4EVERUK: An Open Label Study of Postmenopausal Women With Oestrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Treated With Everolimus (RAD001) With Exemestane, With Exploratory Epigenetic Marker Analysis

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01743560
• Collaborator: (none)
• Enrollment: 52
• Locations: 11
• Arm: 1
• Actual Duration (Months): 42.4
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Determine the overall response rate (ORR) at 48 weeks to everolimus (RAD001, 10mg daily p.o.) and exemestane (25mg daily p.o.) treatment in postmenopausal women with oestrogen receptor positive breast cancer who have previous experienced recurrence or progression on non-steroidal aromatase inhibitor (NSAI) therapy.

Condition or Disease	Intervention/Treatment	Phase
Oestrogen Receptor Positive Advanced Breast Cancer	Drug: RAD001; Drug: Exemestane	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IV Multicentre, Open Label Study of Postmenopausal Women With Oestrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Treated With Everolimus (RAD001) in Combination With Exemestane, With Exploratory Epigenetic Marker Analysis
• Actual Study Start Date: Jan 31, 2013
• Actual Primary Completion Date: Aug 15, 2016
• Actual Study Completion Date: Aug 15, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Everolimus and Exemestane Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive RAD001 at a dose of 10mg daily p.o. and exemestane 25mg daily p.o. for 48 weeks.

Drug: RAD001; All postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer were treated with oral tablet RAD001 at a dose of 10mg daily and oral tablet exemestane 25mg daily. The study treatment for an individual patient was to begin on Study Day 1 and continue until the last patient enrolled completed the study at day 336 or until disease progression; unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occurs first.; Other Names: Everolimus ; Drug: Exemestane; All postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer were to be treated with oral tablet RAD001 at a dose of 10mg daily and oral tablet exemestane 25mg daily. The study treatment for an individual patient was to begin on Study Day 1 and continue until the last patient enrolled completed the study at day 336 or until disease progression; unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occurs first.

Outcome Measures

Primary Outcome Measures

1. Best Overall Response of Everolimus and Exemestane Treatment in Postmenopausal Women With Hormone Receptor Positive Locally Advanced or Metastatic Breast Cancer [At 48 weeks]

   The best Overall Response (OR) for each patient is determined from the sequence of investigator overall lesion responses according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1.). To be assigned a best OR of Complete Responese (CR) at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best OR of Partial Response (PR) at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.The Overall Response Rate (ORR) was defined as the proportion of patients with a best OR of confirmed CR or PR by week 48.

2. Overall Response Rate of Everolimus and Exemestane Treatment in Postmenopausal Women With Hormone Receptor Positive Locally Advanced or Metastatic Breast Cancer [At 48 weeks]

   The Overall Response Rate (ORR) was defined as the proportion of patients with a best OR of confirmed CR or PR by week 48. Treatment success is defined as: The best Overall Response (OR) for each patient is determined from the sequence of investigator overall lesion responses according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1.). To be assigned a best OR of Complete Responese (CR) at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best OR of Partial Response (PR) at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.

Secondary Outcome Measures

1. Progression-free Survival (PFS) Events as Per Investigators - FAS [Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks]

   Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review.

2. Progression-free Survival (PFS) by Median Time in Weeks as Per Investigators - FAS [Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks]

   Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review.

3. Progression-free Survival (PFS) - % Event-free Probability Estimate - FAS [Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks]

   Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review. The PFS was analyzed using the Kaplan Meier method.

4. Overall Survival (OS) Events (Number of Deaths) - FAS [Start of treatment to the date of death up to approximately 48 weeks]

   Overall survival (OS) is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact. Time to median OS was not estimable.

5. Overall Survival (OS) - % Event-free Probability Estimate - FAS [Start of treatment to the date of death up to approximately 48 weeks]

   Overall survival (OS) is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact.

