Clinical trial NCT02269670
Conditions: Estrogen Receptor-positive Breast Cancer HER2-negative Breast Cancer Progesterone Receptor-positive Breast Cancer Recurrent Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer
Sponsor: Emory University
Start date: 2014-11-25; Completion date: 2021-01-25
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well everolimus and hormone therapy work in treating patients with hormone receptor positive breast cancer that has continued to spread (progressed) or returned after a period of improvement (recurred) on everolimus and exemestane hormone therapy. Everolimus is a chemotherapy drug that may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen and progesterone are hormones that can cause the growth of breast cancer cells. Hormone therapy may fight breast cancer by lowering the amount of estrogen and progesterone the body makes. Giving everolimus with a different type of hormone therapy may be an effective treatment for breast cancer in patients who progressed on everolimus with exemestane.

Detailed description:
PRIMARY OBJECTIVE:

Progression free survival in patients with advanced or metastatic breast cancer receiving everolimus plus hormonal therapy beyond first progression.

SECONDARY OBJECTIVES:

1. Clinical benefit rate (sum of stable disease, partial response, complete response).
2. Response rate (partial response and complete response).
3. Overall survival.
4. Safety, side effects and tolerability profile of everolimus.

OUTLINE:

Patients receive everolimus orally (PO) daily and a hormone therapy regimen chosen at the discretion of the investigator (anastrozole PO daily; letrozole PO daily; tamoxifen citrate PO daily; fulvestrant intramuscularly \[IM\] or PO on days 1, 15, and 29, and then monthly; megestrol acetate PO 4 times daily \[QID\]; or other regimen). Treatment continues in the absence of disease progression or unacceptable toxicity.

Arms: arm 1: Patients receive everolimus PO daily and a hormone therapy regimen chosen at the discretion of the investigator (anastrozole PO daily; letrozole PO daily; tamoxifen citrate PO daily; fulvestrant IM or PO on days 1, 15, and 29, and then monthly; megestrol acetate PO QID; or other regimen). Treatment continues in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: everolimus intervention 2: anastrozole intervention 3: letrozole intervention 4: tamoxifen citrate intervention 5: fulvestrant intervention 6: megestrol acetate
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO intervention 4: Given PO intervention 5: Given IM or PO intervention 6: Given PO

Protocol documents:
ICF_000.pdf: 
Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 1 of 13                                                        Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
 
 
 
 
 
 
 
 
 
 
 
 
 
Winship2563-13: Phase II study of everolimus beyond first progression in postmenopausal women with 
advanced, hormone receptor positive breast cancer 
 
 
 
Informed consent date: January 30, 2018 
 
NCT02269670 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 2 of 13                                                        Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
 
You Are Being Asked to Be in a Research Study 
 
What Is a Research Study? 
The main purpose of research studies is to gain knowledge. This knowledge may be used to 
help others. Research studies are not intended to benefit you directly, though some might.   
 
Do I Have to Do This? 
No. Being in this study is entirely your choice.  If you decide to join this study, you can 
change your mind later on and withdraw from the research study.  
 
Taking part in a study is separate from medical care. The decision to join or not join the 
research study will not affect your status as a patient.   
 
What Is This Document? 
This form is an informed consent document. It will describe the study risks, procedures, and 
any costs to you. 
 
This form is also a HIPAA Authorization document. It will describe how your health information 
will be used and by whom. 
 
Signing this form indicates you are willing to take part in the study and allow your health 
information to be used. 
 
What Should I Do Next? 
1. Read this form, or have it read to you. 
2. Make sure the study doctor or study staff explains the study to you. 
3. Ask questions (e.g., time commitment, unfamiliar words, specific procedures, etc.)  
4. If there will be medical treatment, know which parts are research and which are 
standard care. 
5. Take time to consider this, and talk about it with your family and friends. 
 
 
 
 
 
 


Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 3 of 13                                                        Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
Emory University, Grady Health System and Saint Joseph’s Hospital 
Consent to be a Research Subject / HIPAA Authorization  
 
 
Title:  Winship2563-13: Phase II study of everolimus beyond first progression in postmenopausal women with advanced, 
hormone receptor positive breast cancer  
 
Principal Investigator:  Elisavet Paplomata, MD 
 
Study-Supporter:  Novartis Pharmaceuticals 
 
Introduction 
You are being asked to be in a medical research study. This form is designed to tell you everything you need to think 
about before you decide if you want to be a part of the study.  It is entirely your choice.  If you decide to take part, you 
can change your mind later on and withdraw from the research study. The decision to join or not join the research 
study will not cause you to lose any medical benefits.  If you decide not to take part in this study, your doctor will 
continue to treat you. 
 
Before making your decision: 
• 
Please carefully read this form or have it read to you 
• 
Please listen to the study doctor or study staff explain the study to you  
• 
Please ask questions about anything that is not clear 
 
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether you would like to 
participate. You may wish to discuss your decision with family or friends. Do not sign this consent form unless you have 
had a chance to ask questions and get answers that make sense to you.  By signing this form you will not give up any 
legal rights. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This Web site 
will not include information that can identify you. At most the Web site will include a summary of the results. You can 
search this Web site at any time. 
 
Study Overview 
Breast cancers that express the receptor for estrogen and/or progesterone are initially sensitive to hormonal therapies, 
such as tamoxifen and aromatase inhibitors. Unfortunately, resistance to hormonal agents develops inevitably.   
 
Everolimus targets a protein called mTOR, which appears to become more active in breast cancers that are no longer 
controlled by hormonal therapies. Everolimus is approved for the treatment of kidney cancers. It has been recently 
approved in combination with the aromatase inhibitor Exemestane for metastatic breast cancer, which does not 
respond to hormonal agents. Smaller studies have also shown that everolimus is active in combination with other 
hormonal agents.  
 
Everolimus has been FDA approved in combination with the endocrine treatment Exemestane for these breast cancer 
patients, whose tumors express hormone receptors. The purpose of this study is to investigate if we can continue 
everolimus in combination with a different endocrine therapy in patients who progress after that combination. The 
alternative option for these patients would be treatment without everolimus or chemotherapy.  
 


Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 4 of 13                                                        Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
This study will enroll patients who are already on everolimus for metastatic breast cancer but have progression of their 
cancer; after getting on the study, the patients will continue to take everolimus at the same dose and will change their 
endocrine/hormonal therapy. 
 
If you enroll in this study and your cancer gets worse, you will be taken off the study.  
 
It is hoped that everolimus will help control the disease and stop the tumor from growing. This assessment will be based 
on imaging studies, which will be done regularly during the study or based on new complaints, which are suspicious for 
progression of the disease.  
 
How Many People Will Take Part In The Study? 
About 38 people will take part in this study, all of who will take everolimus with a hormonal therapy.  
 
Procedures   
At an initial “screening” visit, you will be asked about your current condition, your medical history, and any medications 
you may be taking.  You will undergo a series of tests to evaluate your disease.  These include: 
• 
A physical examination 
• 
Measurement of your blood pressure, heart rate, and temperature. An electrocardiogram (EKG) will also be 
done to check your heart rhythm.  
• 
Obtaining your height and weight 
• 
Approximately one tablespoon of blood for routine tests 
• 
CT (computed tomography) scan will be done if you have not had one recently.  The CT will find and measure 
the location of your disease.  
• 
A bone scan may also be done if your study doctor finds it necessary. 
 
We will perform a pregnancy test if you are a woman who could have children.  You must not be pregnant, 
breastfeeding, or planning to have children (male patients included) in order to join the study. 
 
If you meet the “entry criteria” from testing at your initial visit, we will give you a time to come back.  At that next visit 
we will formally enter you in the study.  If your screening visit was more than 14 days ago, we will have to repeat many 
of the same tests.  These would include measuring your weight, temperature, blood pressure, and heart rate.  If your 
imaging was done more than 4 weeks earlier, we will need to repeat them.  We will also need samples of your blood for 
laboratory testing.  We will use these results as your baseline readings.  
 
If you are found to be eligible for the study, and agree to participate, you will continue to take everolimus but will 
change your hormonal treatment. Everolimus will be taken by mouth every day.  Your endocrine treatment will either be 
a pill or an injection in the muscle. This will be explained to you in detail.  
 
At the start of your study treatment (day 1 of cycle 1), your doctor will perform a physical exam and take your vital signs, 
weight, and temperature.  You will have routine blood tests performed.  
 
Each cycle will be 28 days (4 weeks). On Day 1 of each new cycle and before the next dose of study therapy can be given, 
a physical examination will be made.  Blood pressure and heart rate (your “vital signs”), temperature, and weight will be 
measured.  Standard blood tests will be carried out to check your blood counts, liver and kidney function and 
electrolytes. The dose and timing of your therapy may be changed based upon test results or due to any serious side 
effect you may be experiencing.  If delays in treatment do occur, it may also result in you having to attend extra visits.  If 
the side effects are severe and do not come under control, you may be withdrawn from the study if the study doctor 
feels this is in your best interests.  If the study therapy is delayed by more than four weeks due to side effects, then you 
will be withdrawn from the study. 


Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 5 of 13                                                        Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
 
Throughout the study, the effect of the study treatment on your cancer (as judged by its change in size) will be assessed 
every 8 weeks initially, and then after 3 months every 12 weeks. Tumor assessments will be a CT scan, and maybe a 
bone-scan if your doctor finds it useful.  
 
How will my medicine be provided?  
The medicine that you will take will be dispensed by the pharmacy and delivered to the principal investigator or study 
team member.  The principal investigator or health care providers on his/her research team will provide the medicine to 
you.  If you have questions about the medicine, you should ask the principal investigator or study nurse.  You may also 
call the pharmacy if you have questions about the medicine. The number for the pharmacy is included on your medicine 
package. 
 
Who owns my study information and samples? 
If you join this study, you will be donating your samples and study information.  You will not receive any compensation if 
your samples or information are used to make a new product. If you withdraw from the study, data and samples that 
were already collected may be still be used for this study.   
 
Risks and Discomforts  
While on study, you are at risk for these side effects.  You should discuss these with the researcher and/or your regular 
doctor.  There may also be other side effects that we cannot predict.  Other drugs will be given to make side effects less 
serious and uncomfortable.  Many side effects go away shortly after the chemotherapy drugs are stopped, but in some 
cases side effects can be serious or permanent. 
 
The risks involved in this study are the possible side effects of the study treatment and those of taking blood.  Additional 
risks include those from medicine tests and CT scans and x-rays.  There is a risk that the study drugs will not be effective 
in controlling your cancer.  However, you will be closely monitored and should the drugs not be effective you will be 
removed from the study. 
 
Everolimus: 
 
        Common side effects: 
• 
Fatigue 
• 
Diarrhea 
• 
Nausea  
• 
Abdominal pain 
• 
Mouth sores 
• 
Constipation 
• 
Anemia 
• 
Low platelet counts 
• 
Low white blood cell count 
 
      Less frequent side effects:  
• 
Vomiting 
• 
Neuropathy 
• 
Anorexia 
• 
Fever 
• 
Shortness of breath 
• 
Back pain 


Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 6 of 13                                                        Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
• 
Coughing 
• 
Edema 
• 
Headache 
• 
Hand-foot syndrome 
• 
Heartburn 
• 
Difficulty sleeping 
• 
Rash 
• 
Sore throat 
• 
Dizziness 
• 
Flushing 
• 
Increased tearing of eyes 
• 
Elevated cholesterol and/or triglycerides 
 
      Other side effects: 
• 
Low potassium 
• 
Chest pain 
• 
Infection 
• 
Change in taste 
• 
Allergic reaction 
• 
Hair loss 
• 
Blood in urine 
• 
Non-infectious pneumonitis (inflammation of the lung) 
• 
Muscle weakness 
• 
Gallstones and gall bladder damage 
• 
The development of gout (painful joints due to an increase in a protein called uric acid in your blood) which 
may require therapy 
• 
Decreased heart function 
• 
Elevated liver tests 
 
Other risks and inconveniences: 
Obtaining blood samples may cause some discomfort, bruising, bleeding from the site of sampling, formation of a blood 
clot, and in rare cases, infection, dizziness and fainting. The blood pressure cuff may also cause discomfort or bruising to 
the upper arm. 
 
Risks and side effects of endocrine therapy:  
 
If your doctor chooses a endocrine therapy that is a pill, then you will be asked to take a pill by mouth, usually once a day 
the same time, however some endocrine treatments may be given at a more frequent schedule, which will be explained 
to  you in detail.  
The most common side effects of endocrine therapy are:  
• 
Risk of stroke and cardiovascular disease 
• 
Risk of uterine cancer 
• 
Hot flushes 
• 
Vaginal discharge 
• 
Sexual dysfunction which may include decreased libido, decrease in orgasmic response, vaginal 
dryness, pelvic pain, infertility, and/or changes in the labia or perineum. 
• 
Menstrual abnormalities 
• 
Risk of osteoporosis and fractures 


Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 7 of 13                                                        Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
• 
High cholesterol 
• 
Fatigue 
• 
Poor sleep 
• 
Bone or joint aches and stiffness 
 
If your doctor chooses to give you an injection, it will be in the muscle and may be associated with the following 
complications:  
• 
Abscess  
• 
Hematoma  
• 
Injury to blood vessels and peripheral nerves  
• 
Pain at the injection site  
• 
Tingling or numbness  
• 
Infection  
• 
Bleeding  
• 
Allergic reaction 
 
Radiation-Related Risks: 
You will be exposed to radiation from nuclear medicine and CT scans. These procedures are necessary for your medical 
care and will occur even if you do not participate in this study. The radiation dose estimate that you will receive is equal 
to or less than the radiation exposure allowed to be received by a radiation worker for 3 years. The principal risk associated 
with a radiation dose is the possibility of developing a radiation-induced cancer later in life. Although the risk from 
radiation is cumulative it is not expected to adversely affect your condition or treatment. The Emory University Radiation 
Safety Committee has reviewed and approved the use of radiation in this research study. 
 
Reproductive risks: 
The risks to an unborn fetus or nursing child from everolimus are not known.  These medications may damage sperm and 
may harm the baby if you become pregnant.   
 
Therefore, women who are pregnant or nursing (breastfeeding) a child may not participate in this trial.  You must confirm 
that, to the best of your knowledge, you are not now pregnant, and that you (or your partner) do not intend to become 
pregnant during the trial.  A negative pregnancy test at the screening for all women of childbearing potential is a 
requirement for study entry. 
 
If there is any possibility that you (or your partner) may become pregnant during the study, the study doctor will discuss 
appropriate birth control measures with you. If you are pregnant, you will be withdrawn from the trial without your 
consent. 
 
If you will be taking the study drug home, keep it out of the reach of children or anyone else who may not be able to read 
or understand the label.  Do not let anyone else take the study drug besides you. 
 
