BOLERO-6: A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01783444
• Collaborator: (none)
• Enrollment: 309
• Locations: 83
• Arms: 3
• Actual Duration (Months): 65.1
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a three-arm, randomized, open label, multi-center phase II study investigating the combination of everolimus (10mg daily) with exemestane (25mg daily) versus everolimus (10mg daily) versus capecitabine (1250mg/m2 twice daily for 14 days, 3-week cycle) in patients with estrogen-receptor positive, HER2 negative, advanced breast cancer after recurrence or progression on letrozole or anastrozole.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Capecitabine; Drug: Exemestane; Drug: Everolimus	Phase 2

Detailed Description

The reference therapy (control arm) used in the course of this trial was the combination arm of everolimus plus exemestane. The investigational therapies in the context of this study were everolimus monotherapy and capecitabine monotherapy. All treatments were taken orally until disease progression, intolerable toxicity or withdrawal of patient's informed consent.

Patients were randomly assigned with equal allocation to one of the treatment arms:

1. Exemestane (25mg daily) in combination with everolimus (10mg daily)

2. Everolimus (10mg daily)

3. Capecitabine (1250mg/m2 twice daily) orally for two weeks, followed by a one week rest period in 3-weeks cycles.

Treatment assignment was stratified by the presence of visceral disease (yes vs. no). Visceral refered to lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion or malignant ascites.

Randomization and Treatment Phase:

At Visit 3 all eligible patients were randomized in 1:1:1 ratio to receive everolimus (10mg daily oral tablets) in combination with exemestane (25 mg daily oral tablets), everolimus (10mg daily oral tablets) or capecitabine monotherapy (1250mg/m2 twice daily orally for two weeks followed by a one week rest period in 3-weeks cycles). Assignment was stratified by the presence of visceral disease (yes vs. no). Visceral refered to lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion or malignant ascites. After randomization, study treatment started and continued until progression, intolerable toxicity or consent withdrawal. Further treatment after progression and study treatment discontinuation was at the investigator's discretion. Dose adjustment (reduction, interruption) according to safety findings was allowed. Regular safety and efficacy reviews by Data Monitoring Committee (DMC) were performed. Tumor assessments were performed every 6 weeks until disease progression. Additional evaluation were performed to confirm response at 4 weeks after it was first observed. After at least 150 PFS events had been documented per RECIST 1.1 by local assessment in each of the two following groups: (i) everolimus + exemestane arm plus everolimus monotherapy arm, and (ii) everolimus + exemestane arm plus capecitabine monotherapy arm, the frequency of tumor assessments was changed to every 12 weeks or as clinically indicated.

Follow-up phase:

Patients were followed for safety for 30 days after study treatment discontinuation. If a patient did not discontinue study treatment due to disease progression, lost to follow-up or consent withdrawal, then tumor assessments continued to be performed every 6 weeks until disease progression, death, lost to follow-up or investigator decision in patient best interest.

Survival Data Collection:

All patients were followed for survival status at least every 3 months regardless of treatment discontinuation reason and up to two years after randomization of last patient. Survival information could be obtained via phone and information were documented in the source documents and eCRF. Additional survival follow-up might be performed more frequently if a survival update was required for reporting the results or to meet safety or regulatory needs.

Study Design

• Study Type: Interventional
• Actual Enrollment: 309 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Three-arm, Randomized, Open Label, Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in the Treatment of Postmenopausal Women With Estrogen Receptor Positive, Locally Advanced, Recurrent, or Metastatic Breast Cancer After Recurrence or Progression on Prior Letrozole or Anastrozole.
• Actual Study Start Date: Feb 26, 2013
• Actual Primary Completion Date: Jul 2, 2018
• Actual Study Completion Date: Jul 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Capecitabine 1250 mg/m2 Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).	Drug: Capecitabine; Capecitabine, tablets for oral use, 1250 mg/m² twice daily for 2 weeks followed by one week rest (3-week-cycle) (locally supplied); Other Names: Capecitabine monotherapy
Experimental: Everolimus 10 mg Everolimus (10 mg daily) (investigational arm).	Drug: Everolimus; Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied); Other Names: Everolimus monotherapy RAD001
Active Comparator: Everolimus 10 mg + Exemestane 25 mg Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Drug: Exemestane; Exemestane, tablets for oral use, 25 mg per day in (locally supplied); Other Names: Control arm ; Drug: Everolimus; Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied); Other Names: Everolimus monotherapy RAD001

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Everolimus Alone [Date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to 39 months]

   Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was compared between the everolimus + exemestane combination therapy with the everolimus monotherapy.

Secondary Outcome Measures

1. Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Capecitabine Alone [Date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to 39 months]

   Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was compared between the everolimus + exemestane combination therapy with the everolimus monotherapy.

2. Overall Survival (OS) [Every 3 months following end of treatment visit, assessed for approximately 54 months]

   Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive.

3. Overall Response Rate (ORR) [From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 43 months]

   Overall Response Rate (ORR) as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST 1.1 This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at baseline are absent at subsequent visit. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Only descriptive statistics.

4. Clinical Benefit Rate (CBR) [From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 43 months]

   Clinical Benefit Rate (CBR) is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 24 weeks based on local investigator's assessment according to RECIST 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR, Stable disease (SD), neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; CBR = CR+PR+SD. Only descriptive statistics.

