Clinical trial NCT02031536
Conditions: Gastrinoma Glucagonoma Insulinoma Liver Metastases Pancreatic Polypeptide Tumor Recurrent Islet Cell Carcinoma Somatostatinoma
Keywords: everolimus randomized metastatic pancreatic neuroendocrine tumors liver
Sponsor: ECOG-ACRIN Cancer Research Group
Start date: 2014-04-10; Completion date: 2017-07-19
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well everolimus works in treating patients with pancreatic neuroendocrine tumors metastatic to the liver previously treated with surgery. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving everolimus after surgery may kill any tumors cells that remain.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate if the addition of adjuvant everolimus to the R0 or R1 surgical resection of pancreatic neuroendocrine tumor metastases to the liver will result in an improvement in disease free survival.

SECONDARY OBJECTIVES:

I. To evaluate if the addition of adjuvant everolimus to the R0 or R1 surgical resection of pancreatic neuroendocrine tumor metastases to the liver will result in an improvement in overall survival.

II. To evaluate the toxicity associated with adjuvant everolimus following resection in patients with metastatic pancreatic neuroendocrine tumors to the liver.

OUTLINE: Patients are randomized to 1 of 2 treatment arms in a 1:1 ratio.

ARM A: Patients receive everolimus orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive placebo PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

PROJECTED ACCRUAL: 150 patients

Arms: arm 1: Patients receive everolimus PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive placebo PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: everolimus intervention 2: placebo
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol documents:
ICF_001.pdf: 
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Testing the Addition of Everolimus (Chemotherapy) After Surgery to 
Remove Metastatic Pancreatic Neuroendocrine Tumors from the Liver 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of 
Adjuvant Everolimus Following the Resection of Metastatic Pancreatic 
Neuroendocrine Tumors to the Liver 
Version Date: April 21, 2014  
WHAT IS THE USUAL APPROACH TO MY METASTATIC PANCREATIC 
NEUROENDOCRINE CANCER? 
You are being asked to take part in this research study because you have pancreatic 
neuroendocrine cancer which spread to your liver and was surgically removed. 
People who are not in a research study are usually monitored after their surgery in 
case their cancer returns.  
WHAT ARE MY OTHER CHOICES IF I DO NOT TAKE PART IN THIS STUDY? 
If you decide not to take part in this study, you have other choices for your care. For 
example: 
• you may choose to have the usual approach described above 
• you may choose to take part in a different research study, if one is available 
• or you may choose not to be treated or monitored for cancer but you may want to 
receive comfort care to relieve symptoms if your cancer returns. 
WHY IS THIS STUDY BEING DONE? 
The purpose of this research study is to compare any good and bad effects of using 
the study drug, everolimus (also known as Afinitor), along with the usual monitoring 
after surgical removal of pancreatic neuroendocrine cancer tumor that has spread to 
the liver, to using the usual monitoring alone after surgery. The addition of 
everolimus to the usual monitoring could decrease the chance that your tumor(s) will 
come back but it could also cause side effects. This research study will allow the 
researchers to know whether this different approach is better, the same, or worse 
than the usual approach. To be better, the study drug should improve how long 
patients with your type of cancer are able to live without their cancer returning by 12 
months (1 year) or more compared to the usual approach. The chemotherapy drug, 
everolimus, is already FDA-approved to treat progressive neuroendrocrine tumors of 
pancreatic origin (PNET) that is unresectable, locally advanced, or metastatic, but 


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has not been FDA-approved for treating patients who have had surgical resection of 
pancreatic neuroendocrine tumor metastases to the liver. Experiments have shown 
that everolimus can prevent cells such as cancer from growing in number.. For this 
study, everolimus is supplied by Novartis Pharmaceuticals Corporation. 
There will be about 150 people taking part in this research study. 
WHAT ARE THE STUDY GROUPS? 
This research study has two study groups. Group 1 will receive the study drug 
everolimus and Group 2 will receive a placebo, a tablet that looks like the study drug 
but contains no medication. 
A computer will by chance assign you to treatment groups in the research study. 
This is called randomization. This is done by chance because no one knows if one 
study group is better or worse than the others. You will have an equal (50%) chance 
of being placed in either group. You and your doctor will not know which group you 
are assigned until you have completed treatment, unless needed for a medical 
emergency. Another way to find out what will happen to you during this research 
study is to read the chart below. Start reading at the left side and read across to the 
right, following the lines and arrows. 
 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
You will receive the everolimus/placebo once a day for up to 12 cycles (about 1 
year.) Each cycle is 4 weeks long. After each 4-week cycle, you will visit your doctor 
for an evaluation. Further treatment will depend on whether your doctor thinks the 
treatment is helping you and you are tolerating the drug well. After you finish 
everolimus/placebo treatment, your doctor will continue to watch you for side effects 
and follow your condition for up to 5 years from when you first join the study.  
Randomize 
(The computer will 
randomly put you in a 
study group) 
Group 2 
Placebo once a day  
for 12 cycles  
(about 1 year). 
(Usual approach group) 
You agree to 
take part in the 
study 
Group 1  
Everolimus once a day 
for 12 cycles  
(about 1 year) 
(Study approach group) 


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WHAT EXTRA TESTS AND PROCEDURES WILL I HAVE IF I TAKE PART IN THIS 
STUDY? 
Most of the exams, tests, and procedures you will have are part of the usual care for 
your cancer. However, there are some extra exams, tests, and/or procedures that 
you will need to have if you take part in this research study. 
Before you begin the study: 
You will need to have the following extra exams, tests, and/or procedures to find out 
if you can be in the research study: 
• Blood tests to make sure your internal organs are functioning normally and your 
red and white cell counts are adequate. About 1 tablespoon of blood will be 
drawn. 
• CT scan of chest, abdomen and pelvis or MRI of abdomen and pelvis and CT 
scan of chest 
• Blood tests to measure Chromogranin (CgA), neuron-specific enolase (NSE) 
level and hemoglobin A1c will be performed at the same time when scans are 
performed. About 1 tablespoon of blood will be drawn. 
• Blood test to check for hepatitis antibodies, pregnancy, and/or blood sugar levels, 
if your doctor thinks it is necessary. If you need to be tested for hepatitis, 
pregnancy, or blood sugar, about 1 tablespoon of blood will be drawn.  
Small pieces of cancer tissue removed during your previous surgery and/or biopsies 
will be taken for the research study before you begin study drug. This sample is 
required in order for you to take part in this research study because the research on 
the sample is an important part of the research study.  
No additional surgeries or biopsies are required to collect the tumor tissue for this 
research study.  
If the exams, tests, and procedures show that you can take part in the research 
study, and you choose to take part, then you will need the following extra tests and 
procedures. They are not part of the usual care for your type of cancer. 
During the study: 
• Blood tests every month for as long as you are receiving everolimus/placebo 
(about 1 year). About 1 tablespoon of blood will be drawn each month.  
• Urine pregnancy test, if a woman is capable of getting pregnant, every month for 
as long as you are receiving everolimus/placebo (about 1 year), if your doctor 
thinks it is necessary. 
• CT scan of chest, abdomen and pelvis or MRI of abdomen and pelvis and CT 
scan of chest every 3 months for 2 years, then every 6 months until 5 years from 
when you entered the study.  
• Blood tests to measure Chromogranin (CgA), neuron-specific enolase (NSE) 
level and hemoglobin A1c will be performed at the same time when scans are 
performed. About 1 tablespoon of blood will be drawn. 


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• Blood tests, including a serum pregnancy test, if a woman is capable of getting 
pregnant, will be performed when you finish taking everolimus/placebo. 
• Samples of your tissue from a previous biopsy or from your surgery will be sent 
to a central laboratory to be examined by central reviewers. No additional 
procedures will be performed to collect this tissue for these reviews. This central 
review will be used to confirm the results of the local institutional review, but will 
not affect your participation in this trial. The results of the review will be returned 
to your doctor and may be placed in your medical record. 
WHAT POSSIBLE RISKS CAN I EXPECT FROM TAKING PART IN THIS STUDY? 
If you choose to take part in this research study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or 
doctor’s office than usual 
• You may be asked sensitive or private questions which you normally do not 
discuss 
• The study drug may not be better, and could possibly be worse, than the usual 
approach for your cancer. 
• There is a risk someone could get access to the personal information in your 
medical records or other information researchers have kept about you. Someone 
might be able to trace this information back to you. The researchers believe the 
chance that someone will identify you is very small, but the risk may change in 
the future as people come up with new ways of tracing information. In some 
cases, this information could be used to make it harder for you to get or keep a 
job. There are laws against misuse of genetic information, but they may not give 
full protection. The researchers believe the chance these things will happen is 
very small, but cannot promise that they will not occur.  
• There can also be a risk in finding out new genetic information about you. New 
health information about inherited traits that might affect you or your blood 
relatives could be found during a study.  
The drug used in this research study may affect how different parts of your body 
work such as your liver, kidneys, heart, and blood. The study doctor will be testing 
your blood and will let you know if changes occur that may affect your health. These 
risks are described in more detail below. 
There is also a risk that you could have other side effects from the study drug. 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may 
never go away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
• There may be some side effects or risks that are not known. 


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Here are important points about how you and the study doctor can make side effects 
less of a problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you 
are having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
It is very important for you to take the study drug just as the study doctor tells you. 
Do not skip any doses unless your doctor tells you to skip doses. You should take 
everolimus/placebo about the same time each day, either consistently with or 
without food.  
If you throw up after taking the study drug, you should NOT take another tablet that 
day. Let your study doctor know that you got sick. If you forget to take the study drug 
one day, do not take any extra doses the next day. Call your study doctor and ask 
for advice.  
Tell your study doctor before you any take any other drug besides 
everolimus/placebo. This includes homeopathic, alternative or herbal medicines, and 
vitamins. Please avoid eating grapefruit and citrus fruits or drinking their juices for as 
long as you are on the study. The juices in these fruits can change the way your 
body treats or breaks down everolimus/placebo. Other drugs or citrus juices may 
change how the study drug works or make your side effects worse.  
Everolimus/placebo may cause your immune system not to work as well as 
usual.You should not receive live vaccines or have close contact with people who 
have received live vaccines for as long as you are taking everolimus/placebo. 
Examples of live vaccines include intranasal influenza, measles, mumps, rubella, 
oral polio, BCG, yellow fever, varicella (Chicken Pox), and typhoid vaccines. 
The tables below show the most common and the most serious side effects that 
researchers know about. There might be other side effects that researchers do not 
yet know about. If important new side effects are found, the study doctor will discuss 
these with you. 