Benefits  
Information from this study may help you and/or other people with metastatic breast cancer that is no longer controlled 
by hormonal therapies. 
 
You may receive no direct benefit from being in this study.  However, your taking part may help breast cancer patients 
get better care in the future. 
 
Other Treatment outside this Study 
Instead of being in this study, you have these options: 


Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 8 of 13                                                        Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
1. Supportive care (care to help you feel more comfortable, including hospice care) 
2. Treatment with other drugs (chemotherapy, anti-angiogenic therapies). 
3. Radiation therapy 
4. Surgery 
5. Other hormonal therapies 
6. Other experimental therapy 
 
New Information 
It is possible that the researchers will learn something new during the study about the risks of being in it.  If this 
happens, they will tell you about it. Then you can decide if you want to continue to be in this study or not.  You may be 
asked to sign a new consent form that includes the new information if you decide to stay in the study. 
 
Compensation  
You will not be offered payment for being in this study.   
 
How will you protect my private information that you collect in this study? 
Whenever possible, a study number, rather than your name, will be used on study records.  Your name and other 
identifying information will not appear when we present or publish the study results. 
 
Study records can be opened by court order.  They also may be provided in response to a subpoena or a request for the 
production of documents.  
 
Storing and Sharing your Information 
Your samples, genomic data and health information will be stored and shared with other researchers. The samples and 
information will be available for any research question, such as research to understand what causes certain diseases (for 
example heart disease, cancer, or psychiatric disorders), development of new scientific methods, or the study of where 
different groups of people may have come from. 
 
Medical Record 
If you have been an Emory, Grady Health System and Saint Joseph’s Hospital patient before, then you already have an 
Emory, Grady Health System and Saint Joseph’s Hospital medical record.  If you have never been an Emory, Grady Health 
System and Saint Joseph’s Hospital patient, you do not have one.   An Emory, Grady Health System and Saint Joseph’s 
Hospital medical record will be made for you if an Emory, Grady Health System and Saint Joseph’s Hospital provider or 
facility gives you any services or procedures for this study.   
 
 Copies of the consent form/HIPAA authorization that you sign will be put in any Emory, Grady Health System and Saint 
Joseph’s Hospital medical record you have now or any time during the study.   
 
Emory, Grady Health System and Saint Joseph’s Hospital may create study information about you that can help with 
your care.  For example, the results of study tests or procedures.  These study results will be put in your Emory, Grady 
Health System and Saint Joseph’s Hospital medical record. Anyone who has access to your medical records will be able 
to have access to all the study information placed there.  The confidentiality of the study information in your medical 
record will be protected by laws like the HIPAA privacy rule.  State and federal laws may not protect the research 
information from disclosure.  
 
The results of some study tests and procedures will be used only for research purposes and will not be placed in your 
medical record.  For this study, those items include:  None 
 


Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 9 of 13                                                        Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
Tests and procedures done at non-Emory, Grady Health System and Saint Joseph’s Hospital places may not become part 
of your Emory, Grady Health System and Saint Joseph’s Hospital medical record. Also, if you decide to be in this study, it 
is up to you to let your other health providers know.  
 
In Case of Injury 
If you get ill or injured from being in the study, Emory, Grady Health System and Saint Joseph’s Hospital will help you to 
get medical treatment.   Emory, Grady Health System and Saint Joseph’s Hospital and the sponsor have not, however, 
set aside any money to pay you or to pay for this medical treatment. The only exception is if it is proven that your injury 
or illness is directly caused by the negligence of an Emory, Grady Health System and Saint Joseph’s Hospital or sponsor 
employee.  “Negligence” is the failure to follow a standard duty of care.  
If you become ill or injured from being in this study, your insurer will be billed for your treatment costs.  If you do not 
have insurance, or if your insurer does not pay, then you will have to pay these costs.   
If you believe you have become ill or injured from this research, you should contact Dr. Elisavet Paplomata at telephone 
number 404-778-1900. You should also let any health care provider who treats you know that you are in a research 
study.  
Costs 
Everolimus (RAD001) will be provided by Novartis Pharmaceuticals, the company who makes this medication.  There will 
be no cost to you for the everolimus or the serum pregnancy test you receive as part of this study.     
 
You will have to pay for the items or services for which the study sponsor does not pay. The sponsor will not pay for your 
regular medical care. If you have insurance, Emory and Saint Joseph’s Hospital will submit claims to your insurance for 
items and services that the sponsor does not cover.  Emory and Saint Joseph’s Hospital will send in only those claims for 
items and services that it reasonably believes your insurance will pay and that the sponsor has not paid.  
 
The actual amount that you have to pay depends on whether or not you have health insurance and whether or not that 
insurance will pay for any research study costs. Generally, insurance companies will not pay for items and services that 
are required just for a research study. Some insurance companies will not pay for regular medical treatment or 
treatment for complications if you are in a study.  How much you will have to pay for any co-payments, deductibles or 
co-insurance depends on your plan.  Emory, Grady Health System and Saint Joseph’s Hospital and the sponsor will not 
pay for these costs.  
 
It is a good idea to contact your insurance provider and tell them you want to be in this research study.  Ask them what 
they will pay for and what they will not pay for.  You can also ask the study team for help in figuring out what you will 
have to pay.  
 
If you do not have insurance, Emory, Grady Health System and Saint Joseph’s Hospital will review your case as part of its 
program for low-income patient care.  The standard policies of that program will apply.  The program will figure out if 
you have to pay any costs for taking part in the study and what those costs will be. 
 
Withdrawal from the Study 
You have the right to leave a study at any time without penalty. For your safety, however, you should consider the study 
doctor’s advice about how to go off the study treatment. If you leave the study before the final planned study visit, the 
researchers may ask you to have some of the final steps done.   
 
The researchers and sponsor also have the right to stop your participation in this study without your consent if: 
• 
They believe it is in your best interest; 


Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 10 of 13                                                       Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
• 
You were to object to any future changes that may be made in the study plan; 
• 
Staying in the study would be harmful; 
• 
You need treatment not allowed in this study; 
• 
You fail to follow instructions; 
• 
You become pregnant; 
• 
The study is cancelled; 
• 
Your cancer progresses; 
• 
or for any other reason. 
 
 
Authorization to Use and Disclose Protected Health Information 
 
The privacy of your health information is important to us.  We call your health information that identifies you, your 
“protected health information” or “PHI.”  To protect your PHI, we will follow federal and state privacy laws, including the 
Health Insurance Portability and Accountability Act and regulations (HIPAA).  We refer to all of these laws as the “Privacy 
Rules.”  Here we let you know how we will use and disclose your PHI for the main study and for any optional studies in 
which you may choose to participate. 
 
PHI that Will be Used/Disclosed:   
The PHI that we will use or share for the main research study includes: 
• 
Medical information about you including your medical history and present/past medications. 
• 
Results of exams, procedures and tests you have before and during the study. 
• 
Laboratory test results. 
 
Purposes for Which Your PHI Will be Used/Disclosed: 
We will use and share your PHI for the conduct and oversight of the research study.  We will use and share your 
PHI to provide you with study related treatment and for payment for such treatment.  We will also use and 
share your PHI to conduct normal business operations.  We may share your PHI with other people and places 
that help us conduct or carry out the study, such as laboratories, data management centers, data monitors, 
contract research organizations, Institutional Review Boards (IRBs) and other study sites. If you leave the study, 
we may use your PHI to determine your health, vital status or contact information. We will use and disclose your 
PHI for the administration and payment of any costs relating to subject injury from the study.   
 
Use and Disclosure of Your Information That is Required by Law:   
We will use and disclose your PHI when we are required to do so by law. This includes laws that require us to 
report child abuse or abuse of elderly or disabled adults. We will also comply with legal requests or orders that 
require us to disclose your PHI. These include subpoenas or court orders.   
 
Authorization to Use PHI is Required to Participate: 
By signing this form, you give us permission to use and share your PHI as described in this document. You do not 
have to sign this form to authorize the use and disclosure of your PHI.  If you do not sign this form, then you may 
not participate in the research study or receive research-related treatment.  You may still receive non-research 
related treatment.   
 
People Who will Use/Disclose Your PHI: 
The following people and groups will use and disclose your PHI in connection with the research study: 
 


Study No.: IRB00071229 
Emory University IRB 
IRB use only 
Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 11 of 13                                                       Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
• 
The Principal Investigator and the research staff will use and disclose your PHI to conduct the study and 
give you study related treatment. 
• 
Emory, Grady Health System and Saint Joseph’s Hospital may use and disclose your PHI to get payment 
for study related treatment and to run normal business operations. c 
• 
The Principal Investigator and research staff will share your PHI with other people and groups to help 
conduct the study or to provide oversight for the study. 
• 
Winship Cancer Institute is the Sponsor of the study.  The Sponsor may use and disclose your PHI to 
make sure the research is done correctly and to collect and analyze the results of the research.  The 
Sponsor may disclose your PHI to other people and groups like study monitors to help conduct the study 
or to provide oversight for the study.   
• 
The research team and the Sponsor may use and disclose your PHI, including disclosure to insurance 
carriers to administer payment for subject injury.  
• 
The following people and groups will use your PHI to make sure the research is done correctly and 
safely: 
o Emory, Grady Health System and Saint Joseph’s Hospital offices that are part of the Human 
Research Participant Protection Program and those that are involved in study administration 
and billing.  These include the Emory IRB, the Emory Research and Compliance Offices, and the 
Emory Office for Clinical Research.  
o Government agencies that regulate the research including:  [Office for Human Research 
Protections; Food and Drug Administration]. 
o Public health agencies. 
o Research monitors and reviewer. 
o Accreditation agencies. 
o Pharmaceutical Collaborators, the manufacturers of Everolimus, and their authorized agents 
 
• 
Sometimes a Principal Investigator or other researcher moves to a different institution. If this happens, 
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PI:  Elisavet Paplomata, MD                                               Page 12 of 13                                                       Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
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Study No.: IRB00071229 
Emory University IRB 
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Document Approved On: 1/30/2018 
 
 
PI:  Elisavet Paplomata, MD                                               Page 13 of 13                                                       Version Date:  01/29/2016 
Protocol #:  Winship2563-13                                                                                                                                  IRB Form 10272015 
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Prot_001.pdf: 
Version 7. 12/07/2015 
1
 
 
 
 
 
PROTOCOL 
 
 
STUDY TITLE:   
Phase II study of everolimus beyond progression in 
postmenopausal women with advanced, hormone 
receptor positive breast cancer. 
 
STUDY DRUG:  
 
 
Everolimus 
 
Provided by:   
 
 
Novartis 
 
Investigator:   
 
 
Elisavet Paplomata 
 
 
 
 
 
1365 Clifton Road, Atlanta, GA 30322 
Tel: 404-778-1900 
epaplom@emory.edu 
 
 
Statistician: 
 
 
 
Yuan Liu, Ph.D. 
Department of Biostatistics & Bioinformatics, 
Rollins School of Public Health 
1365-B Clifton Rd. NE, Room 4112, Atlanta, GA 
30322 
Tel: 404-778-1989 
yliu31@emory.edu 
 
 
 
STUDY COORDINATOR:  
Donita Welch 
 
 
 
 
 


Version 7. 12/07/2015 
2
Protocol Version/Date:  
Version #1 
09/09/2013 
 
 
 
 
Version #2  
09/13/2013 
 
 
 
 
Version #3 
10/17/2013 
 
 
 
 
Version #4 
2/6/2014 
 
 
 
 
Version #5 
10/03/2014 
 
 
 
 
Version #6 
3/25/2015 
 
 
 
 
Version #7   
12/07/2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 7. 12/07/2015 
3
 
 
 
 
 
TABLE OF CONTENTS  
 
       Page 
1. 
INTRODUCTION ............................................................................................ 
6 
1.1 
Disease Background.............................................................................. 
6 
1.2 
Mechanisms of hormone-resistance ...................................................... 
6 
1.3 
Rationale for mTOR inhibition in hormone receptor-positive disease . 
8 
1.4 
Everolimus clinical Studies ................................................................... 
9 
1.5 
Overview of EVEROLIMUS ................................................................ 
13 
1.5.1    EVEROLIMUS pharmacokinetics ............................................ 
14 
1.5.2    Pharmacodynamic studies ......................................................... 
15 
1.6       Rationale of continuing targeted therapies beyond progression ........... 
19  
2. 
OBJECTIVES ...................................................................................................     20 
2.1 
Primary Objectives ................................................................................     20 
2.2 
Secondary Objectives ............................................................................     20 
3.      STUDY DESIGN..............................................................................................     21 
3.1 
Rationale for Study Design ...................................................................     21 
3.2 
Study Design .........................................................................................     21 
3.3 
Drugs used in this study  ....................................................................... 
23 
3.4 
Description of the Study ....................................................................... 
24 
3.5 
Outcome Measures................................................................................     24 
3.6       Safety Plan ............................................................................................     24 
3.6.1    Management of stomatitis/oral mucositis/mouth ulcers ........     25 
3.6.2    Management of hyperlipidemia and hyperglycemia .............. 
26 
3.6.2.1 Management of hyperlipidemia ............................................. 
26 
3.6.2.2 Management of hyperglycemia .............................................. 
26 
3.6.3    Management of non-infectious pneumonitis ......................... 
29 
 
 
4. 
MATERIALS AND METHODS ......................................................................     30 
4.1 
Inclusion Criteria .................................................................................. 
30 
4.2       Exclusion Criteria .................................................................................     31 
 
4.2.1      Screening for hepatitis ............................................................ 
33 
4.3      Study Medication ...................................................................................     34 
 
4.3.1      Dosing modifications .............................................................. 
35 
4.4      Concomitant and Excluded Therapy ......................................................     35 
            4.4.1      Antineoplastic Therapy ...........................................................     36 
            4.4.2      Bisphosphonates ..................................................................... 
36 
            4.4.3      Hematopoietic Growth and Antibiotics .................................. 
37 
            4.4.4      Anti-emetics ............................................................................ 
37 
            4.4.5      Analgesics ............................................................................... 
37 
            4.4.6      Systemic corticosteroids ......................................................... 
37 


Version 7. 12/07/2015 
4
 
4.4.7      P-glycoprotein (P-gp) inhibitors .............................................     37 
 
4.4.8      Cytochrome p450 enzymes ..................................................... 
37 
4.5 
Study Assessments ................................................................................     40 
4.5.1 
Assessments during Treatment ..............................................     40 
4.5.2 
Follow-Up Assessments.........................................................     40 
4.6 
Discontinuation of Protocol-Specified Therapy ...................................     40 
4.7 
Subject Discontinuation ........................................................................     40 
4.8 
Study Discontinuation ...........................................................................    40 
4.9 
Statistical Methods ................................................................................     41 
4.9.1       Data Cleaning ......................................................................... 
41 
4.9.2       Efficacy Analysis ................................................................... 
41 
4.9.3 
Sample Size Estimation .........................................................     41 
4.9.4 
Statistical Methods .................................................................     42 
4.9.5 
Missing Data .......................................................................... 
42 
4.10 
Data Quality Assurance ........................................................................     42 
4.11 
Compliance With Laws and Regulations .............................................. 
42 
 