5. Time to Eastern Cooperative Oncology Group (ECOG) Performance Deterioration [Baseline, every 6 weeks up to about 43 months]

   The Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale used to assess physical health of subjects,ranging from 0 (most active) to 5 (least active). Definitive deterioration is defined as no improvement in the ECOG status following observation of the deterioration.

6. Time to 10% Definitive Deterioration in the Global Health Status / Quality of Life [Baseline, every 6 weeks up to about 43 months]

   The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen. Definitive 10% (5-point) deterioration is defined as a decrease in score by at least 10% (5-points) compared to baseline, with no later increase above this threshold observed during the course of the study.

7. Mean Change in Treatment Satisfaction Questionnaire for Medication (TSQM) Between Week 3 and 12 [Week 3, Week 12]

   TSQM was used to measure the Patients' self-reported satisfaction or dissatisfaction with the study treatment. The differences in mean scale scores between weeks 3 and 12 comparing treatment satisfaction in the different treatment arms: everolimus + exemestane combination therapy versus everolimus monotherapy, and everolimus + exemestane combination therapy versus capecitabine monotherapy. The TSQM version 1.4 domain scores range from 0 to 100 with higher scores representing a higher satisfaction on that domain.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Women with locally advanced, recurrent, or metastatic breast cancer along with confirmation of estrogen-receptor positive (ER+). Measurable disease defined as at least one lesion ≥ 10 mm by CT or MRI that can be accurately measured in at least one dimension (CT scan slice thickness ≤ 5 mm) OR • Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as defined above.

Key Exclusion Criteria:

• Patients who received more than one chemotherapy line. Patients with only non-measurable lesions other than lytic or mixed (lytic and blastic) bone metastasis.Previous treatment with exemestane, mTOR inhibitors, PI3K inhibitors or AKT inhibitors.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California at Los Angeles Mattel Children's Hospital	Los Angeles	California	United States	90095
2	Sharp Memorial Hospital SharpClinicalOncologyResearch	San Diego	California	United States	92123
3	Florida Cancer Specialists Dept of Oncology (2)	Fort Myers	Florida	United States	33901
4	Florida Cancer Specialists FL Cancer Specialists	Fort Myers	Florida	United States	33901
5	Lahey Clinic Dept of Lahey Clinic (2)	Burlington	Massachusetts	United States	01805
6	New England Hematology/ Oncology Associates, P.C. SC	Newton	Massachusetts	United States	02462
7	Glacier View Research Institute - Cancer SC	Kalispell	Montana	United States	59901
8	Trinitas Comprehensive Cancer Center SC	Elizabeth	New Jersey	United States	07207
9	Hackensack University Medical Center Dept of Oncology	Hackensack	New Jersey	United States	07601
10	Rutgers-New Jersey Medical School SC	Newark	New Jersey	United States	07101
11	Oncology Hematology Care Inc Oncology Hematology Care 2	Cincinnati	Ohio	United States	45242
12	Oklahoma Cancer Specialists and Research Institute Oklahoma Cancer Specialists	Tulsa	Oklahoma	United States	74136
13	Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology	Chattanooga	Tennessee	United States	37404
14	The Jones Clinic SC	Germantown	Tennessee	United States	38138
15	University of Tennessee SC	Knoxville	Tennessee	United States	27920-6969
16	Sarah Cannon Research Institute SC (2)	Nashville	Tennessee	United States	37203
17	The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD	Fort Worth	Texas	United States	76104
18	University of Virginia Health Systems SC-4	Charlottesville	Virginia	United States	22908-0334
19	Northwest Medical Specialties Dept of Onc	Tacoma	Washington	United States	98405
20	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1025ABI
21	Novartis Investigative Site	Posadas	Misiones	Argentina
22	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000KZE
23	Novartis Investigative Site	Rio Negro	Viedma	Argentina	8500
24	Novartis Investigative Site	Cordoba		Argentina	X5016KEH
25	Novartis Investigative Site	Randwick	New South Wales	Australia	2031
26	Novartis Investigative Site	Wahroonga	New South Wales	Australia	2076
27	Novartis Investigative Site	Malvern	Victoria	Australia	3144
28	Novartis Investigative Site	Parkville	Victoria	Australia	3050
29	Novartis Investigative Site	Liege		Belgium	4000
30	Novartis Investigative Site	Salvador	BA	Brazil	41253-190
31	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul	Brazil	90610-000
32	Novartis Investigative Site	Natal	RN	Brazil	59075 740
33	Novartis Investigative Site	Passo Fundo	RS	Brazil	99010-260
34	Novartis Investigative Site	Sao Paulo	SP	Brazil	01317-002
35	Novartis Investigative Site	Aarhus		Denmark	8000 C
36	Novartis Investigative Site	Copenhagen		Denmark	DK-2100
37	Novartis Investigative Site	Næstved		Denmark	DK-4700
38	Novartis Investigative Site	Odense C		Denmark	DK 5000
39	Novartis Investigative Site	Roskilde		Denmark	4000
40	Novartis Investigative Site	Vejle		Denmark	7100
41	Novartis Investigative Site	Budapest	HUN	Hungary	1145
42	Novartis Investigative Site	Debrecen		Hungary	4032
43	Novartis Investigative Site	Tatabanya		Hungary	2800
44	Novartis Investigative Site	Hyderabad	Andhra Pradesh	India	500 034
45	Novartis Investigative Site	Pune	Maharashtra	India	411013
46	Novartis Investigative Site	Kolkatta	West Bengal	India	700 053
47	Novartis Investigative Site	Mumbai		India	400 012
48	Novartis Investigative Site	Limerick	Co Limerick	Ireland
49	Novartis Investigative Site	Dublin 4		Ireland	D04 T6F
50	Novartis Investigative Site	Galway		Ireland
51	Novartis Investigative Site	Ashrafieh		Lebanon	166830
52	Novartis Investigative Site	Beirut		Lebanon	1107 2020
53	Novartis Investigative Site	Beirut		Lebanon
54	Novartis Investigative Site	Hazmieh		Lebanon	470
55	Novartis Investigative Site	Saida		Lebanon	652
56	Novartis Investigative Site	Kota Kinabalu	Sabah	Malaysia	88586
57	Novartis Investigative Site	Kuala Lumpur		Malaysia	59100
58	Novartis Investigative Site	Jesus Maria	Lima	Peru	11
59	Novartis Investigative Site	San Borja	Lima	Peru	41
60	Novartis Investigative Site	Surquillo	Lima	Peru	34
61	Novartis Investigative Site	Arequipa		Peru
62	Novartis Investigative Site	Arkhangelsk		Russian Federation	163045
63	Novartis Investigative Site	Moscow		Russian Federation	115478
64	Novartis Investigative Site	St Petersburg		Russian Federation	197758
65	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
66	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
67	Novartis Investigative Site	Madrid		Spain	28033
68	Novartis Investigative Site	Madrid		Spain	28040
69	Novartis Investigative Site	Eskilstuna		Sweden	SE-631 88
70	Novartis Investigative Site	Joenkoeping		Sweden	551 85
71	Novartis Investigative Site	Stockholm		Sweden	SE-171 76
72	Novartis Investigative Site	Uppsala		Sweden	SE-751 85
73	Novartis Investigative Site	Vasteras		Sweden	721 89
74	Novartis Investigative Site	Vaxjo		Sweden	SE-351 85
75	Novartis Investigative Site	Songkhla	Hat Yai	Thailand	90110
76	Novartis Investigative Site	Muang Lopburi	Lopburi	Thailand	15000
77	Novartis Investigative Site	Muang		Thailand	40002
78	Novartis Investigative Site	Adana		Turkey	01330
79	Novartis Investigative Site	Istanbul		Turkey	34303
80	Novartis Investigative Site	Izmir		Turkey	35340
81	Novartis Investigative Site	East Kilbride		United Kingdom	G75 8RG
82	Novartis Investigative Site	Middlesborough		United Kingdom	TS4 3BW
83	Novartis Investigative Site	Nottingham		United Kingdom	NG5 1PB

