Trial Outcomes & Findings for Fulvestrant With or Without Bortezomib in Patients With Inoperable Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer (NCT NCT01142401)

NCT ID: NCT01142401

Last Updated: 2023-11-27

Results Overview

The number of patients, treated with fulvestrant alone and fulvestrant plus bortezomib, who remained progression-free (Arms A vs. B). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 118 participants
• Primary outcome timeframe: At 12 months
• Results posted on: 2023-11-27

Participant Flow

118 patients were enrolled from 17 institutions between May 2010 and October 2013

118 postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A) or in combination with bortezomib (Arm B). Two patients randomized to Arm B never received protocol therapy. Of 59 patients randomized to fulvestrant alone, Arm A, 27 crossed over to receive fulvestrant plus bortezomib (Arm C) at progression on fulvestrant alone.

Participant milestones

Measure	Arm A: Fulvestrant Alone Patients received fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only). Courses repeated every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may crossover to Arm C. Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm B: Fulvestrant + Bortezomib Patients received fulvestrant IM as in Arm A and bortezomib IV on days 1, 8, and 15. Courses repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm C: Crossover From Arm A at Progression to Fulvestrant + Bortezomib Patients who crossed over from Arm A received fulvestrant IM on day 1 and bortezomib IV on days 1, 8, and 15. Courses repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies
Randomized Phase STARTED	59	59	0
Randomized Phase COMPLETED	59	57	0
Randomized Phase NOT COMPLETED	0	2	0
Crossover Phase STARTED	0	0	27
Crossover Phase COMPLETED	0	0	27
Crossover Phase NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	Arm A: Fulvestrant n=59 Participants Patients received fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only). Courses repeated every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may crossover to Arm C. Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm B: Fulvestrant + Bortezomib n=57 Participants Patients received fulvestrant IM as in Arm A and bortezomib IV on days 1, 8, and 15. Courses repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Total n=116 Participants Total of all reporting groups
Age, Continuous	57 years n=59 Participants	59 years n=57 Participants	57 years n=116 Participants
Sex: Female, Male Female	59 Participants n=59 Participants	57 Participants n=57 Participants	116 Participants n=116 Participants
Sex: Female, Male Male	0 Participants n=59 Participants	0 Participants n=57 Participants	0 Participants n=116 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment United States	59 participants n=59 Participants	57 participants n=57 Participants	116 participants n=116 Participants

PRIMARY outcome

Timeframe: At 12 months

The number of patients, treated with fulvestrant alone and fulvestrant plus bortezomib, who remained progression-free (Arms A vs. B). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Outcome measures

Measure	Arm A: Fulvestrant n=59 Participants Patients received fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only). Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may have crossed over into another treatment group (Arm C). Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm B: Fulvestrant + Bortezomib n=57 Participants Patients received fulvestrant as in arm A and bortezomib IV on days 1, 8, and 15. Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies
Number of Participants With Progression Free Survival (PFS) at 12 Months	8 Participants	16 Participants

PRIMARY outcome

Timeframe: At 6 months

Outcome measures

Measure	Arm A: Fulvestrant n=59 Participants Patients received fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only). Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may have crossed over into another treatment group (Arm C). Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm B: Fulvestrant + Bortezomib n=57 Participants Patients received fulvestrant as in arm A and bortezomib IV on days 1, 8, and 15. Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies
Number of Participants With Progression Free Survival (PFS) at 6 Months	16 Participants	22 Participants

SECONDARY outcome

Timeframe: Up to 24 weeks

Population: \# of participants randomized to Arm A (Fulvestrant alone) who crossed over to fulvestrant plus bortezomib at progression (Arm C) and had clinical benefit.

This outcome measure determined if the addition of bortezomib to fulvestrant improved the clinical benefit rate (defined as objective response plus stable disease for at least 24 weeks from day+1). Clinical Benefit Rate (CBR) is defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents.

Outcome measures

Measure	Arm A: Fulvestrant n=27 Participants Patients received fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only). Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may have crossed over into another treatment group (Arm C). Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm B: Fulvestrant + Bortezomib Patients received fulvestrant as in arm A and bortezomib IV on days 1, 8, and 15. Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies
Clinical Benefit Rate (CBR) of Adding Bortezomib to Fulvestrant in Arm C	5 Participants	—

SECONDARY outcome

Timeframe: From first treatment day until study end, assessed up to 7 years

Tabulation of the number of participants who survived from the date of first treatment until study end (up to 7 years).