6. Change From Baseline EORTC Quality of Life Questionnaire of Cancer Patients QLQ-C30 at Each Time Point [Baseline 12,24,36,48 weeks]

   The QLQ-C30 is composed of multi-item scales and single-item measures including 5 functional scales, 3 symptom scales, a global health status-QoL scale, and 6 single items. Each of the multi-item scales includes a different set of items - no item occurs in more than 1 scale. High scale score=higher response level; a high score for a functional scale=a healthy level of function, high score for the global health status/QoL=high quality of life but a high score for a symptom scale / item=high level of symptomatology/problems. The principle for scoring these scales: 1.) Estimate the average of the items that contribute to the scale = raw score. 2.) Linear transformation to standardize the raw score, so that scores range from 0 to 100. Results should be interpreted with caution as the numbers of patients with available data over time were limited, and because of high variances as evidenced by large standard deviations

7. Percentage of Patient Responses in EuroQoL 5-dimension Questionnaire - FAS [Baseline 12,24,36,48 weeks]

   EuroQoL Quality of Life Scale (EQ-5D) is a standardized instrument to assess health state values is a standardized instrument to assess health state values. The EQ-5D essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D descriptive system is comprised of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Percentage of participants' responses were presented by visits. Results should be interpreted with caution as the numbers of patients with available data over time were limited.

8. Change From Baseline in EuroQoL 5-dimension Visual Analogue Scores - FAS [Baseline 12,24,36,48 weeks]

   EuroQoL Quality of Life Scale (EQ-5D) is a standardized instrument to assess health state values. The EQ-5D essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (VAS). For the visual analogue scale, participants draw a line from a box to the point on the thermometer-like scale corresponding to their health state, 0-100 (100 = Best health state). Weights are used to score the responses to the 5 domains, with scores ranging from 0 to 1 (where a score of 1 represents a perfect state). Scores for the visual analogue scale reflect the position where participant's line crosses the thermometer-like scale. Results should be interpreted with caution as the numbers of patients with available data over time were limited, and because of high variances as evidenced by large standard deviations

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histological or cytological confirmation of oestrogen receptor positive (ER+) and/or progesterone receptor positive (PgR+), human epidermal growth factor receptor 2 (HER2) negative breast cancer.

• Availability of archival tumour tissue (the tissue block or slides will be sent to the central laboratory for analysis).

• Postmenopausal women. The investigator must confirm postmenopausal status.

Postmenopausal status is defined either by:

• Age ≥ 55 years and one year or more of amenorrhea

• Age < 55 years and one year or more of amenorrhea and postmenopausal levels of FSH and LH per local institutional standards

• Prior hysterectomy and has postmenopausal levels of Follicle stimulating hormone (FSH) and Luteinizing Hormone (LH) per local institutional standards Surgical menopause with bilateral oophorectomy

• Disease progression following prior therapy with NSAI, defined as:

• Recurrence while on or after completion of an adjuvant treatment including letrozole or anastrozole, or

• Progression while on or following the completion of letrozole or anastrozole treatment for locally advanced or metastatic breast cancer

Note: Non-steroidal aromatase inhibitors (i.e. letrozole or anastrozole) do not have to be the last treatment prior to enrollment. Other prior anticancer therapy, e.g. tamoxifen, fulvestrant, exemestane are also allowed. Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to previous therapy prior to enrollment.

• Radiological evidence of recurrence or progression on last systemic therapy prior to enrollment.

Patients must have:

• At least one lesion that can be accurately measured or

• Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease

• Adequate bone marrow and coagulation function as shown by:

• Absolute neutrophil count (ANC) ≥ 1.5 109/L

• Platelets ≥ 100 ×109/L

• Hemoglobin (Hb) ≥ 9.0 g/dL

• International Normalized Ratio (INR) ≤ 2 .

• Adequate liver function as shown by:

• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN (or ≤ 5 if hepatic metastases are present)

• Total serum bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients known to have Gilbert Syndrome)

• Adequate renal function as shown by:

• Serum creatinine ≤ 1.5 × ULN

• Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 × ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved

• Eastern Cooperative Oncology Group (ECOG) performance status of PS </ 2

• Written informed consent obtained before any screening procedure and according to local guidelines.

Exclusion Criteria:

• HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).

• Pre-menopausal, pregnant, lactating women.

• Known hypersensitivity to mammilian target of Rapamycin (mTOR) inhibitors, e.g. sirolimus (rapamycin) or to their excipients.