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Oct 27, 2017
• Study Protocol - Apr 18, 2017

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01783444
• Other Study ID Numbers: CRAD001Y2201; 2012-003757-28
• First Posted: Feb 5, 2013
• Last Update Posted: Feb 26, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Everolimus; Exemestane; Capecitabine; locally advanced; metastatic; breast cancer; breast cancer positive for human epidermal growth factor receptor 2; HER2; HER2 positive; breast cancer progression; estrogen-receptor positive breast cancer; ER
• Additional relevant MeSH terms: Breast Neoplasms; Capecitabine; Everolimus; Exemestane

Study Results

Participant Flow

Recruitment Details	This study was conducted at 84 centers in 18 countries worldwide: Belgium (1), Denmark (6), Hungary (3), Ireland (3), Spain (4), Sweden (6), United Kingdom (3), United States (19), Argentina (6), Brazil (5), Peru (4), India (4), Lebanon (5), Malaysia (2), Russia (3), Thailand (3), Turkey (3) Australia (4)
Pre-assignment Detail	A total of 300 subjects were planned and total of 309 subjects were randomized to everolimus plus exemestane (control arm) (N = 104), everolimus alone (N = 103), or capecitabine (N = 102).

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Everolimus 10 mg	Capecitabine 1250 mg/m2
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Everolimus (10 mg daily) (investigational arm).	Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
Period Title: Treatment Phase
STARTED	104	103	102
Safety Set	104	103	102
COMPLETED	0	0	0
NOT COMPLETED	104	103	102
Period Title: Treatment Phase
STARTED	96	93	91
COMPLETED	0	0	0
NOT COMPLETED	96	93	91

Baseline Characteristics

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Everolimus 10 mg	Capecitabine 1250 mg/m2	Total
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Everolimus (10 mg daily) (investigational arm).	Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).	Total of all reporting groups
Overall Participants	104	103	102	309
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.9 (10.47)	61.3 (9.08)	59.7 (10.50)	60.6 (10.03)
Sex: Female, Male (Count of Participants)
Female	104 100%	103 100%	102 100%	309 100%
Male	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	78 75%	85 82.5%	91 89.2%	254 82.2%
Black	1 1%	2 1.9%	0 0%	3 1%
Asian	11 10.6%	8 7.8%	8 7.8%	27 8.7%
Native American	3 2.9%	2 1.9%	0 0%	5 1.6%
Other	11 10.6%	6 5.8%	3 2.9%	20 6.5%
ECOG Performance Status (Count of Participants)
No Restrictions	54 51.9%	48 46.6%	57 55.9%	159 51.5%
Only Light Work	42 40.4%	50 48.5%	39 38.2%	131 42.4%
Only Self Care	5 4.8%	3 2.9%	4 3.9%	12 3.9%
Missing	3 2.9%	2 1.9%	2 2%	7 2.3%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Everolimus Alone
Description	Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was compared between the everolimus + exemestane combination therapy with the everolimus monotherapy.
Time Frame	Date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to 39 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), which consisted of all randomized patients, was considered.

