Trial Outcomes & Findings for Study of Fulvestrant +/- Everolimus in Post-Menopausal, Hormone-Receptor + Metastatic Breast Ca Resistant to AI (NCT NCT01797120)

Last Updated: 2018-05-30

Results Overview

Progression-free survival documented by Physical Exam, CT Scan or MRI in post-menopausal patients with hormone-receptor positive metastatic breast cancer that is resistant to aromatase inhibitor therapy treated with fulvestrant and everolimus compared to fulvestrant alone from randomization to documented disease progression or death. 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

131 participants

Primary outcome timeframe

Every 3 months until progression or up to 3 years

Results posted on

2018-05-30

Participant Flow

A total of 131 patients were enrolled from 23 institutions between May 2013 and November 2015.

Participant milestones

Participant milestones
Measure	Fulvestrant & Everolimus Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Everolimus: Everolimus 10 mg (2 tablets) daily x 12 cycles. If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.	Fulvestrant & Placebo Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Overall Study STARTED	66	65
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	66	65

Reasons for withdrawal

Reasons for withdrawal
Measure	Fulvestrant & Everolimus Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Everolimus: Everolimus 10 mg (2 tablets) daily x 12 cycles. If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.	Fulvestrant & Placebo Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Overall Study Disesae progression	37	49
Overall Study Adverse Event	13	5
Overall Study Withdrawal by Subject	6	6
Overall Study Symptomatic progression	2	1
Overall Study Non-compliance	1	0
Overall Study Physician Decision	3	0
Overall Study still on treatment	2	4
Overall Study never start protocol therapy	2	0

Baseline Characteristics

Study of Fulvestrant +/- Everolimus in Post-Menopausal, Hormone-Receptor + Metastatic Breast Ca Resistant to AI

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Fulvestrant & Everolimus n=66 Participants Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Everolimus: Everolimus 10 mg (2 tablets) daily x 12 cycles. If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.	Fulvestrant & Placebo n=65 Participants Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.	Total n=131 Participants Total of all reporting groups
Age, Continuous	64 years n=5 Participants	59 years n=7 Participants	63 years n=5 Participants
Sex: Female, Male Female	66 Participants n=5 Participants	65 Participants n=7 Participants	131 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	56 Participants n=5 Participants	49 Participants n=7 Participants	105 Participants n=5 Participants
Race/Ethnicity, Customized Black	8 Participants n=5 Participants	11 Participants n=7 Participants	19 Participants n=5 Participants
Race/Ethnicity, Customized Others	2 Participants n=5 Participants	5 Participants n=7 Participants	7 Participants n=5 Participants

PRIMARY outcome

Timeframe: Every 3 months until progression or up to 3 years

Population: all randomized patients

Outcome measures

Outcome measures
Measure	Fulvestrant & Everolimus n=66 Participants Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Everolimus: Everolimus 10 mg (2 tablets) daily x 12 cycles. If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.	Fulvestrant & Placebo n=65 Participants Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Progression-free Survival	10.3 months Interval 7.6 to 13.8	5.1 months Interval 3.0 to 8.0

SECONDARY outcome

Timeframe: Every 3 months until progression or up to 3 years

Population: all randomized patients

Clinical benefit rate is defined as number of patients with objective response (complete response or partial response) or stable disease for at least 24 weeks divided by number of patients randomized in each arm. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease; Complete Response (CR) is defined as disappearance of all target lesions.

Outcome measures

Outcome measures
Measure	Fulvestrant & Everolimus n=66 Participants Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Everolimus: Everolimus 10 mg (2 tablets) daily x 12 cycles. If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.	Fulvestrant & Placebo n=65 Participants Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Clinical Benefit Rate	0.636 proportion of patients Interval 0.509 to 0.751	0.415 proportion of patients Interval 0.294 to 0.544

SECONDARY outcome

Timeframe: Every 3 months until progression or up to 3 years

Population: all randomized patients

Objective response rate is defined as number of patients with complete or partial response (by Physical Exam, CT or MRI) divided by number of patients randomized in each arm

Outcome measures

Outcome measures
Measure	Fulvestrant & Everolimus n=66 Participants Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Everolimus: Everolimus 10 mg (2 tablets) daily x 12 cycles. If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.	Fulvestrant & Placebo n=65 Participants Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Objective Response Rate	0.182 proportion of patients Interval 0.098 to 0.296	0.123 proportion of patients Interval 0.055 to 0.228

SECONDARY outcome

Timeframe: Every 3 months until progression or up to 3 years

Population: all randomized patients

Overall survival will be characterized using Kaplan-Meier plots and other descriptive metrics.