• Known hypersensitivity to exemestane, to the active substance or to any of the excipients.

• Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose galactose malabsorption.

• Radiotherapy within four weeks prior to enrollment except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to enrollment. Patients must have recovered from radiotherapy toxicities prior to enrollment.

• Currently receiving hormone replacement therapy, unless discontinued prior to enrollment.

• Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below:

Prolonged systemic corticosteroid treatment during study, except for topical applications (e.g. rash),inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) should not be given. However:

• short duration (<2 weeks) of systemic corticosteroids is allowed (e.g. chronic obstructive pulmonary disease, anti-emetic)

• low doses of corticosteroids for brain metastasis treatment is allowed

• Patients with symptomatic visceral metastasis (e.g. significant dyspnoea related to pulmonary lymphangitic carcinomatosis and lung metastases or clinically meaningful symptomatic liver metastasis)

• Symptomatic brain or other Central Nervous system (CNS) metastases.

• Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin, low molecular weight heparin (LMWH) and acetylsalicylic acid or equivalent, as long as the INR is 2.0)

• Any severe and / or uncontrolled medical conditions such as:

• Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia

• Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN

• Acute and chronic, active infectious disorders (except for Hep B and Hep C positive patients) and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome)

• Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates.

• Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (rifabutin, rifampicin, clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir, telithromycin) within the last 5 days prior to enrollment

• History of non-compliance to medical regimens

• Patients unwilling to or unable to comply with the protocol

• Another malignancy within 5 years prior to randomization, with the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Epping	Essex	United Kingdom	CM16 6TN
2	Novartis Investigative Site	Inverness	Invernesshire	United Kingdom	IV2 3RE
3	Novartis Investigative Site	Ipswich	Suffolk	United Kingdom	IP4 5PD
4	Novartis Investigative Site	Sutton	Surrey	United Kingdom	SM2 5PT
5	Novartis Investigative Site	Cardiff		United Kingdom	CF14 2TL
6	Novartis Investigative Site	Denbighshire		United Kingdom	LL18 5UJ
7	Novartis Investigative Site	East Kilbride		United Kingdom	G75 8RG
8	Novartis Investigative Site	East Yorkshire		United Kingdom	HU16 5JQ
9	Novartis Investigative Site	Edinburgh		United Kingdom	EH4 2XU
10	Novartis Investigative Site	London		United Kingdom	SW3 6JJ
11	Novartis Investigative Site	Portsmouth		United Kingdom	PO6 3LY

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01743560
• Other Study ID Numbers: CRAD001YGB11; 2012-003689-41
• First Posted: Dec 6, 2012
• Last Update Posted: Jul 18, 2019
• Last Verified: Jul 1, 2019

• Keywords provided by Novartis Pharmaceuticals: Breast Neoplasms; Neoplasms; Breast diseases; Skin diseases; Exemestane; Antibiotics, Antineoplastic; Everolimus; Antineoplastic Agents; Therapeutic Uses; Pharmacologic Actions; Immunosuppressive Agents; Physiological Effects of Drugs; Aromatase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action
• Additional relevant MeSH terms: Breast Neoplasms; Everolimus; Exemestane

Study Results

Participant Flow

Pre-assignment Detail	Sixty-seven patients were screened and 52 patients were enrolled.

Arm/Group Title	Everolimus and Exemestane
Arm/Group Description	Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.
Period Title: Overall Study
STARTED	52
Full Analysis Set (FAS)	49
Safety Analysis Set (SAF)	49
COMPLETED	9
NOT COMPLETED	43

Baseline Characteristics

Arm/Group Title	Everolimus and Exemestane
Arm/Group Description	Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.
Overall Participants	49
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.3 (8.71)
Sex: Female, Male (Count of Participants)
Female	49 100%
Male	0 0%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	48 98%
Other	1 2%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	71.1 (15.44)