Outcome measures

Measure	Arm A: Fulvestrant n=59 Participants Patients received fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only). Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may have crossed over into another treatment group (Arm C). Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm B: Fulvestrant + Bortezomib n=57 Participants Patients received fulvestrant as in arm A and bortezomib IV on days 1, 8, and 15. Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies
Number of Participants Who Survived Until Study End (up to 7 Years)	39 Participants	42 Participants

SECONDARY outcome

Timeframe: At 24 weeks

Outcome measures

Measure	Arm A: Fulvestrant n=27 Participants Patients received fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only). Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may have crossed over into another treatment group (Arm C). Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm B: Fulvestrant + Bortezomib Patients received fulvestrant as in arm A and bortezomib IV on days 1, 8, and 15. Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies
Progression Free Survival at 24 Weeks (Arm C)	5 Participants	—

SECONDARY outcome

Timeframe: Up to 7 years

Most common toxicities in the fulvestrant arm alone (Arm A) and the fulvestrant/bortezomib combination arm (Arm B). Most common toxicities are defined as adverse events having occurred in >10% of the participants within either (or both) Arm A or Arm B.

Outcome measures

Measure	Arm A: Fulvestrant n=59 Participants Patients received fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only). Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may have crossed over into another treatment group (Arm C). Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm B: Fulvestrant + Bortezomib n=57 Participants Patients received fulvestrant as in arm A and bortezomib IV on days 1, 8, and 15. Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies
Frequency of Most Common Toxicities Hemoglobin-Low	41 percentage of participants	61 percentage of participants
Frequency of Most Common Toxicities White Blood Cell-Low	32 percentage of participants	42 percentage of participants
Frequency of Most Common Toxicities Hyperglycemia/Glucose-High	44 percentage of participants	51 percentage of participants
Frequency of Most Common Toxicities Hypoglycemia/Glucose-Low	5 percentage of participants	12 percentage of participants
Frequency of Most Common Toxicities SGOT (AST-High)	25 percentage of participants	32 percentage of participants
Frequency of Most Common Toxicities SGPT (ALT-High)	14 percentage of participants	21 percentage of participants
Frequency of Most Common Toxicities Neutrophil Count Decreased/ANC-low	10 percentage of participants	12 percentage of participants
Frequency of Most Common Toxicities Platelet Count Decreased/Platelets-Low	8 percentage of participants	30 percentage of participants
Frequency of Most Common Toxicities Hypocalcemia/Calcium-Low	10 percentage of participants	12 percentage of participants
Frequency of Most Common Toxicities Hyponatremia/Sodium-Low	8 percentage of participants	12 percentage of participants
Frequency of Most Common Toxicities Nausea	29 percentage of participants	63 percentage of participants
Frequency of Most Common Toxicities Vomiting	14 percentage of participants	32 percentage of participants
Frequency of Most Common Toxicities Diarrhea	8 percentage of participants	47 percentage of participants
Frequency of Most Common Toxicities Constipation	34 percentage of participants	46 percentage of participants
Frequency of Most Common Toxicities Heartburn/Dyspepsia	10 percentage of participants	18 percentage of participants
Frequency of Most Common Toxicities Anorexia	15 percentage of participants	23 percentage of participants
Frequency of Most Common Toxicities Headache	12 percentage of participants	25 percentage of participants
Frequency of Most Common Toxicities Pain (general)	59 percentage of participants	54 percentage of participants
Frequency of Most Common Toxicities Peripheral Neuropathy (Motor, Pain, Sensory)	31 percentage of participants	49 percentage of participants
Frequency of Most Common Toxicities Injection Site Reaction	24 percentage of participants	12 percentage of participants
Frequency of Most Common Toxicities Dyspnea	32 percentage of participants	19 percentage of participants
Frequency of Most Common Toxicities Cough	29 percentage of participants	23 percentage of participants
Frequency of Most Common Toxicities Fatigue	56 percentage of participants	56 percentage of participants
Frequency of Most Common Toxicities Limb Edema	19 percentage of participants	37 percentage of participants
Frequency of Most Common Toxicities Insomnia	25 percentage of participants	35 percentage of participants
Frequency of Most Common Toxicities Hot Flashes	37 percentage of participants	32 percentage of participants
Frequency of Most Common Toxicities Dizziness	7 percentage of participants	19 percentage of participants
Frequency of Most Common Toxicities Arthralgia	36 percentage of participants	28 percentage of participants
Frequency of Most Common Toxicities Myalgia	10 percentage of participants	18 percentage of participants
Frequency of Most Common Toxicities Anxiety	8 percentage of participants	19 percentage of participants
Frequency of Most Common Toxicities Fever	15 percentage of participants	12 percentage of participants
Frequency of Most Common Toxicities Pruritis	7 percentage of participants	16 percentage of participants
Frequency of Most Common Toxicities Rash/Desquamation	8 percentage of participants	11 percentage of participants
Frequency of Most Common Toxicities Depression	8 percentage of participants	16 percentage of participants
Frequency of Most Common Toxicities Anemia	32 percentage of participants	42 percentage of participants
Frequency of Most Common Toxicities Dry Eye	0 percentage of participants	12 percentage of participants
Frequency of Most Common Toxicities Hypertension	12 percentage of participants	21 percentage of participants
Frequency of Most Common Toxicities Rash (General)	7 percentage of participants	23 percentage of participants
Frequency of Most Common Toxicities Eye Disorders (not otherwise specified)	7 percentage of participants	12 percentage of participants
Frequency of Most Common Toxicities Urinary Disorders (General)	15 percentage of participants	11 percentage of participants
Frequency of Most Common Toxicities Thrombocytopenia	41 percentage of participants	61 percentage of participants
Frequency of Most Common Toxicities Neutropenia	8 percentage of participants	30 percentage of participants
Frequency of Most Common Toxicities Upper Respiratory Disorders (General)	12 percentage of participants	23 percentage of participants
Frequency of Most Common Toxicities Musculoskeletal Pain Disorders (not otherwise specified)	17 percentage of participants	18 percentage of participants
Frequency of Most Common Toxicities Mucositis Oral	8 percentage of participants	11 percentage of participants