5. 
REPORTING OF ADVERSE EVENTS ..........................................................     42 
5.1 
Adverse Event and Reporting Definitions ............................................     42 
5.2 
Reporting of Serious Adverse Events Associated With Everolimus .... 
43  
5.2.1 
MedWatch 3500 Reporting Guidelines .................................     45 
5.2.2 
Data and Safety Monitoring Plan ........................................... 
46 
 
6. 
INVESTIGATOR REQUIREMENTS .............................................................     47 
6.1 
Study Initiation......................................................................................     47 
6.2 
Study Completion .................................................................................     47 
6.3 
Informed Consent..................................................................................     47 
6.4 
Institutional Review Board or Ethics Committee Approval ................. 
48 
6.5 
Study Monitoring  Requirements .......................................................... 
48 
6.6 
Study Medication Accountability .........................................................     48 
6.7 
Disclosure of Data .................................................................................     49 
6.8 
Retention of Records .............................................................................     49 
 
REFERENCES ..........................................................................................................     50 
 
FIGURES 
Figure 1: 
The mTOR pathway ........................................................................... 
7 
Figure 2:          Everolimus and letrozole inhibit breast cancer cell growth .............. 
9 
Figure 3: 
Bolero-2 progression-free survival Kaplan-Meier plot…………. ..... 
11 
Figure 4-5: 
TAMRAD trial TTP and OS plots………. ........................................ 
12 
Figure 6: 
The structural formula of everolimus ................................................ 
13 
Figure 7: 
The effect of everolimus in mTORC1 downstream effectors ............ 
14 
Figure 8:         Study Schema ..................................................................................... 
22 
 
LIST OF TABLES 


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5
Table 1 
Adverse events suspected to be drug –related in> 10% of patients with 
advanced cancers reported in Phase I EVEROLIMUS monotherapy 
studies  ............................................................................................... 
17 
Table 2 
Adverse events reported in >10% of patients in phase II/III studies of 
everolimus in breast cancer studies……………………………………. 18 
Table 3 
Criteria of dose-modification in case of suspected EVEROLIMUS toxicity  
 
and re-initiation of EVEROLIMUS treatment ................................... 
27 
Table 4 
Management of non-infectious pneumonitis ..................................... 
29 
Table 5 
Study treatment schedule adjustments and dose levels  .....................     35 
Table 6 
Clinically relevant drug interaction: substrates, inducers, and inhibitors of 
isoenzyme CYP3A ............................................................................. 
38 
 
APPENDICES 
Appendix A: Study Flowchart 
Appendix B:  Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
Appendix C: NCI Common Toxicity Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6
 
 
 
 
 
 
 
 
1.  
INTRODUCTION 
 
1.1       Disease Background 
Breast cancer is the most common malignancy among women in the United States 
and approximately 70% of these cancers are hormone receptor positive. 
Endocrine therapy is the cornerstone of treatment for hormone receptor positive 
breast cancer, either in the adjuvant or in the metastatic setting (1).  
Hormone receptor-positive breast cancer tends to have a more favorable prognosis 
than hormone receptor-negative disease and the use of endocrine therapy has 
dramatically decreased breast cancer mortality. However, a subset of hormone 
receptor-positive breast cancers demonstrate primary (intrinsic) resistance to 
endocrine therapy, and eventually all hormone receptor-positive metastatic breast 
cancers develop resistance to hormonal therapies (acquired resistance) (2). 
Aromatase inhibitors (AIs) are the standard fist-line regimen in post-menopausal 
women with estrogen/progesterone receptor positive breast cancer. Anastrozole 
was the first AI approved in hormone receptor positive breast cancer in post-
menopausal patients, followed by letrozole and exemestane (3-5)(6).  
At disease progression or in the presence of side effects, treatment options include 
different classes of AIs or switching to tamoxifen or fulvestrant, since there is 
evidence that patients can respond to different agents (7). Most patients who have 
failed several hormonal agents in the metastatic setting have been traditionally 
treated with chemotherapy, which is associated with increased toxicity. 
However, on July 20, 2012, the Food and Drug Administration (FDA) approved 
the combination of everolimus with exemestane for the treatment of 
postmenopausal women with advanced hormone receptor-positive, HER2-
negative breast cancer. The combination was used upon recurrence or relapse 
after treatment with a non-steroidal aromatase inhibitor (anastrozole, letrozole). 
The combination of everolimus and exemestane has become the new standard of 
care in patients who fail an aromatase inhibitor and there is evidence that 
everolimus reverses hormone resistance.  
 
1.2  
Mechanisms of hormone-resistance 
Much of our current understanding of the molecular mechanisms responsible for 
hormone-resistance comes from clinical and pre-clinical models. Clinical and 


Version 7. 12/07/2015 
7
preclinical data indicate that hormone receptors interact with growth factor 
receptors, including Her2/neu, EGFR and IGFIR, which possibly play a role in 
hormone resistance.  
Transfection of HER2 into estrogen receptor (ER)-positive breast cancer cells 
renders them resistant to tamoxifen (8).  Breast cancers that have high levels of 
HER2 expression are felt to be somewhat intrinsically resistant to hormonal 
therapies, including tamoxifen and aromatase inhibitors (9, 10). Aberrant 
signaling through the AKT-PI3K pathway has been also suggested as a 
mechanism of resistance to endocrine therapy. The AKT pathway activates 
various downstream regulators which when phosphorylated, lead to inhibition of 
apoptosis, cell survival and proliferation, Figure 1 (2).  
 
 
 
Figure 1. Crosstalk between the estrogen receptor and EGFR/HER2/IGF1R pathway can lead 
to cell growth independent of hormonal activation. The PI3K/Akt/mTOR pathway is a major 
downstream cellular circuit, which also leads to gene expression and cell proliferation.  
The estrogen receptor can also be regulated by these membrane receptors, which act as coactivators 
and lead to phosphorylation of estrogen receptors in the absence of estrogen (ligand-independent 
receptor activation). 
Abbreviations: EGFR, epidermal growth factor receptor; IGF1R, insulin-like growth factor-1 
receptor; mTOR, mammalian target of rapamycin; HER2, human epidermal growth factor receptor-
2; ER, estrogen receptor; TSC1/2, tuberous sclerosis complex proteins 1/2; PI3K, 


Version 7. 12/07/2015 
8
phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase; Src, steroid receptor 
coactivator. 
 
 
1.3 
Rationale for mTOR inhibition in hormone receptor-positive disease 
The PI3K/Akt/mTOR pathway is a major cellular circuit, which plays a 
significant role in nutrient uptake, cell proliferation and gene expression (11). 
Downstream of PI3K and Akt, mTOR is a serine/threonine protein kinase, which 
is activated by the inhibition of the tuberous sclerosis complex proteins (TSC1/2). 
mTOR exerts its effects via two protein complexes. mTORC1 is a complex 
consisting of mTOR (Raptor), mLST8, and proline-rich Akt substrate. It is the 
main target of rapamycin and rapamycin analogs, and it exerts its action by 
activating S6K1 (40S ribosomal protein S6 kinase 1) and eukaryotic initiation 
factor 4E-binding protein, thus leading to protein production, lipid production, 
glycolysis, and inhibition of apoptosis. mTORC2 has been less well studied but 
there is evidence that prolonged exposure to rapamycin can also induce inhibition 
of mTORC2. mTORC2 is believed to modulate cell lipid metabolism and cell 
growth via the activation of Akt (12, 13). 
Via the inhibition of TSC1/2, the transmembrane receptors EGFR/HER2/IGFIR 
can lead to the activation of mTORC1 (Figure 1). This way, they create a pathway 
of hormone resistance, where mTOR leads to tumor growth independent of 
estrogen receptor activation in hormone receptor –positive tumors.  
mTOR has been documented to play a role in tamoxifen-resistant preclinical 
models. MCF-7, hormone receptor-positive breast cancer cell lines, that express 
constitutively active Akt were found to be able to proliferate under reduced 
estrogen conditions and were resistant to tamoxifen, both in vitro as well as in 
vivo in xenograft models. However, co-treatment with rapamycin inhibited mTOR 
activity and restored sensitivity to tamoxifen, suggesting that tamoxifen resistance 
is mediated by the mTOR pathway (14).  
mTOR inhibition has also been demonstrated to be more effective preclinically in 
cell lines with increased Akt signaling, PTEN loss and/or increased upstream 
signaling (15, 16).  Additionally, mTOR inhibitors, such as rapamycin and 
everolimus, have been demonstrated to increase Akt activity, while decreasing 
downstream effectors of cell signaling. This increase in Akt activity is felt to be 
due to a feedback mechanism (17, 18). Sirolimus (formerly known as rapamycin) 
inhibits the mTOR pathway by blocking mTORC1 functions. Sirolimus also 
inhibits the negative feedback to the PI3K signaling and AKT (16).  
Everolimus (RAD001), is an orally bioavailable mTOR inhibitor, which has been 
shown to inhibit tumor growth and exert antitumor activity in vivo and in animal 
models (19, 20). Everolimus appears to act synergistically with hormone receptor 
inhibitors and in preclinical models it causes apoptotic cell death and produces 
tumor regression, Figure 2 (19-21).  
 


Version 7. 12/07/2015 
9
 
 
 
Figure 2, taken from Boulay A, Rudloff J, Ye J et al. Dual inhibition of mTOR and estrogen receptor 
signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 2005; 11: 5319–5328. 
 
 
 
 
Beeram et al (19) reported that mTOR kinase inhibitor can reverse endocrine 
resistance in breast cancer tumors in vivo. The authors generated an MCF-7 cell 
line with constitutively activated Akt. That model demonstrated resistance to the 
aromatase inhibitors letrozole and fulvestrant. The authors showed that co-
treatment with everolimus restored sensitivity of the breast cancer cell lines to 
both endocrine agents. 
In summary, these preclinical data strongly support that mTOR inhibition could 
play a significant role in the treatment of hormone receptor-positive breast cancer, 
especially in resistant tumors. 
 
 1.4 
Everolimus clinical studies 
In a phase II randomized trial comparing neoadjuvant letrozole with or without 
everolimus, in patients with estrogen receptor positive breast cancer, everolimus 
was found to significantly increase the efficacy of letrozole (22). The clinical 
response rate was higher in the everolimus arm and also marked reduction in the 
progesterone receptor, cyclin D1 expression and Ki67 expression was found in 
patients treated with the combination treatment.  
The BOLERO-2 trial compared everolimus and exemestane versus exemestane 
alone in patients with hormone-receptor positive advanced breast cancers who had 
experienced recurrence or progression while on a non-steroidal aromatase 
inhibitor (anastrozole or letrozole) (23). A total of 724 women in 24 countries 
Figure 2: Combinations 
of RAD001 (everolimus) 
and letrozole result in 
enhanced 
antiproliferative activity 
in androstenedione 
driven MCF7 cells.  
The use of increasing 
doses of both drugs 
results in synergistic 
activity, inhibiting 
growth of estrogen 
receptor-positive MCF-7 
cells.  


Version 7. 12/07/2015 
10 
were randomly assigned to exemestane and everolimus or exemestane and 
placebo in this phase III study. The BOLERO-2 study showed that the addition of 
everolimus to exemestane improved the progression-free survival (6.9 vs 2.8 
months by local assessment, HR 0.43; 95% confidence interval [CI], 0.35 to 0.54; 
P<0.001). The PFS by central assessment was 10.6 versus 4.1 months respectively 
(Figure 3). The most common grade 3 or 4 adverse events in the everolimus group 
were stomatitis, anemia, dyspnea, hyperglycemia, fatigue, and pneumonitis. 
The TAMRAD (tamoxifen and everolimus) trial compared tamoxifen and 
everolimus to tamoxifen alone in postmenopausal women with estrogen-receptor 
positive metastatic breast cancer who had failed aromatase inhibitor therapy (24). 
The clinical benefit rate (complete response + partial response + stable disease) at 
6 months in the intent to treat population was 61% (95% CI, 47 to 74) in the 
combination arm versus 42% (95% CI, 29 to 56) in the tamoxifen alone arm 
(exploratory P = .045). The results were similar in the per protocol population 
(59%; 95% CI, 44 to 73 v 41%; 95% CI, 27 to 56).  
The median TTP in the ITT population increased to 8.6 months (95% CI, 5.9 to 
13.9) with tamoxifen plus everolimus from 4.5 months (95% CI, 3.6 to 8.7) with 
tamoxifen alone (exploratory P=_.002). This difference in TTP corresponded to a 
46% reduction in the risk of progression associated with tamoxifen plus 
everolimus (HR, 0.54; 95% CI, 0.36 to 0.81). In an exploratory subgroup analysis, 
the everolimus benefit was mostly for patients with secondary hormone 
resistance, with a reduction in the risk of progression associated with everolimus 
of 54% in this subgroup (HR, 0.46; 95% CI, 0.26 to 0.83). 
In contrast, patients with primary resistance benefited to a lesser degree (HR, 
0.70; 95% CI, 0.40 to 1.21 (Figure 4). There was also a survival benefit in the 
patients treated with everolimus. 35% of patients discontinued OR had DOSE 
REDUCTIONS of everolimus due to side effects, stomatitis being the most 
common toxicity (Figure 5). 
Based on the above, everolimus has been shown to exert antitumor activity and it 
appears to act synergistically with hormonal therapy in patients with 
estrogen/progesterone-receptor positive breast cancer, potentially reversing 
hormone resistance. This data mainly suggests that initially sensitive tumors 
undergo an adaptive upregulation of the PI3K/AKT/mTOR pathway, with 
subsequent cross-talk with ER signaling. This results in constitutive activation of 
cell growth pathways, rendering the patient resistant to hormone treatment. This 
hypothesis predicts the effectiveness of a PI3K/AKT/mTOR pathway inhibitor in 
combination with hormone therapy in patients with secondary hormone 
resistance.  


Version 7. 12/07/2015 
11 
 
 
Baselga J, Campone M, Piccart M et al (2012) Everolimus in postmenopausal hormone-receptor-
positive advanced breast cancer. The New England journal of medicine 366 (6):520-529. 
doi:10.1056/NEJMoa1109653 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: 
BOLERO-2. 
Everolimus and 
exemestane 
significantly 
improved PFS 
compared to 
exemestane 
alone.  