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Possible Side Effects of Everolimus/Placebo: 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving everolimus/placebo, more than 20 and up to 100 may 
have: 
• Mouth lining changes (stomatitis) ranging from redness, irritation, swelling in the 
mouth to mouth ulcers 
• Fatigue 
• Weakness 
• Nausea  
• Vomiting 
• Dry mouth 
• Skin or nail changes (including acne, rash, redness, itching, dryness or irritation) 
• Diarrhea 
• Abdominal pain (belly pain) 
• Loss of appetite  
• Weight loss 
• Increased blood pressure 
• Pain or swelling of the arms or legs 
• Fever  
• Abnormal or loss of taste  
• Loss of red blood cells, also called anemia  
• Inflammation of the throat 
• Bleeding of the nose 
• Inflammation of the lining of the digestive system and other mucous membranes 
• Shortness of breath  
• Headache 
• Migraine 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving everolimus/placebo, from 4 to 20 may have: 
• Change of sleep patterns 
• Sleeplessness 
• Difficulty breathing 
• Back pain 
• Pain in arms and legs 
• Joint pain 
• Dizziness 
• Dry mouth 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving everolimus/placebo, from 4 to 20 may have: 
• Muscle spasms 
• Lowering of the number of your blood cells that help fight infection 
• Lowering of the blood cells that help the blood to clot and a lowering of the protein 
in your blood (hemoglobin) that helps carry oxygen 
• Changes to the levels of blood sugar (glucose) which could lead to diabetes 
• The levels of cholesterol and triglycerides or liver enzymes (transaminases) in 
your blood could increase (increased levels of cholesterol are an important factor 
of risk of heart disease)  
• The level of waste products from the liver (bilirubin) could increase, which could 
mean your liver is not working as well 
• Secondary amenorrhea (delayed menstruation)  
• Inflammation in the lungs (pneumonitis) 
 
RARE, AND SERIOUS 
In 100 people receiving everolimus/placebo, 3 or fewer may have: 
• Embolism or blockage in your lungs 
• Toxicity to your kidneys that causes the level of creatinine in your blood and 
protein in your urine to increase. In very rare cases, this toxicity could lead to 
kidney failure. 
Let your study doctor know of any questions you have about possible side effects. 
You can ask the study doctor questions about side effects at any time. 
Reproductive risks:  
You should not become pregnant or father a baby while on this research study 
because the drugs in this study can affect a fetus. 
If a woman becomes pregnant while on this research study or within 28 days after 
the last dose of study drug, she will be asked information concerning the outcome of 
her pregnancy. If a female partner of a male patient becomes pregnant while the 
male patient is on the study or within 28 days after the last dose of study drug, the 
pregnant female partner should be advised to call her healthcare provider 
immediately and be aware that the investigator will ask to follow her pregnancy.  
Women should not breastfeed a baby while on this research study.  
It is important that you understand that you need to either practice “abstinence” (that 
is avoiding sexual activity) or use birth control while on this research study. Check 
with your doctor about what kind of birth control methods to use and how long to use 
them. 
Avoiding sexual activity is the only certain method to prevent pregnancy. However, if 
you choose to be sexually active, you must agree to use an appropriate double 


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barrier method of birth control (such as female use of a diaphragm, intrauterine 
device (IUD), sponge and spermicide, in addition to the male use of a condom) or 
involve female use of prescribed “birth control pills” or a prescribed birth control 
implant. Both double barrier contraception and birth control pills or implants must be 
used for at least one week prior to the start of the research study and continuing for 
up to 8 weeks after the last dose of the study drugs. If you choose to be sexually 
active during the study, you must accept that pregnancy could still result, exposing 
you or your sexual partner to potential loss of pregnancy as well as other unknown 
effects on the developing fetus. 
WHAT POSSIBLE BENEFITS CAN I EXPECT FROM TAKING PART IN THIS STUDY? 
It is not possible to know at this time if the study drug is better than the usual care for 
this cancer so this research study may or may not help you. But, this research study 
will help researchers learn things that will help people in the future. 
CAN I STOP TAKING PART IN THIS STUDY? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is 
important to let the study doctor know as soon as possible so you can stop safely. If 
you stop, you can decide whether or not to let the study doctor continue to provide 
your medical information to the organization running the study. 
The study doctor will tell you about new information or changes in the study that may 
affect your health or your willingness to continue in the study. 
The study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If you need medicine or treatment not allowed in on the study 
• If new information becomes available 
• If you do not follow the study rules 
• If you become pregnant 
• If the study is stopped by the sponsor, IRB or FDA. 
WHAT ARE MY RIGHTS IN THIS STUDY? 
Taking part in this research study is your choice. No matter what decision you make, 
and even if your decision changes, there will be no penalty to you. You will not lose 
medical care or any legal rights. 
For questions about your rights while in this study, call the 
________________________ (insert name of center) Institutional Review Board at 
__________________ (insert telephone number). (Note to Local Investigator: 
Contact information for patient representatives or other individuals at a local 
institution who are not on the IRB or research team but take calls regarding clinical 


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trial questions can also be listed here.) 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
The everolimus/placebo will be supplied at no charge while you take part in this 
research study. It is possible that the everolimus/placebo may not continue to be 
supplied while you are on the study. Although not likely, if this occurs, your study 
doctor will talk to you about your options. 
You and/or your health plan/insurance company will need to pay for all of the other 
costs of preventing or treating your cancer while in this research study, including the 
cost of study drug preparation and administration, tests, procedures, or medicines to 
manage any side effects, unless you are told that certain tests are being done at no 
charge. Before you decide to be in the research study, you should check with your 
health plan or insurance company to find out exactly what they will pay for. 
You will not be paid for taking part in this research study. 
WHAT HAPPENS IF I AM INJURED OR HURT BECAUSE I TOOK PART IN THIS STUDY? 
If you are injured or hurt as a result of taking part in this research study and need 
medical treatment, please tell your study doctor. The study sponsors will not offer to 
pay for medical treatment for injury. Novartis, the drug supplier, will not pay any 
money to you or your medical bills. Your insurance company may not be willing to 
pay for research study-related injury. If you have no insurance, you would be 
responsible for any costs. 
If you feel this injury was a result of medical error, you keep all your legal rights to 
receive payment for this even though you are in a research study. 
WHO WILL SEE MY MEDICAL INFORMATION? 
Your privacy is very important to us and the researchers will make every effort to 
protect it. Your information may be given out if required by law. For example, certain 
states require doctors to report to health boards if they find a disease like 
tuberculosis. However, the researchers will do their best to make sure that any 
information that is released will not identify you. Some of your health information, 
and/or information about your specimen, from this study will be kept in a central 
database for research. Your name or contact information will not be put in the 
database. 
The ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) is conducting this 
study. ECOG-ACRIN is a cancer research group that conducts studies for the 
National Cancer Institute. Your doctor is a member of ECOG-ACRIN or another 
group that is participating in this study. To help protect your privacy, ECOG-ACRIN 
has obtained a Confidentiality Certificate from the Department of Health and Human 
Services (DHHS).  With this Certificate, ECOG-ACRIN cannot be forced (for 
example, by court subpoena) to disclose information that may identify you in any 


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federal, state or local civil, criminal, administrative, legislative or other proceeding. 
Disclosure will be necessary, however, upon request of DHHS for audit or program 
evaluation purposes. 
There are organizations that may inspect your records. These organizations are 
required to make sure your information is kept private, unless required by law to 
provide information. Some of these organizations are: 
• ECOG-ACRIN, the study sponsor, and Novartis, the drug company supporting 
the study and/or their authorized representatives. 
• The Institutional Review Board, IRB, is a group of people who review the 
research with the goal of protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the U.S., 
and similar ones if other countries are involved in the study. 
• The Cancer Trials Support Unit (CTSU), a service provided by the National 
Cancer Institute (NCI) to provide greater access to cancer trials. 
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OPTIONAL STUDIES SECTION:  
This section is about optional studies you can choose to take part in. 
This part of the consent form is about optional studies that you can choose to take 
part in. You will not get health benefits from any of these studies. The researchers 
leading this optional study hope the results will help other people with cancer in the 
future. 
The results will not be added to your medical records and you or your study doctor 
will not know the results. 
You will not be billed for these optional studies. You can still take part in the main 
study even if you say ‘no’ to any or all of these studies. If you sign up for but cannot 
complete any of the studies for any reason, you can still take part in the main study. 
Optional Sample Collections for Laboratory Studies and/or Biobanking for 
Possible Future Studies 
Researchers are trying to learn more about cancer and other health problems. Much 
of this research is done using samples of tissue, blood, urine, or other fluids. 
Through these studies, researchers hope to find new ways to prevent, detect, treat, 
or cure health problems. 
Some of these studies may be about genes. Genes carry information about features 
that are found in you and in people who are related to you. Researchers are 
interested in the way that genes affect how your body responds to treatment. 
At this time, we are requesting that you allow the collection, submission and storage 
of blood and tumor tissue samples for research projects that may be done at a later 
date. The tumor tissue will be from previous procedures (biopsies or surgeries). No 
additional procedures will be performed to collect the tumor tissue for future projects. 
These specimens will be stored in a “Biobank”. The Biobanks are run by ECOG-
ACRIN staff and researchers and they are financially supported by the National 
Cancer Institute. 
What is involved if you provide your samples for research? 
If you agree to take part, here is what will happen next: 
1. Blood and tissue samples will be sent and stored for future research: 
a. Tissue samples left over after the central reviews will be stored for future 
research. 
b. About 2 tablespoons of blood will be collected from a vein in your arm before 
you begin protocol therapy and when you discontinue or finish the protocol 
treatment. These draws will most likely be done at the same time as the blood 
draws performed to monitor your health. Another stick should not be 
necessary. 