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Everolimus 10 mg
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Everolimus (10 mg daily) (investigational arm).
Measure Participants	104	103
Median (90% Confidence Interval) [Months]	8.41	6.77

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Everolimus 10 mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 90%; 0.57 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Capecitabine Alone
Description	Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was compared between the everolimus + exemestane combination therapy with the everolimus monotherapy.
Time Frame	Date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to 39 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), which consisted of all randomized patients, was considered.

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Capecitabine 1250 mg/m2
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
Measure Participants	104	102
Median (90% Confidence Interval) [Months]	8.41	9.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Everolimus 10 mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 90%; 0.96 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive.
Time Frame	Every 3 months following end of treatment visit, assessed for approximately 54 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), which consisted of all randomized patients, was considered.

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Everolimus 10 mg	Capecitabine 1250 mg/m2
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Everolimus (10 mg daily) (investigational arm).	Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
Measure Participants	104	103	102
Median (90% Confidence Interval) [Months]	23.06	29.27	25.56

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Everolimus 10 mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.27
	Confidence Interval	(2-Sided) 90%; 0.95 to 1.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Capecitabine 1250 mg/m2
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 90%; 0.99 to 1.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	Overall Response Rate (ORR) as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST 1.1 This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at baseline are absent at subsequent visit. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Only descriptive statistics.
Time Frame	From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 43 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), which consisted of all randomized patients, was considered.

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Everolimus 10 mg	Capecitabine 1250 mg/m2
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Everolimus (10 mg daily) (investigational arm).	Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
Measure Participants	104	103	102
Number (90% Confidence Interval) [Percentage of Participants]	21 20.2%	12 11.7%	23 22.5%

5. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	Clinical Benefit Rate (CBR) is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 24 weeks based on local investigator's assessment according to RECIST 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR, Stable disease (SD), neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; CBR = CR+PR+SD. Only descriptive statistics.
Time Frame	From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 43 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), which consisted of all randomized patients, was considered.

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Everolimus 10 mg	Capecitabine 1250 mg/m2
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Everolimus (10 mg daily) (investigational arm).	Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
Measure Participants	104	103	102
Number (90% Confidence Interval) [Percentage of Participants]	59 56.7%	43 41.7%	53 52%

6. Secondary Outcome

Title	Time to Eastern Cooperative Oncology Group (ECOG) Performance Deterioration
Description	The Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale used to assess physical health of subjects,ranging from 0 (most active) to 5 (least active). Definitive deterioration is defined as no improvement in the ECOG status following observation of the deterioration.
Time Frame	Baseline, every 6 weeks up to about 43 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), which consisted of all randomized patients, was considered.

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Everolimus 10 mg	Capecitabine 1250 mg/m2
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Everolimus (10 mg daily) (investigational arm).	Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
Measure Participants	104	103	102
Median (90% Confidence Interval) [Weeks]	72.57	126.57	120.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Everolimus 10 mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 90%; 0.72 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Capecitabine 1250 mg/m2
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 90%; 0.78 to 1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Time to 10% Definitive Deterioration in the Global Health Status / Quality of Life
Description	The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen. Definitive 10% (5-point) deterioration is defined as a decrease in score by at least 10% (5-points) compared to baseline, with no later increase above this threshold observed during the course of the study.
Time Frame	Baseline, every 6 weeks up to about 43 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), which consisted of all randomized patients, was considered.

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Everolimus 10 mg	Capecitabine 1250 mg/m2
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Everolimus (10 mg daily) (investigational arm).	Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
Measure Participants	104	103	102
Median (90% Confidence Interval) [Weeks]	30.86	23.86	61.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Everolimus 10 mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 90%; 0.46 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Capecitabine 1250 mg/m2
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 90%; 0.93 to 1.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Mean Change in Treatment Satisfaction Questionnaire for Medication (TSQM) Between Week 3 and 12
Description	TSQM was used to measure the Patients' self-reported satisfaction or dissatisfaction with the study treatment. The differences in mean scale scores between weeks 3 and 12 comparing treatment satisfaction in the different treatment arms: everolimus + exemestane combination therapy versus everolimus monotherapy, and everolimus + exemestane combination therapy versus capecitabine monotherapy. The TSQM version 1.4 domain scores range from 0 to 100 with higher scores representing a higher satisfaction on that domain.
Time Frame	Week 3, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), which consisted of all randomized patients, was considered. Only participants who had both post-baseline assessments were included.