Version 7. 12/07/2015 
12 
 
 
Bachelot T, Bourgier C, Cropet C, et al. (2012) Randomized phase II trial of everolimus in 
combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth 
factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a 
GINECO study. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 30 (22):2718-2724. doi:10.1200/JCO.2011.39.0708 
 
 
 
 
 
 
Bachelot T, Bourgier C, Cropet C, et al. (2012) Randomized phase II trial of everolimus in 
combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth 
factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a 
GINECO study. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 30 (22):2718-2724. doi:10.1200/JCO.2011.39.0708 
 
 
 
 
 
 
Figure 4: 
TAMRAD.  
Time to progression 
(TTP) in the ITT 
population.  
Figure 5: 
Median OS was 
32.9 months for the 
tamoxifen arm 
while it was not 
reached with 
tamoxifen plus 
everolimus; this 
translates to a 55% 
reduction in the risk 
of death  
 


Version 7. 12/07/2015 
13 
1.5  Overview of everolimus 
On July 20, 2012, the Food and Drug Administration (FDA) approved everolimus 
tablets (Afinitor®, made by Novartis Pharmaceuticals Corporation) for the 
treatment of postmenopausal women with advanced hormone receptor-positive, 
HER2-negative breast cancer in combination with exemestane, after failure of 
treatment with letrozole or anastrozole. The approval was based on the BOLERO-
2 trial and approved dosing is 10 mg/day. 
 
EVEROLIMUS (everolimus) is a synthetic derivative of rapamycin with 
improved pharmacodynamics and pharmacokinetic properties. EVEROLIMUS 
has been in clinical development since 1996 as an immunosuppressant in solid 
organ transplantation.  
EVEROLIMUS has been investigated as an anticancer agent based on its 
potential to act 
 Directly on the tumor cells by inhibiting tumor cell growth and proliferation 
 Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via 
potent inhibition of tumor cell VEGF production and VEGF-induced 
proliferation of endothelial cells)  
 
 
Figure 6: The structural formula of everolimus (taken from Afinitor brochure, 
www.afinitor.com) 
 
 


Version 7. 12/07/2015 
14 
Everolimus binds and forms a complex with the intracellular FK506–binding 
protein 12 (FKBP-12), thus inhibiting the mTORC1 complex and phosphorylating 
P70 S6 ribosomal protein kinase. Everolimus also reduces elongation factor 4E–
binding protein (4E-BP1), which is involved in protein synthesis. In addition, 
everolimus inhibits the expression of hypoxia-inducible factor 1 (HIF-1) and 
reduces the expression of vascular endothelial growth factor (VEGF). S6K1 and 
4EBP1 are downstream effectors of mTOR, which contribute to hormone 
resistance (Figure 7).  
 
 
Figure 7: Everolimus by inhibiting the mTORC1 complex and phosphorylating P70 S6 ribosomal 
protein kinase, reduces elongation factor 4E–binding protein (4E-BP1), which is involved in 
protein synthesis. In addition, everolimus inhibits the expression of hypoxia-inducible factor 1 
(HIF-1) and reduces the expression of vascular endothelial growth factor (VEGF).  
 
1.5.1 Everolimus Pharmacokinetics 
Everolimus reaches peak concentrations within 1 to 2 hours after a single oral 
dose, and following oral daily administration, steady state is achieved within one 
week. Age, sex or weight do not appear to affect the pharmacokinetic properties 
of everolimus; plasma protein binding is about 74%. Everolimus is extensively 
metabolized in the gastrointestinal tract and is a substrate for CYP3A4, CYP3A5, 
CYP2C8 and P-glycoprotein, which can lead to potentially significant drug 
interactions. The elimination half-life is from 18 to 35 hours but is prolonged by 
about 53% in patients with cirrhosis 
Effect of food: in healthy subjects, high fat meals reduce systemic exposure to 
doses of 10 mg/day by 22% and the peak blood concentration Cmax by 54%. 
Light fat meals reduce AUC by 32% and Cmax by 42%.  
Distribution: The apparent distribution volume (Vz/F) after a single dose is 
4.7 L/kg.  


Version 7. 12/07/2015 
15 
Metabolism: EVEROLIMUS is mainly metabolized by 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-glycoprotein. In vitro studies 
showed that EVEROLIMUS is a competitive inhibitor of CYP3A4 and of 
CYP2D6 substrates, potentially increasing the concentrations of medicinal 
products eliminated by these enzymes. In two phase III clinical trials in patients 
following kidney transplantation, strong inhibitors of CYP3A4 (azoles, 
antifungals, cyclosporine, erythromycin) have been shown to reduce the clearance 
of EVEROLIMUS therapy thereby increasing EVEROLIMUS blood levels. 
Similarly, Rifampin, a strong inducer of CYP3A4, increases the clearance of 
EVEROLIMUS thereby reducing EVEROLIMUS blood levels. Caution should 
be exercised when co-administering EVEROLIMUS with CYP3A4 inhibitors or 
inducers. 
Pharmacokinetic drug-to-drug interactions with cancer agents are being evaluated. 
Gemcitabine and paclitaxel did not alter EVEROLIMUS pharmacokinetics to a 
clinically relevant extent whereas imatinib notably increased EVEROLIMUS 
exposure with a mean increase in AUC by a multiple of 3.7 for EVEROLIMUS 
administered weekly and two-fold for EVEROLIMUS administered daily. 
Exposure to EVEROLIMUS in the presence of letrozole did not exceed that in 
monotherapy (study 2108). Co-administration of EVEROLIMUS did not 
influence pharmacokinetics of gemcitabine, imatinib or letrozole. Exposure to 
paclitaxel in the presence of EVEROLIMUS was slightly decreased (average by 
23%). 
EVEROLIMUS pharmacokinetics in transplant patients was investigated in 
special populations such as subjects with hepatic or renal impairment, various 
ethnic groups and pediatric renal transplant patients. In subjects with mild–
moderate hepatic impairment, mean AUC to EVEROLIMUS is increased by 3-
fold whilst renal impairment does not affect the pharmacokinetics of 
EVEROLIMUS. Age, weight (both over the adult range) and gender do not affect 
the pharmacokinetics of EVEROLIMUS to a clinically relevant extent. Also, 
pharmacokinetics does not alter in Japanese or Asian patients whereas black 
patients have 21% higher clearance compared to non-blacks. In children, the 
apparent clearance of EVEROLIMUS increases linearly with body surface. The 
clearance per square meter of body surface area is 12-fold higher compared with 
adult patients. 
 
1.5.2 Pharmacodynamic studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition in a peripheral 
biomarker (S6 kinase inhibition in peripheral blood mononuclear cells) suggests 
that 5-10 mg daily should be an adequate dose to produce a high-degree of 
sustained target inhibition. Furthermore, molecular pharmacodynamic (MPD) 
studies using IHC in biopsied tumor tissue assessed the degree of inhibition and 


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16 
its duration (for p-S6, p-4E-BP1 and p-Akt expression) with the daily and weekly 
dosing. There was almost complete inhibition of p-S6 at all doses and schedules 
studied (p=0.001).  
Data are available from phase I clinical studies of EVEROLIMUS given as a 
single agent to 147 patients with advanced solid tumors. Such studies included 
various doses and schedules (weekly dosing, range 5-70 mg and daily dosing 5-10 
mg). Approximately, 46% of patients reported rash or erythema and 40% of the 
patients presented with stomatitis/mucositis.  
The most frequent adverse events suspected to be drug-related observed in three 
studies using EVEROLIMUS as a single agent are listed in Table 1. The most 
frequent side effects (>10% of patients) seen in breast cancer studies compared to 
placebo are shown in Table 2 (25).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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17 
Table 1.Adverse events suspected to be drug-related in ≥10% of patients with advanced cancers 
reported in Phase I EVEROLIMUS monotherapy studies  
 
Weekly 
 
Daily 
 
Total 
n=147 
 5-30 mg 
n=30 
50 mg 
n=18 
70 mg 
n=38 
 
5mg 
n=16 
10 mg 
n=45 
 
No. Pts with AEs 
 
 
 
 
 
 
 
 
Any event 
23 (1) 
17 (2) 
38 (10) 
 
14 (1) 43 (14) 
 
135 (28) 
By event 
 
 
 
 
 
 
 
 
- 
Rash  
5 
8 
18 
 
10 
27 (1) 
 
68 (1) 
- 
Stomatitis/mucositis 
6 
8 (2) 
16 (2) 
 
6 (1) 
23 (3) 
 
59 (8) 
- 
Fatigue 
8 
7 (1) 
14 (1) 
 
1 
17 (1) 
 
47 (3) 
- 
Nausea 
5 
4 
8 
 
2 
18 (1) 
 
37 (1) 
- 
Anorexia 
1 
6 
10 
 
3 
15 
 
35 
- 
Diarrhea 
1 
7 
7 
 
- 
9 
 
24 
- 
Vomiting 
4 
5 
5 
 
- 
10 
 
24 
- 
Headache 
7 
4 
6 
 
6 
4 
 
20 
- 
Pruritus 
2 
1 
6 
 
3 
4 
 
16 
- 
Infections1 
1 
3 
3 (1) 
 
1 
6 (2) 
 
14 (3) 
- 
Constipation 
- 
1 
2 
 
2 
9 
 
14 
The numbers of patients (by dose level and dose schedule) who have reported grade ≥31 
toxicities is given in brackets. 
1. events included in brackets reached no more than grade 3 severity 
2 Infections noted as drug-related included: 
 
 
Herpes simplex:  
5 pts (1 at 50 mg/wk; 1 at 5mg/d; 3 at 10 mg/d) 
 
 
Oral candidiasis: 
5 pts (1 at 50 mg/wk; 3 at 70 mg/wk, 1 at 10 mg/d) 
 
 
Pneumonia (gr3)  
1 pt (10 mg/d) 
 
 
Pustular rash 
1 pt (20 mg/wk) 
 
 
Rhinitis 2 pts (50 mg/wk) 
 
 
URT Infection 1 pt (50 mg/wk 
 
 
Urinary Tract Infection 1 pt (50 mg/wk) 
 
 
 
 
 
 
 
 
 
 
 


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18 
Table 2: Adverse events (%) reported in >10% of patients in phase II/III studies of everolimus in 
breast cancer. The grade 3-4 AEs are highlighted. 
 
  Adverse events 
      Overall  
   Grade 3-4 
     Overall   
   Grade 3-4 
Baselga et al, 2009 (22) 
     Everolimus + Letrozole 
        Placebo + Letrozole 
Stomatitis 
36.5 
2.2 
6.1 
- 
Rash 
20.4 
0.7 
7.6 
- 
Asthenia 
17.5 
- 
9.8 
0.8 
Hot flush 
10.9 
- 
16.7 
- 
Hypercholesterolemia 
16.1 
0.7 
6.1 
- 
Thrombocytopenia 
18.2 
1.5 
0.8 
- 
Fatigue 
12.4 
1.5 
4.5 
- 
Anorexia 
12.4 
- 
3.8 
- 
Hyperglycemia 
13.1 
5.1 
3 
- 
Headache 
10.9 
- 
5.3 
- 
Increased ALT 
11.7 
1.5 
3.8 
- 
Pruritus 
13.1 
- 
- 
- 
Anemia 
11.7 
- 
0.8 
- 
Baselga et al, 2012 (23) 
Everolimus + Exemestane 
Placebo + Exemestane 
Stomatitis 
56 
8 
11 
1 
Rash 
36 
1 
6 
- 
Fatigue 
33 
3 
26 
1 
Diarrhea 
30 
2 
16 
1 
Decreased appetite 
29 
1 
10 
- 
Nausea 
27 
<1 
27 
1 
Cough 
22 
1 
11 
- 
Dysgeusia 
21 
<1 
5 
- 
Headache 
19 
<1 
13 
- 
Decreased weight 
19 
1 
5 
- 
Dyspnea 
18 
4 
9 
1 
Arthralgia 
16 
1 
16 
- 
Anemia 
16 
6 
4 
<1 
Epistaxis 
15 
- 
1 
- 
Vomiting 
14 
<1 
11 
<1 
Peripheral edema 
14 
1 
6 
<1 
Pyrexia 
14 
<1 
6 
<1 
Increased AST 
13 
3 
6 
1 
Constipation 
13 
<1 
11 
<1 
Hyperglycemia 
13 
4 
2 
<1 
Pneumonitis 
12 
3 
- 
- 
Thrombocytopenia 
12 
3 
<1 
<1 
Asthenia 
12 
2 
3 
0 
Increased ALT 
11 
3 
3 
2 
Pruritus 
11 
<1 
3 
- 
Insomnia 
11 
<1 
8 
- 
Back pain 
11 
- 
8 
1 
Bachelot et al, 2009 (24) 
Everolimus + Tamoxifen  
Tamoxifen alone 
Pain 
82 
9 
86 
18 
Fatigue 
72 
6 
53 
11 
Nausea 
35 
4 
35 
- 
Stomatitis 
56 
11 
7 
- 


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19 
Anorexia 
43 
7 
18 
4 
Hot flushes 
22 
- 
33 
- 
Infection 
35 
7 
19 
5 
Rash 
44 
4 
7 
- 
Diarrhea 
39 
2 
11 
- 
Constipation 
17 
- 
23 
- 
Vomiting 
17 
- 
12 
4 
Pneumonitis 
17 
2 
4 
4 
Anemia 
69 
2 
35 
4 
Leukopenia 
54 
2 
18 
- 
Lymphopenia 
48 
2 
21 
4 
Neutropenia 
48 
2 
19 
5 
 
Non-infectious pneumonitis is a class effect of mTOR inhibitors. It has been 
reported in up to 19% of patients treated with everolimus in clinical trials. The 
incidence of grade 3 and 4 toxicity was up to 4% and 0.2% respectively.  
Reduced blood cell counts at the initiation of treatment are frequent but remain 
mostly within the normal range or limited to grade 1 although grade 3 neutropenia 
was a DLT in one patient as was grade 3 thrombocytopenia in a patient receiving 
EVEROLIMUS with letrozole, where pharmacodynamic interaction is unlikely. 
This suggest that some patients may be particularly sensitive to the 
myelosuppressive effect of EVEROLIMUS making it necessary to monitor 
carefully blood cell counts at initiation of treatment. 
Metabolic changes (hyperlipidemia and hyperglycemia) may be observed during 
treatment with EVEROLIMUS. Hyperlipidemia has been reported as an ADR in 
10% of patients although review of the laboratory values suggests that as many as 
a quarter of patients develop grade 1-2 hyperlipidemia on treatment, mostly 
hypercholesterolemia. Hyperglycemia has been reported as an adverse event in 
7% of patients. Grade 3 hyperglycemia has been observed, especially in diabetics 
receiving EVEROLIMUS treatment.  
 