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c. If available, additional samples of the tissue that was collected at the time of 
your biopsies and/or surgeries, including frozen tumor, will be sent to the 
Biobank.  
2. Your samples and some related health information will be stored in the Biobank, 
along with samples and information from people who took part in this or other 
research studies. The samples will be kept until they are used up. Information 
from your medical record will be updated from time to time. 
3. Only qualified researchers can submit a request to use the materials stored in the 
Biobanks. A committee of experts at ECOG-ACRIN, and/or the National Cancer 
Institute, will review each request to use the samples for research. All research 
projects using these samples will also be reviewed by an ethics or institutional 
review board to ensure that the request is necessary and proper. Researchers 
will not be given your name or any other information that could directly identify 
you.  
4. Neither you nor your study doctor will be notified when research will be 
conducted or given reports or other information about any research that is done 
using your samples.  
5. Results from the research may be placed in centralized storage systems call 
databases. It is possible that some of your genetic information and your health 
information may be placed in these databases. It is also possible that some of 
these databases may be public. 
What are the possible risks in providing your samples for research? 
1. The most common risks related to drawing blood from your arm are brief pain 
and possibly a bruise.  
2. There is a risk that someone could get access to the personal information in your 
medical records or other information researchers have stored about you. 
3. There is a risk that someone could trace the information in a central database 
back to you. Even without your name or other identifiers, your genetic information 
is unique to you. The researchers believe the chance that someone will identify 
you is very small, but the risk may change in the future as people come up with 
new ways of tracing information. 
4. In some cases, this information could be used to make it harder for you to get or 
keep a job or insurance. There are laws against the misuse of genetic 
information, but they may not give full protection. There can also be a risk in 
knowing genetic information. New health information about inherited traits that 
might affect you or your blood relatives could be found during a study. The 
researchers believe the chance these things will happen is very small, but cannot 
promise that they will not occur. 
When my samples are used for research, how will information about me be 
kept private? 
Your privacy is very important to the researchers and they will make every effort to 
protect it. Here are just a few of the steps they will take: 


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1. When your sample(s) is sent to the researchers, no information identifying you 
(such as your name) will be sent. Samples will be identified by a unique code 
only.  
2. The list that links the unique code to your name will be kept separate from your 
sample and health information. Any Biobank and ECOG-ACRIN staff with access 
to the list must sign an agreement to keep your identity confidential. 
3. Researchers to whom ECOG-ACRIN sends your sample and information will not 
know who you are. They must also sign an agreement that they will not try to find 
out who you are. 
4. Information that identifies you will not be given to anyone, unless required by law. 
5. If research results are published, your name and other personal information will 
not be used. 
What are the Possible Benefits of allowing my samples to be used for 
research? 
You will not benefit from taking part. The researchers, using the samples from you 
and others, might make discoveries that could help people in the future. Your 
samples may be helpful to research whether or not your cancer returns.  
Are there any costs or payments associated with providing my samples for 
research? 
There are no costs to you or your insurance. You will not be paid for taking part. If 
any of the research leads to new tests, drugs, or other commercial products, you will 
not share in any profits. 
What if I change my mind about allowing my samples to be used for research? 
If you decide you no longer want your samples to be used, you can call the study 
doctor, _________________, (insert name of study doctor for main trial) at 
________________________ (insert telephone number of study doctor for main 
trial) who will let the researchers know. Then, any sample that remains in the bank 
will no longer be used and related health information will no longer be collected. 
Samples or related information that have already been given to or used by 
researchers will not be returned. 
What if I have more questions? 
If you have questions about the use of your samples for research, contact the study 
doctor, ________________, (insert name of study doctor for main trial), at 
_____________________ (insert telephone number of study doctor for main trial). 


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Please circle your answer to show whether or not you would like to take part in each 
option: 
SAMPLES FOR FUTURE RESEARCH STUDIES: 
May we have some samples of your blood and additional tissue samples, if 
available, for future health research? 
I agree to provide additional samples for research.   
YES 
NO 
May we keep any tissue samples left over from the central reviews for future health 
research? 
My samples and related information may be kept in a Biobank for use in future 
health research. 
YES 
NO 
This is the end of the section about optional studies. 


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WHERE CAN I GET MORE INFORMATION? 
You may visit the NCI Web site at http://cancer.gov/ for more information about 
studies or general information about cancer. You may also call the NCI Cancer 
Information Service to get the same information at: 1-800-4-CANCER (1-800-422-
6237). 
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. 
WHO CAN ANSWER MY QUESTIONS ABOUT THIS STUDY? 
You can talk to the study doctor about any questions or concerns you have about 
this study or to report side effects or injuries. Contact the study doctor 
__________________ (insert name of study doctor[s]) at __________________ 
(insert telephone number). 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group 
of people who review the research to protect your rights) at __________________ 
[telephone number].  
MY SIGNATURE AGREEING TO TAKE PART IN THE MAIN STUDY 
I have read this consent form or had it read to me. I have discussed it with the study 
doctor and my questions have been answered. I will be given a signed copy of this 
form. I agree to take part in the main study and any additional studies where I circled 
‘yes’.  
 
Participant’s signature ________________________________ 
 
Date of signature _____________________________________ 
 
Signature of person(s) conducting the informed consent discussion 
___________________ 
 
Date of signature _____________________________________ 

Prot_SAP_002.pdf: 
E2212 
 
1 
A Randomized, Double-Blinded, Placebo-Controlled 
Phase II Study of Adjuvant Everolimus Following the 
Resection of Metastatic Pancreatic Neuroendocrine 
Tumors to the Liver 
STUDY CHAIR: 
Steven K. Libutti, M.D.  
STUDY CO-CHAIR: 
Pamela L. Kunz, M.D. 
STUDY STATISTICIAN: 
Paul Catalano, Sc.D. 
PATHOLOGY CO-CHAIR: 
Guang-Yu Yang, M.D., Ph.D. 
SURGICAL CO-CHAIR: 
Steven K. Libutti, M.D.  
LABORATORY STUDIES CO-CHAIR: 
Steven K. Libutti, M.D. 
Luis A. Diaz, M.D. 
GASTROINTESTINAL COMMITTEE CO-CHAIRS: 
Peter O’Dwyer, M.D. 
Terence Z. Wong, M.D., Ph.D. 
 
 
Version Date:  April 21, 2014 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
United States Only 
 
 
January 17, 2014 
ALLIANCE / Alliance for Clinical Trials in Oncology 
NRG / NRG Oncology Foundation, Inc 
SWOG / SWOG 
 
 
 
 
PRE-ACTIVATION DATE 
NOTE: This study is supported by the NCI Cancer 
Trials Support Unit (CTSU). Institutions not 
aligned with ECOG-ACRIN will participate 
through the CTSU mechanism. 
 
December 23, 2013 
 
Addendum #1 –3/14 
Addendum #2 – 5/14 
 
 
Addendum #3 – 5/14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agents 
IND# 
NSC# 
Supply 
IND Sponsor 
Everolimus/Placebo 
N/A 
NSC 733504 
Novartis 
IND Exempt 
Rev. 5/14 


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Table of Contents 
Schema ...................................................................................................................... 5 
1. Introduction ........................................................................................................ 6 
1.1 Trial Design ................................................................................................ 6 
1.2 Background For Potential Laboratory Research Studies ........................... 7 
2. Objectives ........................................................................................................... 9 
2.1 Primary objective: ..................................................................................... 9 
2.2 Secondary objectives: ............................................................................... 9 
3. Selection of Patients ......................................................................................... 10 
3.1 Eligibility: Criteria .................................................................................... 10 
4. Randomization Procedures ............................................................................... 15 
4.1 Randomization ........................................................................................ 17 
4.2 Eligibility Verification .............................................................................. 17 
4.3 Stratification Factors ............................................................................... 17 
4.4 Additional Requirements ........................................................................ 18 
4.5 Investigator’s Drug Brochure and Safety Alerts ...................................... 18 
4.6 IND Status ................................................................................................ 19 
4.7 Emergency Unblinding ............................................................................ 19 
4.8 Instructions for Patients Who Do Not Start Assigned Protocol Treatment19 
5. Treatment Plan ................................................................................................. 20 
5.1 Administration Schedule ......................................................................... 20 
5.2 Adverse Event Reporting Requirements ................................................. 20 
5.3 Dose Modifications ................................................................................. 27 
5.4 Supportive Care ....................................................................................... 34 
5.5 Duration of Therapy ................................................................................ 35 
5.6 Duration of Follow-up ............................................................................. 35 
6. Measurement of Effect ..................................................................................... 36 
6.1 Local, Regional Disease ........................................................................... 36 
6.2 Distant Disease ........................................................................................ 36 
6.3 Disease-Free Survival .............................................................................. 36 
6.4 Survival .................................................................................................... 36 
6.5 Second primary cancer............................................................................ 36 
7. Study Parameters .............................................................................................. 37 
8. Drug Formulation and Procurement ................................................................. 39 
8.1 Everolimus/Placebo ................................................................................ 39 
9. Statistical Considerations .................................................................................. 48 
9.1 Endpoints ................................................................................................ 48 
9.2 Sample size with power justification ...................................................... 48 
9.3 Analysis plan including plans for formal interim analysis ....................... 48 
9.4 Safety Monitoring ................................................................................... 49 
9.5 Study Monitoring .................................................................................... 49 


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9.6 Gender and Ethnicity .............................................................................. 50 
10. Specimen Submissions ...................................................................................... 51 
10.1 Submissions to the (PCORL) - MANDATORY ........................................... 51 
10.2 ECOG-ACRIN Sample Tracking System .................................................... 54 
10.3 Use of Specimens in Research ................................................................ 55 
10.4 Sample Inventory Submission Guidelines ............................................... 55 
11. Laboratory Research Studies ............................................................................ 56 
11.1 Diagnostic Review and Classification (MANDATORY) ............................. 56 
11.2 Research Studies ..................................................................................... 56 
11.3 Lab Data Transfer Guidelines .................................................................. 57 
12. Electronic Data Capture .................................................................................... 58 
12.1 Records Retention ................................................................................... 58 
13. Patient Consent and Peer Judgment ................................................................ 59 
14. References ........................................................................................................ 59 
Appendix I  Pathology Submission Guidelines ........................................................ 61 
Appendix II  Patient Thank You Letter ..................................................................... 65 
Appendix III  Patient Tablet Calendar ...................................................................... 66 
Appendix IV  ECOG Performance Status.................................................................. 68 
Appendix V  Drugs Which May Affect Everolimus Metabolism .............................. 69 
Appendix VI  Instructions for Reporting Pregnancies on a Clinical Trial ................. 70 
Appendix VII  E2212 Drug Request Form ................................................................ 72 
Appendix VIII  Hepatitis Screening .......................................................................... 73 
 


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STUDY CHAIR 
STUDY CO-CHAIR 
Steven K. Libutti, M.D. 
Montefiore Medical 
3400 Bainbridge Avenue 
Map Building, Fourth Floor 
Bronx, NY 10467 
Phone: 718-920-4231 
Fax: 718-798-0309 
Email: slibutti@montefiore.org  
 
Pamela L. Kunz, M.D. 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305-5826 
Phone: 650-725-8738 
Fax: 650-498-4696 
Email: pkunz@stanford.edu 
 
