Conditions: Breast Cancer
Keywords: Breast Cancer Hormone Receptor Positive Metastatic Breast Cancer Hormone-sensitive Postmenopausal Body Mass Index BMI Everolimus Afinitor RAD001 Exemestane Aromasin Metformin
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if exemestane and everolimus combined with metformin can help to control breast cancer in patients who are obese or overweight and post-menopausal with hormone-receptor-positive breast cancer that has spread to other parts of the body.

Exemestane is designed to decrease the ability of estrogen to help cancer cells grow. This could cause the cancer cells to die.

Metformin is commonly used to control blood sugar levels in patients with diabetes. It is designed to lower insulin levels, which may slow or stop the growth of breast cancer cells.

Everolimus is designed to block cells from dividing. This may cause cancer cells to die. Everolimus may also stop the growth of new blood vessels that help tumors grow.

Detailed description:
Study Drug Administration:

If you are found to be eligible to take part in this study, you will take an exemestane and everolimus tablet by mouth every day. You will also take tablets of metformin by mouth 2 times a day. The drugs should be taken at about the same time each day.

The study drugs will be given in 28-day cycles.

Study Visits:

On Day 1:

* You will have a physical exam, including a measurement of your weight and vital signs.
* You will be asked about any side effects you may be having.
* You will be asked about any drugs you may have taken or may be taking.
* Your performance status will be recorded.
* Blood (about 1-2 teaspoons) will be drawn for routine tests.
* Blood (about 1 teaspoon) will be drawn for blood sugar tests. If you have a history of diabetes, you will need to fast for 8 hours before these blood sugar tests.

At Weeks 4 and 12:

* You will have a physical exam, including a measurement of your vital signs.
* You will be asked about any side effects you may be having.
* You will be asked about any drugs you may have taken or may be taking.
* Blood (about 1-2 teaspoons) will be drawn for routine tests.
* Blood (about 1 teaspoon) will be drawn for blood sugar tests. If you have a history of diabetes, you will need to fast for 8 hours before these blood sugar tests.

At Weeks 8, 16 and then every 2 months after that, and after your last dose of study drugs:

* You will have a physical exam, including a measurement of your vital signs.
* You will be asked about any side effects you may be having.
* You will be asked about any drugs you may have taken or may be taking.
* Blood (about 1-2 teaspoons) will be drawn for routine tests.
* Blood (about 4 teaspoons) will be drawn for biomarker testing (at weeks 8, 16 and 24 only).
* Blood (about 1 teaspoon) will be drawn for blood sugar tests. If you have a history of diabetes, you will need to fast for 8 hours before these blood sugar tests.
* You will have imaging scans to check the status of the disease.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

This is an investigational study. Exemestane is FDA approved and commercially available for the treatment of metastatic breast cancer. Metformin is FDA approved and commercially available for the treatment of diabetes. Everolimus is FDA approved and commercially available to treat metastatic breast cancer, advanced kidney cancer in some patients and a certain type of brain tumor. The use of this drug combination is investigational.

Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Patients take one 25 mg tablet of exemestane once daily, everolimus 10 mg orally per day and metformin 500 mg orally per day for three days. If there are no dose limiting toxicities, dose of metformin will be increased by 500 mg orally every three days to reach the target dose of 1,000 mg orally twice daily. Drugs will be taken immediately after a meal at the same time each day.

Interventions: intervention 1: Everolimus intervention 2: Exemestane intervention 3: Metformin
Intervention descriptions: intervention 1: 10 mg by mouth once daily. intervention 2: 25 mg by mouth once daily. intervention 3: 500 mg by mouth per day for three days. If there are no dose limiting toxicities, the dose of metformin will be increased by 500 mg orally every three days to reach the target dose of 1,000 mg orally twice daily.

Protocol document:
Prot_SAP_000.pdf: 
2011-1239 
April 10, 2014
Page 1 
 
 
 
 
Circulating FGF21 Levels and Efficacy of Exemestane, Everolimus and Metformin in 
Postmenopausal Women with Hormone Receptor Positive Metastatic Breast Cancer and 
 
 
 
 
 
Chair: 
Vicente Valero, MD, F.A.C.P. 
Professor 
Department of Breast Medical Oncology 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Boulevard, Unit 1354 
Houston, TX 77030 
Tel: (713) 792-2817 
Fax: (713) 563-0739 
vvalero@mdanderson.org 
 
 
 
Co-Chair: 
Sai-Ching J. Yeung, MD, PhD 
Associate Professor 
Department of Emergency Medicine 
Department of Endocrine Neoplasia and Hormonal Disorders 
 
The University of Texas MD Anderson Cancer Center 
 
 
 
 
 
 
 
Funding Source: PROMISE grant, Susan G. Komen for the Cure 


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TABLE OF CONTENTS 
 
Table of Contents 
 
2 
Abbreviations List 
 
3 
 
7 
1.1  Primary 
 
7 
1.2  Secondary 
 
7 
 
8 
2.1  Obesity and breast 
 
8 
2.2  Treatment options for ER/PR positive advanced breast 
.. 
11 
2.3  Metformin as potential cancer 
 
13 
2.4  Fibroblast growth factor 
 
14 
3.0  Study 
 
14 
4.0  Eligibility 
 
14 
4.1  Inclusion 
 
14 
4.2  Exclusion 
 
16 
5.0  Treatment 
 
17 
6.0 Patient 
 18 
6.1  Assessments during the 
 
19 
7.0  Drug inform
19 
7.1   Exeme
 
19 
 
20 
7.3   Metformi
 
22 
8.0   
 
22 
9.0   Management of specific 
 
22 
9.1   Management of stomatitis/oral mucositis/mouth ulcers
 
22 
9.2   Management of hyperlipidemia and hyperglycem
 
23 
9.3   Management of dia
 
24 
9.4   Management of non-infectious pneum
 
24 
9.5   Management 
 
25 
9.6   Management of hematologic 
 
25 
9.7   Management of rash and similar dermatologic adverse events 
 
25 
9.8   Management of metabolic 
 
25 
9.9   Follow-up 
 
26 
9.10   Permitted study drug adjustm
 
26 
10.0   Concomitant 
 
26 
11.0   Assessment of effi
 
28 
11.1   Radiological assessment 
 
29 
 
30 
12.0   Toxicity m
 
30 
12.1  Adverse event reporting requirem
 
30 
12.1.1  Serious adverse 
 
31 
12.1.2   Non-serious adverse 
 31 


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12.2   Adverse drug reaction 
 
31 
12.3   Instructions for rapid notification of serious adverse 
 
32 
12.3.1 Reporting 
 32 
12.3.2  Reporting 
 
32 
13.0  Duration of 
 
32 
13.1  Procedures 
 
33 
14.0 Correlative 
 33 
15.0  Statistical 
 35 
 37 
Table 1. Clinically Relevant Drug Interactions: Inducers and Inhibitors of 
Isoenzyme 
 
42 
Table 2. Everolimus 
 
43 
Table 3. Dose Modification Guidelines for Hematologic 
 
44 
Table 4. Dose Modification Guidelines for Non-Hematologic 
 
45 
Table 5. Management of Non-Infectious Pneumo
 
46 
Table 6. Visit Evaluation 
 
47 


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List of abbreviations 
 
ABC 
Advanced or Metastatic Breast Cancer: Advanced Breast Cancer 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AI 
Aromatase Inhibitor 
AKT / PKB 
Protein Kinase B 
ALT 
Alanine Aminotransferase / Glutamic Pyruvic Transaminase / sGPT 
ALP 
Alkaline Phosphatase 
ANC 
Absolute Neutrophil Count 
aPTT 
activated Partial Thromboplastin Time 
ASCO American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
Area Under the Concentration Time Curve 
BAP 
Bone Alkaline Phosphatase 
BC 
Breast Cancer 
bFGF 
Basic Fibroblast Growth Factor 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CBR 
Clinical Benefit Rate 
CFR 
Code of Federal Regulation 
CI 
Confidence Interval 
CL/F 
Oral Clearance 
Cmax 
Maximum Concentration 
CMC 
Chemistry / Manufacturing / Controls 
CNS 
Central Nervous System 
CPK 
Creatine Phosphokinase 
CPO 
Country Pharma Organization 
CR 
Complete Response 
CRD 
Clinical Research and Development 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTA 
Clinical Trials Application 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
C-terminal cross linking telopeptide of type I collagen 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
CYP3A4 
Cytochrome P450 3A4 isoenzyme 
DCR 
Disease Control Rate 
DDI 
Drug-Drug Interaction 


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DLCO Diffusing Capacity for Carbon Monoxide 
DLT 
Dose Limiting Toxicities 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
ECOG Eastern Cooperative Oncology Group 
(e)CRF 
(electronic) Case Report / Record Form 
EDC 
Electronic Data Capture 
EDTA 
ethylenediaminetetraacetic acid 
EGFR Epidermal Growth Factor Receptor 
eIF 
eukaryotic translation initiation factor 
4E-BP1 
4E-binding proteins 1 
ELISA 
Enzyme Linked ImmunoSorbent Assay 
EMEA 
European Medicines Evaluation Agency 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
 End of Treatment 
ER 
 Estrogen Receptor 
EU 
 European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration (USA) 
FEV1 
Forced Expiratory Volume in one second 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyltransferase 
GI 
Gastrointestinal 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
GTP 
Guanosine Triphosphate 
HER2 
Human Epidermal Growth Factor Receptor 2 
Hgb 
Hemoglobin 
HIF 
Hypoxia-Inducible Factor 
HIV 
Human Immunodeficiency Virus 
HMG-CoA 
3-Hydroxy-3methyl-glutaryl coenzyme A 
HPLC 
High Performance Liquid Chromatography 
HR 
Hazard Ratio 
HR 
Hormone Receptor 
HUMECS 
 Human Umbilical Vein Endothelial Cells 
i.v. 
intravenous(ly) 
IB 
 Brochure 
IC50 
Inhibitory Concentration at 50% 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IMS 
Integrated Medical Safety 
IND 
Investigational New Drug Application (USA) 


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INR 
International Normalized Ratio IRB Institutional Review Board 
ITT 
Intent-To-Treat 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoprotein 
LH-RH 
Luteinizing hormone-releasing hormone 
MBC 
Metastatic Breast Cancer 
MPD 
Molecular Pharmacodynamics MRI Magnetic Resonance Imaging 
mTOR 
mammalian Target of Rapamycin 
NADPH 
Nicotinamide Adenine Dinucleotide Phosphate 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
PR 
Progesterone Receptor 
PI3K 
Phosphatidylinositol 3-Kinase 
PK 
Pharmacokinetics 
PLGF 
Placental Growth Factor 
PR 
Partial Response 
PS 
Performance Status 
PTEN 
Phosphatase and Tensin Homolog (deleted on chromosome 10) 
QoL 
Quality of Life 
RAPTOR 
Regulatory Associated Protein of mTOR 
RBC 
Red Blood Cell Count 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RIA 
Radioimmunoassay 
RICTOR 
Rapamycin-Insensitive Companion of mTOR 
RNA 
Ribonucleic acid 
S6K1 
serine / threonine kinase p70S6 kinaseS6 Kinase 1 
SAE 
Serious Adverse Events 
SD 
Stable Disease 
SmPC Summary of Product Characteristics 
SNPs 
Single Nucleotide Polymorphisms 
SOP 
Standard Operating Procedure 
t1/2 
 Half Life 
TKI 
Tyrosine Kinase Inhibitor 
tmax 
Time to Maximum Concentration 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
WBC 
Total White Blood Cell Count 
WHO 
World Health Organization 


2011-1239 
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1.0 
OBJECTIVES 
 
1.1 Primary Objective 
 
The primary objective of this study is to assess the efficacy of exemestane and everolimus 
combined with metformin in overweight and obese post-menopausal women with metastatic 
breast cancer. The primary endpoint is progression-free survival (PFS), defined as the time from 
the date of registration to the date of the first documented progression or death due to any cause. 
 
For patients with measurable disease at baseline, progression will be determined according to 
RECIST 1.1 [1]. 
 