1.6 
Rationale of continuing targeted therapies beyond progression 
The concept of continuing a targeted therapy in order to offer a complementary 
mode of action and overcome resistance to chemotherapy is not new in oncology.  
Bennouna et al (26) conducted a phase 3 study of continuation of bevacizumab 
(Avastin) after first progression in patients with metastatic colon cancer. It had 
been previously shown that bevacizumab had clinical activity in combination with 
chemotherapy in patients with metastatic colon cancer. However, at time of 
progression, it was unknown if the continuation of bevacizumab with a second-
line chemotherapy regimen would have continued benefit. They found that 
continuing bevacizumab beyond progression improved median overall survival 
and median PFS.   


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20 
Treatment with trastuzumab (Herceptin) beyond disease progression was also 
shown to improve TTP (time to progression) in HER2 overexpressing breast 
cancer. The German Breast Group presented a phase 3 trial, where patient who 
had previously received trastuzumab were randomized either to capecitabine 
alone or capecitabine with trastuzumab. The trial met its primary end point and 
showed that continuation of trastuzumab beyond disease progression offered 
clinical benefit (27). A post hoc analysis of this study showed that patients who 
received third line HER2-directed therapy also experienced significantly longer 
overall survival than those who did not, indicating than targeted therapy may add 
additional benefit even across further lines of treatment (28).  
Thus, both of these studies indicate that targeted therapies act synergistically with 
cancer therapy and this synergy can be exploited beyond progression in pretreated 
patients. It is possible that even though resistance to chemotherapy occurs from 
changes to tumor cell biology, resistance to targeted agents is unlikely to occur 
through the same mechanisms, and thus a targeted therapy will continue to offer 
clinical benefit with acceptable toxicities.  
Using the same rationale, we believe that one mechanism of resistance to 
hormonal agents occurs through the activation of the PI3K/Akt/mTOR pathway. 
When patients progress on the combination of everolimus and exemestane, it is 
unknown if the treatment failure is due to resistance to either agent or both. We 
hypothesize that when the mTOR pathway remains activated, it acts as an escape 
mechanism and leads to hormone resistance; thus, continued inhibition of the 
mTOR pathway is required.   
 
2. 
OBJECTIVES 
 
 
Evaluate the progression free survival in patients with breast cancer who 
receive everolimus beyond progression. 
 
2.1 Primary Objectives 
 
 
Progression free survival in patients with advanced or metastatic breast 
cancer receiving everolimus plus hormonal therapy beyond first 
progression. 
 
2.2 Secondary Objectives 
 
1. Clinical benefit rate (sum of stable disease, partial response, complete 
response) 
2. Response rate (partial response and complete response) 
3. Overall survival 
4. Safety, side effects and tolerability profile of everolimus 
 
 


Version 7. 12/07/2015 
21 
 
3. STUDY DESIGN 
 
3.1 
Rationale of study design 
 
As stated above, EVEROLIMUS has been FDA approved in combination 
with EXEMESTANE in post-menopausal patients with advanced/metastatic 
hormone receptor-positive breast cancer who have progressed/recurred after 
treatment with a non-steroidal aromatase inhibitor (anastrozole or letrozole). 
The BOLERO-2 study found that patients receiving the combination of 
everolimus and exemestane had a median PFS of 10.6 months vs 4.1 months 
with exemestane alone (by central assessment).  
 
Thus, based on the current FDA approval, patients who have been started on 
everolimus with exemestane, have already progressed on a non-steroidal 
aromatase inhibitor, such as letrozole or anastrozole. At the time of disease 
progression on exemestane and everolimus, patients may be candidates for 
subsequent lines of hormonal therapy with tamoxifen or fulvestrant prior to 
beginning cytotoxic chemotherapy.  
 We hypothesize that progression of disease in the patients receiving 
everolimus plus exemestane may not represent failure of everolimus to 
control disease but rather hormone resistance to exemestane.  
 Since different hormonal agents have different modes of action and 
everolimus has been show25 
 n in preclinical studies to help overcome resistance to various hormonal 
agents, we hypothesize that by switching hormonal therapy and continuing 
inhibition of the mTOR pathway with everolimus, these patients will benefit 
by continuing everolimus.  
 As stated above (1.5.2), everolimus will inhibit the PI3K/Akt/mTOR 
pathway, which is an “escape mechanism” for hormone resistant cells, 
which is an effect that will continue beyond progression.  
 We thus hypothesize that even by re-instituting a hormone therapy that has 
been failed before, we will overcome resistance to that treatment with the 
use of everolimus. Alternatively, if we combine everolimus with a hormonal 
therapy which was not used before, everolimus is likely to help overcome 
resistance to this agent and prolong PFS.  
 
3.2  
Study Design  
 
 
 This study will enroll patients who experience disease progression while on 
EVEROLIMUS and EXEMESTANE (FDA approved indication).  
 After enrollment, patients will continue EVEROLIMUS but hormone 
therapy will be switched to any hormonal agent other than exemestane.  
 Please see study schema (Figure 8) 
 
 


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22 
 
 
 
Figure 8: Study Schema 
All patients enrolled will be most recently on exemestane plus everolimus, however all 
hormonal treatments prior to exemestane are allowed. Based on the current FDA 
approval of everolimus, all patients who receive everolimus with exemestane will already 
have received a non-steroidal aromatase inhibitor. 
 
 
 


Version 7. 12/07/2015 
23 
 
3.3 Drugs used in this study 
 
 Everolimus (study drug). Patients enrolled will already be on everolimus. 
The patients will continue to receive everolimus 10 mg daily PO OR THEIR 
MOST RECENT DOSE IF THERE WERE PREVIOUS DOSE 
REDUCTIONS. 
 Hormonal therapy. Since the patients most recently progressed on 
Exemestane, hormone therapy will need to be switched to another hormone 
agent, the choice of which will be left to investigator discretion.  
 We expect that the eligible patients will have received 1-5 prior lines of 
hormonal therapy, (e.g. Tamoxifen, Fulvestrant, Anastrozole, Letrozole). 
However, the most recent therapy will be EVEROLIMUS plus 
EXEMESTANE. 
 When a patient is switched from Exemestane to another type of hormone 
therapy, priority will be given to one of the agents not previously used (i.e. 
prior to being treated with Everolimus plus Exemestane).  
 It is allowed to use a hormonal therapy that the patient has taken in the past, 
as long as the reason for discontinuation was not significant toxicity. If the 
patient has discontinued a prior hormonal treatment due to significant side 
effects (grade III or IV or life threatening side effects), it is recommended to 
avoid using a drug belonging to that class.  
 
 The dosing recommendations for most commonly used hormonal agents 
are listed below: 
 
a. Anastrozole (Arimidex): Anastrozole is a non-steroidal aromatase inhibitor 
(AI). Recommended dose is 1 mg oral daily.  
b. Letrozole (Femara): Letrozole is a non-steroidal aromatase inhibitor (AI). 
Recommended dose is 2.5 mg oral daily.  
c. Tamoxifen: Tamoxifen is a SERM (Selective Estrogen Receptor 
Modulator). Recommended dose is 20 mg oral daily.  
d. Fulvestrant (Faslodex): Fulvestrant is an Estrogen Receptor Antanonist. It is 
given I.M. (intramuscularly) and recommended dosing is 500 mg on days 1, 
15, and 29; maintenance with 500 mg monthly.  
e. Megestrol acetate (Megace): Megestrol acetate is a progestin, which is 
usually dosed at 40 mg orally 4 times a day.  
 
 
 
 
 


Version 7. 12/07/2015 
24 
 
 
3.4 
Description of the study 
This is an open label, single arm, phase II study in patients with advanced 
hormone refractory breast cancer. Patients will be followed for progression free 
survival, response rate, clinical benefit rate, overall survival and safety. 
At the time of disease progression the patient will be removed from the study but 
will still be followed for overall survival analysis.  
38 (thirty eight) patients will be recruited. 
  
 
3.5  
Outcomes Measures 
 
PFS (Progression Free Survival) will be measured as time to progression or 
death from any cause from the initiation of alternate hormonal treatment in 
combination with everolimus. 
Clinical benefit rate (response rate plus stable disease) will also be assessed after 
8, 16 and 24 weeks of treatment and then every 3 months (12 weeks). 
Response rate will be measured after 8, 16 and 24 weeks of therapy and then 
every 3 months (12 weeks) using RECIST criteria. Response rate will be 
measured as the sum of partial and complete response.  
OS (Overall Survival) will be measured as time to death from any cause from the 
initiation of alternate hormonal treatment in combination with everolimus. 
See Appendix A, Study Flowchart 
 
3.6 
Safety Plan 
The safety of everolimus in combination with hormonal therapy will be 
monitored continuously over the study period. Patients will be evaluated at each 
study visit for the duration of their participation in the study for side effects 
(clinical or laboratory). See Appendix A, Study Flowchart 
Adverse events most frequently observed with EVEROLIMUS are rash, 
stomatitis/oral mucositis, fatigue, headache, anorexia, nausea, vomiting, diarrhea, 
non-infectious pneumonitis and infections.  Overall, the most frequently observed 
laboratory abnormalities include neutropenia, thrombocytopenia, 
hypercholesterolemia, and/or hypertriglyceridemia. The majority of these AEs 
have been of mild to moderate severity (CTCAE grade 1-2).  
Refer to text and tables 3 and 4 for the management of toxicities and dose 
adjustments of everolimus. DOSE REDUCTIONS WILL BE DONE BY ONE 


Version 7. 12/07/2015 
25 
LEVEL, which is defined as 2.5 mg daily, i.e. a patient receiving 10 mg will be 
subsequently treated with 7.5 mg and a patient taking 7.5 mg will be reduced to 5 
mg. Please see table 5 for management of dose modifications (page 35).  
 
3.6.1  Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis is one of the most common side effects encountered in patients treated 
with mTOR inhibitors and was seen in up to 81% of patients in phase I studies 
with everolimus in breast cancer; in phase II and III studies, the overall incidence 
of stomatitis was ~50%. Most of the patients had mild symptoms, while only 10% 
had grade 3 or 4 toxicity.  
The oral lesions are similar to aphthous or herpetic ulcers and are well 
demarcated, oval, and superficial. They contain a white necrotic center and they 
are surrounded by an erythematous ring. They can cause mouth pain, dysphagia 
and loss of taste (dysgeusia). Stomatitis should be distinguished from 
chemotherapy-induced mucositis, which usually affects the entire gastrointestinal 
tract and can be associated with diarrhea. The toxicity appears to be dose 
dependent and it most often appears during the first cycle (25).  
Stomatitis/oral mucositis/mouth ulcers due to EVEROLIMUS should be treated 
using local supportive care, in combination with appropriate dose interruptions 
and reductions when indicated. 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 and please refer to TABLE 3 for dose modification 
recommendations (non hematological toxicity): 
a) For mild toxicity (grade 1), use conservative measures such as  
non-alcoholic mouthwash or salt water (0.9%) mouthwash several times a day 
until resolution. No dose changes for everolimus are recommended. 
b) 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®). Please see table 3 for dose interruption 
recommendations.  
c) Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend 
to worsen mouth ulcers. It is preferable to avoid these agents. 
d) Antifungal agents must be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should 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 


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26 
diagnosed. Similarly, antiviral agents such as acyclovir should be avoided 
unless a viral infection is diagnosed. 
e) For grade 4 toxicity (life threatening symptoms), everolimus will be 
discontinued.  
 
 
3.6.2 
Management of hyperlipidemia and hyperglycemia  
mTOR inhibitors interfere with lipid and glucose metabolism and can lead to 
hyperlipidemia and hyperglycemia. Severe hypertriglyceridemia can lead to 
pancreatitis and elevated cholesterol can increase the risk of cardiovascular 
disease.  
3.6.2.1 Management of hyperlipidemia 
a) Treatment of hyperlipidemia should take into account the pre-treatment status 
and dietary habits. Blood tests to monitor hyperlipidemia must be taken in the 
fasting state.  
b) For all grades of hyperlipidemia it is recommended to initiate diet 
modification and exercise per American Heart Association guidelines.  
c) Grade 2 or higher hypercholesterolemia (>300 mg/dL) or grade 2 or higher 
hypertriglyceridemia (>300 mg/dL) should be treated with a statin or 
appropriate lipid-lowering medication, in addition to lifestyle modifications. 
d) Patients should 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 inhibitors.  Note: 
Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is 
associated with an increased risk of a rare but serious skeletal muscle toxicity 
manifested by rhabdomyolysis, markedly elevated creatine kinase (CPK) 
levels and myoglobinuria, acute renal failure and sometimes death. The risk 
versus benefit of using this therapy should be determined for individual 
patients based on their risk of cardiovascular complications of hyperlipidemia. 
e) For grade 2 hyperlipidemia, no dose adjustment is required for everolimus.  
f) For grade 3 toxicity, temporary interruption of everolimus with following 
dose reduction by one level (2.5 mg) is recommended.    
g) For grade 4 toxicity (cholesterol >500 mg/dl or triglycerides >1,000 mg/dl), 
everolimus should be discontinued 
3.6.2.2 Management of hyperglycemia 
mTOR inhibitors can cause hyperglycemia by affecting insulin metabolism. 
Hyperglycemia can be seen in diabetic or non-diabetic patients. Studies of 
everolimus in breast cancer report an incidence of up to 17 % (25). 
We suggest that optimal glucose control should be achieved before starting a 


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27 
patient on everolimus and thereafter glucose levels should be monitored during 
treatment according to the study schema.  
Management recommendations are based on fasting glucose (FBG) 
measurements.  
a) No intervention is required for grade 1 hyperglycemia (>upper limit of 
normal-160 mg/dl). We recommend monitoring as per study schema.  
b) Grade 2 or higher hyperglycemia (fasting glucose >160 mg/dl) should be 
treated according to American Diabetes Association guidelines.  
c) Grade 2 hyperglycemia (fasting glucose >160-250 mg/dl) does not require 
interruption or dose reductions for everolimus.  
d) For grade 3 hyperglycemia (fasting glucose >250-500 mg/dl), everolimus 
should be temporarily interrupted and re-initiated at a lower dose (reduced 
by one level of 2.5 mg). 
e) If grade 4 toxicity (fasting glucose >500 mg/dl) occurs, everolimus should 
be discontinued.  
 
Table 3 Criteria for dose-modification in case of suspected EVEROLIMUS toxicity and re- 
initiation of EVEROLIMUS treatment 
Toxicity 
Actions 
Non-hematological toxicity 
Grade 1 
 
Symptomatic management, no dose 
modification required.  
 
Grade 2  
(except  metabolic adverse events* 
and  pneumonitis – refer to Table 4) 
Interrupt EVEROLIMUS until recovery to 
grade 1. Then reintroduce 
EVEROLIMUS at current dose.  
If grade 2 toxicity recurs, interrupt until 
recovery to grade 1, then restart 
everolimus with one level reduction (by 2.5 
mg daily, refer to table 6). 
 