Outcome Measures

1. Primary Outcome

Title	Best Overall Response of Everolimus and Exemestane Treatment in Postmenopausal Women With Hormone Receptor Positive Locally Advanced or Metastatic Breast Cancer
Description	The best Overall Response (OR) for each patient is determined from the sequence of investigator overall lesion responses according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1.). To be assigned a best OR of Complete Responese (CR) at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best OR of Partial Response (PR) at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.The Overall Response Rate (ORR) was defined as the proportion of patients with a best OR of confirmed CR or PR by week 48.
Time Frame	At 48 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Everolimus and Exemestane
Arm/Group Description	Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.
Measure Participants	49
Patients with measurable disease at baseline	39 79.6%
Patients with non-measurable disease at baseline	10 20.4%
Best at WK 48 - Complete Response (CR)	0 0%
Best at WK 48 - Partial Response (PR)	7 14.3%
Best at WK 48 - Stable Disease (SD)	18 36.7%
Best at WK 48 - Progressive Disease (PD)	15 30.6%
Unknown	1 2%
Missing	8 16.3%

2. Primary Outcome

Title	Overall Response Rate of Everolimus and Exemestane Treatment in Postmenopausal Women With Hormone Receptor Positive Locally Advanced or Metastatic Breast Cancer
Description	The Overall Response Rate (ORR) was defined as the proportion of patients with a best OR of confirmed CR or PR by week 48. Treatment success is defined as: The best Overall Response (OR) for each patient is determined from the sequence of investigator overall lesion responses according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1.). To be assigned a best OR of Complete Responese (CR) at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best OR of Partial Response (PR) at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.
Time Frame	At 48 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Everolimus and Exemestane
Arm/Group Description	Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.
Measure Participants	49
Number (95% Confidence Interval) [Percentage of participants]	14.3 29.2%

3. Secondary Outcome

Title	Progression-free Survival (PFS) Events as Per Investigators - FAS
Description	Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review.
Time Frame	Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Everolimus and Exemestane
Arm/Group Description	Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.
Measure Participants	49
Deaths	8
Progression of disease	25
Number of censored observations	16

4. Secondary Outcome

Title	Progression-free Survival (PFS) by Median Time in Weeks as Per Investigators - FAS
Description	Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review.
Time Frame	Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Everolimus and Exemestane
Arm/Group Description	Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.
Measure Participants	49
Median (95% Confidence Interval) [weeks]	23.6

5. Secondary Outcome

Title	Progression-free Survival (PFS) - % Event-free Probability Estimate - FAS
Description	Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review. The PFS was analyzed using the Kaplan Meier method.
Time Frame	Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Everolimus and Exemestane
Arm/Group Description	Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.
Measure Participants	49
Event free at 12 weeks	67.9 138.6%
Event free at 24 weeks	49.1 100.2%
Event free at 36 weeks	28.9 59%
Event free at 48 weeks	18.4 37.6%

6. Secondary Outcome

Title	Overall Survival (OS) Events (Number of Deaths) - FAS
Description	Overall survival (OS) is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact. Time to median OS was not estimable.
Time Frame	Start of treatment to the date of death up to approximately 48 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Everolimus and Exemestane
Arm/Group Description	Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.
Measure Participants	49
Deaths	8
Number of censored observations	41

7. Secondary Outcome

Title	Overall Survival (OS) - % Event-free Probability Estimate - FAS
Description	Overall survival (OS) is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact.
Time Frame	Start of treatment to the date of death up to approximately 48 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Everolimus and Exemestane
Arm/Group Description	Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.
Measure Participants	49
Event free at 12 weeks	93.3 190.4%
Event free at 24 weeks	83.9 171.2%
Event free at 36 weeks	74.2 151.4%
Event free at 48 weeks	74.2 151.4%

8. Secondary Outcome

Title	Change From Baseline EORTC Quality of Life Questionnaire of Cancer Patients QLQ-C30 at Each Time Point
Description	The QLQ-C30 is composed of multi-item scales and single-item measures including 5 functional scales, 3 symptom scales, a global health status-QoL scale, and 6 single items. Each of the multi-item scales includes a different set of items - no item occurs in more than 1 scale. High scale score=higher response level; a high score for a functional scale=a healthy level of function, high score for the global health status/QoL=high quality of life but a high score for a symptom scale / item=high level of symptomatology/problems. The principle for scoring these scales: 1.) Estimate the average of the items that contribute to the scale = raw score. 2.) Linear transformation to standardize the raw score, so that scores range from 0 to 100. Results should be interpreted with caution as the numbers of patients with available data over time were limited, and because of high variances as evidenced by large standard deviations
Time Frame	Baseline 12,24,36,48 weeks