STUDY CHAIR LIAISON (SCL) 
Monique White 
Montefiore Medical 
3400 Bainbridge Avenue 
Map Building, Fourth Floor 
Bronx, NY 10467 
Phone: 718-862-8840 
Fax: 718-862-8854 
Email: mnwhite@montefiore.org  
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Data collection will be performed 
exclusively in Medidata Rave: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Please refer to the patient 
enrollment section for 
instructions on using the 
OPEN system. 
Please refer to the Forms 
Completion Guidelines for the Forms 
Submission Schedule.  
The study protocol and all related forms and documents must be downloaded from the protocol-
specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Sites must use the 
current form version and adhere to the instructions and submission schedule outlined in the protocol. 
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, 
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
For patient eligibility or treatment-related questions Contact the Study PI of the Coordinating Group. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU 
Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org 
The CTSU Web site is located at   https://www.ctsu.org 
 
Rev. 5/14 


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Schema 
 
Accrual Goal: 150 patients
Cycle = 4 week (28 days)
R
A
N
D
O
M
I
Z 
E
Stratification
• R0 versus R1 resection
• Primary tumor resection with 
metastasectomy versus primary 
tumor resection prior to 
metastasectomy 
• RF or microwave ablation plus 
resection versus resection alone
Everolimus 10 mg
PO daily
Placebo 10 mg 
PO daily
Long-term Follow-up
Arm A1
Arm B1
1. Treatment will continue for up to 12 cycles (approximately 1 year).
Long-term Follow-up
 
 


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1. 
Introduction 
Pancreatic neuroendocrine tumors (PNETs) have a spectrum of behavior from indolent 
to quite aggressive with the liver being the most common site of metastases. Patients 
with metastatic disease have a median survival of 24 months (1-3). To date, medical 
treatment options have been limited and include: chemotherapy-based streptozocin and 
doxorubicin, which has debated efficacy; sunitinib, a tyrosine-kinase inhibitor that 
appears to have antitumor activity (4-7). More recently, studies of the mammalian target 
of rapamycin (mTOR), a serine-threonine kinase, demonstrates its role in tumor growth 
(8).  Everolimus, an oral inhibitor of mTOR, appears to confer a statistically significant 6-
month prolongation in median disease free survival over placebo in patients with 
advanced PNETs (4.6 vs. 11.0 months) with a reasonable side effect profile (9). 
Despite advances in the medical treatment options for advanced PNETs, only 
cytoreductive strategies, by way of hepatic resection or ablation, have been shown to 
significantly improve overall survival or to provide an opportunity for cure (10-12).  While 
the majority of patients recur (94% by 5 years), and while it is difficult to obtain an R0 
resection, the morbidity and mortality rates are acceptably low, and surgical resection of 
liver metastases seems to increase median survival to 125 months (1, 10), more if the 
patients undergo further hepatectomy following recurrence. For patients undergoing an 
R0 or R1 resection of liver metastases from a PNET, the median recurrence free survival 
is 15 months in the largest series and comparable in others (1, 13, 14). Given this 
knowledge of the survival benefit from surgical metastasectomy and the antiproliferative 
effect of everolimus, we propose to study a combined medical and surgical approach, to 
evaluate this combined strategy on both recurrence free survival and overall survival.   
Additionally, there is precedent for using targeted agents in the adjuvant setting – 
specifically imatinib following resection of gastrointestinal stromal tumors (GISTs), which 
improves recurrence free survival (15, 16). GISTs harbor mutations in the KIT proto-
oncogene (85%) and platelet-derived growth factor alpha receptor (3-5%). Imatinib 
specifically targets these pathways involved in GIST carcinogenesis including KIT, 
PDGFR A, and other ABL and BCR-ABL tyrosine kinases. Everolimus likewise targets a 
relevant pathway in NET carcinogenesis as PNETs are known to have mutations in 
mTOR (17).  The concept of adjuvant therapy following surgical metastasectomy as a 
means of improving time to recurrence has also been validated in the treatment of stage 
IV colorectal cancer (18). 
 
Trial Design 
The trial design would be a prospective, randomized placebo controlled study of 
adjuvant everolimus (orally at 10 mg per day) versus placebo after surgical 
resection (with or without ablation) of liver metastases from a PNET to an R0 or 
R1 resection. Patients will be randomized after surgery. Patients will receive 
study drug (ARM A) or placebo (ARM B) for approximately 12 months following 
resection or until recurrence whichever comes first. The current standard of care 
following resection is no treatment; therefore, placebo is an acceptable control 
arm in this patient population. The primary endpoint will be recurrence free 
survival with overall survival as a secondary endpoint. Given that everolimus in 
patients with advanced PNET improves progression free survival from 4.6 to 11.0 
months as seen in the RADIANT-3 study (a > 50% improvement), we would 
predict that the addition of everolimus to surgical metastasectomy would improve 
disease free survival from 15 to 27 months (conservatively < 50% improvement). 


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A prospective randomized double-blinded study is necessary in order to assess 
impact on disease free survival.  
 
Background For Potential Laboratory Research Studies 
Genes are frequently mutated in pancreatic neuroendocrine tumors.  
Genes 
Frequency Mutated (n=68) 
MEN1 
44% (30) 
DAXX 
25% (17) 
ATRX 
18% (12) 
PTEN 
7% (2) 
TSC2 
9% (6) 
PIK3CA 
1% (1) 
The mutations in the PTEN/PIK3CA/MROT pathway suggests that tumors with 
activating mutations in this pathway may be preferentially sensitive to treatment 
with mTOR inhibitors, these patients with tumors that are mutant for PIK3CA, 
PTEN or TSC may benefit in terms of DFS and OS. Further characterization of 
the tumors by exploring genes such as MEN1, DAXX, ATRX and mutations in 
chromatin remodeling may give insight to patient outcome. Mutations in 
chromatic remodeling have been demonstrated to confer a survival benefit in 
patients with metastatic neuroendocrine tumors (mOS of 5 years vs. 13 years; 
HR 0.14; p=0.02). 
Small fragments of DNA (165 bp) are released by tumors into the circulation and 
can be distinguished from DNA fragments released by normal cells using the 
mutations found in the tumor. Circulating tumor DNA (ctDNA) is only detectable 
when there is tumor present and quickly disappears from the circulation (half-life 
~ 2 hours) after tumor resection. A recent study by our laboratory, applied a 
digital genomic method to detect and quantify ctDNA in patients with colorectal 
cancer (21). This approach termed “BEAMing”, which was named after 
components of this method (Beads, Emulsification, Amplification and Magnetics). 
This method uses standard laboratory tools and reagents to create a water-in-oil 
emulsion wherein each aqueous microdroplet houses an individual fragment of 
DNA bound to a bead. This setting allows billions of compartmentalized 
polymerase chain reactions (PCR) to be performed in parallel in a single test 
tube. The products of these reactions coat each bead with thousands of copies of 
DNA fragments that are identical to the single DNA molecule originally present. 
In this case, the result is millions of beads coated entirely with either mutant or 
wild-type DNA. To distinguish mutant from wild-type coated beads, allele-specific 
fluorescent probes complementary to the known wild-type or mutant sequences 
are simultaneously added to the beads for hybridization. The beads are then 
accessed via flow cytometry to detect rare mutant DNA molecules among a 
much larger number of normal DNA molecules. BEAMing is a digital assay and is 
able to count the frequency of individual DNA fragments in a sample.  
In a cohort of patients with colorectal cancer, tumor response and progression 
was tracked in patients using ctDNA as a biomarker of tumor burden. For each 
patient, the mutation profile for his or her tumor was identified from 
microdissected paraffin embedded tissue.  BEAMing assay was used to quantify 


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ctDNA over time in each patient undergoing multi-modality treatment for 
colorectal cancer over the course of 1-2 years. The results from this study 
demonstrated that ctDNA could be used a biomarker of tumor burden and that 
dynamic changes in ctDNA levels correlated with tumor response and 
progression (Figure, below). Of note, ctDNA was detected in 100% of patients 
evaluated. In addition, ctDNA was significantly more sensitive than the standard 
protein biomarker used in colorectal cancer monitoring (CEA – Carcinoembryonic 
Antigen). One of the most promising aspects of this study was showing that 
ctDNA was sufficiently sensitive to detect minimal residual disease after surgical 
resection with curative-intent (Figures, below), thereby detecting micrometastatic 
disease and recurrence before it was evident with traditional protein biomarkers 
or imaging.  
 
 


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2. 
Objectives 
 
Primary objective:  
2.1.1 
To evaluate if the addition of adjuvant everolimus to the R0 or R1 
surgical resection of pancreatic neuroendocrine tumor metastases to 
the liver will result in an improvement in disease free survival. 
 
Secondary objectives: 
2.2.1 
To evaluate if the addition of adjuvant everolimus to the R0 or R1 
surgical resection of pancreatic neuroendocrine tumor metastases to 
the liver will result in an improvement in overall survival. 
2.2.2 
To evaluate the toxicity associated with adjuvant everolimus following 
resection in patients with metastatic pancreatic neuroendocrine 
tumors to the liver. 


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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
 
