Other events: 54 other events

Deaths: 38 deaths

Arm 2 (Carboplatin)

Serious events: 11 serious events

Other events: 30 other events

Deaths: 26 deaths

Cross-Over

Serious events: 12 serious events

Other events: 19 other events

Deaths: 14 deaths

Serious adverse events

Other adverse events

Additional Information

Teresa Melton

Vanderbilt-Ingram Cancer Center

Phone: 615-936-7423

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Arm 1 (Atezolizumab, Carboplatin) n=56 participants at risk Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Arm 2 (Carboplatin) n=50 participants at risk Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression. Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	Cross-Over n=19 participants at risk Patients on Arm 2 have the option to cross-over to Arm 1 upon disease progression and receive atezolizumab by IV over 30-60 minutes
General disorders Limb edema	7.1% 4/56 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	4.0% 2/50 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	5.3% 1/19 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
General disorders Flu-Like Symptoms	5.4% 3/56 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	2.0% 1/50 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.5% 2/19 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
General disorders Chills	7.1% 4/56 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	2.0% 1/50 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Investigations Lymphocyte count decreased	32.1% 18/56 • Number of events 40 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	28.0% 14/50 • Number of events 31 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.5% 2/19 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Investigations White blood cell decreased	33.9% 19/56 • Number of events 56 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	28.0% 14/50 • Number of events 27 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.5% 2/19 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Investigations Alanine aminotransferase increased	25.0% 14/56 • Number of events 16 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	14.0% 7/50 • Number of events 8 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	15.8% 3/19 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Investigations Creatinine increased	3.6% 2/56 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	6.0% 3/50 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.5% 2/19 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Investigations Hemoglobin increased	5.4% 3/56 • Number of events 9 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	6.0% 3/50 • Number of events 5 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Gastrointestinal disorders Mucositis oral	7.1% 4/56 • Number of events 7 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.0% 5/50 • Number of events 5 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Gastrointestinal disorders Dyspepsia	8.9% 5/56 • Number of events 10 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	4.0% 2/50 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	5.3% 1/19 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Gastrointestinal disorders Gastroesophageal reflux disease	1.8% 1/56 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	6.0% 3/50 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Metabolism and nutrition disorders Hypomagnesemia	26.8% 15/56 • Number of events 32 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	30.0% 15/50 • Number of events 21 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	15.8% 3/19 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Metabolism and nutrition disorders Anorexia	17.9% 10/56 • Number of events 11 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	18.0% 9/50 • Number of events 11 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	15.8% 3/19 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Metabolism and nutrition disorders Hypoalbuminemia	12.5% 7/56 • Number of events 8 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	4.0% 2/50 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	5.3% 1/19 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Metabolism and nutrition disorders Hypocalcemia	10.7% 6/56 • Number of events 7 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	6.0% 3/50 • Number of events 8 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	5.4% 3/56 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	4.0% 2/50 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.4% 3/56 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	2.0% 1/50 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Nervous system disorders Peripheral sensory neuropathy	12.5% 7/56 • Number of events 8 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	12.0% 6/50 • Number of events 6 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	5.3% 1/19 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Nervous system disorders Dysgeusia	5.4% 3/56 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	4.0% 2/50 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Nervous system disorders Peripheral motor neuropathy	5.4% 3/56 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	2.0% 1/50 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	5.3% 1/19 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Musculoskeletal and connective tissue disorders Chest wall pain	14.3% 8/56 • Number of events 8 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	2.0% 1/50 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Musculoskeletal and connective tissue disorders Pain in extremity	10.7% 6/56 • Number of events 11 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	6.0% 3/50 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Musculoskeletal and connective tissue disorders Arthralgia	5.4% 3/56 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	8.0% 4/50 • Number of events 6 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Musculoskeletal and connective tissue disorders Myalgia	1.8% 1/56 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.0% 5/50 • Number of events 7 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Musculoskeletal and connective tissue disorders Bone pain	5.4% 3/56 • Number of events 5 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	4.0% 2/50 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Skin and subcutaneous tissue disorders Rash maculo-papular	14.3% 8/56 • Number of events 10 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	4.0% 2/50 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	15.8% 3/19 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Skin and subcutaneous tissue disorders Alopecia	7.1% 4/56 • Number of events 6 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	4.0% 2/50 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	15.8% 3/19 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Skin and subcutaneous tissue disorders Pruritus	8.9% 5/56 • Number of events 6 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	2.0% 1/50 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Respiratory, thoracic and mediastinal disorders Upper respiratory infection	5.4% 3/56 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.0% 5/50 • Number of events 6 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Respiratory, thoracic and mediastinal disorders Sinusitis	3.6% 2/56 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	6.0% 3/50 • Number of events 3 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Psychiatric disorders Insomnia	14.3% 8/56 • Number of events 10 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	8.0% 4/50 • Number of events 6 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	5.3% 1/19 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Psychiatric disorders Anxiety	10.7% 6/56 • Number of events 7 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.0% 5/50 • Number of events 5 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	5.3% 1/19 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Psychiatric disorders Depression	8.9% 5/56 • Number of events 5 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	4.0% 2/50 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	5.3% 1/19 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Vascular disorders Hypotension	1.8% 1/56 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.0% 5/50 • Number of events 6 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.5% 2/19 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Vascular disorders Hypertension	5.4% 3/56 • Number of events 7 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	8.0% 4/50 • Number of events 5 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Vascular disorders Hot flashes	7.1% 4/56 • Number of events 5 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	2.0% 1/50 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Endocrine disorders Hypothyroidism	12.5% 7/56 • Number of events 9 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	2.0% 1/50 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.5% 2/19 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Endocrine disorders Hyperthyroidism	5.4% 3/56 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/50 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	0.00% 0/19 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Injury, poisoning and procedural complications Bruising	5.4% 3/56 • Number of events 4 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	4.0% 2/50 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	5.3% 1/19 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.
Reproductive system and breast disorders Breast pain	1.8% 1/56 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	2.0% 1/50 • Number of events 1 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.	10.5% 2/19 • Number of events 2 • Deaths were assessed for up to 3 years. Adverse Events were assessed for an average of 2 years.