Outcome Measure Data

Analysis Population Description

number of participants varied across visits

Arm/Group Title	Week 12	Week 24	Week 36	Week 48
Arm/Group Description	Change from baseline at week 12	Change from baseline at Week 24	Change from baseline at week 36	Change from baseline at week 48
Measure Participants	27	17	13	28
Global health status/QoL	-9.0 (22.04)	-3.6 (19.71)	1.9 (16.37)	-8.3 (22.48)
Physical functioning	-5.1 (19.16)	-1.0 (14.52)	4.9 (13.79)	-10.8 (29.97)
Role functioning	-4.5 (33.19)	3.1 (23.74)	8.3 (23.03)	-12.3 (30.52)
Emotional functioning	2.6 (21.36)	-3.1 (14.87)	7.5 (9.90)	0.6 (21.59)
Cognitive functioning	-8.6 (21.37)	-5.2 (17.97)	1.3 (22.01)	-3.7 (21.35)
Social functioning	-9.9 (25.00)	-9.4 (24.32)	3.8 (15.45)	-14.7 (31.74)
Fatigue	8.6 (26.92)	9.5 (15.93)	0.9 (16.64)	7.3 (24.66)
Nausea/ vomiting	-1.2 (15.96)	2.9 (16.91)	-3.8 (15.45)	-2.4 (23.88)
Pain	1.2 (26.12)	3.9 (24.67)	-1.3 (20.93)	0.6 (24.64)
Dyspnea	18.5 (37.36)	8.3 (25.82)	2.6 (25.32)	10.7 (27.30)
Insomnia	3.7 (26.69)	2.0 (29.98)	0 (23.57)	-3.6 (37.78)
Appetite loss	30.9 (40.22)	23.5 (28.30)	12.8 (28.99)	16.7 (35.72)
Constipation	4.9 (32.95)	11.8 (28.73)	10.3 (21.01)	8.3 (19.51)
Diarrhea	4.9 (25.66)	8.3 (37.52)	-5.1 (22.96)	7.4 (28.24)
Financial problems	-1.2 (21.64)	-10.4 (26.44)	-10.3 (21.01)	-2.6 (18.67)