Eligibility: Criteria 
3.1.1 
Patients must have histologically or pathologically confirmed 
metastatic low or intermediate grade pancreatic neuroendocrine 
tumor(s) to the liver as per the Klimstra guidelines (20). 
3.1.2 
Patients must have recovered from an R0 or R1 resection of all 
disease (including resection of a primary PNET if present). Patients 
may have had resection plus microwave or radiofrequency ablation, 
provided that no ablated lesion was ≥ 5 cm prior to ablation. 
3.1.3 
Patients must be within 4 to 8 weeks from the completion of surgery at 
time of randomization.  
3.1.4 
Patients must have paraffin-embedded fixed metastatic tumor tissue 
available for submission for central review per Sections 10 and 11. 
Core biopsy or surgical specimens required. 
3.1.5 
 Patients must have post-operative CT or MRI to confirm no evidence 
of disease within 4 weeks prior to randomization. Patients must be 
able to tolerate CT or MRI imaging including contrast agents as 
required for the protocol. 
3.1.6 
Patients must NOT have either clinically apparent central nervous 
system metastases or carcinomatous meningitis ≤ 6 months prior to 
randomization. 
3.1.7 
Women must NOT be pregnant or breast-feeding due to possible risk 
involved in taking everolimus. 
All females of childbearing potential must have a blood test within 2 
weeks prior to randomization to rule out pregnancy. A female of 
childbearing potential is any female, regardless of sexual orientation 
or whether they have undergone tubal ligation, who meets the 
following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy or 2) has not been naturally postmenopausal for at 
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least 24 consecutive months (i.e. has had menses at any time in the 
preceding 24 consecutive months). 
Female? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.8 
Women of child-bearing potential and sexually active males must be 
strongly advised to use an accepted and highly effective method of 
contraception or abstain from sexual intercourse for the duration of 
their treatment through 8 weeks after their last dose of protocol 
therapy. Women of child-bearing potential, sexually active males, and 
the female partners of male participants should be advised of the risk 
or becoming pregnant or fathering a child while receiving protocol 
treatment. Should a woman become pregnant while participating in 
this study, she should inform her treating physician immediately. If a 
man impregnates a woman while participating in this study, he should 
inform his treating physician immediately. See Section 8.1.14 for 
information on methods of contraception. 
3.1.9 
Prior treatment with sunitinib and/or cytotoxic chemotherapy are 
allowed provided last dose was > 30 days prior to randomization. 
3.1.10 
Prior chemoembolization is allowed provided last dose was > 30 days 
prior to randomization. 
3.1.11 
Patients must NOT have received prior everolimus.  
3.1.12 
Patients may not be receiving any other investigational agents while 
on study treatment. Prior treatment with other investigational agent is 
allowed provided last dose was > 30 day prior to randomization. 
3.1.13 
Patients must have normal organ and marrow function as defined 
below within ≤ 4 weeks prior to randomization: 
3.1.13.1 
Total bilirubin ≤ 1.5 X institutional upper limit of normal 
(ULN)  
ULN: _________ Bilirubin:_________ Date:________ 
3.1.13.2 
AST(SGOT)/ALT(SGPT) ≤ 5 X institutional ULN  
ULN: _________ AST_________ Date:________ 
ULN: _________ ALT_________ Date:________ 
3.1.13.3 
Serum creatinine ≤ 1.5 X institutional ULN or creatinine 
clearance ≥ 60 mL/min for patients with creatinine levels 
above 1.5 X institutional normal. 
ULN: _________ Creatinine: ________ Date:________ 
Creatinine clearance: ________ Date:________ 
3.1.13.4 
Fasting serum total cholesterol ≤ 300 mg/dL OR ≤ 7.75 
mmol/L AND fasting triglycerides ≤ 2.5x ULN.  
NOTE: 
If one or both of these thresholds are exceeded, 
the patient can only be randomized after 
initiation of appropriate lipid lowering 
medication 
_____
_____


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Fasting serum cholesterol: ________ Date:________ 
Fasting triglycerides: ________ Date:________ 
Lipid lowering medication: ______ (Yes or No) 
3.1.13.5 
 Absolute neutrophil count ≥ 1,500/mm3 
Neutrophil count: _______ Date:________ 
3.1.13.6 
Leukocytes ≥ 3,000/mm3 
Leukocytes: _______ Date:________ 
3.1.13.7 
 Platelets ≥ 100,000/mm3 
Platelets: _________ Date:________ 
3.1.13.8 
Hemoglobin ≥ 9 g/dL 
Hemoglobin: _________ Date: ________ 
3.1.14 
Patients must NOT have ongoing cardiac dysrhythmia of NCI CTCAE 
v4.0 Grade ≥ 2, uncontrolled atrial fibrillation of any grade, or QTc 
interval > 470 msec. 
3.1.15 
Patients with a history of the following within ≤ 12 months of 
randomization are not eligible. 
• 
Arterial thromboembolic events: Yes____ Date:______ No:_____ 
• 
Unstable angina: Yes_____ Date:_____ No:_____ 
• 
Myocardial Infarction: Yes_____ Date:______ No:______ 
3.1.16 
Patients must NOT have experienced thrombotic events (deep vein 
thrombosis, pulmonary embolism) ≤ 3 months prior to randomization.  
3.1.17 
Patients must NOT have liver disease such as cirrhosis, chronic 
active hepatitis, or chronic persistent hepatitis at randomization. 
Patients at increased risk for hepatitis B or hepatitis C per Appendix 
VIII must be screened for hepatitis prior to randomization. 
3.1.18 
Patients must NOT have history of severely impaired pulmonary 
function for their age due to the risk of noninfectious pneumonitis. 
Patients with known history of abnormal pulmonary function must 
have documentation of DLCO of  > 50% predicted and SaO2 of > 87% 
at rest on room air ≤ 4 weeks prior to randomization. 
3.1.19 
Patients with unexplained pulmonary infiltrates must have pulmonary 
function tests within the institutional limits of normal ≤ 4 weeks prior to 
randomization. 
3.1.20 
Patients with known history of HIV seropositivity are ineligible due to 
lack of safety data on combining antiretroviral therapy, the 
immunosuppressive effects of everolimus and the risk of opportunistic 
infection.  
3.1.21 
Patients with poorly controlled diabetes mellitus as defined by HbA1c 
> 8% despite adequate therapy are ineligible. Patients with a known 
history of impaired fasting glucose or diabetes mellitus must have 
blood glucose and antidiabetic treatment monitored closely throughout 
the trial and adjusted as necessary. 
_____
_____


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3.1.22 
Patients must NOT have any severe and/or uncontrolled medical 
conditions such as: 
a. unstable angina pectoris, symptomatic congestive heart failure, 
myocardial infarction ≤ 6 months prior to randomization, serious 
uncontrolled cardiac arrhythmia, or any other clinically significant 
cardiac disease 
b. Symptomatic congestive heart failure of New York Heart 
Association Class III or IV 
c. active (acute or chronic) or uncontrolled severe infection, liver 
disease such as cirrhosis, decompensated liver disease, and 
chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive 
HbsAg, quantifiable HCV-RNA) 
d. active, bleeding diathesis 
3.1.23 
Patients must NOT have previous or concurrent malignancy. 
Exceptions are made for patients who meet any of the following 
conditions: 
• 
Non-melanoma skin cancer, in situ cervical cancer, breast cancer 
in situ, or superficial bladder cancer (noninvasive papillary 
carcinoma or carcinoma in situ). 
OR 
• 
Prior malignancy completely excised or removed and patient has 
been continuously disease free for > 5 years. 
Date of last evidence of disease: ___________ 
3.1.24 
Patients may not be receiving any other investigational agents while 
on study treatment. Prior treatment with other investigational agent is 
allowed provided last dose was ≥ 30 days prior to randomization.  
3.1.25 
Patients must NOT have received live attenuated vaccines ≤ 1 week 
prior to randomization. Patients should also be advised not to receive 
live attenuated vaccines during the study and to 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. 
3.1.26 
Patients must NOT be on chronic treatment with corticosteroids or 
other immunosuppressive agents. Topical or inhaled corticosteroids 
are allowed. 
3.1.27 
Patients should be advised to avoid drugs or foods that are known 
potent CYP3A4 inhibitors or inducers, included but not limited to those 
outlined in Appendix V. 
3.1.28 
Patients must NOT have history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to everolimus. 
3.1.29 
Patients must NOT have known intolerance or hypersensitivity to 
everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus). 
_____
_____
_____
_____
_____


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3.1.30 
Patients must NOT have absorption issues that would limit the ability 
to absorb everolimus.  
3.1.31 
Patients must NOT have a history of non-compliance to medical 
regimens or who are considered potentially unreliable or will not be 
able to complete the entire study.  
3.1.32 
Patients must be at least ≥ 18 years of age. 
3.1.33 
Patients must have ECOG performance status ≤ 1. (Refer to 
Appendix IV) 
3.1.34 
Patients must have life expectancy ≥ 12 weeks. 
 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to use 
the eligibility checklist as source documentation. 
 
_____
_____


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4. 
Randomization Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group. Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet (FDA Form 1572 with original 
signature, current CV, Supplemental Investigator Data Form with signature, and 
Financial Disclosure Form with original signature) to the Pharmaceutical Management 
Branch, CTEP, DCTD, NCI. These forms are available on the CTSU Web site (enter 
credentials at https://www.ctsu.org; then click on the Register tab) or by calling the PMB 
at 240-276-6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org. 
Requirements for E2212 site registration: 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
Submitting Regulatory Documents 
Before an ECOG-ACRIN Institution may enter patients, protocol specific regulatory 
documents must be submitted to the CTSU Regulatory Office at the following address:   
 
CTSU Regulatory Office 
 
Coalition of National Cancer Cooperative Groups 
 
1818 Market Street, Suite 1100 
 
Philadelphia, PA 19103 
 
FAX: (215) 569-0206 
Required Protocol Specific Regulatory Documents 
1. CTSU Regulatory Transmittal Form. 
2. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
3. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter. 
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NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
The CTSU encourages you to link to the following RSS2.0 webpage so that more 
information on RSS2.0 as well as the submission forms can be accessed. Log in to 
http://www.ctsu.org and click on the Regulatory tab to access the RSS web page. If you 
have questions regarding regulatory document submission, please telephone the CTSU 
Help Desk at 1-888-823-5923 or E-mail CTSUContact@westat.com.   
Patients must not start protocol treatment prior to randomization. 
Treatment must start within five working days after randomization. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to this study.  
OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool 
to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
Access requirements for OPEN:  
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for the CTSU 
members' web site.  
• 
To perform registrations, the site user must have been assigned the 'Registrar' role 
on the relevant Group or CTSU roster.  
• 
To perform registrations on protocols for which you are a member of the Lead Group, 
you must have an equivalent 'Registrar' role on the Lead Group roster. Role 
assignments are handled through the Groups in which you are a member. 
• 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead 
Group registrations) you must have the role of Registrar on the CTSU roster. Site 
and/or Data Administrators can manage CTSU roster roles via the new Site Roles 
maintenance feature under RSS on the CTSU members' web site. This will allow 
them to assign staff the "Registrar" role. 
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NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
Randomization  
Please note that no blinded starter supplies will be available for this study. At the 
time of patient randomization each patient will be assigned a specific blinded 
drug ID number (e.g. DR117). This blinded drug ID number should be included 
on the drug request form that is submitted to the ECOG-ACRIN Drug Team. (See 
Section 8 for complete details.) 
Please note that when a patient has been successfully randomized, the 
confirmation of randomization will indicate that the patient is on arm X. The 
patient will actually be randomized to arm A or B, but as this is a double-
blind trial, that information cannot be displayed. 
At time of randomization, the following information will be requested:  
4.1.1 
Protocol Number 
4.1.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
4.1.3 
Patient Identification 
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
 
Stratification Factors 
Stratification will only be used to ensure balance between groups, not for subset 
analysis. There are three stratification factors as follows: 
4.3.1 
R0 versus R1 resection 
4.3.2 
Primary tumor resection  
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4.3.2.1 
Primary tumor resection with metastasectomy 
4.3.2.2 
Primary tumor resection prior to metastasectomy 
4.3.3 
Resection ± ablation 
4.3.3.1 
RF or microwave ablation plus resection 
4.3.3.2 
Resection alone 
 