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Everolimus 10 mg	Capecitabine 1250 mg/m2
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Everolimus (10 mg daily) (investigational arm).	Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
Measure Participants	104	103	102
Side-effects	-4.8 (28.88)	-9.1 (21.88)	-2.6 (22.45)
Effectiveness	-2.2 (20.15)	1.2 (26.51)	1.2 (21.61)
Convenience	-0.6 (12.00)	1.0 (16.41)	0.5 (17.67)
Global satisfaction	-1.0 (17.32)	1.8 (20.80)	2.3 (16.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Everolimus 10 mg
	Comments	Side-effects
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.3
	Confidence Interval	(2-Sided) 90%; -3.3 to 11.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Capecitabine 1250 mg/m2
	Comments	Side-effects
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 90%; -9.9 to 5.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Everolimus 10 mg
	Comments	Effectiveness
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 90%; -10.4 to 3.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Capecitabine 1250 mg/m2
	Comments	Effectiveness
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 90%; -9.7 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Everolimus 10 mg
	Comments	Convenience
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 90%; -5.8 to 2.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Capecitabine 1250 mg/m2
	Comments	Convenience
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 90%; -5.5 to 3.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Everolimus 10 mg
	Comments	Global Satisfaction
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) 90%; -8.3 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Everolimus 10 mg + Exemestane 25 mg, Capecitabine 1250 mg/m2
	Comments	Global Satisfaction
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 90%; -8.4 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Post-Hoc Outcome

Title	All Collected Deaths
Description	On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 224 weeks (treatment duration ranged from 1.3 to 220.0 weeks). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 5 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.
Time Frame	up to 224 weeks (on-treatment), up to approximately 5 years (study duration)

Outcome Measure Data

Analysis Population Description

Clinical database population; all treated patients

Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg	Everolimus 10 mg	Capecitabine 1250 mg/m2
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Everolimus (10 mg daily) (investigational arm).	Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
Measure Participants	104	103	102
On-treatment deaths	9 8.7%	5 4.9%	2 2%
Post-treatment deaths	62 59.6%	55 53.4%	57 55.9%
All deaths	71 68.3%	60 58.3%	59 57.8%