In the absence of measurable disease at baseline, patients with bone lesions only, lytic or 
mixed (lytic + sclerotic), will be allowed to enter the study and the following will be considered 
disease progression among these patients: 
 
 The appearance of one or more new lytic lesions in bone 
 The appearance of one or more new lesions in tissues other than bone 
 Unequivocal progression of the size(s) of existing bone lesion(s) 
 
1.1 
Secondary objectives 
 
1.1.1 To determine the predictive role of serum FGF21 levels in overweight and obese 
postmenopausal women with metastatic breast cancer treated with exemestane, 
everolimus and metformin on PFS. 
 
1.1.2 To identify novel predictive markers of response to metformin added to exemestane and 
everolimus in overweight and obese postmenopausal women with hormone receptor- 
positive metastatic breast cancer. 
 
 
 
1.1.3 To assess the overall response rate (ORR) and the clinical benefit rate (CBR) in this 
population. ORR is defined as the proportion of patients whose best overall response is 
either complete response (CR) or partial response (PR) according to RECIST. CBR is 
defined as the proportion of patients with CR, PR or stable disease (SD) with a duration 
of 24 weeks or longer. 
 
1.1.4 To determine the tolerability and toxicity of exemestane, everolimus and metformin in this 
population. Safety will be assessed by the Common Terminology Criteria (CTCAE), 
version 3.0. Incidence of adverse events, serious adverse events, changes from baseline in 
vital signs and laboratory results (hematology, blood chemistry) will be reported. 


2011-1239 
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2.0 
BACKGROUND 
 
2.1 
Obesity and breast cancer 
 
Breast cancer is the most common cancer in women, and the second leading cause of female 
cancer death. More than 200,000 women are diagnosed with breast cancer yearly, and 40,000 
breast cancer related deaths were expected in 2011 in the US [2, 3]. There is a need to identify and 
take steps to alter modifiable breast cancer risks.  Among the identified risk factors for breast 
cancer [4], obesity in postmenopausal women and use of estrogen are two readily modifiable 
risk factors. Unfortunately, the prevalence of obesity is rapidly increasing and has reached 
epidemic proportions. 
 
The Rising Prevalence of Obesity:  The World Health Organization (WHO) recognized obesity 
as one of the top 10 global health problems. The WHO estimates that around one billion people 
throughout the world are overweight and that over 300 million of these are obese and if current 
trends continue, the number of overweight persons will increase to 1.5 billion by 2015 
(http://www.who.int). Overweight and obesity are defined by the WHO as a BMI of 25 30 and 
>30 kg/m2, respectively. Normal percentages of fat in the body mass are 9 18% in males and 
14 28% in females, but it may be as high as 60 70% in morbid obesity. As a consequence of the 
worldwide obesity epidemic, there is an explosion of obesity- and overweight-related illnesses [5]. 
Given the association between breast cancer and obesity, it is critical to address the impact of 
obesity on breast cancer based on our understanding of the mechanisms by which obesity 
promotes cancer. 
 
The Impact of Obesity on Breast Cancer Carcinogenesis: Obesity is associated with an increased 
risk of developing postmenopausal breast cancer [6].  Twenty percent of all postmenopausal 
breast cancers may be attributable to obesity [7].  Up to 50% of postmenopausal breast cancer 
deaths in the US may be attributed to obesity [8]; the data from the Cancer Prevention Study II 
supported that up to 18,000 deaths in US women older than 50 years could 
be avoided if these women were lean (BMI <25 kg/m2) throughout their adult life [8].  Estrogens, 
both exogenous and endogenous, are etiologic factors for breast cancer [9, 10].  Estrogens 
stimulate cell proliferation through nuclear receptor-mediated gene regulation as well as other 
effects that increased mutation rates and aneuploidy. The biosynthesis of estrogens in adipocytes 
in postmenopausal women is particularly important in the pathogenesis of estrogen receptor 
(ER)-positive breast carcinoma [11].  Hyperinsulinemia [12-15] is associated with increased risk 
of breast cancer, and it remains a significant risk factor independent of adiposity or fat 
distribution [15].  The effect of obesity on breast cancer risk is mediated by both insulin 
resistance and estrogen metabolism [16].  Both retrospective and prospective observational 
studies support a potential role of IGFs in breast carcinogenesis [17].  Obese patients also have 
elevated serum levels of leptin (an adipokine) contributing to increased risk of developing breast 
cancer compared with lean patients with the normal leptin levels [18]. Adiponectin (another 
adipokine) is a risk factor for breast cancer in postmenopausal females [19]. Thus, estrogens, 
adipokines such as leptin and adiponectin, insulin and IGF-1 have been viewed as important 
factors in estrogen receptor-positive (ER+) breast cancer carcinogenesis. 


2011-1239 
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The Impact of Obesity on Breast Cancer Progression: Obesity is also associated with worse 
prognosis of breast cancer after disease onset [20-23]. Obesity at the time of diagnosis predicts 
poor prognosis and adverse outcomes in both pre- and post-menopausal women with breast 
cancer [20].  Obesity is a preventable risk factor for breast cancer death [21]. The adverse 
effect of obesity on breast cancer prognosis is not an artifact of delayed diagnosis in obese 
patients, but is due to hormonal changes associated with obesity [24]., Obese women had 35% 
more estrone and 130% more estradiol in the plasma than lean women [25]. Concentrations of 
free estradiol are 2-3 times higher in obese women than in lean women. These hormonal 
differences potentially explain the association between obesity and breast cancer prognosis [25]. 
IGF-1 protected breast cancer cells from apoptosis induced by chemotherapy [26].  Inhibition of 
IGF-I receptor results in suppression of breast cancer cell adhesion, invasion, and metastasis 
[27].  Adipokine, estrogen and insulin/IGF-1 signaling pathways are again involved in the impact 
of obesity on breast cancer progression. 
 
Molecular Mechanisms Mediating the Impact of Obesity on Breast Cancer:  In breast cancer, at 
least three signaling pathways have been postulated to explain its association with breast cancer: 
insulin/IGF-1, adipokines and estrogens. There are synergistic interactions among these 
pathways. The combination of estradiol and IGF-1 results in synergistic proliferation of breast 
cancer cells [28]. Estrogens stimulate breast cancer proliferation at least in part via 
paracrine/autocrine growth factors (TGF-  and IGF-1) [29, 30], their receptors and down-stream 
signaling components [31].  For instance, the 
-untranslated region of the TGF-  gene contains 
two imperfect estrogen responsive elements (EREs) [32, 33], and IGF-I receptor is induced by 
interactions between ER-  and Sp1 in breast cancer cells [34]. Estradiol induces the expression 
of insulin receptor substrate 1 (IRS-1) and the p85/p110 subunits of phosphoinositide 3' kinase 
(PI3K) [35], and also enhanced tyrosine phosphorylation of IRS-1 after IGF-1 stimulation, 
followed by enhanced mitogen activated protein kinase (MAPK) and protein kinase B (Akt) 
activation. Estradiol also enhances the effect of IGF-1 on expression of cyclin D1 and cyclin E, 
and phosphorylation of retinoblastoma protein (Rb) [28, 36, 37].  Estradiol stimulated c-Myc 
expression but had little direct effect on expression of c-Jun, Jun B, Jun D [38], or c-Fos, but it 
induces expression of TGF-  [29, 33] which induces expression of c-Jun, Jun B, and c-Fos [38]. 
Similarly, while estradiol has no effect on p21, it induces IGF-1 which increases p21 expression 
and reduces p27 expression [36]. 


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Figure 1. A molecular model for the impact of obesity on breast cancer. Obesity triggers three 
signaling pathways to promote breast cancer cell growth: (1) High levels of insulin and IGF-I 
caused by obesity can stimulate breast cancer cell growth. (2) Adipocyte, serving as an endocrine 
cell, can modify sex steroid metabolism leading to production of estrogen. (3) Adipocyte releases 
a number of hormones or cytokines, including TNF , leptin, and adiponectin. As a result, these 
factors can stimulate or promote breast cancer cell growth or angiogenesis. Obese postmenopausal 
breast cancer patients have more estrogen and more IGF-1 and insulin than lean women, thus the 
combination of anti-obesity or insulin-sensitizing drugs with aromatase inhibitors may serve as an 
important treatment strategy for obese ER+ postmenopausal breast cancer patients. M, metformin; 
Ev, everolimus; E2, estradiol; FGF21, fibroblast growth factor-21; AI, aromatase inhibitor; 
AMPK, adenosine 5-monophosphate (AMP)-activated protein kinase; PTEN, phosphatase and 
tensin homolog; ER , estrogen receptor; mTOR, mammalian target of rapamycin; E2, estradiol; 
IL6, interleukin 6; Akt, protein kinase B; TNF, Tumor necrosis factor; IGF, insulin like growth 
factor; VEGF, Vascular endothelial growth factor; CycD1, Cyclin D1. 
 
While estrogens stimulate expression of IGF-1 and components in its signaling pathway, IGF-1 
reciprocates. The IGF-1 ligand-receptor system is an important regulator of metabolic enzymes 


2011-1239 
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involved in estrogen production. IGF-I activates transcription of endogenous ER in human 
breast cancer cells [39]. IGF-1 potentiates the effects of estradiol on ERE sites [40].  Inhibition 
of estrogen action by IGFBP-1 suggests that IGF-1 signaling may be required for maximal 
activation of estrogen receptors [39]. 
 
Breast cancer cells express adiponectin receptors (AdipoR1 and AdipoR2) but not adiponectin. 
Expression of AdipoR1 is higher in breast cancer than in adjacent or control tissues [41].  Lean 
women with high adiponectin levels had a substantial reduction in the risk of breast cancer. 
Adiponectin inhibits angiogenesis by inducing endothelial cell apoptosis [42].  In contrast, it had 
no effect on breast cancer cell apoptosis, and it inhibits breast cancer cell proliferation by 
activation of ERK1/2 but not AMP-activated protein kinase (AMPK) or p38MAPK [41]. 
 
The molecular basis for the link between obesity and breast cancer is formed by the complex 
interaction of at least three signaling pathways: insulin/IGF-1, adipokines and estrogens 
(Figure 1). There is crosstalk among the pathways leading to amplification of mitogenic signal 
[43].  Estrogen signaling may be especially important in obese postmenopausal patients with 
ER+ breast cancer. Therefore, obesity and these signaling pathways are therapeutic targets for 
obese breast cancer patients. 
 
2.2 
Treatment options for ER/PR positive advanced breast cancer 
 
Treatment goals for advanced breast cancer (ABC) are palliative in nature, primarily focused at 
reducing tumor size, slowing progression and metastasis and reducing complications such as 
fatigue, bone fracture and hypercalcemia. 
 
The presence of estrogen receptor (ER) and/or progesterone receptor (PR) is one of the most 
important predictive and prognostic markers in human breast cancers. Approximately 70% of all 
invasive breast cancers are positive for ER and/or PR expressions at the time of diagnosis. 
Consequently, anti-estrogen therapies that antagonize ER functions (such as tamoxifen) or inhibit 
estrogen production (e.g. aromatase inhibitors [AIs]) have been extensively developed in oncology 
[44]. Deprivation of estrogenic signaling with the anti-estrogen tamoxifen has been the main form 
of hormonal treatment for over 30 years. Tamoxifen is indicated for the treatment across the whole 
continuum of breast cancer, ranging from risk reduction for women with increased risk of breast 
cancer, as an adjuvant treatment and also for metastatic disease. Besides tamoxifen, progesterone 
analogues or progestins have been used for the treatment of breast 
cancer for almost 50 years. Although the exact mechanism of action of progestins has not been 
established, their effect on estrogen levels is thought to play a role. Megestrol acetate, a synthetic 
derivative of progesterone, is the only progestin indicated in the USA for use in postmenopausal 
ABC patients. Once the standard second-line therapy after tamoxifen, progestins are now mainly 
used for patients whose cancer does not respond well to other hormonal treatments. 
 