Additional Requirements  
4.4.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston.  
4.4.2 
Pathological samples are required to be submitted for central 
diagnostic review as indicated in Section 10.  
4.4.3 
Biological samples to be submitted for research as outlined in Section 
10. 
4.4.4 
Data collection for this study will be done exclusively through 
Medidata Rave. Access to the trial in Rave is granted through the 
iMedidata application to all persons with the appropriate roles in RSS. 
To access iMedidata/Rave the site user must have an active CTEP 
IAM account (https://eapps-ctep.nci.nih.gov/iam). In addition, site 
users that are a member of ECOG-ACRIN must have the mapped 
ECOG-ACRIN roles or explicit Rave roles (Rave CRA, Read-Only, 
Site Investigator) in RSS at the enrolling site. Site users that are not 
members of ECOG-ACRIN must have the Rave roles on the CTSU 
roster at the enrolling sites. The Site Administrator or Data 
Administrator at the enrolling site may assign the appropriate roles 
from the Site Roles tab on the CTSU website. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be listed in the upper right pane of the iMedidata screen. 
Users that have not previously activated their iMedidata/Rave 
accounts will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on 
the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on the CTSU 
website under the Rave tab at http://www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.5 
Investigator’s Drug Brochure and Safety Alerts 


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The Investigator Drug Brochure (IDB) for everolimus is available for download 
from the ECOG-ACRIN webpage. The IDB provides relevant and current 
scientific information about the investigational product. The IDB should be 
submitted to your IRB/EC according to GCP regulations. The IDB and any 
correspondence to the Institutional Review Board (IRB)/Ethics Committee (EC) 
should be kept in the E2212 regulatory files.  
Should any SAE report on this study qualify as a safety alert report requiring 
expedited reporting, the SAE report will be sent by the respective pharmaceutical 
company to regulatory authorities globally (including the FDA) and ECOG-
ACRIN. If applicable, ECOG-ACRIN will disseminate these safety alert reports to 
all ECOG-ACRIN investigators in the bimonthly group mailings. These reports 
should be forwarded to your IRB/EC within 90 days of receipt for review. 
Reporting instructions are provided with each safety alert. These safety alerts 
and any correspondence to your IRB/EC should be maintained in your E2212 
study files. 
 
IND Status  
When used in this protocol. Everolimus/placebo are each classified as an 
“unapproved use of an approved agent” and by definition considered 
investigational agents. However, while it is not an indication currently approved 
by the FDA, the use of everolimus/placebo in this protocol is exempt from the 
requirements of an IND and described under Title 21 CFR 312.2(b). 
 
Emergency Unblinding 
The information provided below is for the use by a physician, nurse, CRA 
or pharmacist treating the patient. These contact numbers should not be 
used by patients. Patients should be instructed to call their doctor’s office 
in the event of an emergency or adverse event that may result in the need 
to unblind the patient. 
In the event of an emergency or severe adverse reaction necessitating 
identification of the medication for the welfare of the patient, please contact the 
Study Chair, Dr. Steven Libutti M.D., at 718-920-4231 or Email 
slibutti@montefiore.org, first to ensure the reason for unblinding is valid. Then 
call a member of the ECOG-ACRIN Operations Office – Boston drug team at 
(617) 632-3610 Monday through Friday between 9:00 AM and 5:00 PM Eastern 
Time. For unblinding outside of these hours, contact AnswerConnect at 1-866-
296-8940. This service will request the reason for unblinding and then page the 
on-call ECOG-ACRIN staff who will return your call and provide the unblinded 
treatment assignment if applicable. Remember, AnswerConnect should only be 
contacted outside of normal business hours and only in the event of an 
emergency. The ECOG-ACRIN Operations Office – Boston or AnswerConnect 
will require the protocol number (i.e., “E2212”), the patient ID number (e.g., 
“44444”), and the patient initials (e.g., “FL”) to unblind the patient.  Note that if a 
patient is unblinded, he/she must discontinue protocol treatment. 
 
Instructions for Patients Who Do Not Start Assigned Protocol Treatment 
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the E2212 Forms Completion Guidelines. 


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5. 
Treatment Plan 
 
Administration Schedule 
One cycle = 28 days. 
NOTE: 
Everolimus/placbo is packaged in blister cards of ten 5 mg tablets; 
patients should receive 6 blister cards (30 doses) for each 28 day 
cycle. The start of each treatment cycle may be scheduled up to 2 
days later than the expected Day 1 of that cycle. 
Patients should take everolimus/placebo, 10 mg, orally once daily at the same 
time every day, either consistently with food or consistently without food.  
A missed dose may still be taken up to 6 hours after the normally scheduled time. 
If more than 6 hours have elapsed, patient should be instructed to skip the dose 
for that day. The next day, they should take everolimus/placebo at the usual time. 
Patients should not take 2 doses to make up for the one that they missed. 
If vomiting occurs, no attempt should be made to replace the vomited dose. 
Everolimus/placebo tablets should not be crushed or chewed. Tablets should be 
swallowed whole with a glass of water. For patients unable to swallow tablets, 
everolimus/placebo tablets should be dispersed completely in a glass of water 
(containing approximately 30 mL) by gently stirring, immediately prior to drinking. 
The glass should be rinsed with the same volume of water and the rinse should 
be completely swallowed to ensure that the entire dose is administered. 
5.1.1 
Treatment/ARM A 
Everolimus 10 mg PO daily 
Repeat cycles every 28 days for a maximum duration of 12 cycles. 
5.1.2 
Treatment/ARM B 
Placebo PO daily 
Repeat cycles every 28 days for a maximum duration of 12 cycles. 
 
Adverse Event Reporting Requirements 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
• 
Routine reporting:  Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave.   
• 
Expedited reporting:  In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
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5.2.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution:  An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
• 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred.   
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 


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CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to 
• 
the AE Team at ECOG-ACRIN (617-632-3610)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours.  
NCI Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both  
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade  
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
• 
when the adverse event occurred (within 30 days of the last 
administration of everolimus/placebo vs. ≥ 30 days after the last 
administration of everolimus/placebo) 
• 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E2212 and outline 
the specific expedited adverse event reporting requirements for 
study E2212. 


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5.2.5 
Steps to determine if an adverse event is to be reported in an 
expedited manner 
5.2.5.1 
Guidelines for adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the 
last administration of the everolimus/placebo. 
 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the 
table below in Section 5.2.6. 
Yes 
No 
Identify the type and 
grade of the event 
using CTCAE v4.0. 
Determine if the patient 
was hospitalized for ≥ 
24 hours for the event. 
With this information, review 
the chart in Section 5.2.6 to 
determine if event is 
reportable via CTEP-AERS. 
Refer to Section 5.2.7 to 
determine if the event 
meets the protocol specific 
reporting requirements for 
this study. If so, report the 
event via CTEP-AERS. 
Refer to Section 5.2.7 to determine 
if the event meets the protocol 
specific reporting requirements for 
this study.  If so, report the event 
via CTEP-AERS. 
Is the event 
reportable? 
No 
Yes 
Report the event via 
CTEP-AERS. 


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5.2.5.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
everolimus/placebo. 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.5.2, AND has 
an attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 4 and 5 adverse events  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported via CTEP-AERS even if the patient 
is off study. 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
• 
Grade 3 adverse events 
5.2.6 
Expedited Reporting Requirements for Arm X (Arm A or B) on 
Protocol E2212 
Investigational Agents:  Everolimus/Placebo 
Commercial Agents:  None 
NOTE: 
Although the agents used on this protocol are IND exempt, 
the adverse event investigational reporting requirements 
will be used on this protocol. 
Late Phase 2 and Phase 3 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
of investigational agent/intervention. 
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REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
• “24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
• “10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
5.2.7 
Additional instructions, requirements and exceptions for 
protocol E2212 
Additional Instructions: 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
birth defect events via CTEP-AERS, please contact the AEMD Help 
Desk at aemd@tech-res.com or 301-897-7497. This will need to be 
discussed on a case-by-case basis. 
 
E2212 specific expedited reporting requirements: 
• 
Pregnancy 
Pregnancies and suspected pregnancies (including a positive or 
inconclusive pregnancy test regardless of age or disease state) 


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occurring while the subject is on Everolimus/Placebo, or within 
28 days of the subject’s last dose of Everolimus/Placebo, are 
considered immediately reportable events. The pregnancy, 
suspected pregnancy, or positive/inconclusive pregnancy 
test must be reported via CTEP-AERS within 24 hours of 
the Investigator’s knowledge.   
Please refer to Appendix VI for detailed instructions on how 
to the occurrence of a pregnancy as well as the outcome of 
all pregnancies. 
5.2.8 
Other recipients of adverse event reports and supplemental data 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and Novartis within 24 hours of receipt. 
A drug supporter representative may call a site for additional or 
supplemental information regarding a serious adverse event. Any 
additional written AE information requested by the drug supporter 
MUST be submitted to BOTH ECOG-ACRIN and the drug supporter. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.9 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol). Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 


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• 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or  
c.) treatment related secondary malignancy. 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even if 
ECOG-ACRIN was not the patient's most recent trial. 
NOTE: Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should be 
submitted via CTEP-AERS or by the Second Primary Form. 
 