9. Secondary Outcome

Title	Percentage of Patient Responses in EuroQoL 5-dimension Questionnaire - FAS
Description	EuroQoL Quality of Life Scale (EQ-5D) is a standardized instrument to assess health state values is a standardized instrument to assess health state values. The EQ-5D essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D descriptive system is comprised of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Percentage of participants' responses were presented by visits. Results should be interpreted with caution as the numbers of patients with available data over time were limited.
Time Frame	Baseline 12,24,36,48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Day 1	Week 12	Week 24	Week 36	Week 48
Arm/Group Description	Baseline
Measure Participants	49	49	49	49	49
Mobility-no problem	38.8 79.2%	20.4 NaN	18.4 NaN	14.3 NaN	16.3 NaN
Mobility-slight problem	18.4 37.6%	14.3 NaN	10.2 NaN	8.2 NaN	16.3 NaN
Mobility-moderate problem	32.7 66.7%	20.4 NaN	8.2 NaN	2.0 NaN	14.3 NaN
Mobility-severe problem	6.1 12.4%	2.0 NaN	0 NaN	2.0 NaN	6.1 NaN
Mobility-unable to walk	0 0%	0 NaN	0 NaN	0 NaN	4.1 NaN
Self-care - no problem	69.4 141.6%	44.9 NaN	34.7 NaN	24.5 NaN	40.8 NaN
Self-care - slight problem	18.4 37.6%	4.1 NaN	0 NaN	0 NaN	10.2 NaN
Self-care - moderate problem	6.1 12.4%	8.2 NaN	2.0 NaN	2.0 NaN	4.1 NaN
Self-care -severe problem	2.0 4.1%	0 NaN	0 NaN	0 NaN	2.0 NaN
Self-care - unable	0 0%	0 NaN	0 NaN	0 NaN	0 NaN
Usual activities - no problems	30.6 62.4%	14.3 NaN	22.4 NaN	14.3 NaN	18.4 NaN
Usual activities - slight problems	22.4 45.7%	16.3 NaN	2.0 NaN	8.2 NaN	14.3 NaN
Usual activities - moderate problems	28.6 58.4%	22.4 NaN	12.2 NaN	2.0 NaN	12.2 NaN
Usual activities - severe problems	10.2 20.8%	4.1 NaN	0 NaN	2.0 NaN	6.1 NaN
Usual activities -unable to do	4.1 8.4%	0 NaN	0 NaN	0 NaN	6.1 NaN
Pain/discomfort - none	20.4 41.6%	14.3 NaN	10.2 NaN	12.2 NaN	18.4 NaN
Pain/discomfort - slight	30.6 62.4%	16.3 NaN	18.4 NaN	8.2 NaN	20.4 NaN
Pain/discomfort - moderate	40.8 83.3%	22.4 NaN	8.2 NaN	6.1 NaN	14.3 NaN
Pain/discomfort - severe	4.1 8.4%	4.1 NaN	0 NaN	0 NaN	4.1 NaN
Pain/discomfort - extreme	0 0%	0 NaN	0 NaN	0 NaN	0 NaN
Anxiety/depression - none	44.9 91.6%	22.4 NaN	18.4 NaN	16.3 NaN	22.4 NaN
Anxiety/depression - slight	34.7 70.8%	22.4 NaN	12.2 NaN	10.2 NaN	20.4 NaN
Anxiety/depression - moderate	16.3 33.3%	12.2 NaN	6.1 NaN	0 NaN	8.2 NaN
Anxiety/depression - severe	0 0%	0 NaN	0 NaN	0 NaN	6.1 NaN
Anxiety/depression - extreme	0 0%	0 NaN	0 NaN	0 NaN	0 NaN

10. Secondary Outcome

Title	Change From Baseline in EuroQoL 5-dimension Visual Analogue Scores - FAS
Description	EuroQoL Quality of Life Scale (EQ-5D) is a standardized instrument to assess health state values. The EQ-5D essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (VAS). For the visual analogue scale, participants draw a line from a box to the point on the thermometer-like scale corresponding to their health state, 0-100 (100 = Best health state). Weights are used to score the responses to the 5 domains, with scores ranging from 0 to 1 (where a score of 1 represents a perfect state). Scores for the visual analogue scale reflect the position where participant's line crosses the thermometer-like scale. Results should be interpreted with caution as the numbers of patients with available data over time were limited, and because of high variances as evidenced by large standard deviations
Time Frame	Baseline 12,24,36,48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Week 12	Week 24	Week 36	Week 48
Arm/Group Description	Change from baseline at week 12	Change from baseline at Week 24	Change from baseline at week 36	Change from baseline at week 48
Measure Participants	25	16	12	27
Mean (Standard Deviation) [units on a scale]	-7.9 (18.98)	-6.1 (12.47)	-6.3 (10.03)	-11.6 (22.58)