Grade 3 
(except metabolic adverse events* and 
pneumonitis- see Table 4) 
Interrupt EVEROLIMUS until recovery to 
grade 1. Then reintroduce 
EVEROLIMUS with one level reduction 
(by 2.5 mg daily, refer to table 6).  


Version 7. 12/07/2015 
28 
 
Grade 4 
Discontinue EVEROLIMUS. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets 
<75, ≥ 50x109/L)  
Interrupt EVEROLIMUS until recovery to 
grade 1 (>75 x109/L). Then reintroduce 
EVEROLIMUS by one level reduction (2.5 
mg daily, refer to table 6).  If 
thrombocytopenia again returns to grade 2, 
interrupt EVEROLIMUS until recovery to 
grade 1. Then reintroduce 
EVEROLIMUS at current dosing but every 
other day. 
Grade 3 Thrombocytopenia (platelets <50, ≥ 25 x109/L) Interrupt EVEROLIMUS until recovery to 
grade ≤1 (platelets ≥ 75 x109/L).  Then 
resume EVEROLIMUS reduced by one 
level (2.5 mg/day, refer to table 6) and 
given every other day.  If grade 3 
thrombocytopenia recurs, discontinue 
EVEROLIMUS. 
Grade 4 Thrombocytopenia 
(platelets < 25 x109/L) 
Discontinue EVEROLIMUS. 
Grade 3 Neutropenia (neutrophils <1, 
≥0.5 x109/L) 
Interrupt EVEROLIMUS until recovery to 
grade 1 (neutrophils ≥ 1.5 x 109/L). Then 
resume EVEROLIMUS by one level 
reduction (2.5 mg/day, refer to table 6).  If 
ANC again returns to Grade 3, hold 
EVEROLIMUS until the ANC ≥ 1.5 x 
109/L.  Then resume EVEROLIMUS 
dosing at one level reduction every other 
day.  Discontinue patient from study 
therapy for a third episode of grade 3 
neutropenia. 
Grade 4 Neutropenia (neutrophils < 
0.5 x109/L) 
Interrupt EVEROLIMUS until recovery to 
grade  1  (neutrophils ≥ 1.5 x 109/L). 
Then resume EVEROLIMUS at reduced 
by one level (2.5 mg/day, refer to table 6) 
every other day. If grade 3 or grade 4 
neutropenia occurs despite this dose 
reduction, discontinue EVEROLIMUS. 
Grade 3 febrile neutropenia (not life-
threatening) 
Interrupt EVEROLIMUS until resolution 
of fever and neutropenia to grade ≤ 1. Hold 
further EVEROLIMUS until the ANC ≥ 


Version 7. 12/07/2015 
29 
 
 
3.6.3 Management of non-infectious pneumonitis 
Both asymptomatic radiological changes (grade 1) and symptomatic non-
infectious pneumonitis (grade 2 = not interfering with activities of daily living or 
grade 3 = interfering with activities of daily living and oxygen indicated) have 
been noted in patients receiving everolimus therapy. Non-infectious pneumonitis 
has been associated with everolimus and other mTOR inhibitors. In order to 
monitor for asymptomatic (grade 1) pulmonary infiltrates, a chest X-ray every 3 
months is required if a CT scan of chest is not used for disease evaluations. 
Additional chest X-rays/CT scans may be done, when clinically necessary. If non-
infectious pneumonitis develops, consultation with a pulmonologist should be 
considered. Management of non-infectious pneumonitis suspected to be 
associated with everolimus and dose modifications instructions are provided in 
TABLE 4.   
The usual dose of steroids for the management of non-infectious pneumonitis is 
prednisone, 1 mg/kg. The steroids can be tapered slowly after clinical 
improvement and improvement of pulmonary function tests.  
Non-infectious pneumonitis may be difficult to distinguish from lymphangitic 
tumor spread. If there is doubt about the cause of the clinical or radiologic 
abnormalities, bronchoscopic biopsies or repeat imaging after interruption of 
everolimus may be helpful.  
 
Table 4 
Management of non-infectious pneumonitis 
 
Worst 
Grade 
Pneumo
nitis 
Required Investigations 
Management 
of Pneumonitis 
EVEROLIMUS Dose 
Adjustment 
1,500/mm3 and fever has resolved. Then 
resume EVEROLIMUS at reduced by one 
level (2.5 mg/day, refer to table 6) every 
other day. If febrile neutropenia recurs, 
discontinue EVEROLIMUS. 
Grade 4 febrile neutropenia (life-
threatening) 
Discontinue EVEROLIMUS. 
Any hematological or non-
hematological toxicity requiring 
interruption for ≥ 3 weeks 
Discontinue EVEROLIMUS 
* For metabolic adverse events (hyperlipidemia and hyperglycemia) see text 
(section 3.6.2) 


Version 7. 12/07/2015 
30 
Grade 1 
CT scans with lung 
windows. 
No specific 
therapy is 
required 
Administer 100% of 
EVEROLIMUS dose. 
Grade 2 
CT scan with lung 
windows.  Consider 
pulmonary function 
testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat each 
subsequent Cycle until 
return to within normal 
limits. Consider a 
bronchoscopy.  
Symptomatic 
only. Rule out 
infection. 
Prescribe 
corticosteroids 
if cough is 
troublesome. 
Reduce EVEROLIMUS dose 
by one level (2.5 mg, refer to 
table 6) until recovery to < 
grade 1. EVEROLIMUS 
may also be interrupted if 
symptoms are troublesome. 
Patients will be withdrawn 
from the study if they fail to 
recover to < grade 1 within 3 
weeks. 
Grade 3 
CT scan with lung 
windows and pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat each 
subsequent Cycle until 
return to within normal 
limits. Bronchoscopy is 
recommended. 
Prescribe 
corticosteroids 
if infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Hold treatment until 
recovery to < grade 1. May 
restart protocol treatment 
within 3 weeks at a reduced 
dose (by one level=2.5 mg, 
refer to table 6) if evidence 
of clinical benefit.  Patients 
will be withdrawn from the 
study if they fail to recover 
to ≤ grade 1 within 3 weeks. 
 
Grade 4 
CT scan with lung 
windows and required 
pulmonary function 
testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat each 
subsequent Cycle until 
return to within normal 
limits. Bronchoscopy is 
recommended. 
Prescribe 
corticosteroids 
if infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Discontinue treatment. 
 
All interruptions or changes to study drug administration must be recorded. 
 
4.  
MATERIALS AND METHODS 
4.1  
Inclusion Criteria 
Patients will be included in the study based on the following criteria: 


Version 7. 12/07/2015 
31 
 ER and/or PR-positive at primary diagnosis and at metastatic diagnosis where 
tissue is available (defined as > or = 1% of staining nuclei).  
 Progressive or recurrent breast cancer defined as disease progression or 
recurrence while on a combination of exemestane with everolimus.  
 HER2/neu-negative breast cancer by standard criteria (IHC < 3+ or FISH-
negative if IHC 2+) at primary diagnosis. 
 Histologically confirmed, measurable or evaluable disease.  Patients should 
have at least one measurable lesion. If applicable, RECIST criteria should be 
used. 
 Life expectancy> 6 months. 
 Age >18 years. 
 ECOG performance status 
2

. 
 Adequate bone marrow function as indicated by the following: 
ANC >1,500/L  
Platelets 100,000/L 
Hemoglobin >10 g/dL 
 Adequate renal function, as indicated by creatinine1.5 upper limit of 
normal (ULN). 
 Adequate liver function, as indicated by bilirubin 1.5 ULN. 
 INR ≤ 1.3 (or ≤ 3 on anticoagulants). 
 AST or ALT <2 ULN unless related to primary disease. 
 Signed informed consent. 
 Adequate birth control. 
 Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting 
triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are 
exceeded, the patient can only be included after initiation of appropriate lipid 
lowering medication. 
4.2  
Exclusion Criteria 
Patients will be excluded from the study based on the following criteria: 
 Prior treatment with everolimus other than in combination with hormonal 
therapy for treatment of breast cancer or prior treatment with another mTOR 
inhibitor (sirolimus, temsirolimus) for any indication.  
 HER2 positive disease as defined by 3+ IHC or positive FISH (both in 
primary and metastatic sites).  


Version 7. 12/07/2015 
32 
 Active infection: temperature >100F, fever of unknown origin, active 
symptoms or signs of infection as defined by the investigator.  
 Uncontrolled central nervous system metastases. 
 Life-threatening, visceral metastases. 
 Pregnant or lactating women. 
 Prior chemotherapy within the last 4 weeks. 
 Prior radiation therapy within the last 4 weeks; prior radiation therapy to 
indicator lesion (unless objective disease recurrence or progression within the 
radiation portal has been documented since completion of radiation). 
 Concomitant malignancies or previous malignancies within the last 5 years, 
with the exception of adequately treated basal or squamous cell carcinoma of 
the skin or carcinoma in situ of the cervix. 
 History of significant cardiac disease, cardiac risk factors or uncontrolled 
arrhythmias 
 Hypersensitivity to trial medications (everolimus). 
 Emotional limitations, which the investigator judges could limit the patient’s 
ability to follow up and comply with study procedures. 
 Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent 
 Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN 
 Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent 
hepatitis 
 A known history of HIV seropositivity. 
 Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of EVEROLIMUS (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small 
bowel resection). 
 Patients with an active, bleeding diathesis. 
 Female patients who are pregnant or breast feeding, or adults of reproductive 
potential who are not using effective birth control methods. If barrier 
contraceptives are being used, these must be continued throughout the trial by 
both sexes. Hormonal contraceptives are not acceptable as a sole method of 
contraception.  (Women of childbearing potential must have a negative urine 
or serum pregnancy test within 7 days prior to administration of 
EVEROLIMUS). 
 Symptomatic intrinsic lung disease or extensive tumor involvement of the 
lungs, resulting in dyspnea at rest. 
 Taking any of the following agents: 


Version 7. 12/07/2015 
33 
 Chronic treatment with systemic steroids or another immunosuppressive 
agent (use of steroids as part of management of everolimus toxicities will 
be allowed). 
 Live vaccines. 
 Patients who have received live attenuated vaccines within 1 week of start 
of Everolimus and during the study. Patient should also avoid close 
contact with others who have received live attenuated vaccines. Examples 
of live attenuated vaccines include intranasal influenza, measles, mumps, 
rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid 
vaccines; 
 Drugs or substances known to be inhibitors or inducers of the isoenzyme 
CYP3A. 
 Please see section 4.4 for excluded therapies during the entirety of the 
study.  
4.2.1 Screening for hepatitis  
Screening for hepatitis B 
(Depending on the indication please consider hepatitis B and C screening criteria 
below.) 
Prior to randomization/start of Everolimus, the following three categories of 
patients should be tested for hepatitis B viral load and serologic markers, that is, 
HBV-DNA, HBsAg, HBs Ab, and HBc Ab: 
 All patients who currently live in (or have lived in) Asia, Africa, Central and 
South America, Eastern Europe, Spain, Portugal and Greece. 
[http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-
related-to-travel/hepatitis-b.htm] 
 
 Patients with any of the following risk factors: 
 known or suspected past hepatitis B infection, 
 blood transfusion(s) prior to 1990, 
 current or prior IV drug users, 
 current or prior dialysis, 
 household contact with hepatitis B infected patient(s), 
 current or prior high-risk sexual activity, 
 body piercing or tattoos, 
 mother known to have hepatitis B 
 history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right 
upper quadrant pain. 
o Additional patients at the discretion of the investigator 


Version 7. 12/07/2015 
34 
 Patients who test positive for active hepatitis should be excluded based on 
section 4.2, exclusion criteria.  
Screening for hepatitis C 
Patients with any of the following risk factors for hepatitis C should be tested 
using quantitative RNA-PCR: 
 known or suspected past hepatitis C infection (including patients with past 
interferon ‘curative’ treatment), 
 blood transfusions prior to 1990, 
 current or prior IV drug users, 
 current or prior dialysis, 
 household contact of hepatitis C infected patient(s), 
 current or prior high-risk sexual activity, 
 body piercing or tattoos. 
At the discretion of the investigator, additional patients may also be tested for 
hepatitis C. 
 Patients who test positive for active hepatitis should be excluded based on 
section 4.2, exclusion criteria.  
 
 
4.3   Study medication (Everolimus) 
Novartis will provide the study drug.  
The Sponsor Investigator of the study will ensure maintenance of complete and accurate 
records of the receipt, dispensation, and disposal or return of all study drug in accordance 
with 21 Code of Federal Regulations 
Dosage: Everolimus will be provided as an oral formulation as 2.5,  5 or 10 mg tablets 
and will be taken at the dose of 10mg daily or patient’s dose at enrollment.  
Upon receipt, everolimus should be stored according to the instructions specified on the 
drug labels. Everolimus should be opened only at the time of administration, as the drug 
is both hygroscopic and light sensitive. 
These instructions should also be made clear to the patient for storage and self-
administration of everolimus at home. 
4.3.1 Dosing modifications 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to allow the patient to continue the study treatment. Details of 


Version 7. 12/07/2015  
35 
study treatment schedule adjustments and dose levels are provided in Table 5. Indications 
for dose modifications are provided in table 3 and table 4.  
Table 5 
Study treatment schedule adjustments and dose levels  
 
Dose level 
Dose and schedule 
0 (starting dose) 
10 mg daily 
-1  
7.5 mg daily 
-2 
5 mg daily 
-3 
2.5 mg daily 
-4  
2.5 mg every other day 
 
4.4 
Concomitant and excluded therapies 
All medications and non-drug therapies taken within 30 days prior to starting study 
treatment should be reported to the Principal Investigator. 
The investigator should instruct the patient to notify the study site about any new 
medications (including over-the-counter drugs and herbal/alternative medications) he/she 
takes after the start of study treatment. Patients must be instructed not to take any 
additional medications (including over-the-counter products and herbal/alternative 
medications) during the trial without prior consultation with the investigator. All 
medications (other than study treatments) and significant non-drug therapies (including 
physical therapy and blood transfusions) administered after the patient starts study 
treatment must be listed on the Concomitant medications/Significant non-drug therapies 
after start of study drug eCRF. 
Concomitant treatments are discussed in section 3.3.  
The following restrictions apply during the entire duration of the study: 
 No other investigational therapy should be given to patients. 
 No chemotherapy agents other than the study medication should be given to patients. 
If such agents are required for a patient then the patient must first be withdrawn from 
the study. 
 Concurrent administration of EVEROLIMUS and strong CYP3A4 inhibitors (such as 
ketoconazole, itraconazole, ritonavir) and inducers (such as rifampin,,rifabutin) 
should be avoided. Provided there is no alternative treatment available, patients 
should be closely monitored for potential toxicities. 
 Concurrent administration of EVEROLIMUS and moderate CYP3A4 inhibitors (such 
as erythromycin, fluconazole, calcium channel blockers, benzodiazepines) and 
moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin) should 
also be avoided if possible, or used subject to caution (e.g. increased frequency of 
safety monitoring, temporary interruption of EVEROLIMUS). 