Adverse Events

Time Frame	Adverse events were collected from First Patient First Treatment (FPFT) up to 30 days after study drug discontinuation, for a maximum duration of 224 weeks (treatment duration ranged from 1.3 to 220.0 weeks).
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment and 30 days post treatment follow up. Maximum exposure to study treatments = 201 weeks (Everolimus + Exemestane treatment group), 145 weeks (Everolimus treatment group) and 220 weeks (Capecitabine treatment group).
Arm/Group Title	Everolimus 10 mg + Exemestane 25 mg		Everolimus 10 mg		Capecitabine 1250 mg/m2
Arm/Group Description	Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).		Everolimus (10 mg daily) (investigational arm).		Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
All Cause Mortality
	Everolimus 10 mg + Exemestane 25 mg		Everolimus 10 mg		Capecitabine 1250 mg/m2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/104 (8.7%)		5/103 (4.9%)		2/102 (2%)
Serious Adverse Events
	Everolimus 10 mg + Exemestane 25 mg		Everolimus 10 mg		Capecitabine 1250 mg/m2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/104 (35.6%)		30/103 (29.1%)		30/102 (29.4%)
Blood and lymphatic system disorders
Anaemia	1/104 (1%)		3/103 (2.9%)		1/102 (1%)
Febrile neutropenia	0/104 (0%)		0/103 (0%)		1/102 (1%)
Leukopenia	0/104 (0%)		0/103 (0%)		1/102 (1%)
Neutropenia	0/104 (0%)		0/103 (0%)		1/102 (1%)
Pancytopenia	0/104 (0%)		0/103 (0%)		1/102 (1%)
Thrombocytopenia	0/104 (0%)		0/103 (0%)		1/102 (1%)
Cardiac disorders
Atrial fibrillation	1/104 (1%)		0/103 (0%)		0/102 (0%)
Cardiac arrest	1/104 (1%)		0/103 (0%)		0/102 (0%)
Cardiac failure	1/104 (1%)		0/103 (0%)		0/102 (0%)
Cardiac failure acute	1/104 (1%)		0/103 (0%)		0/102 (0%)
Cardiac failure congestive	0/104 (0%)		1/103 (1%)		0/102 (0%)
Cardio-respiratory arrest	1/104 (1%)		1/103 (1%)		0/102 (0%)
Pericardial effusion	1/104 (1%)		0/103 (0%)		0/102 (0%)
Ear and labyrinth disorders
Vertigo positional	1/104 (1%)		1/103 (1%)		0/102 (0%)
Eye disorders
Diplopia	0/104 (0%)		0/103 (0%)		1/102 (1%)
Gastrointestinal disorders
Abdominal pain	2/104 (1.9%)		0/103 (0%)		2/102 (2%)
Ascites	0/104 (0%)		1/103 (1%)		1/102 (1%)
Colitis	0/104 (0%)		1/103 (1%)		0/102 (0%)
Constipation	1/104 (1%)		0/103 (0%)		0/102 (0%)
Diarrhoea	1/104 (1%)		2/103 (1.9%)		3/102 (2.9%)
Diarrhoea haemorrhagic	0/104 (0%)		0/103 (0%)		1/102 (1%)
Dysphagia	1/104 (1%)		0/103 (0%)		1/102 (1%)
Gastric haemorrhage	0/104 (0%)		1/103 (1%)		0/102 (0%)
Gastrointestinal haemorrhage	0/104 (0%)		1/103 (1%)		0/102 (0%)
Ileus	1/104 (1%)		0/103 (0%)		0/102 (0%)
Large intestinal obstruction	1/104 (1%)		0/103 (0%)		0/102 (0%)
Nausea	3/104 (2.9%)		0/103 (0%)		0/102 (0%)
Rectal haemorrhage	1/104 (1%)		0/103 (0%)		0/102 (0%)
Stomatitis	0/104 (0%)		2/103 (1.9%)		1/102 (1%)
Vomiting	2/104 (1.9%)		1/103 (1%)		3/102 (2.9%)
General disorders
Death	1/104 (1%)		0/103 (0%)		0/102 (0%)
Drug intolerance	0/104 (0%)		0/103 (0%)		1/102 (1%)
Fatigue	1/104 (1%)		0/103 (0%)		2/102 (2%)
General physical health deterioration	4/104 (3.8%)		0/103 (0%)		0/102 (0%)
Hernia	0/104 (0%)		1/103 (1%)		0/102 (0%)
Multiple organ dysfunction syndrome	0/104 (0%)		0/103 (0%)		1/102 (1%)
Non-cardiac chest pain	2/104 (1.9%)		0/103 (0%)		0/102 (0%)
Oedema peripheral	0/104 (0%)		1/103 (1%)		0/102 (0%)
Performance status decreased	0/104 (0%)		1/103 (1%)		0/102 (0%)
Hepatobiliary disorders
Bile duct obstruction	0/104 (0%)		1/103 (1%)		0/102 (0%)
Hepatic failure	2/104 (1.9%)		1/103 (1%)		0/102 (0%)
Hyperbilirubinaemia	0/104 (0%)		0/103 (0%)		1/102 (1%)
Infections and infestations
Bacterial pyelonephritis	1/104 (1%)		0/103 (0%)		0/102 (0%)
Ear infection	1/104 (1%)		0/103 (0%)		0/102 (0%)
Erysipelas	0/104 (0%)		0/103 (0%)		1/102 (1%)
Escherichia sepsis	1/104 (1%)		0/103 (0%)		0/102 (0%)
Gastroenteritis	0/104 (0%)		1/103 (1%)		1/102 (1%)
Infected cyst	1/104 (1%)		0/103 (0%)		0/102 (0%)
Infection	0/104 (0%)		1/103 (1%)		0/102 (0%)
Lung infection	1/104 (1%)		0/103 (0%)		1/102 (1%)
Pneumocystis jirovecii pneumonia	1/104 (1%)		0/103 (0%)		0/102 (0%)
Pneumonia	8/104 (7.7%)		4/103 (3.9%)		2/102 (2%)
Pyelonephritis	1/104 (1%)		0/103 (0%)		0/102 (0%)