While therapies which interfere with ER functions such as tamoxifen have significantly 
contributed to mortality reduction in advanced breast cancer patients, at best 50-60% of ER- 
positive patients respond to anti-estrogen therapy. Consequently, a number of aromatase 
inhibitors (AIs) that reduce peripheral estrogen synthesis have been developed for the treatment 


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of ABC. The AIs block the conversion of androgens to estrogens, which is the primary way 
estrogens are produced in post-menopausal women. Aminoglutethimide, a first generation AI, was 
the first non-steroidal (reversible-competitive) inhibitor of aromatase evaluated clinically for the 
treatment of ABC. For many years, Aminoglutethimide was considered suitable second-line 
therapy after tamixofen, as an alternative to progestins. Prompted by the efficacy of 
aminoglutethimide, more selective, less toxic, reversible second generation AIs were developed 
[45]. At present, third generation aromatase inhibitors have been approved for use in 
postmenopausal women with hormone receptor-positive BC after tamoxifen. The third 
generation AIs can be broadly classified into two groups: non-steroidal aromatase inhibitors 
(NSAI), mainly letrozole and anastrozole and steroidal aromatase inactivator, exemestane. 
 
Everolimus and letrozole synergistically inhibit proliferation in BC cells. This combination (L-R) 
was evaluated in a randomized double blind phase II trial against letrozole + placebo (L-P) as a 
4-month neoadjuvant treatment for postmenopausal women with early BC. 270 patients were 
enrolled in this trial (138 L-R vs. 132 L-P). Response rates on L-R and L-P were 68% vs. 59% 
(palpation, p = 0.062) and 58% vs. 47% (ultrasound, p= 0.021) respectively. Pharmacodynamic 
changes in each treatment arm were observed. Marked downregulation in progesterone receptor 
and cyclin D1 were seen in response to letrozole. Phospho-S6 levels showed dramatic down- 
regulation only in response to everolimus. Cell cycle response, as defined by the proportion of 
+ 
patients with < 2.7 % Ki67 tumor cells at day 15, was also significantly higher in the everolimus 
+ letrozole arm (57% everolimus treated patients vs. 30% placebo treated patients were cell cycle 
responder at day 15, p<0.01). Baselga and collaborators [46] concluded that everolimus 
significantly increased the efficacy of letrozole in newly diagnosed ER+ BC, with regard to both 
clinical and cell cycle response. The increased cell cycle response rate on everolimus was found in 
all subsets of tumors, including PTEN-positive, PI3KCA wild-type tumors. The most common 
grade 3/4 adverse events in the L-R arm were hyperglycemia (5%), stomatitis (2%), pneumonitis 
(2%), and infections (2%). All three cases of grade 3 pneumonitis completely resolved after 
discontinuation of everolimus. Daily therapy with everolimus plus letrozole (NSAI) showed no 
PK interaction. This trial demonstrated that mTOR inhibition provides additional efficacy to long 
term estrogen deprivation and has an acceptable level of tolerability in the neoadjuvant setting. A 
daily dose of everolimus 10 mg was recommended for further trials [46]. 
 
A randomized phase II study comparing two schedules of everolimus (10 mg daily and 70 mg 
weekly) in patients with recurrent/metastatic breast cancer [47] also demonstrated that in general, 
adverse effects were those predicted from preclinical and early clinical studies [48] including 
hyperglycemia and hyperlipidemia (generally in patients with preexisting abnormalities), and were 
reversible. The most common grade 3 or 4 adverse events were fatigue, non infectious 
pneumonitis and neutropenia. Pneumonitis occurred more frequently than anticipated, but was 
reversible in all affected patients and in general, manageable, although some patients required 
discontinuation. None of the 16 patients recruited to the weekly 70 mg arm responded, with four 
patients with a stable disease. Among the 33 patients treated in the daily 10 mg arm, response 
was evaluable in 30 patients; one patient had a complete response, three patients had a partial 
response and 15 patients had stable disease. The four responding patients were ER+ and the 
HER2 status was normal in 3 patients and unknown in one. As previously demonstrated in a 


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pharmacodynamic model [49], supported by a clinical tumor pharmacodynamic study [48], in 
which the 10mg daily dosage was achieving more profound and sustained suppression of mTOR 
activity than could be achieved with weekly dosing, Ellard and coworkers [47] suggested that 
continuous daily dosing of everolimus, but not weekly dosing, has single agent activity in this 
disease setting. While ER positive and HER-2 normal status appeared to be predictive for 
response and/or prolonged stable disease, no associations were noted between molecular markers 
and efficacy. 
 
Everolimus in combination with trastuzumab and paclitaxel or vinorelbine is also being studied in 
patients with HER2-overexpressing metastatic breast cancer. In a phase I trial of daily and 
weekly everolimus in combination with weekly vinorelbine and trastuzumab in heavily pretreated 
patients with HER2-overexpressing MBC with prior resistance to trastuzumab, everolimus was 
well tolerated at doses of 5 mg daily and 30 mg weekly. The main toxicities were neutropenia 
and stomatitis. Efficacy data based on the 25 patients on the 5mg daily arm showed 20 patients 
with clinical benefit (ORR= 20%, 1 CR, 4 PR). The median duration of progression free survival 
was 32 weeks. The combination also showed encouraging responses in the subgroup of patients 
who were resistant to both taxanes and trastuzumab. The dose of 
everolimus selected for further development was 5 mg daily [50]. In another phase I of daily and 
weekly everolimus in combination with weekly paclitaxel and trastuzumab in patients with HER2 
overexpressing MBC with prior resistance to trastuzumab, everolimus was well tolerated at doses 
of 5 mg and 10 mg daily and 30 mg weekly. The main toxicities were blood cell disorders, 
stomatitis and metabolic disorders . The combination showed encouraging responses 
in heavily pretreated patients including patients refractory to both taxanes and trastuzumab. 
Disease Control Rate (CR+PR+SD) was 85%. The dose of everolimus selected for the phase II 
part of the trial was 10 mg daily [51]. Morrow and collaborators completed a phase I/II trial of 
trastuzumab and everolimus in patients with metastatic breast cancer who had progressed after 
trastuzumab-based chemotherapy. The dose of everolimus was 10 mg orally daily. The regimen 
was well tolerated, and the clinical benefit rate was 30% [52]. 
 
Baselga and collaborators [53] completed a multicenter randomized phase III trial of everolimus 
in combination with exemestane versus exemestane with placebo in postmenopausal women with 
advanced breast cancer who were refractory to letrozole or anastrozole. This study showed a 
significant prolongation in progression-free survival for patients treated with exemestane plus 
everolimus. However, patients continue to develop progressive disease and novel therapeutic 
approaches are needed. Furthermore, limited outcome data are available for this combination in 
overweight and obese women. 
 
2.3 
Metformin as potential cancer therapy 
 
Metformin has become the most common anti-diabetic medication for Type II diabetes [54]. 
Metformin reduces levels of circulating glucose, increases insulin sensitivity, and reduces insulin 
resistance-associated hyperinsulinemia. Experimental data indicate metformin also has 
anticancer activity in breast cancer models [55, 56]. Epidemiological and retrospective data 
support the antineoplastic effects of metformin, and provide the rationale to study the role of 
metformin for breast cancer therapy in a variety of clinical settings [57]. In one study, patients 


2011-1239 
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with breast cancer and diabetes mellitus had a higher pathologic response to neoadjuvant 
chemotherapy if treated with concomitant metformin [58]. The North American Breast Cancer 
Intergroup is participating in a large randomized trial (MA.32, led by NCI-Canada) to determine 
the efficacy and safety of metformin in the adjuvant setting in patients with early-stage breast 
cancer who have completed local regional therapy and adjuvant chemotherapy. 
 
2.4 
Fibroblast growth factor 21 (FGF21) 
 
FGF21 is a metabolic hormone devoid of mitogenic activity despite being a member of the FGF 
family [59]. It is a starvation hormone that regulates lipid metabolism and insulin sensitivity and 
is currently under clinical development as pharmacologic interventions for type 2 diabetes 
mellitus and obesity. Preclinical data generated by our PROMISE grant team showed that: 
 
a) 
FGF21 increased adiponectin secretion while it decreased the majority of other 
adipokines secreted by mature adipocytes in cell culture. 
b) 
Metformin increased the circulating level of FGF21 in a mouse model of obesity 
and hormone receptor-positive breast cancer. 
 
 
 
3.0 
STUDY RATIONALE 
 
The molecular basis for the link between obesity and breast cancer is formed by the complex 
interaction of at least three signaling pathways: estrogens, insulin/IGF-1/PI3K and adipokines. 
There is crosstalk among the pathways leading to amplification of mitogenic signal. Estrogen 
signaling may be especially important in overweight and obese postmenopausal patients with 
ER/PR+ breast cancer. Therefore, overweight, obesity and these signaling pathways are 
therapeutic targets in this population. 
 
Our over-arching hypothesis is that the biochemical effects of metformin on insulin/IGF-1, 
adipokines and the PI3K pathway will combine with the anti-estrogenic effects of 
exemestane and inhibition of mTOR signaling by everolimus to improve progression-free 
survival in postmenopausal overweight and obese women with ER/PR+ metastatic breast 
cancer. Synergistic crosstalk between estrogen, adipokine and insulin/IGF-1/AKT/mTOR 
signaling underlies the adverse impact of obesity on postmenopausal ER/PR+ breast cancer. 
While aromatase inhibitors decrease estrogen, metformin improves insulin resistance and lowers 
insulin and IGF-1 levels. In addition, metformin therapy has been associated with inhibition of 
the mTOR signaling pathway through activation of AMPK and may act synergistically together 
with the mTOR inhibitor everolimus. 
 
4.0 
ELIGIBILITY CRITERIA 
 
4.1 
Inclusion criteria 
 
1. 
Postmenopausal overweight or obese women with a history of biopsy-proven hormone 
receptor-positive breast cancer and clinical evidence of metastatic disease. Overweight is 


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defined as body mass index (BMI) of 25  29.9 kg/m2 while obese is defined as BMI > 30 
kg/m2. Postmenopausal status is defined by one of the following: a) no spontaneous menses 
for over 1 year, in women 
 b) no spontaneous menses within the past 1 year in 
women < 55 years with postmenopausal gonadotrophin levels (LH and FSH levels > 40 
IU/L) or postmenopausal estradiol levels (by local laboratory range); or c) bilateral 
oophorectomy. 
 
2. 
Prior hormonal therapy for metastatic breast cancer is allowed. Patients who develop 
progressive metastatic disease on a non-steroidal aromatase inhibitor are eligible. Patients 
who develop metastatic disease while receiving a non-steroidal aromatase inhibitor in the 
adjuvant setting are eligible. 
 
3. 
One prior chemotherapy line for metastatic breast cancer is allowed if there is evidence of 
progressive disease. Patients treated with chemotherapy to best response and no evidence 
of progression are not eligible. 
 
4. 
Prior tamoxifen, LH/RH agonist, anastrozole or letrozole therapy in the adjuvant and/or 
neoadjuvant settings is allowed. Prior adjuvant and/or neoadjuvant chemotherapy is 
allowed. 
 
5. 
Patients must have: [1] at least one lesion that can be accurately measured in at least one 
dimension 
 with conventional imaging techniques or 
 with spiral CT or 
MRI; or [2] bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable 
disease; the following will be considered disease progression among these patients: a) the 
appearance of one or more new lytic lesions in bone; b) the appearance of one or more new 
lesions outside of bone; c) unequivocal progression of existing bone lesions. 
 
6. 
Localized radiotherapy, which does not influence the signal of evaluable lesion, is allowed 
prior to the initiation of study medications. 
 
7. 
ECOG performance status 
 
 
8. 
Absolute neutrophil count (ANC) >/= 1000/microliter, platelets >/= 75,000/microliter, 
hemoglobin >/= 8.5 gm/dL; creatinine clearance >60 mg/dL; bilirubin < 1.5 mg/dL (</= 3 
× ULN for patients known to have Gilbert Syndrome); ALT <3 x upper limit of normal (or 
</= 5 if hepatic metastases are present); alkaline phosphatase < 3 x upper limit of normal; 
calcium </= 11.0 mg/dL. 
 
9. 
Fasting serum cholesterol 
mg/dl or 7.75 mmol/L and fasting triglycerides 
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. 
 
10. Bisphosphonate treatment is permitted for the management of bone loss and/or bone 
metastases. 


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11. Patients must be competent to give informed consent and to state that they understand the 
investigational nature of the proposed treatment. 
 
4.2 
Exclusion criteria 
 
1. 
HER2-overexpressing breast cancer (IHC 3+ staining or in situ hybridization positive). 
 
2. 
Diabetes mellitus on active treatment or hemoglobin 
random plasma 
glucose > 200 mg/dL in patients without known diabetes. 
 