Adverse Events

Arm A: Fulvestrant Alone

Serious events: 9 serious events

Other events: 59 other events

Deaths: 11 deaths

Arm B: Fulvestrant + Bortezomib

Serious events: 6 serious events

Other events: 57 other events

Deaths: 15 deaths

Arm C: Crossover From Arm A at Progression to Fulvestrant + Bortezomib

Serious events: 5 serious events

Other events: 27 other events

Deaths: 9 deaths

Serious adverse events

Measure	Arm A: Fulvestrant Alone n=59 participants at risk Patients received fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only). Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may have crossed over to another treatment group (Arm C). Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm B: Fulvestrant + Bortezomib n=57 participants at risk Patients received fulvestrant IM as in Arm A and bortezomib IV on days 1, 8, and 15. Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm C: Crossover From Arm A at Progression to Fulvestrant + Bortezomib n=27 participants at risk Patients who crossed over from Arm A at progression received fulvestrant IM on day 1 and bortezomib IM on days 1, 8, and 15. Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies
Cardiac disorders Cardiac Arrest	1.7% 1/59 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Nausea	1.7% 1/59 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.5% 2/57 • Number of events 2 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Vomiting	1.7% 1/59 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	1.8% 1/57 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Metabolism and nutrition disorders Hyponatremia	0.00% 0/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	1.8% 1/57 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Vascular disorders Hypotension	0.00% 0/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Metabolism and nutrition disorders Hyperglycemia	1.7% 1/59 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Cardiac disorders Cardiac Disorder (Unspecified)	0.00% 0/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	1.8% 1/57 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Metabolism and nutrition disorders Dehydration	1.7% 1/59 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Respiratory, thoracic and mediastinal disorders Pleural Effusion	1.7% 1/59 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	1.8% 1/57 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Number of events 2 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Injury, poisoning and procedural complications Spinal Fracture	1.7% 1/59 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Endometrial cancer	1.7% 1/59 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Injury, poisoning and procedural complications Hip Fracture	1.7% 1/59 • Number of events 1 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.