Dose Modifications  
5.3.1 
General 
If dose reduction is required, reduction is permanent. Missed doses 
may be taken up to 6 hours after normally scheduled time. If more 
than 6 hours have elapsed, patient should be instructed to skip the 
dose for that day. The next day, they should take everolimus/placebo 
at the usual time. Patients should not take 2 doses to make up for the 
one that they missed. 
If multiple toxicities are seen, the dose administered in a subsequent 
cycle should be based on the most severe toxicity experienced in the 
current cycle.  
AEs determined to be unrelated to study treatment will not require 
dose reduction.  
If everolimus/placebo is held for > 4 weeks (28 days), patient 
must discontinue protocol treatment. 
All toxicities should be graded according to the Common 
Terminology Criteria for Adverse Events (version 4.0).  
All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov).  
5.3.2 
Everolimus/Placebo Dose Modifications  
• 
For individual subjects, dose modifications will be based on 
hematologic or non-hematologic toxicity, laboratory test results, 


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and clinical assessment on the day of treatment and during the 
previous cycle. 
• 
If dose delays are required, weekly evaluation with laboratory 
tests and clinical assessments, if applicable, should be performed 
until recovery to the specified grade or until the subject is 
discontinued from the study. 
• 
If toxicities have not resolved within ≤ 4 weeks (28 days), patient 
must discontinue protocol treatment. 
• 
The study chair or study chair liaison should be contacted for dose 
delays and modifications for all other toxicities not listed in this 
section. 
• 
One dose reduction is permitted before everolimus/placebo will be 
discontinued. Patients who require further dose reductions beyond 
the -1 dose level must be discontinued from study treatment.  
Everolimus/Placebo Dose Level Table 
Dose Level 
Dose in mg 
0 
10 mg daily 
-1 
5 mg daily 
5.3.2.1 
Management of Hematologic Toxicity 
Toxicity 
Action 
Grade 2 Platelet count decreased  
No action 
Grade 3 Platelet count decreased 
Interrupt everolimus/placebo until resolution to grade ≤ 1  
If resolution occurs ≤ 7 days, reintroduce everolimus/placebo at 
the dose level prior to interruption. 
If resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce everolimus/placebo at one dose level lower, if 
available. 
Grade 4 Platelet count decreased 
Interrupt everolimus/placebo until recovery to grade ≤ 1. Then 
reintroduce everolimus/placebo at one dose level lower, if 
available.  
Grade 3 Neutrophil count 
decreased 
Interrupt everolimus/placebo until resolution to grade ≤ 1 or 
baseline value 
If AE resolution occurs ≤ 7 days, reintroduce everolimus/placebo 
at the same dose level. 
If AE resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce everolimus/placebo at one dose level lower, if 
available. 
Grade 4 Neutrophil count 
decreased or grade 4 Anemia 
Interrupt everolimus/placebo until recovery to grade ≤ 1 or 
baseline value. Reintroduce everolimus/placebo at one dose level 
lower, if available. 
Febrile neutropenia 
Interrupt everolimus/placebo until resolution to grade ≤ 1 (or 
baseline value) and no fever. Reintroduce everolimus/placebo at 
one dose level lower, if available. 
Recurrence of grade 3 hematologic 
toxicity after dose reduction 
Reduce dose to the next lower dose level, if available. 


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Recurrence of grade 4 
hematologic toxicity (including 
febrile neutropenia) after dose 
reduction 
Discontinue protocol treatment. 
Any hematologic toxicity 
requiring everolimus/placebo 
interruption for > 28 days 
Discontinue protocol treatment. 


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5.3.2.2 
Non-Hematologic Toxicity  
Toxicity 
Action 
AST or ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain current dose level 
AST or ALT elevation 
Grade 3 (> 5.0 - 20.0 ULN) 
Interrupt everolimus/placebo administration until resolution to ≤ 
grade 1 (or ≤ grade 2 if baseline values were within the range of 
grade 2). If resolution occurs ≤ 7 days, everolimus/placebo should 
be re-started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, hold 
everolimus/placebo until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce everolimus/placebo at one dose level lower, 
if available. 
AST or ALT elevation 
Grade 4 (> 20 x ULN) 
Interrupt everolimus/placebo administration until resolution to ≤ 
grade 1 (or ≤ grade 2 if baseline values were within the range of 
grade 2). If resolution occurs ≤ 7 days, everolimus/placebo should 
be re-started at one dose level lower. If resolution takes > 7 days, 
discontinue everolimus/placebo. 
Intolerable grade 3 AE, except 
hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia 
Interrupt everolimus/placebo administration until resolution to ≤ 
grade 1 or baseline grade / value. 
If resolution occurs within ≤ 7 days, everolimus/placebo should be 
re-started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, hold 
everolimus/placebo until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce everolimus/placebo at one dose level lower, 
if available. 
Patients will be withdrawn from the study if they fail to recover to ≤ 
grade 1 or baseline grade / value within 28 days. 
Any other grade 4 non-
hematologic 
Hold everolimus/placebo until recovery to grade ≤ 1 or baseline 
value 
Reintroduce everolimus/placebo at one dose level lower, if 
available. 
Grade 3 or 4 clinical liver failure 
(asterixis or 
encephalopathy/coma) 
Discontinue everolimus/placebo 
Recurrence of intolerable grade 
2 mucositis or grade 3 event 
after dose reduction 
Reduce dose to the next lower dose level, if available. 
Recurrence of grade 4 non-
hematologic toxicity after 
dose reduction 
Discontinue protocol treatment. 
Any non-hematologic toxicity 
requiring Everolimus/Placebo 
interruption for > 28 days 
Discontinue protocol treatment. 
 


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5.3.2.2.1 
Mucositis1 
Category 
Grade 
Everolimus/placebo dose 
modification 
Mucositis oral 
Grades 1 
No dose modification. 
Grades 2-4 
Hold until ≤ grade 1 then 
reduce by one dose level. 
1 
Please refer to Section 5.4.2 for mucositis and stomatitis 
supportive care information. 
5.3.2.2.2 
Stomatitis1 
Adverse Drug Reaction 
Severity 
Everolimus/Placebo Dose Adjustment and 
Management Recommendations 
Stomatitis 
Grade 1 
No dose adjustment required. 
Grade 2 
Hold until grade ≤1. 
Re-initiate everolimus/placebo at same dose. 
If stomatitis recurs at grade 2, hold until ≤ grade 1 then 
reduce by one dose level. 
Grade 3 
Hold until ≤ grade 1 then reduce by one dose level. 
Grade 4 
Discontinue protocol therapy and treat with appropriate 
medical therapy. 
1. Please refer to Section 5.4.2 for mucositis and stomatitis supportive care information. 
5.3.2.2.3 
Diarrhea 
Appearance of grade 1-2 diarrhea attributed 
to study drug toxicity may be treated with 
supportive care such as loperamide, 
initiated at the earliest onset (for example 4 
mg orally followed by 2 mg orally every 2 
hours until resolution of diarrhea). 
5.3.2.2.4 
Metabolic Events: Hyperlipidemia and 
Hyperglycemia 
Hyperglycemia has been reported in clinical 
trials. Monitoring of fasting serum glucose is 
recommended prior to the start of 
everolimus/placebo and periodically 
thereafter. Optimal glycemic control should 
be achieved before starting a patient on 
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Category 
Grade 
Everolimus/Placebo Dose Adjustment and 
Management Recommendations 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia) 
Grade 1 
No dose adjustment required. 
Initiate appropriate medical therapy and monitor. 
Grade 2 
No dose adjustment required. 
Manage with appropriate medical therapy and 
monitor. 
Grade 3 
Hold until ≤ grade 1 then reduce by one dose level. 
Manage with appropriate medical therapy and 
monitor. 
Grade 4 
Discontinue protocol therapy and treat with 
appropriate medical therapy. 
5.3.2.2.5 
Pulmonary Toxicity 
Category 
Grade 
Everolimus/placebo dose modification 
Vital 
Capacity 
Abnormal 
Grades 1 
Obtain CT scan with lung windows. Continue previous dose of treatment. 
Grade 2 
Obtain CT scan with lung windows. Obtain pulmonary function testing 
including spirometry, DLCO, and room air O2 saturation at rest. Hold protocol 
treatment until toxicity improves to ≤ grade 1, then resume with one dose 
level reduction of treatment. Steroids may be used at the discretion of the 
treating physician for relief of symptoms associated with pulmonary toxicity. 
Grade 3 
Obtain CT scan with lung windows and pulmonary function testing including 
spirometry, DLCO, room air O2 saturation at rest, and bronchoscopy. Hold 
protocol treatment until recovery to ≤ grade 1, then resume treatment with 
one dose level reduction. Steroids may be used at the discretion of the 
treating physician for relief of symptoms associated with pulmonary toxicity. 
Grade 4 
Obtain CT scan with lung windows and pulmonary function testing including 
spirometry, DLCO, room air O2 saturation at rest, and bronchoscopy. 
Discontinue protocol treatment. Steroids may be used at the discretion of the 
treating physician for relief of symptoms associated with pulmonary toxicity. 
5.3.2.2.6 
Non-Infectious Pneumonitis 
Non-infectious pneumonitis is a class effect 
of rapamycin derivatives. Cases of non-
infectious pneumonitis (including interstitial 
lung disease) have also been described in 
patients taking Everolimus. Some of these 
have been severe and on rare occasions, a 
fatal outcome was observed. 
A diagnosis of non-infectious pneumonitis 
should be considered in patients presenting 
with non-specific respiratory signs and 
symptoms such as hypoxia, pleural effusion, 
cough or dyspnea, and in whom infectious, 
neoplastic and other non-medicinal causes 
have been excluded by means of 
appropriate investigations. Patients should 


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be advised to report promptly any new or 
worsening respiratory symptoms. 
Consultation with a pulmonologist is 
recommended for any case of pneumonitis 
that develops during the study. 
Worst grade 
pneumonitis 
Suggested investigations 
Management of 
pneumonitis 
Everolimus/placebo dose 
adjustment 
Grade 1 
CT scans with lung windows. 
No specific 
therapy is required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
CT scan with lung windows. 
Consider pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy 
and/or BAL. Monitoring at each 
visit until return to ≤ grade 1. 
Return to initial monitoring 
frequency if no recurrence. 
Symptomatic only. 
Consider 
corticosteroids 
and/or other 
supportive therapy 
if symptoms are 
troublesome. 
Rule out infection and consider 
interruption of 
Everolimus/placebo until 
symptoms improve to Grade ≤ 
1. 
Re-initiate Everolimus/placebo 
at one dose level lower.  
Discontinue 
Everolimus/placebo if failure to 
recover within ≤ 28 days. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing 
includes: spirometry, DLCO, 
and room air O2 saturation at 
rest. Monitoring at each visit 
until return to ≤ grade 1. Return 
to initial monitoring frequency if 
no recurrence. Bronchoscopy 
with biopsy and/or BAL is 
recommended. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Rule out infection and interrupt 
Everolimus/placebo until 
symptoms improve to Grade ≤ 
1. 
Consider re-initiating 
Everolimus/placebo at one 
dose level lower. 
Discontinue protocol therapy if 
failure to recover within ≤ 28 
days. 
Grade 4 
CT scan with lung windows and 
required pulmonary function 
testing, if possible, includes: 
spirometry, DLCO, and room air 
O2 saturation at rest. 
Monitoring at each visit until 
return to ≤ grade 1. Return to 
initial monitoring frequency if no 
recurrence. Bronchoscopy with 
biopsy and/or BAL is 
recommended if possible. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Rule out infection and 
discontinue protocol 
ttreatment. 