3. 
Treatment with metformin in the 30 days prior to enrollment. 
 
4. 
Known hypersensitivity or intolerance to metformin. 
 
5. 
Previous treatment with exemestane or mTOR inhibitors. 
 
6. 
Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin). 
 
7. 
History of acromegaly, 
me, 
 disease, 
 (treated 
or untreated). 
 
8. 
Patients with unstable angina, uncontrolled ischemic cardiac disease or symptomatic 
congestive heart failure (e.g. Class III or IV New York Heart 
 Functional 
Classification). 
 
9. 
Other investigational drugs within the past 3 weeks or concurrently. 
 
10. Patients with known chronic liver diseases (e.g., chronic active hepatitis, and cirrhosis). 
 
11. Another malignancy within 5 years prior to registration, with the exception of adequately 
treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non- 
melanomatous skin cancer. 
 
12. Radiotherapy within four weeks prior to registration 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 registration. Patients must have recovered from 
radiotherapy toxicities. 
 
13. History of brain or other central nervous system metastases. 
 
14. Bilateral diffuse lymphangitic carcinomatosis. 
 
15. Presence of life-threatening metastatic visceral disease, defined as extensive hepatic 
involvement, or any degree of brain or leptomeningeal involvement (past or present), or 
symptomatic pulmonary lymphangitic spread. Subjects with discrete pulmonary 


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parenchymal metastases are eligible, provided their respiratory function is not 
compromised as a result of disease. 
 
16. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at 
the time of study entry except in cases outlined below: Topical applications (e.g. rash), 
inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra- 
articular) are allowed. Patients on stable low dose of corticosteroids for at least two weeks 
before enrollment are allowed. 
 
17. Any severe and / or uncontrolled medical conditions such as: 
 
 
Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction 
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 who have gastrointestinal disease that may 
significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome); 
 
Active skin, mucosa, ocular or GI disorders of Grade > 1; 
 
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 will be considered to exclude restrictive pulmonary disease, pneumonitis or 
pulmonary infiltrates. 
 
18. Patients being treated with drugs recognized as being strong inhibitors or inducers of the 
isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itroconazole, 
Voriconazole, Ritinavir, Telithromycin) within the last 5 days prior to registration (List of 
clinically relevant drug interaction listed in Table 1). 
 
5.0 
TREATMENT PLAN 
 
Exemestane is formulated as tablets of 25 mg strength (Aromasin, Pfizer, New York NY). 
Everolimus is formulated as tablets of 5.0 mg strength is commercially available. Metformin is 
formulated as extended release tablets of 500 mg strength (Glucophage XR, Bristol-Myers 
Squibb Company, New York, NY). 
 
All patients will take exemestane orally once daily and everolimus 10 mg orally once 
daily. The starting dose of metformin will be 500 mg daily for 3 days. If there are no 
dose-limiting toxicities, the dose of metformin will be increased by 500 mg every 3 days 
to reach the target dose of 2000 mg/day (1,000 mg orally twice daily). Drugs will be 
taken immediately after a meal at the same time each day. 
 
Patients will be treated until disease progression, unacceptable toxicity, or until the patient 


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withdraws consent. For patients who are unable to tolerate the protocol-specified dosing 
schedule, dose adjustments are permitted (Table 2). 
 
6.0       PATIENT EVALUATION 
 
Table 6 lists all of the assessments and indicates with an 
 visits when they are performed. 
All data obtained from these assessments must be supported in the 
 source 
documentation. 
 
 
 
Screening and baseline 
 
Written informed consent must be obtained before any study specific medical procedures are 
performed. 
 
 
 
Screening assessments to confirm eligibility must be performed prior to the first dose of study 
drug. 
 
 Laboratory  baseline  assessments  (including  hematology, chemistry,  coagulation, and 
urinalysis), physical examination including performance status, height and weight must 
be performed within 28 days prior to first dose of study treatment. Note:   Day 1 
laboratory assessments do not need to be repeated if screening is completed within 7 
days. 
 
 Patients  with  potassium, sodium,  and/or  calcium  levels  that  are  below  the  LLN  at 
screening must have their potassium, sodium and/or calcium replenished through 
supplementation and the levels must be within normal limits prior to the first dose of 
study drug. 
 
 
 
All attempts should be made to complete the visits within 48 hours of the day indicated on the 
evaluation schedule. One month is considered as 4 weeks (i.e., 28 days). 
 
The following assessments must be obtained within 28 days prior to treatment administration to 
establish eligibility: 
 
 Physical Exam; 
 Relevant medical history; 
 Current medical conditions; 
 Concomitant medications; 
 Vital signs, height and weight; 
 ECOG performance status; 
 Hematology tests include a complete blood count (CBC). A total white blood cell (WBC) 
with absolute differentials (including neutrophil count plus bands, lymphocyte, 
monocyte, eosinophil, basophil counts), hemoglobin (Hgb), and a platelet count. Serum 
Chemistry must include: BUN or uric acid, creatinine, LDH, total protein, electrolytes 


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(sodium, potassium and calcium), total bilirubin, , albumin, alkaline phosphatase, 
AST/sGOT and HbA1C after fasting glucose. Serum fasting lipid profile must include: 
total cholesterol and triglycerides. 
 Tumor assessment as standard diagnostic imaging test(s) to determine diagnosis and 
extent of cancer. These include CT of the chest and abdomen and a bone scan or skeletal 
survey. Positive areas on bone scans must be assessed by X-ray, CT scan with bone 
windows or MRI Skin lesions should be photographed in addition to measuring. Brain 
scan (CT scan or MRI with i.v. contrast) must be performed if CNS symptoms are 
present. 
 
6.1 
Assessments During the Study 
 
The following assessments are to be performed at weeks 4, 8, 12, and every 2 months (± 7 days) 
of medication. Laboratory assessments may be performed up to 3 days before the actual clinic 
visit in order to allow for flexibility in scheduling. 
 
 History and physical examination; 
 ECOG Performance Status; 
 Vital signs; 
 Record any non-serious and serious adverse events and assign appropriate toxicity grade 
(NCI CTCAE version 3); 
 Record all concomitant medication(s) added and/or changed; 
 Hematology tests include a complete blood count (CBC). A total white blood cell (WBC) 
with absolute differentials (including neutrophil count plus bands, lymphocyte, 
monocyte, eosinophil, basophil counts), hemoglobin (Hgb), and a platelet count. Serum 
Chemistry must include: BUN or uric acid, creatinine, LDH, total protein, electrolytes 
(sodium, potassium and calcium), total bilirubin, , albumin, alkaline phosphatase, 
AST/HbA1C after fasting glucose. Serum fasting lipid profile must include: total 
cholesterol and triglycerides. 
 
Tumor assessment of target metastatic lesions using the same imaging modality as baseline (e.g., 
CT, MRI) will be performed every 2 months (+/-7 days). 
 
7.0 
DRUG INFORMATION 
 
7. 1 
Exemestane 
 
Exemestane is 6-methylenandrosta-1,4-diene-3,17-dione. It is structurally related to 
androstenedione, acting as a false substrate for aromatase, and is processed to an intermediate that 
binds irreversibly to the active site of aromatase causing suicide inhibition
 It inhibits the 
in vivo aromatization of androstenedione to estrone by an average of 97.9% [60].  It significantly 
lowers circulating estrogen concentrations in postmenopausal women, but has no detectable 
effect on adrenal biosynthesis of corticosteroids or aldosterone. 


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Exemestane has demonstrated efficacy in the treatment of postmenopausal patients with ABC 
[61]. It is indicated for adjuvant treatment of postmenopausal women with Estrogen receptor 
positive (ER+) early BC who have received two to three years of tamoxifen and are switched to 
exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy. It is 
also indicated for the treatment of ABC in postmenopausal women whose disease has progressed 
following tamoxifen therapy. 
 
The recommended daily dose of exemestane is 25 mg via oral administration. Exemestane is 
rapidly absorbed from the gastrointestinal tract. Its bioavailability is limited by first-pass 
metabolism, but is increased when taken with food. Exemestane is widely distributed, and is 
extensively bound to plasma proteins. It appears to be more rapidly absorbed in women with 
breast cancer [time to peak blood levels (tmax) of 1.2 hours] than in healthy women (tmax of 2.9 
hours).  The terminal half life for exemestane is 18-24 hours. The time needed to reach maximal 
estradiol suppression is 7 days [62-64]. Exemestane is metabolized by CYP3A4 and 
aldoketoreductases. It does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 
2C9, 2D6, 2E1 and 3A4. Although no formal drug-drug interaction studies have been conducted, 
significant effects on exemestane clearance by CYP isoenzyme inhibitors appear unlikely [64, 
65]. A randomized trial compared exemestane to fulvestrant in patients with ER+ metastatic 
breast cancer who had been previously treated with a non-steroidal AI (anastrozole or letrozole). 
The time to progression was the same for both groups (3.7 months) [66]. 
 
7.2 
Everolimus 
 
Everolimus has been in clinical development in solid organ transplantation since 1996 and is 
approved in more than 60 countries. Everolimus is commercially available for use as prophylaxis 
for organ rejection in adult patients receiving an allogeneic renal or cardiac transplant and is 
administered in association with cyclosporine and glucocorticoids. Starting in November 2002, 
everolimus has been in development to treat cancer patients both as monotherapy and in 
combination with a number of other anticancer agents. 
 
Everolimus is a derivative of rapamycin that acts as a signal transduction inhibitor. The target of 
this class of agents is mTOR, a multi-functional signal transduction protein, which obtains 
signals from many upstream inputs, and propagates the information via regulation of multiple 
downstream pathways. A serine-threonine kinase, mTOR acts as a nutrient sensor and monitor of 
the cellular metabolic state, regulating protein synthesis and ultimately cell growth and cell 
proliferation, angiogenesis and survival. mTOR serves a key role in normal mammalian cell 
physiology, and is centrally involved in tumor-cell physiology, (for example, facilitating cell- 
cycle progression from G1-S phase) and consequently inhibition of this target has received 
considerable attention as an anti-cancer approach [67]. 
 
mTOR regulates global mRNA translation [68]. Indeed, downstream from mTOR is the serine / 
threonine kinase p70S6 kinase (S6K), of which there are two forms (S6K1 and S6K2). S6K 
phosphorylates key residues on the ribosomal protein S6, permitting its activation and full 
function as a protein involved in ribosomal biogenesis. The mTOR kinase also modulates 
phosphorylation of 4E-BP1, releasing its inhibition of eIF-4E and consequently permitting 


2011-1239 
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efficient cap-dependent translation [67]. Specifically, the rapamycin-sensitive signaling pathway 
of mTOR occurs through the mTOR-RAPTOR complex (mTORC1), while a rapamycin- 
insensitive pathway occurs when mTOR is complexed with RICTOR (mTORC2) [69]. 
Rapamycins inhibit the activity of mTOR by directly adhering to FKBP-12 which binds to 
mTORC1 (i.e. the mTOR-RAPTOR complex), and also indirectly inhibit the mTOR-RICTOR 
complex (mTORC2) by sequestering free mTOR and thus also preventing its assembly into 
mTORC2 complexes. Therefore, mTOR is a downstream component in the PI3K/Akt/mTOR 
pathway which is known to be dysregulated in numerous human cancers. 
 
Molecular epidemiological studies show that in addition to a high frequency of activation in 
specific cancers, activation of the PI3K/Akt/mTOR pathway is frequently a characteristic of 
worsening prognosis through increased aggressiveness, progression and resistance to treatment 
[70]. A variety of preclinical studies have confirmed the role of this pathway in tumor 
development. Gain of function models have demonstrated that constitutive activation of kinases 
such as Akt can lead to the inexorable development of cancers resembling those in patients 
which are characterized by frequent activation of the same kinase. This is complemented by the 
demonstration of anti-tumor activity of kinase inhibitors acting in vitro and in vivo. Everolimus 
is capable of inhibiting the growth of a wide spectrum of tumor cell lines and tumors. The mTOR 
inhibitory activity presumably contributes to the antiproliferative activity of everolimus against 
tumor cell lines. However, everolimus may also exert an antitumor effect through the inhibition 
of angiogenesis in vivo. Indeed, both rapamycin and everolimus potently inhibit proliferation of 
endothelial cells [71] and have antiangiogenic activity in vivo [71, 72]. 
 