Other adverse events

Measure	Arm A: Fulvestrant Alone n=59 participants at risk Patients received fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only). Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may have crossed over to another treatment group (Arm C). Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm B: Fulvestrant + Bortezomib n=57 participants at risk Patients received fulvestrant IM as in Arm A and bortezomib IV on days 1, 8, and 15. Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies	Arm C: Crossover From Arm A at Progression to Fulvestrant + Bortezomib n=27 participants at risk Patients who crossed over from Arm A at progression received fulvestrant IM on day 1 and bortezomib IM on days 1, 8, and 15. Courses were repeated every 28 days in the absence of disease progression or unacceptable toxicity. Bortezomib: Given IV Fulvestrant: Given IM Laboratory Biomarker Analysis: Correlative studies
Psychiatric disorders Anxiety	8.5% 5/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	19.3% 11/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	14.8% 4/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Psychiatric disorders Depression	8.5% 5/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	15.8% 9/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	18.5% 5/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Blood and lymphatic system disorders Anemia	32.2% 19/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	42.1% 24/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	44.4% 12/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Blood and lymphatic system disorders Neutropenia	8.5% 5/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	29.8% 17/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.2% 6/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Blood and lymphatic system disorders Thrombocytopenia	40.7% 24/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	61.4% 35/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	55.6% 15/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Metabolism and nutrition disorders Hyperglycemia	42.4% 25/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	50.9% 29/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	44.4% 12/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Metabolism and nutrition disorders Hypoglycemia	5.1% 3/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	12.3% 7/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Metabolism and nutrition disorders SGOT_AST-High	25.4% 15/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	31.6% 18/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.2% 6/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Metabolism and nutrition disorders SGPT_ALT-High	13.6% 8/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	21.1% 12/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	18.5% 5/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Metabolism and nutrition disorders Hyponatremia	8.5% 5/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	10.5% 6/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Nausea	27.1% 16/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	59.6% 34/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	44.4% 12/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Vomiting	11.9% 7/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	29.8% 17/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.2% 6/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Diarrhea	8.5% 5/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	47.4% 27/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	51.9% 14/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Constipation	33.9% 20/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	45.6% 26/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	40.7% 11/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Heartburn/Dyspepsia	10.2% 6/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	17.5% 10/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Anorexia	15.3% 9/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.8% 13/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	14.8% 4/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Nervous system disorders Headache	11.9% 7/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	24.6% 14/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	25.9% 7/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Nervous system disorders Pain	59.3% 35/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	54.4% 31/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	37.0% 10/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Nervous system disorders Peripheral Neuropathy	30.5% 18/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	49.1% 28/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	29.6% 8/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Skin and subcutaneous tissue disorders Rash/Desquamation	8.5% 5/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	10.5% 6/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	11.1% 3/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Skin and subcutaneous tissue disorders Injection Site Reaction	23.7% 14/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	12.3% 7/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	14.8% 4/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Skin and subcutaneous tissue disorders Pruritis	6.8% 4/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	15.8% 9/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Respiratory, thoracic and mediastinal disorders Dyspnea	32.2% 19/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	19.3% 11/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.2% 6/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Respiratory, thoracic and mediastinal disorders Cough	28.8% 17/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.8% 13/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	11.1% 3/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Musculoskeletal and connective tissue disorders Arthralgia	35.6% 21/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	28.1% 16/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	25.9% 7/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Musculoskeletal and connective tissue disorders Myalgia	10.2% 6/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	17.5% 10/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	14.8% 4/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
General disorders Fatigue	55.9% 33/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	56.1% 32/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	40.7% 11/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
General disorders Limb Edema	18.6% 11/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	36.8% 21/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	25.9% 7/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
General disorders Fever	15.3% 9/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	12.3% 7/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
General disorders Insomnia	25.4% 15/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	35.1% 20/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.2% 6/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
General disorders Dizziness	6.8% 4/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	19.3% 11/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	11.1% 3/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