Version 7. 12/07/2015  
36 
 Competitive inhibition could occur when EVEROLIMUS is combined with drugs that 
are also CYP3A4 substrates. Therefore caution should be exercised in such cases. 
 Co-administration with substrates, inducers, or inhibitors of P-glycoprotein should be 
avoided, if possible, or used subject to caution (e.g. increased frequency of safety 
monitoring, temporary interruption of EVEROLIMUS).  
 Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein activity 
and should therefore be avoided.  
 In addition, patients should avoid Seville oranges and star fruit, as well as the juice of 
these fruits, which are potent CYP3A4-inhibitors.  
 EVEROLIMUS may affect the response to vaccinations making the response to the 
vaccination less effective. Live vaccines should be avoided while a patient is treated 
with EVEROLIMUS. 
 Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no 
interaction with EVEROLIMUS is expected. However, drug-drug interaction studies 
between macrolide antibiotics and warfarin have produced mixed outcomes and the 
disparity in these findings has led to the conclusion that multiple factors may alter the 
clearance of warfarin. The coadministration of EVEROLIMUS and oral 
anticoagulants is possible but should be subject to verification of coagulation (INR) 
once steady state 
4.4.1 Antineoplastic therapy 
The administration of anticancer agents other than study medication, including 
chemotherapy, investigational agents, and biologic agents is NOT permitted while 
patients are enrolled in this study. The need for other anti-cancer therapy will be 
attributed to disease progression and will require the patient to be withdrawn from study 
treatment.  
Palliative radiotherapy for local peripheral metastases not being used as target lesions is 
permitted, but the need for such therapy may be an indication of disease progression and 
should be discussed prior to administration. Radiotherapy for central metastases (e.g., 
vertebral, mediastinal) is not permitted. Patients requiring such therapy prior to 
completion of the study should be considered to have progression of disease and study 
treatment should be discontinued.  
4.4.2      Bisphosphonates 
Patients who enter the study on bisphosphonates may continue this therapy. The need to 
start bisphosphonate therapy on study will be considered as an indication of disease 
progression and the patient will be discontinued from protocol therapy.  
4.4.3     Hematopoietic growth factors and antibiotics 
Hematopoietic growth factors and antibiotics should not be administered 
prophylactically. Antibiotics can be administered as required for treatment of infections, 
however drug interactions should be considered and antibiotics that can interact with 
everolimus should be avoided (please refer to table 6). Recombinant erythropoietin-like 
product (such as Procrit®) may be received throughout the study. 


Version 7. 12/07/2015  
37 
4.4.4      Anti-emetics  
Approximately 25% of patients experience nausea when treated with EVEROLIMUS 
alone and 16% experience vomiting. The majority of nausea and vomiting events is of 
Grade 1 or 2. EVEROLIMUS is best classified as having moderate emetogenic potential, 
therefore prophylactic treatment with appropriate anti-emetic agents as per local 
institutional guidelines is recommended.  
4.4.5     Analgesics 
Baseline analgesics for tumor-related pain should be maintained during the study.  
However, an increase in analgesic use or a step up on the WHO analgesic ladder for 
control of tumor-related pain may indicate disease progression. If an increase in analgesic 
medication from baseline is required during the study, the patient should be evaluated for 
progression of disease. 
4.4.6     Systemic corticosteroids 
Prolonged (greater than 2 weeks in duration) treatment with systemic corticosteroid 
treatment is not allowed during the study except for the treatment of non-infectious 
pneumonitis or everolimus toxicities as described in section 3.6. Prolonged treatment 
with topical steroids should be discussed with the Principal Investigator.  
4.4.7      P-glycoprotein (P-gp) inhibitors 
Patients receiving any concomitant medications known to inhibit P-gp function (e.g., 
verapamil, diltiazem, nicardipine, cyclosporine, quinine) will not be excluded from the 
study but these medications should be avoided. 
4.4.8      Cytochrome p450 enzymes 
EVEROLIMUS is mainly metabolized by CYP3A4 in the liver and to some extent in the 
intestinal wall. Therefore the following advice should be followed: 
 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 
enrollment should not be enrolled into the study 
 Wherever possible, drugs or substances known to be inhibitors or inducers of the 
isoenzyme CYP3A should be avoided as systemic therapy in association with 
EVEROLIMUS as these can alter its metabolism (see Table 5). 
 Patients should also refrain from herbal/alternative remedies and grapefruit juice. 


Version 7. 12/07/2015  
38 
Table 6 
Clinically relevant drug interaction: substrates, inducers and inhibitors of 
isoenzyme CYP3A 
Substrates 
Antibiotics1:  
clarithromycin* 
erythromycin  
 
telithromycin* 
 
Anti-arrhythmics: 
quinidine 
 
Benzodiazepines: 
alprazolam 
diazepam 
midazolam 
triazolam 
 
Immune Modulators: 
cyclosporine 
tacrolimus (FK506) 
 
HIV Protease Inhibitors: 
indinavir* 
ritonavir* 
saquinavir* 
 
Prokinetic: 
cisapride 
 
Antihistamines: 
astemizole 
chlorpheniramine 
Calcium Channel Blockers: 
amlodipine 
diltiazem 
felodipine 
nifedipine 
nisoldipine 
nitrendipine 
verapamil 
 
HMG CoA Reductase Inhibitors2:  
 
cerivastatin 
lovastatin 
 
simvastatin 
 
Miscellaneous: 
 
buspirone 
 
haloperidol  
methadone 
pimozide 
quinine 
 
sildenafil 
tamoxifen 
trazodone 
vincristine 
aprepitant 
 
Inducers 
Carbamazepine 
Phenobarbital 
Phenytoin 
Rifabutin* 
Rifampin* 
St John’s wort 
Troglitazone 
Inhibitors 


Version 7. 12/07/2015  
39 
Amiodarone 
Cimetidine 
Clarithromycin 
Diltiazem 
Erythromycin 
Fluvoxamine* 
Grapefruit juice 
Seville orange juice or product 
Indinavir 
Itraconazole* 
Ketoconazole* 
Voriconazole* 
Posaconazole* 
Mibefradil 
Nefazodone* 
Nelfinavir* 
Troleandomycin 
Verapamil 
 
Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: properties and 
polymorphisms, NaunynSchmiedebergs Arch Pharmacol. 2004 Jan;369(1):89-104 and 
[http://www.medicine.iupui.edu/flockhart/clinlist.htm] 
* asterisk denotes strong inhibition/ induction 
Please note: 
 
Strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80% decrease in clearance 
of sensitive CYP substrates 
 
Moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 50-80% 
decrease in clearance of sensitive CYP substrates. 
(Distinction is not always categorical as interaction can vary according to conditions).  
1. Macrolide antibiotics: Azithromycin is not a CYP3A substrate. It may therefore be employed where 
antibiotic therapy with a macrolide is desirable in a patient being treated with EVEROLIMUS 
2. Statins: Atorvastatin and pravastatin may be administered concomitantly with EVEROLIMUS, since a 
PK interaction study has shown that there is no relevant PK interaction 
 
 
 
 
 
 
 
 
 
 
 
 


Version 7. 12/07/2015  
40 
4.5 
Study Assessments- please refer to appendix A, Study Flowchart 
 Monitor CBC, chemistries every visit. Monitor TSH and lipid profile every 4 weeks 
and then every 12 weeks (after 24 weeks in the study).  
4.5.1 Assessments during Treatment 
 Monitor CBC, chemistries, TSH, lipid profile per study flowchart. 
4.5.2 Follow-Up Assessments 
Patients will have repeat staging performed every 8, 16, 24 weeks and then every 3 
months with CT scans ± bone scans.  Repeat staging may be performed earlier if there is 
clinical evidence to suggest disease progression. 
4.6 
Discontinuation of Protocol-Specified Therapy 
Protocol-specified therapy may be discontinued for any of the following reasons: 
 Progressive disease 
 Unacceptable toxicity 
 Patient election to discontinue therapy (for any reason) 
 Physician’s judgment 
 
4.7 
Subject Discontinuation 
Any patient, who suffers from a serious adverse event or intolerable side effect thought to 
be caused by, or associated with the study treatment, will be withdrawn from the study 
and receive alternative treatment recommendations from the principle investigator. Any 
participant who encounters an unexpected life emergency situation that is noncompliant 
or conflicts with the study protocol will be withdrawn. Any patient who revokes his/her 
consent to participation or voluntarily withdraw from the study will also be discontinued 
from the clinical trial. In addition, subjects will be withdrawn if the principal investigator 
determines that discontinuation from the study is in the best interests of the patients.  
All patients discontinued from the study will receive a final safety evaluation and all 
unused proportion of study medications will be recalled and collected from them. And the 
reasons for premature discontinuation will be captured separately in the corresponding 
Drug Administration CRF. And all study treatment discontinuations will be recorded in 
the Study Completion CRF. 
 
4.8 
Study Discontinuation 
The principal investigator or the study sponsors have the rights to terminate this study in 
its entirety at any time. Reasons for premature discontinuation of the clinical trial may 
include but not limited to the following: 
 The incidence or severity of adverse events, progressive disease, unacceptable 
toxicity in this or other studies indicates a potential health hazard to subjects 


Version 7. 12/07/2015  
41 
 Subject enrollment is unsatisfactory or patients elect to discontinue therapy 
 Data recording is inaccurate or incomplete 
 Compliance with the study protocol or FDA regulations is violated 
Detailed rationale for this action and consequences of the termination will be 
documented. Also, all participants will be formally notified in writing of study 
discontinuation and advised of any potential risks to their health.  
 
4.9 
Statistical Methods 
 
4.9.1 
Data Cleaning 
Prior to performing any analysis, standard data screening and cleaning procedures will be 
performed, which consist of (1) screening the data for implausible values and possible 
data-entry errors, (2) identifying potential outliers, (3) assessing the extent and pattern of 
missing data, and (4) checking whether appropriate statistical assumptions such as 
normality are satisfied when necessary. 
 
4.9.2 
Efficacy Analysis 
 
Endpoints 
The primary objective of this phase II clinical trial is to evaluate the progression free 
survival in patients who receive everolimus in combination with a hormonal agent in 
study subjects. 
 
Response rate (partial response plus complete response) will be measured after 8, 16 and 
24 weeks of therapy and then every 3 months (12 weeks) using RECIST criteria. 
 
Clinical benefit rate (response rate plus stable disease) will be assessed after 8, 16 and 24 
weeks of treatment and then every 3 months (12 weeks). 
 
OS (overall survival) will be measured as time to death from any cause from the initiation 
of alternate hormonal treatment in combination with everolimus. 
 
Safety, tolerability and side effect profile of everolimus will be continuously monitored 
by the WCI DSMB. 
 
Moreover, we will investigate overall survival among patients switching to different 
hormonal agents but all combined with everolimus. 
 
 
4.9.3 
Sample Size Estimation:   
 
Based on the work of Baselga et al (2012), we expect the median PFS to be 
approximately 4 months in the population studied treated with Everolimus, while it is 
approximately 2.5 months without everolimus. Single arm design was used, and we 


Version 7. 12/07/2015  
42 
estimate about about 48 months accrual time period, and each patients will be followed 
for about 24 months. Assuming an exponentially distributed progression free survival 
time, we will need to enroll 34 patients to secure 85% statistical power under a type I 
error of 0.05 by a one-sided test 
(https://stattools.crab.org/Calculators/oneArmSurvivalColored.html ). After considering 
about 10% of drop-off rate, 38 patients will be enrolled in this study. 
 
 
4.9.4 Statistical Methods 
 
The median PFS/OS and survival rate at different time points for this study will be 
estimated by Kaplan-Meier method along with 95% confidence interval. For other 
clinical outcome, such as response rate, will be measured at different time points, e.g. 8, 
16, and 24 weeks, and be summarized as percentage of stable disease, complete remission 
or partial remission along with 95% confidence interval.  
 
4.9.5 
 Missing Data 
All missing measurements will be excluded from the analysis. 
 
4.10 
Data Quality Assurance 
Accurate, consistent, and reliable data will be ensured through the use of standard 
practices and procedures. 
 
4.11 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current U.S. Food and Drug 
Administration (FDA) Good Clinical Practices (GCPs), and local ethical and legal 
requirements. 
 
 
5. 
REPORTING OF ADVERSE EVENTS 
5.1 
Adverse Event and Reporting Definitions 
With the occurrence of an adverse event, the first concern will be for the safety of 
the subject.  Investigators are required to report to Novartis Drug Safety any 
serious adverse event, whether expected or unexpected, and which is assessed 
by the investigator to be reasonably or possibly related to or caused by the study 
medication.   
An adverse event(AE) is any untoward medical occurrence in a subject 
participating in an investigational study or protocol regardless of causality 
assessment.  An adverse event can be an unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, syndrome or disease 


Version 7. 12/07/2015  
43 
associated with or occurring during the use of an investigational product whether 
or not considered related to the investigational product. 
Serious adverse events (SAE) are adverse events occurring at any dose which 
meet one or more of the following serious criteria: 
Results in death (i.e. the AE caused or led to death) 
Is life-threatening (i.e. the AE placed the subject at immediate risk of death; it 
does not apply to an AE which hypothetically might have caused the death if it 
were more severe) 
Requires or prolongs inpatient hospitalization (i.e. the AE required at least a 24-
hour inpatient hospitalization or prolonged a hospitalization beyond the expected 
length of stay; hospitalizations for elective medical/surgical procedures, 
scheduled treatments, or routine check-ups are not SAEs by this criterion) 
Is disabling (i.e. the AE resulted in a substantial disruption of the subject’s ability 
to carry out normal life functions) 
Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus 
of a subject exposed to the study drug prior to conception or during pregnancy) 
Does not meet any of the above serious criteria but may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed above 
Expected adverse events are those adverse events that are listed or characterized 
in the Package Insert or current Investigator Brochure.  
Unexpected adverse events are those not listed in the Package Insert (P.I.) or 
current Investigator Brochure (I.B.).  This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B.  For 
example, under this definition, hepatic necrosis would be unexpected if the P.I. or 
I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
5.2 
Reporting of Serious Adverse Events  
All SAEs that are serious and reasonably or probably related to the use of 
everolimus (this applies to both expected and unexpected events) should 
be recorded on a MedWatch 3500 Form: 
 
Novartis Pharmaceuticals CS&E 
 FAX (888-299-4565) 
The principal investigator has the obligation to report all serious adverse events to 
the FDA, IRB, and Novartis Pharmaceuticals Clinical Safety and Epidemiology 
Department (CS&E). 