An important aspect of the anti-tumor effect of everolimus is indeed its potential to act both on 
tumor cells directly (to inhibit growth) and indirectly (by inhibiting angiogenesis and displaying 
anti-vascular properties). The observation of in vivo sensitivity of xenografts comprised of tumor 
cells showing insensitivity to everolimus in vitro is attributed to the 
 to act on the 
vascular component of the supporting peritumoral stroma. The anti-angiogenic property of 
everolimus has been confirmed through experiments demonstrating the effect of everolimus in 
countering vascular endothelial growth factor (VEGF)-induced proliferation of human umbilical 
endothelial cells (HUVECs) in vitro, VEGF-driven angiogenesis in a chamber implant murine 
model, and neovascularisation in murine orthotopic melanoma and xenograft models [72-74]. 
 
Everolimus pharmacokinetics. Everolimus is rapidly absorbed after oral administration, with a 
median tmax of 1-2 hours post dose. The extent of absorption is estimated at above 11%. The 
area under the blood concentration-time curve (AUC) is dose-proportional over the dose range 
tested while maximum blood concentration (Cmax) appears to plateau at dose levels higher than 
20 mg. The elimination half-life in cancer patients averaged 30 hours, which is similar to that in 
healthy subjects. Inter-patient variability is moderate with the coefficient of variation (CV) of 
approximately 50%. In healthy subjects, high fat meals reduced systemic exposure to Afinitor 10 
mg (as measured by AUC0-
 the peak plasma concentration Cmax by 54%. Light 
fat meals reduced AUC0-
 Cmax by 42%. Food, however, had no apparent effect 
on the post absorption phase concentration-time profile [Everolimus (RAD001) Investigator 
Brochure, Clinical Study Report RAD001C2120].  Steady-state trough levels are highly 
predictive of AUC, with a coefficient of determination of 0.96, as has been reported in renal 


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transplantation patients [75]. Everolimus is mainly metabolized by the cytochrome P450 
isoenzyme 3A4 (CYP3A4) in the liver and to some extent in the intestinal wall. Everolimus is 
also a substrate of P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of 
systematically absorbed everolimus may be influenced by medicinal products that interact with 
CYP3A4 and/or P-gp. Strong CYP3A inhibitors (such as ketoconazole, itraconazole, ritonavor) 
and inducers (such as rifampicin, rifabutin) should be avoided. In Study C2108, everolimus, at a 
daily dose of either 5 mg or 10 mg, was added to the daily letrozole regimen of 2.5 mg in breast 
cancer patients. Letrozole is mainly mediated by CYP3A4 and CYP2A6 with minor contribution 
of renal clearance. Due to the low affinity of letrozole to CYP3A4, the potential for 
pharmacokinetic interaction is remote. Pharmacokinetic profiles of letrozole were investigated 
before addition of everolimus and after everolimus reached steady state (day 15). Data suggested 
that, indeed, coadministration of everolimus with 2.5 mg/day letrozole did not influence the 
pharmacokinetics of letrozole. The exposure of everolimus in the presence of letrozole was 
similar to the historical data obtained from the amended Study C2102 CP report [Everolimus 
(RAD001) Investigator Brochure, Clinical Study Report RAD001C2102 and 2108]. 
 
7.3 
Metformin 
 
Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a 
biguanide anti-diabetic agent. Metformin is approved for the treatment of type 2 diabetes 
mellitus. Metformin acts primarily by decreasing endogenous hepatic glucose production. 
Clinically, metformin lowers fasting and postprandial hyperglycemia. The decrease in fasting 
plasma glucose is approximately 25-30%.  Metformin demonstrates an anti-hyperglycemic 
action rather than a hypoglycemic action. Metformin does not cause weight gain and in fact, 
may cause a modest weight loss.  Metformin also can improve the fasting lipid profile by 
decreasing triglyceride, and is known to improve steatohepatitis. 
 
8.0 
DOSE MODIFICATIONS 
 
If the patient experiences drug-related grade 2 toxicity, everolimus and metformin will be 
withheld until the toxicity is resolved to 
 1 with the exception of fatigue and grade 2 
diarrhea treated with loperamide. If diarrhea does not resolve to grade 1 with loperamide then 
hold everolimus and metformin until it resolves to grade 1. Everolimus and metformin may then 
be resumed at the same daily dose. 
 
If the Grade 2 toxicity recurs, Metformin and everolimus will be withheld until the toxicity has 
resolved to 
 1, and the daily dose will be reduced by 50%. If the patient experiences 
Grade 3/4 toxicity, everolimus and metformin will be withheld until the toxicity has resolved to 
 1, and the daily dose of metformin will be reduced by 50%. 
 
Metformin therapy will be temporarily discontinued prior to intravascular administration of 
iodinated contrast media. Metformin will be withheld for 48 hours after the radiologic study is 
performed, and then resumed. 


2011-1239 
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Please refer to Tables 3 and 4 for dose modification guidelines for hematologic and non- 
hematologic toxicities, respectively. 
 
 
 
9.0 
MANAGEMENT OF SPECIFIC TOXICITIES 
 
9.1 
Management of stomatitis/oral mucositis/mouth ulcers 
 
Mouth ulcers, stomatitis and oral mucositis have been seen in patients treated with everolimus. 
Stomatitis/oral mucositis/mouth ulcers due to everolimus will be treated using local supportive 
care. Please note that investigators in earlier trials have described the oral toxicities associated 
with everolimus as mouth ulcers, rather than mucositis or stomatitis. If examination reveals mouth 
ulcers rather than a more general inflammation of the mouth, please classify the adverse event as 
such. Please follow the paradigm below for treatment of stomatitis/oral mucositis/mouth ulcers: 
 
For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouth wash or 
salt water (0.9%) mouth wash several times a day until resolution. 
 
For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate oral 
alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., local 
anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or 
phenol) with or without topical corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog 
® 
in Orabase ). 
 
Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen mouth 
ulcers. It is preferable to avoid these agents. 
 
Antifungal agents will be avoided unless a fungal infection is diagnosed. In particular, systemic 
imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) will be avoided in all 
patients due to their strong inhibition of everolimus metabolism, therefore leading to higher 
everolimus exposures. Therefore, topical antifungal agents are preferred if an infection is 
diagnosed. Similarly, antiviral agents such as acyclovir will be avoided unless a viral infection is 
diagnosed. 
 
 
 
9.2 
Management of hyperlipidemia and hyperglycemia 
 
Treatment of hyperlipidemia will take into account the pre-treatment status and dietary habits. 
Blood tests to monitor hyperlipidemia will be taken in the fasting state. Hyperlipidemia and 
hypertriglyceridemia will be treated according to local best clinical practice. Patients will be 
monitored clinically and through serum biochemistry for the development of rhabdomyolysis 
and other adverse events as required in the product label/data sheets for HMG-CoA reductase 


2011-1239 
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inhibitors, if this class of medications are used to treat dyslipidemia. 
 
Hyperglycemia has been reported in clinical trials of everolimus. Monitoring of fasting serum 
glucose is recommended prior to the start of everolimus therapy, periodically (according to the 
follow up schedule as stated above) thereafter and as warranted by symptoms. Optimal glycemic 
control should be achieved before starting trial therapy. 
 
 
 
9.3 
Management of Diarrhea 
 
Appearance of diarrhea attributed to everolimus, metformin or their combination may be treated 
with loperamide. Other medications for diarrhea may be used as needed. 
 
9.4 
Management of non-infectious pneumonitis 
 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking 
everolimus. Some of these have been severe and on rare occasions, a fatal outcome was 
observed. 
 
A diagnosis of non-infectious pneumonitis will be considered in patients presenting with non- 
specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnea, and 
in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of 
appropriate investigations. Patients will be advised to report promptly any new or worsening 
respiratory symptoms. 
 
Diagnosis is generally suspected in individuals receiving mTOR inhibitors who develop these 
symptoms or in asymptomatic individuals in whom a routine chest CT scan reveals a new ground 
glass-like alveolar infiltrate. 
 
In an analysis of pneumonitis in breast cancer patients treated with everolimus the observed 
incidence of noninfectious pneumonitis in 4 studies totaling 238 patients did not exceed 3% [53]. 
In another study involving 49 patients [47], the incidence was approximately 10-fold higher. 
Although such a marked difference remains poorly explained, some considerations can be 
addressed: 
 
 Different monitoring methods across the studies have been applied: more extensive 
chest assessment by CT scan in NCIC CTG, J2101, and J2102 studies; 
 Sponsor management guidelines for noninfectious pneumonitis based on CTCAE 
grade were developed in 2006, therefore fully implemented only in the J2101 and 
J2102 studies; 
 The regular premedication with corticosteroids before the infusion of weekly 
chemotherapy could in part explain the low incidence observed in J2101 and J2102 
studies. 


2011-1239 
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The frequency of symptomatic pulmonary toxicity (all grades) was approximately 13% in a 
phase III study of RAD001 in patients with metastatic renal cell carcinoma (CRAD001C2240). 
Severe (CTC grade 3) pneumonitis occurred in 4% of patients, and an occasional fatality was 
reported. The lung toxicity was partly or completely reversible in the majority of cases with 
interventions including drug interruption, discontinuation and the use of corticosteroids. 
 
Consultation with a pulmonologist is recommended for any case of pneumonitis that develops 
during the study. Table 5 summarizes the management of non-infectious pneumonitis. 
 
9.5 
Management of infections 
 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, 
viral or protozoan infections, including infections with opportunistic pathogens. Localized and 
systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, 
such as aspergillosis or candidiasis and viral infections including reactivation of hepatitis B 
virus, have been described in patients taking everolimus. Some of these infections have been 
severe (e.g. leading to respiratory or hepatic failure) and occasionally have had a fatal outcome. 
 
Physicians and patients will be aware of the increased risk of infection with everolimus. Treat 
pre-existing infections prior to starting treatment with everolimus. 
 
While taking everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of 
infection is made, institute appropriate treatment promptly and consider interruption or 
discontinuation of everolimus. 
 
If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus and treat 
with appropriate antifungal therapy. 
 
9.6 
Management of hematologic toxicities 
 
A reduction in blood cell counts is frequent when everolimus therapy is initiated. Without 
clinical significance and infrequently, anemia and thrombocytopenia have been reported. Patients 
will be monitored regularly hematologically, especially at the beginning of treatment. Suspected 
drug-related hemorrhages have been exceptional. Nevertheless, everolimus will be considered as 
predisposing patients to hemorrhage, potentially fatal, will they develop severe drug-related 
thrombocytopenia. Patients with ongoing thrombocytopenic or with a known bleeding diathesis 
will be subject to careful evaluation and more frequent monitoring. 
 
Please refer to the Investigator Brochure for more details. 
 
9.7 
Management of rash and similar dermatologic adverse 
 
 
Rash and similar dermatologic 
 common among patients receiving everolimus. The 
proportion of patients experiencing any rash related AE was 29.2% and 33.4% in the everolimus 
treatment groups [76] and the pooled dataset, respectively. Rash and other dermatologic findings 


2011-1239 
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were present in 6.6% of patients in the placebo arm. Although toxicity by grade is not presented, 
most cases of rash and related events were of low grade. 
 
9.8 
Management of metabolic events 
 
Elevations of serum creatinine, usually mild, have been reported in clinical trials. Monitoring of 
renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is 
recommended prior to the start of everolimus therapy and periodically thereafter. 
Hypercholesterolemia, hypertriglyceridemia, had at least a 2-fold increase in incidence in 
patients receiving everolimus compared with placebo. 
 
9.9 
Follow-up for toxicities 
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value will be followed at least once a week for 4 weeks, and subsequently at 
4-week intervals, until resolution or stabilization of the event. All patients will be followed for 
onset of any new serious adverse events for 28 days following the last dose of study treatment. 
 
All patients who discontinue study treatment for any reason other than progression will continue 
to follow the protocol tumor assessments until progression. After progression, patient will be 
followed for survival every 3 months for up to approximately 3 years after the registration of the 
last patient. 
 
If, because of toxicity, a patient requires a dose delay of > 4 weeks from the intended day of 
dose, then the patient will discontinue study treatment. However, the patient will continue to be 
followed for toxicity and tumor assessments as previously described. 
 