Sepsis	1/104 (1%)		0/103 (0%)		0/102 (0%)
Septic shock	0/104 (0%)		0/103 (0%)		1/102 (1%)
Urinary tract infection	3/104 (2.9%)		1/103 (1%)		1/102 (1%)
Urosepsis	0/104 (0%)		0/103 (0%)		1/102 (1%)
Injury, poisoning and procedural complications
Fibula fracture	0/104 (0%)		0/103 (0%)		1/102 (1%)
Humerus fracture	0/104 (0%)		0/103 (0%)		1/102 (1%)
Ilium fracture	0/104 (0%)		0/103 (0%)		1/102 (1%)
Spinal fracture	0/104 (0%)		0/103 (0%)		1/102 (1%)
Upper limb fracture	0/104 (0%)		1/103 (1%)		1/102 (1%)
Wrist fracture	0/104 (0%)		0/103 (0%)		1/102 (1%)
Investigations
Alanine aminotransferase increased	0/104 (0%)		1/103 (1%)		0/102 (0%)
Aspartate aminotransferase increased	0/104 (0%)		1/103 (1%)		0/102 (0%)
Blood triglycerides increased	1/104 (1%)		0/103 (0%)		0/102 (0%)
Blood uric acid increased	1/104 (1%)		0/103 (0%)		0/102 (0%)
Body temperature increased	1/104 (1%)		0/103 (0%)		0/102 (0%)
Ejection fraction decreased	0/104 (0%)		0/103 (0%)		1/102 (1%)
Gamma-glutamyltransferase increased	1/104 (1%)		0/103 (0%)		0/102 (0%)
Platelet count decreased	1/104 (1%)		0/103 (0%)		1/102 (1%)
Metabolism and nutrition disorders
Decreased appetite	0/104 (0%)		0/103 (0%)		1/102 (1%)
Dehydration	1/104 (1%)		1/103 (1%)		3/102 (2.9%)
Electrolyte imbalance	0/104 (0%)		1/103 (1%)		0/102 (0%)
Failure to thrive	1/104 (1%)		0/103 (0%)		0/102 (0%)
Hyperkalaemia	1/104 (1%)		0/103 (0%)		0/102 (0%)
Hypocalcaemia	1/104 (1%)		0/103 (0%)		0/102 (0%)
Hypoglycaemia	0/104 (0%)		1/103 (1%)		0/102 (0%)
Hypokalaemia	0/104 (0%)		1/103 (1%)		2/102 (2%)
Type 2 diabetes mellitus	0/104 (0%)		1/103 (1%)		0/102 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/104 (1.9%)		1/103 (1%)		0/102 (0%)
Bone pain	0/104 (0%)		0/103 (0%)		1/102 (1%)
Mobility decreased	1/104 (1%)		0/103 (0%)		0/102 (0%)
Musculoskeletal chest pain	1/104 (1%)		0/103 (0%)		0/102 (0%)
Musculoskeletal pain	0/104 (0%)		1/103 (1%)		0/102 (0%)
Pain in extremity	1/104 (1%)		0/103 (0%)		0/102 (0%)
Pathological fracture	0/104 (0%)		1/103 (1%)		0/102 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	1/104 (1%)		2/103 (1.9%)		0/102 (0%)
Ovarian cancer	1/104 (1%)		0/103 (0%)		0/102 (0%)
Papillary thyroid cancer	0/104 (0%)		0/103 (0%)		1/102 (1%)
Nervous system disorders
Cerebrovascular accident	0/104 (0%)		0/103 (0%)		1/102 (1%)
Headache	0/104 (0%)		0/103 (0%)		1/102 (1%)
Hypoaesthesia	1/104 (1%)		0/103 (0%)		0/102 (0%)
Seizure	0/104 (0%)		0/103 (0%)		1/102 (1%)
Syncope	2/104 (1.9%)		1/103 (1%)		0/102 (0%)
Transient ischaemic attack	0/104 (0%)		1/103 (1%)		0/102 (0%)
Renal and urinary disorders
Acute kidney injury	3/104 (2.9%)		4/103 (3.9%)		2/102 (2%)
Nephrolithiasis	0/104 (0%)		1/103 (1%)		0/102 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/104 (1.9%)		0/103 (0%)		0/102 (0%)
Bronchial hyperreactivity	0/104 (0%)		1/103 (1%)		0/102 (0%)
Dyspnoea	2/104 (1.9%)		2/103 (1.9%)		1/102 (1%)
Hydrothorax	0/104 (0%)		1/103 (1%)		0/102 (0%)
Pleural effusion	1/104 (1%)		1/103 (1%)		2/102 (2%)
Pneumonitis	2/104 (1.9%)		3/103 (2.9%)		0/102 (0%)
Pulmonary embolism	2/104 (1.9%)		1/103 (1%)		2/102 (2%)
Respiratory failure	1/104 (1%)		3/103 (2.9%)		1/102 (1%)
Skin and subcutaneous tissue disorders
Skin toxicity	0/104 (0%)		0/103 (0%)		1/102 (1%)
Vascular disorders
Deep vein thrombosis	0/104 (0%)		0/103 (0%)		4/102 (3.9%)
Hypotension	0/104 (0%)		0/103 (0%)		3/102 (2.9%)
Hypovolaemic shock	0/104 (0%)		0/103 (0%)		1/102 (1%)
Other (Not Including Serious) Adverse Events
	Everolimus 10 mg + Exemestane 25 mg		Everolimus 10 mg		Capecitabine 1250 mg/m2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	103/104 (99%)		100/103 (97.1%)		99/102 (97.1%)
Blood and lymphatic system disorders
Anaemia	32/104 (30.8%)		26/103 (25.2%)		22/102 (21.6%)
Neutropenia	4/104 (3.8%)		4/103 (3.9%)		14/102 (13.7%)
Thrombocytopenia	4/104 (3.8%)		7/103 (6.8%)		3/102 (2.9%)
Eye disorders
Dry eye	2/104 (1.9%)		1/103 (1%)		7/102 (6.9%)
Lacrimation increased	3/104 (2.9%)		4/103 (3.9%)		9/102 (8.8%)
Gastrointestinal disorders
Abdominal pain	10/104 (9.6%)		9/103 (8.7%)		13/102 (12.7%)
Abdominal pain upper	6/104 (5.8%)		3/103 (2.9%)		6/102 (5.9%)
Constipation	14/104 (13.5%)		15/103 (14.6%)		18/102 (17.6%)