Outcome measures

Outcome measures
Measure	Fulvestrant & Everolimus n=66 Participants Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Everolimus: Everolimus 10 mg (2 tablets) daily x 12 cycles. If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.	Fulvestrant & Placebo n=65 Participants Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Overall Survival	28.3 months Interval 19.5 to 29.6	31.4 months Interval 21.8 to The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment

Adverse Events

Fulvestrant & Everolimus

Serious events: 31 serious events

Other events: 59 other events

Deaths: 30 deaths

Fulvestrant & Placebo

Serious events: 5 serious events

Other events: 38 other events

Deaths: 21 deaths

Serious adverse events

Other adverse events

Additional Information

Carolyn Andrews

PrECOG, LLC

Phone: 267-207-4070

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Fulvestrant & Everolimus n=64 participants at risk Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Everolimus: Everolimus 10 mg (2 tablets) daily x 12 cycles. If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.	Fulvestrant & Placebo n=65 participants at risk Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Gastrointestinal disorders Oral mucositis	10.9% 7/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
General disorders Fatigue	6.2% 4/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	4.6% 3/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Skin and subcutaneous tissue disorders Rash	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Blood and lymphatic system disorders Anemia	3.1% 2/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	1.5% 1/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Gastrointestinal disorders Diarrhea	3.1% 2/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	1.5% 1/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Metabolism and nutrition disorders Hypertriglyceridemia	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Metabolism and nutrition disorders Hyperglycemia	3.1% 2/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Respiratory, thoracic and mediastinal disorders Dyspnea	3.1% 2/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Respiratory, thoracic and mediastinal disorders Pneumonitis	6.2% 4/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Metabolism and nutrition disorders Hyponatremia	3.1% 2/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Hepatobiliary disorders Elevated AST	3.1% 2/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	1.5% 1/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Blood and lymphatic system disorders Lymphocytopenia	3.1% 2/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Hepatobiliary disorders Elevated ALT	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Infections and infestations Esophageal Candidiasis	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Infections and infestations Esophagitis	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Blood and lymphatic system disorders Hypertension	3.1% 2/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Metabolism and nutrition disorders Hypokalemia	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Metabolism and nutrition disorders Hypophosphatemia	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Respiratory, thoracic and mediastinal disorders Hypoxia	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Infections and infestations Laryngeal Inflammation	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Blood and lymphatic system disorders Neutropenia	3.1% 2/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Blood and lymphatic system disorders Thrombocytopenia	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Skin and subcutaneous tissue disorders Pruritus	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Surgical and medical procedures Surgical and Medical Procedures	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Cardiac disorders Thromboembolic Event	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Infections and infestations Urinary Tract Infection	1.6% 1/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.

Other adverse events
Measure	Fulvestrant & Everolimus n=64 participants at risk Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Everolimus: Everolimus 10 mg (2 tablets) daily x 12 cycles. If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.	Fulvestrant & Placebo n=65 participants at risk Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles. Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles). If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
General disorders Headache	9.4% 6/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	9.2% 6/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Respiratory, thoracic and mediastinal disorders Epistaxis	12.5% 8/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
General disorders Chills	10.9% 7/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Respiratory, thoracic and mediastinal disorders Pneumonitis	10.9% 7/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Skin and subcutaneous tissue disorders Pruritus	18.8% 12/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	3.1% 2/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Gastrointestinal disorders Vomitting	10.9% 7/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	4.6% 3/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Gastrointestinal disorders Oral mucositis	40.6% 26/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	12.3% 8/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
General disorders Fatigue	35.9% 23/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	16.9% 11/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Skin and subcutaneous tissue disorders Rash	35.9% 23/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	4.6% 3/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Gastrointestinal disorders Anorexia	34.4% 22/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	6.2% 4/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Blood and lymphatic system disorders Anemia	28.1% 18/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	4.6% 3/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Gastrointestinal disorders Nausea	25.0% 16/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	18.5% 12/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Respiratory, thoracic and mediastinal disorders Cough	23.4% 15/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	1.5% 1/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Gastrointestinal disorders Diarrhea	20.3% 13/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	6.2% 4/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Metabolism and nutrition disorders Hyperglycemia	15.6% 10/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	4.6% 3/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Metabolism and nutrition disorders Hypertriglyceridemia	15.6% 10/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	3.1% 2/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
General disorders Weight loss	14.1% 9/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	4.6% 3/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Skin and subcutaneous tissue disorders Dry skin	12.5% 8/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Gastrointestinal disorders Dysgeusia	12.5% 8/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	9.2% 6/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Respiratory, thoracic and mediastinal disorders Dyspnea	12.5% 8/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	3.1% 2/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Cardiac disorders Hot flashes	7.8% 5/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	6.2% 4/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Blood and lymphatic system disorders Neutropenia	7.8% 5/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	3.1% 2/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Blood and lymphatic system disorders Thrombocytopenia	7.8% 5/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Hepatobiliary disorders AST increased	6.2% 4/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	1.5% 1/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Hepatobiliary disorders ALT increased	6.2% 4/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	1.5% 1/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Gastrointestinal disorders Dry mouth	6.2% 4/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Metabolism and nutrition disorders Hypercholesterolemia	18.8% 12/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	3.1% 2/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Metabolism and nutrition disorders Hypokalemia	6.2% 4/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	1.5% 1/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Gastrointestinal disorders Insomnia	6.2% 4/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	0.00% 0/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Blood and lymphatic system disorders White blood cell decreased	6.2% 4/64 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.	1.5% 1/65 • Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent. All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.