9.10 
Permitted study drug adjustments 
 
For patients who may require dose adjustments because of concomitant medication, please refer 
to Section 10. 
 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to keep the patient on study drug. The following guidelines will be 
followed. These changes will be recorded on the Dosage Administration Record eCRF. 
 
If treatment is interrupted due to toxicity, study drug will not be resumed until recovery to Grade 
 it could be reintroduced at the initial dose or a lower dose level depending on the 
toxicity type and Grade. These changes will be recorded on the Dosage Administration Record 
eCRF. 
 
If a patient has already decreased 2 dose levels, no further dose reduction is permitted. Patients 
requiring an additional dose reduction will be required to discontinue study treatment. 
 
Patients who interrupt therapy for more than 4 weeks will be discontinued from the study. 


2011-1239 
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10.0 
CONCOMITANT THERAPY 
 
Patients will be instructed not to take any additional medications (over-the-counter or other 
products) during the study without prior consultation with the investigator. All medications taken 
within 28 days of starting study treatment will be reported on the Concomitant Medication eCRF 
pages. 
 
The following concomitant treatments are not allowed during the study: 
 
 Chronic concomitant bisphosphonate therapy for the prevention of bone metastases are 
not permitted during the study. Bisphosphonate therapy for the treatment of osteoporosis 
is permitted during the study. Bisphosphonate therapy for the management of bone 
metastases is recommended as standard of care. Please refer to prescribing information 
for details of administration. If bisphosphonate therapy is initiated after registration, the 
reason for its use must be clearly documented. 
 
 Investigational or commercial anticancer agents, such as chemotherapy, immunotherapy, 
targeted therapy, biological response modifiers, or endocrine therapy other than 
exemestane (including steroids) will not be given to patients. 
 
 Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators (e.g. 
raloxifene) are prohibited. 
 
 Prolonged systemic corticosteroid treatment, except for topical applications (e.g. rash), 
inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra- 
articular) will not be given. A short duration (<2 weeks) of systemic corticosteroids is 
allowed (e.g. chronic obstructive pulmonary disease, anti-emetic). 
 
 Hematopoietic growth factors (e.g. erythropoietins, G-CSF and GM-CSF) are not to be 
administered prophylactically. Use of these will be reserved to cases of severe 
neutropenia and anemia as per the labeling of these agents. 
 
 Inhibitors of CYP3A4 and/or PgP: Co-administration with strong inhibitors of CYP3A4 
(e.g., ketoconazole, itraconazole, ritonavir) or P-glycoprotein (PgP) will be avoided. Co- 
administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors will be used with caution. If patient requires co-administration of moderate 
CYP3A4 inhibitors or PgP inhibitors, reduce the dose of everolimus to half the currently 
used dose. Additional dose reductions to every other day may be required to manage 
toxicities. If the inhibitor is discontinued the everolimus dose will be returned to the dose 
used prior to initiation of the moderate CYP3A4/PgP inhibitor. Seville orange, star fruit, 
grapefruit and their juices affect P450 and PgP activity. Concomitant use will be avoided. 


2011-1239 
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Page 28 
 
 
 
 Inducers of CYP3A4 and/or PgP: Avoid the use of strong CYP3A4 inducers. If patient 
requires co-administration of strong CYP3A4 inducers (i.e., phenytoin, carbamazepine, 
rifampin, rifabutin, phenobarbital, St. 
 an increase in the dose of everolimus 
up to twice the currently used daily dose will be considered, using 5mg increments. 
Enzyme induction usually occurs within 7-10 days, therefore everolimus dose will be 
increased by one increment 7 days after the start of the inducer therapy. If no safety 
concerns are seen within the next 7 days, the dose can be increased again one additional 
increment up to a maximum of twice the daily dose used prior to initiation of the strong 
CYP3A4 inducer.  This dose adjustment of everolimus is intended to achieve similar 
AUC to the range observed without inducers. However, there are no clinical data with 
this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer 
is discontinued the everolimus dose will be returned to the dose used prior to initiation of 
the strong CYP3A/PgP inducer. 
 
 Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be 
carried out if required. Whenever possible, these patients will have a tumor assessment of 
the lesion(s) before they actually receive the radiotherapy. No dose modification of study 
treatment is needed during radiotherapy. 
 
 Everolimus may affect the response to vaccinations making it less effective. Live 
vaccines will be avoided while a patient is treated with everolimus. 
 
 Lipid-lowering drugs may be given in case of hyperlipidemia. 
 
Otherwise, the use of other concomitant medication/therapy deemed necessary for the care of the 
patient is allowed. The investigator will instruct the patient to notify the study site about any new 
medications he/she takes after the start of the study drug. All medications (other than study drug) 
and significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient starts study treatment and for up to 28 days after study drug 
discontinuation must be listed on the Concomitant medications/Significant Non-drug Therapy 
After Start of Study Drug eCRF. The first regimen of antineoplastic medication/treatments 
received after study treatment discontinuation must also be recorded in the eCRF antineoplastic 
treatment modules. 
 
 
 
 
 
 
11.0 
ASSESSMENT OF EFFICACY 
 
Patients will have either at least one lesion that can be measured as per RECIST [77] OR have 
bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease as defined 
above. 
 
For patients with measurable disease at baseline (as per RECIST), efficacy (overall tumor 
response and progression) will be evaluated every 8 weeks according to RECIST (see Post-text 


2011-1239 
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Page 29 
 
 
 
supplement 1). 
 
A bone scan or a skeletal survey will be performed at baseline for all patients within 6 weeks 
before registration. Any abnormalities (i.e. hotspots) identified on the bone scan will be 
confirmed by X-ray, CT scan with bone windows or MRI. 
 
Bone lesions identified at baseline will follow the same assessment schedule as for measurable 
lesions. Additional bone scans or skeletal surveys will be performed if clinically indicated. 
Abnormalities found on subsequent bone scans will also be confirmed by X-ray, CT scan, or 
MRI. 
 
The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline for each study tumor assessment after start of study 
treatment. 
 
11.1 
Radiological assessment of tumor 
 
Tumor response will be assessed using RECIST [77]. A CT scan or a MRI of the Chest, 
Abdomen and Pelvis will be performed at screening 
 to the first dose of 
everolimus and 
 with positive baseline Hepatitis B and C results) and 
periodically as indicated in Table 6 (chest CT performed if clinically needed for the surveillance 
of pneumonitis will be available during the regular follow-up). CT Scan and MRI with contrast 
media will be used except for patients who are allergic/sensitive to the radiographic contrast 
media. Ultrasound scans will not be used to measure tumor lesions. 
 
Tumor response will be assessed every 8 weeks (± 1 week) until disease progression and until 
further anti-cancer therapy is initiated. A partial or a complete response warrants a confirmation 
no sooner than 4 weeks after its observation. 
 
All patients who discontinue study treatment for any reason (i.e. an adverse event, administrative 
reasons etc.) other than disease progression and consent withdrawal will continue to have tumor 
assessments as per the schedule and until disease progression and until further anti-cancer 
therapy is initiated. Documented disease progression will be determined by a local radiologist 
and/or the investigator. 
 
All patients will have at least one lesion that can be accurately measured in at least one 
dimension 
 with conventional imaging techniques or 
 with spiral CT or MRI 
OR  bone lesions such as lytic or mixed (lytic + sclerotic) in the absence of measurable disease 
as defined above. 
 
Bone scans or skeletal survey will be performed at baseline. Positive areas on bone scans will be 
assessed by X-ray, CT scan with bone windows or MRI, prior to registration and will continue to 
be assessed using the same modality (X-ray, CT scan or MRI) every 6 weeks until disease 
progression as described above. Additional bone scans or skeletal surveys will be performed if 
clinically indicated. Abnormalities found on subsequent bone scans will also be confirmed by X- 


2011-1239 
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Page 30 
 
 
 
ray, CT scan, or MRI. 
 
If the patient presents with both irradiated and non-irradiated bone lesions (either therapeutic 
high dose or low dose for pain), only the non-irradiated lesions will be followed for tumor 
assessments unless progression is documented after the radiation. 
 
 
 
11.2 
Response assessment 
 
For patients with measurable disease at baseline, progression will be determined according to the 
RECIST [77]. 
 
In the absence of measurable disease at baseline, the following will be considered progression 
among patients with lytic or mixed (lytic + sclerotic) bone lesions: 
 
The appearance of one or more new lytic lesions in bone 
 
The appearance of one or more new lesions outside of bone 
 
Unequivocal progression of existing bone lesions 
 
Note: Pathologic fracture, new compression fracture, or complications of bone metastases will 
not be considered as evidence of disease progression, unless one of the above-mentioned criteria 
is fulfilled. 
 
Patients with symptoms of rapidly progressing disease without radiological (or photographical) 
evidence will not be considered to have progressed for efficacy analyses. 
 
The evaluation of overall lesion response will be performed according to RECIST. For patients 
with only bone lesions, the RECIST will be extended to include the evaluation of overall lesion 
response, which will be based solely on non-target lesion responses. Specifically, in absence of 
new lesions, the overall lesion response at each assessment will be one of the following: 
complete response, stable disease, unknown, or progressive disease based on non-target lesion 
responses. Stable disease would include all assessments not qualifying for complete response, 
progressive disease or unknown. In presence of any new lesion, the overall lesion response will 
be progressive disease. 
 
12.0 
TOXICITY MONITORING 
 
Toxicity will be assessed using the NCI Common Toxicity Criteria for Adverse Events v3.0. 
 
12.1 
Adverse Event Reporting Requirements 
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. An adverse event is any 
undesirable sign, symptom or medical condition occurring after starting study drug (or therapy) 


2011-1239 
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Page 31 
 
 
 
even if the event is not considered to be related to study drug (or therapy). Study drugs (or 
therapy) include exemestane, everolimus and metformin. 
 
Medical conditions/diseases present before starting study treatment are only considered adverse 
events if they worsen after starting study treatment (any procedures specified in the protocol). 
Adverse events occurring before starting study treatment but after signing the informed consent 
form are recorded. Abnormal laboratory values or test results constitute adverse events only if 
they induce clinical signs or symptoms or require therapy, and are recorded. 
 
12.1.1 Serious adverse events 
 
Information about all serious adverse events will be collected and recorded on the MDACC 
 SAE Report Form for Prompt Reporting  if requirements for prompt reporting have 
been met. All serious internal adverse events that do not fall under the prompt reporting 
requirements will be reported during continuing review using the Internal SAE Log. To ensure 
patient safety each serious adverse event occurring during the conduct of the protocol and 
meeting the definition of a SAE must also be reported to the UT MD Anderson Cancer Center 
Institutional Review Board (IRB) in accordance with the timeframes and procedures outlined in 
the Policy on Reporting Serious Adverse Events. 
 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 
1.   is fatal or life-threatening, 
2.   requires prolonged hospitalization, 
3.   results in persistent or significant disability/incapacity, 
4.   is medically significant such that medical or surgical intervention to prevent one of the 
outcomes listed above is required. 
 
Any serious adverse event occurring in a patient after providing informed consent and until 30 
days after stopping the trial will be reported. The period after discontinuing study drug may be 
extended if there is a strong suspicion that the drug has not yet been eliminated. All serious 
adverse events will also be reported for the period in which the study protocol interferes with the 
standard medical treatment given to a patient (e.g. treatment withdrawal during washout period, 
change in treatment to a fixed dose of concomitant medication). 
 
12.1.2 Non-serious adverse events 
 
Events not considered to be serious adverse events are hospitalizations for the: 
 
1.   routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, 
2.   treatment, which was elective or pre-planned, for a pre-existing condition that did not 
worsen, 
3.   treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission. 


2011-1239 
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12.2 
Adverse Drug Reaction Reporting 
 
All adverse experiences occurring after administration of the first dose of study medication and 
on or before the final visit will be reported on the Adverse Experience form in the patient's CRF. 
 
Adverse experiences will be evaluated at each visit/assessment. Adverse experiences not 
previously documented in the study will be recorded in the adverse experience record form 
within the patient's CRF.  The nature of each experience, date and time (where appropriate) of 
onset, outcome, course (i.e. intermittent or constant), maximum intensity, action taken with 
respect to dosage and relationship to treatment will be established. Details of changes to the 
dosage schedule or any corrective treatment will be recorded on the appropriate pages of the 
CRF. 
 