Diarrhoea	36/104 (34.6%)		34/103 (33%)		55/102 (53.9%)
Dry mouth	10/104 (9.6%)		11/103 (10.7%)		12/102 (11.8%)
Dyspepsia	8/104 (7.7%)		5/103 (4.9%)		7/102 (6.9%)
Mouth ulceration	15/104 (14.4%)		13/103 (12.6%)		1/102 (1%)
Nausea	35/104 (33.7%)		21/103 (20.4%)		52/102 (51%)
Stomatitis	51/104 (49%)		45/103 (43.7%)		24/102 (23.5%)
Toothache	5/104 (4.8%)		6/103 (5.8%)		1/102 (1%)
Vomiting	20/104 (19.2%)		14/103 (13.6%)		29/102 (28.4%)
General disorders
Asthenia	25/104 (24%)		9/103 (8.7%)		24/102 (23.5%)
Fatigue	39/104 (37.5%)		32/103 (31.1%)		34/102 (33.3%)
Non-cardiac chest pain	6/104 (5.8%)		4/103 (3.9%)		5/102 (4.9%)
Oedema peripheral	30/104 (28.8%)		22/103 (21.4%)		16/102 (15.7%)
Pyrexia	18/104 (17.3%)		12/103 (11.7%)		9/102 (8.8%)
Infections and infestations
Pneumonia	6/104 (5.8%)		7/103 (6.8%)		2/102 (2%)
Rash pustular	6/104 (5.8%)		0/103 (0%)		0/102 (0%)
Upper respiratory tract infection	8/104 (7.7%)		8/103 (7.8%)		5/102 (4.9%)
Urinary tract infection	12/104 (11.5%)		8/103 (7.8%)		5/102 (4.9%)
Investigations
Alanine aminotransferase increased	16/104 (15.4%)		10/103 (9.7%)		6/102 (5.9%)
Aspartate aminotransferase increased	16/104 (15.4%)		14/103 (13.6%)		9/102 (8.8%)
Blood cholesterol increased	6/104 (5.8%)		9/103 (8.7%)		1/102 (1%)
Blood creatinine increased	8/104 (7.7%)		6/103 (5.8%)		4/102 (3.9%)
Gamma-glutamyltransferase increased	15/104 (14.4%)		16/103 (15.5%)		2/102 (2%)
Platelet count decreased	8/104 (7.7%)		1/103 (1%)		1/102 (1%)
Weight decreased	31/104 (29.8%)		25/103 (24.3%)		15/102 (14.7%)
Metabolism and nutrition disorders
Decreased appetite	35/104 (33.7%)		32/103 (31.1%)		27/102 (26.5%)
Dehydration	9/104 (8.7%)		5/103 (4.9%)		5/102 (4.9%)
Hypercholesterolaemia	3/104 (2.9%)		9/103 (8.7%)		3/102 (2.9%)
Hyperglycaemia	13/104 (12.5%)		18/103 (17.5%)		8/102 (7.8%)
Hypertriglyceridaemia	5/104 (4.8%)		15/103 (14.6%)		9/102 (8.8%)
Hypokalaemia	11/104 (10.6%)		6/103 (5.8%)		5/102 (4.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	11/104 (10.6%)		16/103 (15.5%)		13/102 (12.7%)
Back pain	20/104 (19.2%)		8/103 (7.8%)		12/102 (11.8%)
Bone pain	9/104 (8.7%)		4/103 (3.9%)		7/102 (6.9%)
Muscle spasms	3/104 (2.9%)		6/103 (5.8%)		0/102 (0%)
Musculoskeletal chest pain	10/104 (9.6%)		7/103 (6.8%)		8/102 (7.8%)
Musculoskeletal pain	11/104 (10.6%)		5/103 (4.9%)		9/102 (8.8%)
Myalgia	6/104 (5.8%)		4/103 (3.9%)		3/102 (2.9%)
Neck pain	6/104 (5.8%)		1/103 (1%)		4/102 (3.9%)
Pain in extremity	14/104 (13.5%)		13/103 (12.6%)		16/102 (15.7%)
Nervous system disorders
Dizziness	8/104 (7.7%)		9/103 (8.7%)		6/102 (5.9%)
Dysgeusia	17/104 (16.3%)		20/103 (19.4%)		14/102 (13.7%)
Headache	17/104 (16.3%)		16/103 (15.5%)		13/102 (12.7%)
Neuropathy peripheral	1/104 (1%)		1/103 (1%)		7/102 (6.9%)
Paraesthesia	6/104 (5.8%)		2/103 (1.9%)		3/102 (2.9%)
Psychiatric disorders
Anxiety	6/104 (5.8%)		2/103 (1.9%)		5/102 (4.9%)
Depression	8/104 (7.7%)		5/103 (4.9%)		5/102 (4.9%)
Insomnia	10/104 (9.6%)		8/103 (7.8%)		11/102 (10.8%)
Renal and urinary disorders
Dysuria	6/104 (5.8%)		1/103 (1%)		3/102 (2.9%)
Reproductive system and breast disorders
Breast pain	6/104 (5.8%)		1/103 (1%)		6/102 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	37/104 (35.6%)		16/103 (15.5%)		18/102 (17.6%)
Dyspnoea	18/104 (17.3%)		19/103 (18.4%)		17/102 (16.7%)
Epistaxis	13/104 (12.5%)		11/103 (10.7%)		0/102 (0%)
Oropharyngeal pain	4/104 (3.8%)		7/103 (6.8%)		1/102 (1%)
Pleural effusion	4/104 (3.8%)		5/103 (4.9%)		6/102 (5.9%)
Pneumonitis	22/104 (21.2%)		21/103 (20.4%)		0/102 (0%)
Skin and subcutaneous tissue disorders
Alopecia	6/104 (5.8%)		3/103 (2.9%)		6/102 (5.9%)
Dermatitis acneiform	7/104 (6.7%)		4/103 (3.9%)		0/102 (0%)
Dry skin	11/104 (10.6%)		6/103 (5.8%)		14/102 (13.7%)
Erythema	6/104 (5.8%)		4/103 (3.9%)		3/102 (2.9%)
Palmar-plantar erythrodysaesthesia syndrome	3/104 (2.9%)		3/103 (2.9%)		62/102 (60.8%)
Pruritus	11/104 (10.6%)		8/103 (7.8%)		7/102 (6.9%)
Rash	22/104 (21.2%)		23/103 (22.3%)		12/102 (11.8%)
Skin hyperpigmentation	1/104 (1%)		0/103 (0%)		6/102 (5.9%)
Vascular disorders
Hypertension	15/104 (14.4%)		8/103 (7.8%)		5/102 (4.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.