General disorders Hot Flashes	37.3% 22/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	31.6% 18/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.2% 6/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Investigations Creatinine increased	3.4% 2/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.0% 4/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	11.1% 3/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Metabolism and nutrition disorders Hypocalcemia	10.2% 6/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	12.3% 7/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Investigations Neutrophil Count Decreased	10.2% 6/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	12.3% 7/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Infections and infestations Infection with unknown Absolute Neutrophil Count	8.5% 5/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.0% 4/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
General disorders Chills	6.8% 4/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.0% 4/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Investigations Creatinine-Low	3.4% 2/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	5.3% 3/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Investigations Total Bilirubin Low	5.1% 3/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	1.8% 1/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Skin and subcutaneous tissue disorders Alopecia	3.4% 2/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	5.3% 3/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Eye disorders Blurred Vision	0.00% 0/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	8.8% 5/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Renal and urinary disorders Chronic Kidney Disease	1.7% 1/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Eye disorders Dry Eye	0.00% 0/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	12.3% 7/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Dry Mouth	0.00% 0/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Skin and subcutaneous tissue disorders Dry Skin	3.4% 2/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	5.3% 3/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Nervous system disorders Dysgeusia	0.00% 0/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	5.3% 3/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	5.3% 3/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Injury, poisoning and procedural complications Fall	0.00% 0/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	5.3% 3/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
General disorders Flu Like Symptoms	3.4% 2/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	5.3% 3/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Vascular disorders Hypertension	11.9% 7/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	21.1% 12/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	29.6% 8/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
General disorders Malaise	1.7% 1/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.0% 4/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Mucositis Oral	8.5% 5/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	10.5% 6/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	11.1% 3/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Nervous system disorders Numbness - fingers	6.8% 4/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Skin and subcutaneous tissue disorders Rash (General, not otherwise specified)	6.8% 4/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.8% 13/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	11.1% 3/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Renal and urinary disorders Pressure - left pubic area	0.00% 0/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.0% 4/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Investigations Weight Loss	6.8% 4/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.5% 2/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	18.5% 5/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Respiratory, thoracic and mediastinal disorders Laryngeal Inflammation	3.4% 2/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	8.8% 5/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Gastrointestinal disorders Toothache	3.4% 2/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	1.8% 1/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Eye disorders Eye Disorders (not otherwise specified)	6.8% 4/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	12.3% 7/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	11.1% 3/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Renal and urinary disorders Urinary Disorders (General)	15.3% 9/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	10.5% 6/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Reproductive system and breast disorders Reproductive system and breast disorders (General)	8.5% 5/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	1.8% 1/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Respiratory, thoracic and mediastinal disorders Upper Respiratory Disorders (General)	11.9% 7/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.8% 13/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	29.6% 8/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Respiratory, thoracic and mediastinal disorders Lower Respiratory Disorders (General, not otherwise specified)	6.8% 4/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	1.8% 1/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Ear and labyrinth disorders Ear Disorders (General)	3.4% 2/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	1.8% 1/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Infections and infestations Skin Infections (General)	5.1% 3/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	5.3% 3/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	11.1% 3/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Infections and infestations Infections (General), not otherwise specified	5.1% 3/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.0% 4/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	3.7% 1/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Musculoskeletal and connective tissue disorders Musculoskeletal Pain Disorders (not otherwise specified)	16.9% 10/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	17.5% 10/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	25.9% 7/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Cardiac disorders Sinus Tachycardia	3.4% 2/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	7.4% 2/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Carcinomas	5.1% 3/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	0.00% 0/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Blood and lymphatic system disorders Hemoglobin - Low	40.7% 24/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	61.4% 35/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	55.6% 15/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Investigations White Blood Cells Decreased	32.2% 19/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	42.1% 24/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	44.4% 12/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.
Investigations Platelet Count Decreased	8.5% 5/59 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	29.8% 17/57 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.	22.2% 6/27 • Up to 7 years A 5% frequency threshold was set for the reporting of non-Serious Adverse Events (NSAEs) for this study. If the occurrence of an adverse event was observed in \>5% of participants in any of the three treatment arms the event was reported for all three arms.

Additional Information

Joseph Sparano, MD

Icahn School of Medicine at Mount Sinai

Phone: 212-241-3300

Email: joseph.sparano@mssm.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60