Any serious adverse experiences which occur at any time during the clinical study or within 30 
days of receiving the last dose of study medication, whether or not related to the study drug, will 
be reported immediately to the IRB. 
 
12.3 
Instructions for rapid notification of serious adverse events 
 
12.3.1   Reporting responsibility 
 
Each serious adverse event (but not pregnancies) will be reported by the investigator to IRB 
within 24 hours of learning of its occurrence, even if it is not felt to be treatment-related. Follow- 
up information about a previously reported serious adverse event will also be reported to IRB 
within 24 hours of receiving it. If warranted, an investigator alert may be issued, to inform all 
investigators involved in any study with the same drug (or therapy) that this serious adverse 
event has been reported. 
 
12.3.2   Reporting procedures 
 
The investigator will complete the Serious Adverse Event Report Form in English, assess the 
relationship to study treatment and send the completed form by fax within 24 hours to the PI. The 
PI and co-PI will ensure that the form is accurately and fully completed, and will then fax it to 
IRB within 2 to 3 calendar days for deaths or life-threatening events and 5 calendar days for 
other serious adverse events. The original and the duplicate copies of the Serious Adverse Event 
Form, and the fax confirmation sheet will be kept with the case report forms at the study site. 
 
Follow-up information will describe whether the event has resolved or continues, if and how it 
was treated, and whether the patient continued or discontinued study participation. The form and 
fax confirmation sheet will be retained. 
 
13.0 
DURATION OF THERAPY 


2011-1239 
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In the absence of treatment delays due to adverse event (AE), treatment may continue for the 
duration of funding (up to 5 years) or until one of the following criteria applies: 
 
1.  Disease progression. 
2.  Intercurrent illness that prevents further administration of treatment. 
3.  Unacceptable adverse event(s) or a dose-limiting toxicity that does not resolve within 2 
weeks of stopping therapy. 
4.  
 decision to withdraw from the study. 
5.  General or specific changes in the pa
 condition rendering the patient 
unacceptable for further treatment in the judgment of the investigator. 
6.  Protocol violation (including non-compliance). 
7.  Eligibility criteria not fulfilled. 
 
13.1 
Procedures for Discontinuation 
 
Patients who discontinue will always be asked about the reason(s) for their discontinuation and 
about the presence of any AEs.  If possible, they will be seen and assessed by an investigator(s). 
AEs are to be followed-up, and the patient will return any investigational products. 
 
14.0 
CORRELATIVE STUDIES 
 
The prevalence of obesity is rapidly increasing and has reached epidemic proportions. Obesity is 
associated with an increased risk of developing postmenopausal breast cancer, and it is associated 
with worse prognosis of breast cancer after disease onset [20]. In breast cancer, at least three 
signaling pathways have been postulated to explain its association with breast cancer: 
insulin/IGF-1, adipokines and estrogens. There are synergistic interactions among these 
pathways (Figure 1). There is crosstalk among the pathways leading to amplification of mitogenic 
signal. Estrogen signaling may be especially important in obese postmenopausal 
patients with hormone receptor breast cancer. Therefore, overweight/obesity and these signaling 
pathways are therapeutic targets in breast cancer patients. 
 
Experimental approach, validated assays employed and expertise of PI: The specific aims of 
this translational medicine proposal are: (a) to determine whether changes in insulin resistance 
[as assessed by the Homeostasis Model Assessment (HOMA), estimated from a single fasting 
glucose and insulin], hormones and adipokines (including FGF21) after 4 weeks (+/-3 days) of 
metformin treatment correlate with PFS; (b) to determine whether metformin-induced decreased 
signaling through the mTOR pathway, activation of AMPK (a marker of metformin action), and 
down regulation of ER-alpha expression correlate with a longer PFS; (c) to determine whether 
stromal FGF21 signaling was changed in tumor and stroma biopsies before and after drug 
treatment. 
 
Logistically, this will involve collection of blood prior to and after starting treatment for 
assessment of glucose and glycohemoglobin.  For correlative studies, after fasting blood glucose 
specimens will be collected at baseline and at weeks 4, 8, 16 and 24 (+/- 7 days). Plasma glucose 
in gray top vacutainer tubes (containing sodium fluoride) will be measured expeditiously at the 


2011-1239 
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clinical laboratory because levels of glucose are affected by storage of blood samples. 
Glycohemoglobin will also be measured in the clinical laboratory. Serial blood samples (two 10 
mL lavender-top tubes) will be collected for plasma at weeks 8, 16 and 24 (+/- 7 days), to 
coincide with imaging studies. Multiple aliqouts of plasma will be stored at -80 C. A 
representative diagnostic formalin fixed paraffin embedded tumor block will be requested from 
all patients in the study (estimated >95% of subjects). In patients with tumors safely accessible 
for biopsy, informed consent will be obtained for imaging-guided core biopsy of breast cancer at 
baseline and 8 weeks (+/-3 days) after drug treatment. At each time point, a core biopsy 
specimen will be fixed and embedded in paraffin and processed for immunohistochemistry and 
molecular studies. If any tissue is leftover and the patient agrees, it will be stored in a MD 
Anderson laboratory for future research related to cancer. Before the banked samples can be used 
for research, the people doing the research must get specific approval from the Institutional 
Review Board (IRB) of MD Anderson. The banked samples will be given a code number. No 
identifying information will be directly linked to these samples. Only the principal investigator 
and the laboratory coordinator will have access to the code numbers and be able to link the 
samples to the patient. This is to allow medical data related to the samples to be updated as 
needed. Other researchers using your samples will not be able to link this data to the patient. 
 
Experimental Approach. We will determine whether changes in characteristics such as HOMA, 
age, body mass index (BMI), tumor markers of mTOR signaling, and circulating levels of 
estradiol, progesterone, insulin, IGF-1, IGF-2, leptin, adiponectin, FGF21, TNF-alpha and IL-6 
are prognostic and predictive for PFS.  To address hypothesis 1, a Cox proportional hazards 
model will be used to identify significant predictors of PFS. To address hypothesis 2, the pre- 
and post-treatment tumor biopsies will examine whether decrease in signaling through the 
AKT/mTOR pathway, activation of AMPK (a marker of metformin action), and a down 
regulation of ER-alpha expression occur after drug treatment. The automated objective measure 
of immunostaining described below will be statistically correlated with PFS. To address 
hypothesis 3, the pre- and post-treatment tumor biopsies will examine whether changes in FGF21 
signaling was changed in tumor and stroma biopsies before and after drug treatment. 
 
Laboratory Methods. Glucose and glycohemoglobin (hemoglobin A1c) will be assayed in the 
clinical laboratory, and blood samples will be assayed in 
boratory at MDACC for 
hormones and adipokines. Assay kits from Immuno-Biological Laboratories-America, Inc. 
Minneapolis, MN will be used according to protocols provided by the manufacturer. The 
characteristics of each assay kit are as follows: 
 
1. 
Insulin ELISA -- Catalog Number IB79401; range: 0 / 5 - 500 microIU/mL; sensitivity: 
0.15 µIU/mL. 
2. 
C-Peptide ELISA -- Catalog Number IB79101; range: 0 / 0.2 - 16 ng/mL; sensitivity: 
0.064 ng/mL. 
3. 
IGF-1 ELISA -- Catalog Number E20; range: 0 / 1 - 50 ng/mL; sensitivity: 0.09 ng/mL. 
4. 
IGF-2 ELISA -- Catalog Number E30; range: 0 / 0.45 - 9 ng/mL; sensitivity: 0.02 ng/mL. 
5. 
IGFBP-3 ELISA -- Catalog Number E03; range: 0 / 2 - 150 ng/mL; sensitivity: 0.6 ng/mL. 
6. 
Estradiol 17-Beta ELISA -- Cat Num IB79103; range: 0 / 25 - 2000 pg/mL; sensitivity: 9.7 
pg/mL. 


2011-1239 
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Page 35 
 
 
 
7. 
Progesterone ELISA -- Cat Num IB79105; range: 0 / 0.3 - 40 ng/mL; sensitivity: 0.045 
ng/mL. 
8. 
SHBG ELISA -- Catalog Number IB59106; range: 0 / 3.3 - 295 nmol/L; sensitivity: 0.1 
nmol/L. 
9. 
Leptin ELISA -- Catalog Number 27775; range: 0 / 15.63 - 1000 pg/mL; sensitivity: 2.13 
pg/mL. 
10. Adiponectin ELISA -- Catalog Number E09; range: 0 / 1 - 100 ng/mL; sensitivity: < 0.6 
ng/mL. 
11. TNF-alpha ELISA -- Catalog Number IB49623; range: 0 / 7.8 - 500 pg/mL; sensitivity: 2.3 
pg/mL. 
12. IL-6 ELISA -- Catalog Number IB49612; range: 0 / 1.6 - 100 pg/mL; sensitivity: 0.92 
pg/mL. 
13. FGF21 ELISA  R&D Systems, Catalog Number DF2100; range: 0 / 31.3 - 2000 pg/mL; 
sensitivity: 31 pg/mL 
 
Immunohistochemical Assays. All immunohistochemistry (IHC) assays will be completed by a 
pathologist specialized in breast cancer. Tissue microarrays will be prepared from the tumor 
blocks. If blocks are not available, we will request 15 unstained slides. Briefly, IHC staining will 
be performed on 4-µm slices of formalin fixed paraffin-embedded tissue sections. Estrogen 
receptor (ER-alpha) and progesterone receptor will be immunostained according to standard 
procedures in clinical pathology. Primary antibodies against Insulin Receptor (IR) (CT-3, 1:100; 
Chemicon/Millipore, Billerica, MA), IGF-1R (alpha-subunit, clone 24-31, !:50; Cell Signaling), 
p-AMPK-alpha (Thr172; Upstate/Millipore), p-AKT (Ser473, 736E11, IHC-specific, 1:50; Cell 
Signaling), p-mTOR (Ser2448, 49F9, IHC-specific, 1:100; Cell Signaling) and p-p70S6K 
(Thr389, 1A5, 1:700; Cell Signaling) will be used. The p-AKT and p-p70S6K stainings have 
been validated by Western blotting and other studies. After deparaffinization, rehydration and 
heat-induced epitope retrieval, slides will be immunostaining according standard procedures as 
previously described. Positive control slides and negative control slides will be included within 
each batch for staining. IHC assays will be scored /evaluated based on the staining intensity (SI) 
and percentage of positive cells (PP) within the whole tissue section. Protein expression will be 
objectively and quantitatively measured using a DAKO automatic cellular imaging system 
(ACIS III) equipped with an automatic microscopy and advanced computerized image analysis. 
We define the expression index (EI) as the product of Percentage Staining (PP) and Average 
Brown Intensity (SI) (both quantitative values measured by the ACIS III system). 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
A phase 3 randomized trial compared everolimus and exemestane versus exemestane and 
placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor positive 
metastatic breast cancer who had recurrence or progression while receiving previous therapy 
with a nonsteroidal aromatase inhibitor in the adjuvant setting. The primary end point of this 
study (known as the BOLERO-2 trial) was progression-free survival (PFS). At the interim 
analysis, median PFS was 6.9 months with everolimus plus exemestane and 2.8 months with 
placebo plus exemestane, according to assessments by local investigators (hazard ratio for 
progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). [53]. 


2011-1239 
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Page 36 
 
True DLT Rate 
PET 
N: 
LQ 
Med 
UQ
10% 
0% 
 
40 
40 
40
20% 
1% 
 
40 
40 
40
30% 
9% 
 
40 
40 
40
40% 
44% 
 
23 
40 
40
50% 
85% 
 
11 
19 
30
 
 
 
The primary objective of our study is to assess the efficacy of exemestane and everolimus 
combined with metformin in overweight and obese post-menopausal women with metastatic 
breast cancer. The primary endpoint is progression-free survival (PFS), defined as the time from 
the date of registration to the date of the first documented progression or death due to any cause. 
We will use a median PFS of 7 months as the comparator, based on the local investigators 
assessment of PFS in the BOLERO-2 trial [53]. Using STPLAN, with 40 patients accrued at a 
rate of 2 patients per month (i.e., over a 20-month period), 1-sided 5% alpha, and a post-accrual 
follow-up of 3 months, we would have 80% power to detect a control median PFS of 7 months as 
statistically significantly lower than an experimental group median PFS of 12 months.  We 
will use Cox proportional hazards regression analysis to assess the effects of the usual prognostic 
factors for breast cancer (hormone receptor status, age, HER2 status, nuclear grade, and stage) on 
PFS. 
 