Version 7. 12/07/2015  
44 
All events reported to the FDA by the investigator are to be filed utilizing the 
Form FDA 3500A (MedWatch Form).  
All events must be reported, by FAX (888-299-4565), to Novartis 
Pharmaceuticals CS&E Department within 24 hours of learning of its 
occurrence. This includes serious, related, labeled (expected) and serious, related, 
unlabeled (unexpected) adverse experiences. All deaths during treatment or within 
30 days following completion of active protocol therapy must be reported within 
5 working days. 
Any serious adverse event occurring after the patient has provided informed 
consent and until 4 weeks after the patient has stopped study participation must be 
reported. This includes 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). 
Serious adverse events occurring more than 4 weeks after study discontinuation 
need only be reported if causation to the Novartis study drug (or therapy) is 
suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all 
serious adverse experiences will be forwarded to the product manufacturer by the 
investigator. 
 
 
AND   Emory IRB 
1599-001-1AV 
 
Institutional Review Board 
Emory University, 1599 Clifton Road, 
 
Atlanta, GA 30322 
 
Tel: 404-712-0720 
 
Fax: 404-727-1358 
 
Email: IRB@emory.edu 
 
Webpage:  http://emory.edu/IRB/ 
 
 
5.2.1 MedWatch 3500 Reporting Guidelines: 


Version 7. 12/07/2015  
45 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500 form: 
 Protocol description (and number) 
 Description of event, severity, treatment, and outcome if known 
 Supportive laboratory results and diagnostics 
 Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
Follow-up information:   
Additional information may be added to a previously submitted report by any of 
the following methods: 
 Adding to the original MedWatch 3500 report and submitting as follow-up 
 Adding supplemental summary information and submitting it as follow-up 
with the original MedWatch 3500 form  
 Summarizing new information and faxing it with a cover letter including 
subject identifiers (i.e. D.O.B. initial, subject number), protocol description 
and number, if assigned, brief adverse event description, and notation that 
additional or follow-up information is being submitted). The patient identifiers 
are important so that the new information is added to the correct initial report) 
Occasionally Novartis may contact the reporter for additional information, 
clarification, or current status of the subject for whom and adverse event was 
reported.  For questions regarding SAE reporting, you may contact the Novartis 
Drug Safety representative. 
Study Drug Relationship: 
The investigator will determine which events are associated with the use of study 
drug.  For reporting purposes, an AE should be regarded as possibly related to the 
use of everolimus if the investigator believes: 
 There is a clinically plausible time sequence between onset of the AE and the 
study drug administration; and/or 
 There is a biologically plausible mechanism for the study drug to cause or 
contribute to the AE; and 
 The AE cannot be attributed solely to concurrent/underlying illness, other 
drugs, or procedures. 
 
 


Version 7. 12/07/2015  
46 
5.2.2 Data and Safety Monitoring Plan: 
 
The data safety monitoring plan will be implemented by Dr. Elisavet Paplomata, the 
Principal Investigator (P.I.) of this study.  The plan is based on self-monitoring, internal 
CTO real time monitoring using the quality assurance committee, and monitoring via 
Winship Cancer Institute (“WCI”) Data Safety Monitoring Committee (DSMC) as per 
WCI CTO standard operating procedure. Dr. Paplomata and the investigators, the clinical 
research coordinator and the regulatory affairs coordinator will meet at least on a monthly 
basis to review and discuss study data to ensure subject safety. The research coordinators 
will maintain one spread sheet which will summarize all the patient data for patients 
actively being treated on the trial as well as a roadmap detailing pending tests/treatments 
for each individual patient. During the weekly meeting the group will review the 
eligibility criteria for each new patient. In addition, during these meeting the group will 
review all the toxicity (AE/SAE) logs, case report form completion and roadmap for each 
patient on the trial. Documentation of the discussions during these meetings are 
completed, filed and forwarded to the Winship Cancer Institute (“WCI”) Data Safety 
Monitoring Committee (DSMC) at WCI. 
 
The WCI has two internal monitoring committees. The first is the quality assurance and 
quality monitoring committee, which will perform a review of the first and then on a 
regular ongoing basis for selected patient enrolled on the trial to confirm that the trial is 
being conducted appropriately. The second monitoring process involves DSMC. The 
WCI DSMC is responsible for providing data safety-monitoring oversight for this 
protocol. Any comments that are generated by the WCI DSMC are forwarded to the 
IRB.  The P.I. and the study investigators will discuss any required modifications to this 
study at the weekly meetings. No modifications to this study are implemented until they 
are submitted for review and approved by the Emory University IRB. The comments 
from the WCI DSMC are forwarded to the IRB at the time of the annual renewal of this 
study or sooner if warranted and requested by the WCI DSMC.     
 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute 
will oversee the conduct of this study. This committee will review all pertinent aspects of 
study conduct including patient safety, compliance with protocol, data collection and 
efficacy. The committee will review the charts of 10% of patients enrolled to the study 
and two of the first 5 patients entered to the study. Reviews will occur annually for 
studies that are low risk or moderate risk. High-risk studies will be reviewed every 6 
months. The committee reserves the right to conduct additional audits if necessary at any 
time-point. The Principal Investigator is responsible for notifying the DSMC about the 
accrual of patients when the first 5 have been entered to the study. The PI will also notify 
the DSMC of the study status within 2 months before the next annual review is due. The 
charter for the Winship DSMC is available upon request to the investigator or other 
study-related personnel. 
            
The WCI DMSC does not tolerate protocol deviations, but does recognize that they occur 
unintentionally. Any protocol violations are reviewed and reported to the WCI DSMC, 
IRB, and all other designated regulatory agencies as required by the study protocol.   


Version 7. 12/07/2015  
47 
 
All study data reviewed and discussed during these meetings with the PI and the 
investigators and the WCI DSMC is kept confidential. Any breach in 
confidentiality during the conduct of the study is reported to the PI, WCI DSMC, 
sponsor, and the IRB. 
 
6. 
INVESTIGATOR REQUIREMENTS 
6.1 
Study Initiation 
Before the start of this study, the following documents must be on file with Novartis: 
 Original U.S. FDA Form 1572 (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal 
Investigator 
The names of any sub-investigators must appear on this form.  
Investigators must also complete all regulatory documentation as required 
by local and national regulations. 
 Current curriculum vitae of the Principal Investigator 
 Written documentation of IRB approval of protocol and informed consent 
document 
 A copy of the IRB-approved informed consent document 
 A signed Clinical Research Agreement 
 
6.2 
Study Completion 
 
The following materials are requested by Novartis when a study is considered complete or 
terminated: 
 A summary, prepared by the Principal Investigator, of the study, and/or a 
study manuscript, and/or a study abstract submitted to scientific conferences. 
 
6.3 
Informed Consent 
An informed consent template will be provided, and the final IRB-approved 
document must be provided to Genentech and Novartis for regulatory purposes. 
The informed consent document must be signed by the subject, or the subject’s 
legally authorized representative, before his or her participation in the study.  The 
case history for each subject shall document that informed consent was obtained 
prior to participation in the study.  A copy of the informed consent document 
must be provided to the subject or the subject's legally authorized representative.  
If applicable, it will be provided in a certified translation of the local language. 
Signed consent forms must remain in each subject’s study file and must be 
available for verification by study monitors at any time. 


Version 7. 12/07/2015  
48 
 
6.4 
Institutional Review Board or Ethics Committee Approval 
This protocol, the informed consent document, and relevant supporting 
information must be submitted to the IRB for review and must be approved before 
the study is initiated.  The study will be conducted in accordance with U.S. FDA, 
applicable national and local health authorities, and IRB requirements. 
The principal investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol as deemed 
appropriate, but in any case the IRB must be updated at least once a year.  The 
principal investigator must also keep the IRB informed of any significant adverse 
events. 
Investigators are required to promptly notify their respective IRB of all adverse 
drug reactions that are both serious and unexpected.  This generally refers to 
serious adverse events that are not already identified in the Investigator Brochure 
and that are considered possibly or probably related to the molecule or study drug 
by the investigator.  Some IRBs may have other specific adverse event 
requirements that investigators are expected to adhere.  Investigators must 
immediately forward to their IRB any written safety report or update provided by 
Novartis (e.g., IND safety report, Investigator Brochure, safety amendments and 
updates, etc.). 
 
6.5 
Study Monitoring Requirements 
Site visits may be conducted by an authorized Novartis representative to inspect 
study data, subjects’ medical records, and CRFs in accordance with current U.S. 
GCPs and the respective local and national government regulations and guidelines 
(if applicable). 
The Principal Investigator will permit authorized representatives of Novartis, the 
U.S. FDA, and the respective national or local health authorities to inspect 
facilities and records relevant to this study. 
6.6 
Study Medication Accountability (If Applicable) 
Accurate records of all study drug dispensed from and returned to the study site 
should be recorded by using the institution’s drug inventory log or the NCI drug 
accountability log. 
All partially used or empty containers should be disposed of at the study site 
according to institutional standard operating procedure.  Return unopened, 
expired, or unused study drug with the Inventory of Returned Clinical Material 
form as directed by Novartis for everolimus.  
6.7 
Disclosure of Data 
Subject medical information obtained by this study is confidential, and disclosure 
to third parties other than those noted below is prohibited. 


Version 7. 12/07/2015  
49 
Upon the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or 
her welfare. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, Novartis 
and the IRB for the study site. 
 
6.8 
Retention of Records 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational drug, 
including CRFs, consent forms, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for 2 years after marketing 
application approval.  If no application is filed, these records must be kept 2 years 
after the investigation is discontinued and the U.S. FDA and the applicable 
national and local health authorities are notified. Novartis will notify the Principal 
Investigator of these events. 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with U.S. FDA IND regulations and with the record 
retention policies of the relevant national and local health authorities.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
References 
 


Version 7. 12/07/2015  
50 
1. 
Winer EP. Optimizing endocrine therapy for breast cancer. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 2005 Mar 10;23(8):1609-10. 
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Paplomata E, O'Regan R. New and emerging treatments for estrogen receptor-positive 
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Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, et al. Anastrozole 
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is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal 
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Bliss J, Kilburn L, Coleman R, et al. Disease related outcome with long term follow-up: 
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Puhalla S, Bhattacharya S, Davidson NE. Hormonal therapy in breast cancer: a model 
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Mackay JR KB, Clemens M, et al.  , editor Trastuzumab prolongs progression free 
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Yecies JL, Manning BD. mTOR links oncogenic signaling to tumor cell metabolism. 
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Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical 
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deGraffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, et 
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Baselga J, Campone M, Piccart M, Burris HA, 3rd, Rugo HS, Sahmoud T, et al. 
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Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. 
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Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation 
of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised 
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von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. 
Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive 
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20;27(12):1999-2006. PubMed PMID: 19289619. 
28. 
G. von Minckwitz KS, M. Schmidt et al., editor Final overall survival analysis of the TBP 
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Res, 70 (suppl 24) (2010), p 459s (abstract P6-14-05); 2010. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


Version 7. 12/07/2015  
53 
 
 
 
APPENDIX A- STUDY FLOWCHART
 
Days  
–14 
to -2 
 
 
 
Day   
1  
 
 
 
Daily  
 
First 
24 
weeks: 
First 
24 
weeks: 
After 
24 
weeks: 
Every 
12 
Weeks 
Study 
Termination 
Every 
4 
Weeks 
Every 
8 
Weeks 
Everolimus 
(EVEROLIMUS) 
X 
X 
X 
 
 
 
Hormonal therapy1 
X 
X 
X 
 
 
 
Complete medical 
history 
X 
X 
 
X 
 
X 
 
Complete physical 
exam 
X 
X 
 
X 
 
X 
 
Clinical assessment 
X 
X 
 
X 
 
X 
 
Weight, height 
X 
X 
 
X 
 
X 
 
ECOG performance 
status 
X 
X 
 
X 
 
X 
 
Toxicity evaluation 
X 
X 
 
X 
 
X 
 
Vital signs 
X 
X 
 
X 
 
X 
 
ECG (12-lead) 
X 
 
 
 
 
 
Serum pregnancy 
test  
X 
 
 
 
 
 
Tumor assessment2 
X 
 
 
 
X 
X 
X 
Hematology (CBC, 
diff., platelets)3 
X5 
 
 
X 
 
X 
 
Coagulation 
(PT/INR)4 
X 
 
 
 
 
 
Chemistry panel 
(including TSH and 
lipid panel)5 
X 
 
 
X 
 
X 
 


Version 7. 12/07/2015  
54 
 
 
 
 
 
APPENDIX A STUDY FLOWCHART 
(1) Any hormonal therapy is allowed (for example: tamoxifen, anastrozole, letrozole, fulvestrant, 
estrogen, megestrol acetate, androgens). 
(2) Staging will be performed using CT scans: chest, abdomen and pelvis and bone scan. First staging 
assessment will be done at baseline, every 8 weeks for 24 weeks, then every 12 weeks until 
progression.  
(3) Hematology should include CBC with differential.  
(4) The coagulation profile should include a prothrombin time (PT/INR). 
(5) Chemistry Panel should include: potassium, magnesium (optional), calcium, chloride, bicarbonate, 
creatinine, blood urea nitrogen, fasting glucose, albumin, total protein, AST, ALT, total bilirubin, 
alkaline phosphatase, fasting lipid profile (triglycerides, total cholesterol, HDL, and LDL), TSH.  
These assessments should be performed at screening and every 4 weeks. 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B 
 
 
 
Response Evaluation Criteria in Solid Tumors (RECIST Criteria, version 1.1) 
[E.A. Eisenhauer, P. Therasse, J. Bogaerts, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). EUROPEAN JOURNAL OF CANCER 
45 (2009) 228–247] 
 
The RECIST criteria version 1.1 should be used to assess response to treatment. Only 
subjects with measurable disease should be entered in the study.  
 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows: 
 
Measurable 
 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of: 
• 10mm by CT scan (CT scan slice thickness no greater than 5 mm). 


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55 
• 10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
 20 mm by chest x-ray. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed.  
 
Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological 
lymph nodes with ≥10 to <15mm short axis), as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural 
or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal,organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
 
Evaluable lesions should be followed for the assessment of response.   
 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and will be 
recorded and measured at baseline (this means in instances where patients have only one 
or two organ sites involved a maximum of two and four lesions respectively will be 
recorded). 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into 
the sum. The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
 
Response Criteria- Evaluation of target lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient 


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56 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
 Clinical progressive disease 
Subjects, who in the opinion of the treating physician investigator have had a substantial 
decline in their performance status and have clinical evidence of progressive disease, may 
be classified as having progressive disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX C 
Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 
Please refer to: 
http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-
15_QuickReference_5x7.pdf 
 
Published: May 28, 2009 (v4.02: Sept. 15, 2009) 
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES 
National Institutes of Health- National Cancer Institute