Adverse Events

Time Frame	Adverse Events (AEs) are collected from the First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
Adverse Event Reporting Description	Consistent with EudracCT disclosure specifications, Novartis has reported under the Serious adverse events field "number of deaths resulting from adverse events" all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
Arm/Group Title	Everolimus + Exemestane
Arm/Group Description	Everolimus + Exemestane
All Cause Mortality
	Everolimus + Exemestane
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Everolimus + Exemestane
	Affected / at Risk (%)	# Events
Total	22/49 (44.9%)
Blood and lymphatic system disorders
Anaemia	2/49 (4.1%)
Cardiac disorders
Pericardial effusion	1/49 (2%)
Tachycardia	1/49 (2%)
Gastrointestinal disorders
Abdominal pain	1/49 (2%)
Abdominal pain upper	1/49 (2%)
Colitis	1/49 (2%)
Duodenal ulcer	1/49 (2%)
Gastric ulcer	1/49 (2%)
Haematemesis	1/49 (2%)
Oral pain	1/49 (2%)
Vomiting	2/49 (4.1%)
General disorders
Mucosal inflammation	1/49 (2%)
Infections and infestations
Lower respiratory tract infection	4/49 (8.2%)
Pneumonia	1/49 (2%)
Urinary tract infection	1/49 (2%)
Injury, poisoning and procedural complications
Fall	1/49 (2%)
Overdose	1/49 (2%)
Metabolism and nutrition disorders
Dehydration	1/49 (2%)
Hypercalcaemia	2/49 (4.1%)
Hyperglycaemia	2/49 (4.1%)
Hyperkalaemia	1/49 (2%)
Hypoglycaemia	1/49 (2%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/49 (2%)
Muscular weakness	1/49 (2%)
Musculoskeletal chest pain	1/49 (2%)
Pain in extremity	1/49 (2%)
Nervous system disorders
Hemiparesis	1/49 (2%)
Lethargy	1/49 (2%)
Neuropathy peripheral	1/49 (2%)
Seizure	1/49 (2%)
Somnolence	1/49 (2%)
Spinal cord compression	2/49 (4.1%)
Psychiatric disorders
Confusional state	3/49 (6.1%)
Renal and urinary disorders
Renal failure	2/49 (4.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/49 (2%)
Epistaxis	1/49 (2%)
Non-cardiogenic pulmonary oedema	1/49 (2%)
Pneumonitis	2/49 (4.1%)
Pulmonary embolism	1/49 (2%)
Other (Not Including Serious) Adverse Events
	Everolimus + Exemestane
	Affected / at Risk (%)	# Events
Total	49/49 (100%)
Blood and lymphatic system disorders
Anaemia	8/49 (16.3%)
Thrombocytopenia	4/49 (8.2%)
Gastrointestinal disorders
Abdominal distension	3/49 (6.1%)
Abdominal pain	5/49 (10.2%)
Constipation	8/49 (16.3%)
Diarrhoea	22/49 (44.9%)
Dry mouth	4/49 (8.2%)
Dyspepsia	5/49 (10.2%)
Mouth ulceration	11/49 (22.4%)
Nausea	14/49 (28.6%)
Oral pain	6/49 (12.2%)
Stomatitis	7/49 (14.3%)
Vomiting	8/49 (16.3%)
General disorders
Axillary pain	4/49 (8.2%)
Fatigue	22/49 (44.9%)
Mucosal inflammation	17/49 (34.7%)
Oedema peripheral	3/49 (6.1%)
Peripheral swelling	3/49 (6.1%)
Infections and infestations
Lower respiratory tract infection	4/49 (8.2%)
Oral candidiasis	5/49 (10.2%)
Urinary tract infection	6/49 (12.2%)
Investigations
Alanine aminotransferase increased	4/49 (8.2%)
Aspartate aminotransferase increased	4/49 (8.2%)
Blood cholesterol increased	3/49 (6.1%)
Blood creatinine increased	4/49 (8.2%)
Gamma-glutamyltransferase increased	6/49 (12.2%)
Weight decreased	6/49 (12.2%)
Metabolism and nutrition disorders
Decreased appetite	16/49 (32.7%)
Hypercalcaemia	4/49 (8.2%)
Hyperglycaemia	3/49 (6.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/49 (6.1%)
Back pain	6/49 (12.2%)
Joint swelling	3/49 (6.1%)
Musculoskeletal pain	5/49 (10.2%)
Pain in extremity	7/49 (14.3%)
Nervous system disorders
Dysgeusia	7/49 (14.3%)
Headache	3/49 (6.1%)
Psychiatric disorders
Depressed mood	4/49 (8.2%)
Insomnia	4/49 (8.2%)
Respiratory, thoracic and mediastinal disorders
Cough	18/49 (36.7%)
Dyspnoea	11/49 (22.4%)
Epistaxis	8/49 (16.3%)
Oropharyngeal pain	3/49 (6.1%)
Pneumonitis	3/49 (6.1%)
Productive cough	3/49 (6.1%)
Skin and subcutaneous tissue disorders
Pruritus	6/49 (12.2%)
Rash	18/49 (36.7%)
Vascular disorders
Lymphoedema	3/49 (6.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. 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.