 
 
The method of Thall, Simon, and Estey (1995, Stat Med) will be employed to perform interim 
safety monitoring. We will assume a Beta (1, 5) prior distribution for the DLT rate, which in 
particular has mean DLT rate of 17%.  We will target a 30% DLT rate and we will terminate 
enrollment into the trial if 
 
Pr{DLT rate > 30%| data} > 0.925 
 
That is, if at any time during the study we determine that there is more than a 92.5% chance that 
the DLT rate is more than 30% we will stop enrollment into the study. Stopping boundaries 
corresponding to this probability criterion are to terminate the trial if 
 
[# of patients with DLT/ # of patients evaluated] >= 
 
5/5, 7/9, 8/12, 9/14, 10/17, 11/20, 12/22, 13/25, 14/28, 15/31, 16/33, 17/36, or 18/39 
 
 
 
The operating characteristics of this rule in the trial are shown in the following table: 
Operating Characteristics for Safety Monitoring Rule 


2011-1239 
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Page 37 
 
 
 
PET = Probability of Early Termination; LQ = lower quartile; Med = median; UQ = upper 
quartile 
 
 
 
 
We will conduct exploratory biomarker studies to identify the population most likely to benefit. 
Our preclinical data suggest that metformin increases FGF21 serum levels, and this may enhance 
the efficacy of exemestane and everolimus by dual blockade of the mTOR pathway. If we 
assume the serum FGF21 data follow a log-normal distribution, then using the data from Zhang 
et al. [78] and the log scale, we get a normal distribution with mean = 5.677 and a standard 
deviation of about 0.940. Assuming a 50% clinical benefit rate, 40 patients, a two-sided 5% 
alpha, 80% power, and a two-sample, equal variance t-test, we can detect an increase to a mean 
of 6.509 (a 15% increase) or larger as statistically significant. If the clinical benefit rate is only 
30%, then the smallest detectable mean increases to 6.585. 
 
16.0 
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Table 1. Clinically Relevant Drug Interactions: Inducers and Inhibitors of Isoenzyme CYP3A 
 
 
 
INDUCERS 
 
Barbiturates, carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, 
phenytoin, pioglitazone, rifabutin, rifampin, St. 
tazone, efavirenz, nevirapine, 
topiramate 
 
 
 
INHIBITORS 
 
Strong inhibitors: 
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, voriconazole, 
Posaconazole 
 
Moderate inhibitors: 
aprepitant, atazanavir, cimetidine, ciprofloxacin, darunavir, diltiazem, erythromycin, 
fluconazole, 
grapefruit juice, imatinib, tofisopam, verapamil. 


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Table 2. Everolimus Dose Reductions 
 
 
Dose level 
Dose and schedule 
 
0 = starting dose 
10 mg daily (2 × 5 mg daily) 
 
-1 dose level 
5 mg daily 


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Table 3. Dose Modification Guidelines for Hematologic Toxicities 
 
Toxicity 
Actions 
Thrombocytopenia 
Platelet count 
No change 
50000/ mm3 to 75000/ mm3 
Hold everolimus treatment until recovery to  
75000/mm3 
Reintroduce everolimus at the same dose level 
< 50000/ mm3 
Hold everolimus treatment until recovery to  
75000/mm3 
Reintroduce everolimus at the next lower dose 
level, if available. 
Absolute Neutrophil count (ANC) 
 mm3 : 
No change 
500/ mm3 to 1000/ mm3 
Hold everolimus treatment until recovery to  
1000/ 
mm3 
Reintroduce everolimus at the same dose level 
< 500/ mm3 
Hold until recovery to 
 mm3. 
Reintroduce everolimus at the next lowest dose 
level, if available. 
Febrile neutropenia 
Hold further dosing until 
 
and no fever.  Then resume dosing at the next 
lower dose level if available. 
Toxicity requiring interruption for > 4 
weeks 
Permanently discontinue everolimus treatment 
Physicians should always manage patients according to their medical judgment based on the 
particular clinical circumstances. 


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Table 4. Dose Modification Guidelines for Non-Hematologic Toxicities 
 
Toxicity 
Actions 
Hyperlipidemia and/or 
hypertriglyceridemia 
Any grade: 
Treat according to best clinical practice. No 
specific dose reductions are needed. 
Hyperglycemia 
Any grade: 
Treat according to best clinical practice. No 
specific dose reductions are needed. 
Stomatitis 
Grade 2: 
Interrupt everolimus until resolution to 
de 
1. Restart at the same dose. 
Grade 3: 
Interrupt everolimus until recovery to grade 
 
Reintroduce everolimus at the next lower dose 
level. 
Discontinue everolimus if stomatitis 
recover to 
 1 within 4 weeks. 
Grade 4: 
Discontinue everolimus treatment 
Pneumonitis 
See Table 6-4 
Other toxicities 
Grade 2 and 3 
Interrupt administration until resolution to  
grade 1. Restart at the same dose. 
Grade 4 
Hold everolimus treatment until recovery to  
grade 1.Reintroduce everolimus at the lower 
dose level, if 
available. 
Toxicity requiring interruption for >4 
weeks 
Permanently discontinue treatment. 
No specific dose adjustments are recommended for Grade 1 toxicity. However, physicians 
should 
always manage patients according to their medical judgment based on the particular clinical 
circumstances. 


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Table 5. Management of Non-Infectious Pneumonitis 
 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis 
Everolimus Dose 
Adjustment 
Grade 1 
Asymptomatic, 
radiographic 
findings only 
CT scans with lung 
windows. Repeat at least 
every 12 weeks until return 
to within normal limits. 
No specific 
therapy 
is required 
Administer 100% of study 
treatment dose. 
Grade 2 
Symptomatic, 
not interfering 
with ADL 
CT scan with lung 
windows. Consider pulmonary 
function testing includes: 
spirometry, DLCO, and room 
air O2 saturation 
at rest. Repeat at least 
every 12 weeks until return 
to within normal limits. 
Consider a bronchoscopy 
with biopsy and / or BAL. 
Symptomatic 
only. Consider 
corticosteroids if 
symptoms are 
troublesome. 
Reduce study treatment 
dose 
by 1 dose level (see Table 
6-5) until recovery to  
Grade 1. 
Study treatment may also 
be 
interrupted if symptoms are 
troublesome. Patients will 
discontinue study treatment 
if 
they fail to recover to  
Grade 1 within 3 weeks. 
Grade 3 
Symptomatic, 
interfering with 
ADL; O2 
indicated 
CT scan with lung windows 
and pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. 
Repeat at least every 6 
weeks until return to within 
normal limits. 
Bronchoscopy with biopsy 
and / or BAL is recommended. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as 
medically 
indicated. 
Hold treatment until 
recovery to 
 1. May 
restart study treatment 
within 3 weeks at a 
reduced dose (by one level) 
if evidence of clinical 
benefit. 
Grade 4 
Lifethreatening; 
ventilatory 
support 
indicated 
CT scan with lung windows 
and required pulmonary 
function testing, if possible, 
includes: spirometry, DLCO, 
and room air O2 saturation at 
rest. Repeat at least 
every 6 weeks until return 
to within normal limits. 
Bronchoscopy with biopsy 
and / or BAL is recommended 
if possible. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as 
medically 
indicated. 
Discontinue treatment. 


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Table 6. Visit Evaluation Schedule 
 
Screening 
(days -28 
to 1) 
 
Day 1 
(+/- 7 
days) 
 
4 wks 
(+/- 7 
days) 
 
8 wks 
(+/- 7 
days) 
 
12 wks 
(+/- 7 
days) 
16 wks 
(+/- 7 
days) 
Every 2 
months 
(+/- 7 
days) 
 
 
 
Demography/informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Relevant medical history/current medical 
conditions 
X 
 
 
 
 
 
 
 
Diagnosis and extent of cancer1 
X 
 
 
 
 
 
 
 
Prior antineoplastic therapy 
X 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
 
Hematology2 
X 
X 
X 
X 
X 
X 
X 
X 
Hemoglobin A1C 
 
 
X 
X 
X 
X 
 
 
Coagulation 
X 
 
As clinically indicated 
Biochemistry3 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid Profile4 
X 
 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 
X 
 
Continuous during the study 
Adverse events 
 
 
Continuous during the study 
Tumor evaluation 
 
 
 
 
 
 
 
 
CT or MRI of chest, abdomen5 
X 
 
 
X 
 
X 
X 
X  
CT or MRI of Brain7 
X 
 
 
 
 
 
 
 
Bone Scan or skeletal Survey8 
X 
 
 
 
 
 
 
 
Bone X-Ray, CT or MRI13 
X 
 
 
X 
 
X 
X 
X 
Blood samples for plasma and serum 
soluble biomarkers9 
X 
 
 
X 
 
X 
 
X 
Request of archival tumor block/slides 
X 
 
 
 
 
 
 
 
Blood samples for DNA extraction10 
X 
 
 
 
 
 
 
 
Optional biopsy of metastatic tumor11 
X 
 
 
X 
 
 
 
 
 
1CT of the chest and abdomen. Skin lesions should be photographed in addition to measuring. Brain scan (CT scan or MRI with i.v. contrast) must be performed 


2011-1239
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if CNS symptoms are present. Note: If the patient had history of brain or other CNS metastases, she is ineligible. 2Hematology tests include a complete blood 
count (CBC). A total white blood cell (WBC) with absolute differentials (including neutrophil count plus bands, lymphocyte, monocyte, eosinophil, basophil 
counts), hemoglobin (Hgb), and a platelet count. In the event of Grade 2, Grade 3 or Grade 4 hematological toxicities that require study drug dose 
 
interruptions, hematological tests must be repeated weekly until recovery to the baseline value or Grade 1. 3Serum Chemistry must include: BUN or uric acid, 
creatinine, LDH, total protein, electrolytes (sodium, potassium and calcium), total bilirubin, GGT, albumin, alkaline phosphatase, AST/sGOT fasting glucose. 
4Serum fasting lipid profile must include: total cholesterol and triglycerides. Patients should be in fasting state. 5CT of chest and abdomen must be repeated 
 
tumor assessment visit (including if negative at baseline). Scans for complete and partial responses must be repeated at least at 4 weeks but no later than the next 
scheduled tumor assessment following the first documented response. Skin lesions should be photographed in addition to measuring. 6Except in case of 
discontinuation from treatment due to progression, tumor assessment at EOT is not necessary if the previous evaluation was done within 6 weeks of EOT. 7Brain 
scan (CT scan or MRI with i.v. contrast) must be performed if CNS symptoms are present. Note: If the patient had history of brain or other CNS metastases, 
 
ineligible. 8A bone scan or skeletal survey is to be performed at baseline only. Positive areas on bone scans must be assessed by X-ray, CT scan with bone 
windows or MRI, and should continue to be assessed using the same modality (X-ray, CT scan with bone windows or MRI) every 8 weeks until disease 
progression and new anticancer therapy is started. Additional bone scans or skeletal surveys should be performed if clinically indicated. Abnormalities found on 
subsequent bone scans must also be confirmed by X-ray, CT scan, or MRI. 9Soluble biomarkers will need a sample of 20 mL blood for plasma and 40 mL blood 
for serum. Plasma and serum samples will be collected at screening, at 4 weeks (pre-dose), 8 weeks (pre-dose) and EOT. There can be an important circadian 
rhythm variation of these markers, samples should thus optimally be collected fasting in the morning and specimen collection should be consistent during study 
visits. 10One 5 ml blood sample for DNA extraction will be collected at baseline from all patients. This will be used for DNA analysis of SNPs relevant to 
response to therapy. 11In patients with tumors safely accessible for biopsy, informed consent will be obtained for imaging-guided core biopsy of breast cancer at 
baseline and 8 weeks (+/-3 days) after drug treatment. At each time point, a core biopsy specimen will be fixed and embedded in paraffin and processed for 
immunohistochemistry and molecular studies.