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5.3.2.2.7 
Infections 
Everolimus has immunosuppressive 
properties and may predispose patients to 
bacterial, fungal, viral or protozoal 
infections, including infections with 
opportunistic pathogens. Localized and 
systemic infections, including pneumonia, 
other bacterial infections, invasive fungal 
infections, such as aspergillosis or 
candidiasis and viral infections including 
reactivation of hepatitis B virus, have been 
described in patients taking Everolimus 
Some of these infections have been severe 
(e.g. leading to respiratory or hepatic failure) 
and occasionally have had a fatal outcome. 
Physicians and patients should be aware of 
the increased risk of infection with 
Everolimus/placebo. Treat pre-existing 
infections prior to starting treatment with 
Everolimus/placebo. While taking 
Everolimus/placebo, be vigilant for 
symptoms and signs of infection; if a 
diagnosis of infection is made, institute 
appropriate treatment promptly and 
consider interruption or discontinuation of 
protocol treatment. 
If a diagnosis of invasive systemic fungal 
infection is made, discontinue protocol 
treatment and treat with appropriate 
antifungal therapy. 
 
Supportive Care  
5.4.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.4.2 
Mucositis, Stomatitis, and Mouth Ulcers 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and 
those with gastrointestinal morbidity associated with mouth/dental 
infections, irritation of esophageal mucosa e.g. gastroesophageal 
reflux disease (GERD) and pre-existing stomatitis/mucositis must be 
monitored closely. Patients should be instructed to report the first 
onset of buccal mucosa irritation/reddening to their study physician 
immediately. 
Stomatitis/oral mucositis/mouth ulcers due to Everolimus/placebo 
should be treated using local supportive care. Please note that 
investigators in earlier trials have described the oral toxicities 
associated with Everolimus/placebo as mouth ulcers, rather than 
mucositis or stomatitis. If your examination reveals mouth ulcers 
rather than a more general inflammation of the mouth, please classify 


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the adverse event as such. The suggested paradigm for treatment of 
stomatitis/oral mucositis/mouth ulcers is as follows: 
1. For mild toxicity (grade 1), no dose adjustment required. Manage 
with non-alcoholic mouth wash or salt water (0.9%) mouth wash 
several times a day until resolution. 
2. 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®). 
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme 
derivatives may tend to worsen mouth ulcers.  These agents 
should be avoided. 
4. Antifungal agents should 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/placebo 
metabolism, therefore leading to higher Everolimus/placebo 
exposures. Therefore, topical antifungal agents are preferred if an 
infection is diagnosed. 
 
Duration of Therapy  
Patients will receive protocol therapy unless: 
5.5.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E2212 Forms Completion Guidelines.  
5.5.2 
Patient withdraws consent. 
5.5.3 
Patient experiences unacceptable toxicity.  
5.5.4 
Non-protocol cancer therapies are administered.  
5.5.5 
Disease recurrence per protocol criteria, development of new primary 
cancer, or death. 
5.5.6 
Patient completes 12 cycles of therapy.  
5.5.7 
Patient is unblinded.  
 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until disease recurrence, even if non-protocol 
therapy is initiated, and for survival for 5 years from the date of randomization. All 
patients must also be followed through completion of all protocol therapy.  
 


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6. 
Measurement of Effect 
 
Local, Regional Disease  
The development of a local or regional pancreatic neuroendocrine cancer. 
 
Distant Disease  
The development of a distant recurrence of pancreatic neuroendocrine cancer. 
 
Disease-Free Survival  
Date of randomization to the date of documented recurrence (a return of tumor 
imaged by CT or MRI), new invasive primary cancer, or death without recurrence 
 
Survival  
Date of randomization to date of death. 
 
Second primary cancer 
The diagnosis of a second primary cancer must be confirmed histologically 
whenever possible. 
 


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7. 
Study Parameters 
1. Prestudy CT scan or MRI must be done after surgery and ≤ 4 weeks before randomization. 
2. Prestudy CBC (with differential and platelet count) must be done ≤ 4 weeks before randomization.  
3. All required prestudy chemistries and hepatitis antibody lab panels must be performed ≤ 4 weeks randomization unless 
otherwise specified in Section 3. 
 
Prior to 
Randomization 
Day 1 of 
each cycle 
Every 3 cycles 
(every 12 weeks) 
End of 
Treatment13 
At 
recurrence8 
Follow-
up7 
History and Progress Notes 
X 
X 
 
X 
 
X 
Physical Exam 
X 
X 
 
X 
 
X 
Vital Signs 
X 
X 
 
X 
 
 
Weight/BSA 
X 
X 
 
X 
 
 
ECOG Performance Status 
X 
X 
 
X 
 
 
Adverse Event Assessment11 
 
X 
 
X 
 
X11 
CBC with Differential1 
X 
X 
 
X 
 
 
Serum Chemistry and Electrolytes2 
X 
X 
 
X 
 
 
Lipid Panel2 
X 
X 
 
 
 
 
Blood/Urine Pregnancy Test3,4 
X 
 X4 
 
X 
 
 
Hepatitis Antibody Lab Panels12 
X 
 
 
 
 
 
Patient table calendar 
 
X 
 
X 
 
 
Multiphasic CT Scan (Chest, Abdomen and Pelvis) or MRI of 
Abdomen and Pelvis with CT Scan of Chest 9 
X 
 
X 
X 
X 
X 
CgA, NSE level and hemoglobin A1c10  
X 
 
X 
X 
X 
X 
Tumor Measurement 
 
 
 
 
X 
 
Pathology and surgery reports 
X 
 
 
 
X 
 
Specimen Submissions: Specimens to be submitted within 4 weeks following randomization. See Section 10. 
 
MANDATORY: Pre-trial FFPE tumor5 
X 
 
 
 
 
 
Frozen Surgical Tumor Tissue6 
X 
 
 
 
 
 
Peripheral Blood, ACD vacutainer6 
 
Prior to start 
of treatment 
 
X 
 
 
Plasma from EDTA6 
 
 
X 
 
 
1. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be done ≤ 24 
hours prior to Cycle 1 Day 1, ≤ 72 hours prior to Day 1 of all subsequent cycles.  
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2. Serum electrolytes: Glucose, Na+, K+, bicarbonate, BUN, Cl, creatinine. Other serum chemistries: Albumin, total protein, alkaline phosphatase, 
SGOT(AST), SGPT(ALT), total bilirubin; Ca++. Lipid Panel: Serum fasting cholesterol and serum triglycerides. Serum electrolytes, chemistries, 
and lipid panel must be done ≤ 72 hours prior to each treatment cycle. 
3. Women of childbearing potential only. Serum pregnancy test must be performed ≤ 14 days prior to randomization and at the end of study 
treatment. Urine pregnancy testing should be performed prior to each treatment cycle at the physician’s discretion.  
4. Urine pregnancy testing should be performed prior to each treatment cycle at the physician’s discretion. 
5. Diagnostic metastatic tumor tissue (core biopsy or surgical specimen, liver mets, and diagnostic slides) must be submitted for central diagnostic 
review and classification and for optional laboratory research studies within 4 weeks following randomization as outlined in Section 10. Failure 
to submit the required materials may render the case unevaluable. 
6. Research samples are to be submitted from patients who consent to allow the samples to be submitted for research as outlined in Section 10. It 
is requested that the “prior to start of treatment” blood draws occur 6-8 weeks after surgery, prior to start of protocol therapy. Please indicate 
date of surgery in STS.  
7. Every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2-5 years from study entry. Once there is confirmation of 
recurrence, follow-up scans, CgA, NSE level, and hemoglobin A1c no longer have to be performed; patient must continue to be followed for 
survival. 
8. It is strongly encouraged that disease recurrence documented by scans also be confirmed by biopsy. If there is a recurrence, it is also strongly 
encouraged that patients be fully restaged, including a CT scan of the thorax and abdomen, imaging (preferably MRI, but CT is acceptable) of 
the brain. 
9. Baseline CT or MRI scans must be done after surgery and ≤ 4 weeks prior to randomization. After randomization, the CT Scan or MRI may be 
scheduled with a ± 2 week leeway. The scheduling of the last on-treatment scan may be moved up or delayed up to 6 weeks to also meet the 
end of treatment time frame. 
10. Chromogranin A (CgA), neuron-specific enolase (NSE) level and hemoglobin A1c should be performed at the same time scans are performed. 
If other tumor markers (i.e., glucagon, insulin, VIP, pancreatic polypeptide, gastrin) are obtained at baseline and found to be elevated, it is 
suggested to continue to follow those markers at the time points at which CgA, NSE and hemoglobin A1c are also being followed. 
11. Adverse events should be assessed 30 days after the last dose of study drug. 
12. Patients with increased risk or history of hepatitis only. See Appendix VIII. 
13. End of treatment assessments should be performed ≤ 14 days after going off treatment. 
 
Rev. 
5/14, 5/14 


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8. 
Drug Formulation and Procurement 
 
Everolimus/Placebo 
8.1.1 
Drug Orders 
Everolimus and matching placebo are being provided free of charge 
by Novartis and will be distributed by UVI. The 5 mg tablets of 
everolimus/placebo will be packaged in 10 tablets per blister pack. 
IND Status  
When used in this protocol, everolimus/placebo are each classified as 
an “unapproved use of an approved agent” and by definition 
considered investigational agents. However, while it is not an 
indication currently approved by the FDA, the use of 
everolimus/placebo in this protocol is exempt from the requirements of 
an IND and described under Title 21 CFR 312.2(b). 
Initial Orders: Following submission of the required regulatory 
documents and patient randomization, a supply of everolimus/placebo 
may be ordered. Institutions must electronically submit the completed 
E2212 Drug Request Form to the ECOG-ACRIN Drug Team at 
900.drugorder@jimmy.harvard.edu. The drug order form can be found 
in Appendix VI and is also available for download on the ECOG Web 
Site. If email is not available, the completed form may be faxed to 
ATTN: ECOG-ACRIN Drug Team at 617-632-2063. No blinded starter 
supplies are available for this protocol. 
Important information for drug orders: 
At the time of randomization each patient will be assigned a patient 
specific Blinded Drug ID number, example DR1117. The Blinded Drug 
ID number will appear on the patient’s Confirmation of Registration 
Form. 
The E2212 Drug Request Form must include the patient specific 
Blinded Drug ID number with each drug request in order for the drug 
order to be processed.  Failure to provide this information on the drug 
order form will result in a delay of the drug order being processed and 
shipped. 
This study is a double-blinded treatment protocol. Blinded blister 
packs of everolimus and matching placebo MAY NOT be 
transferred from one patient to another patient. 
Each shipment will contain a 3-month supply of everolimus/placebo. 
Study drug is provided in blister packs. Each blister pack contains 10 
5 mg tablets.  
Institutions should allow 4 business days for receipt of the 
everolimus/placebo from the date the drug request is received by UVI.  
Shipments will be made from UVI Monday through Thursday for 
delivery onsite Tuesday through Friday. 
There will be no weekend or holiday delivery of drugs. 


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Reorders: Institutions should keep in mind that shipments take 4 
business days from the date the drug request is received by the 
ECOG-ACRIN Drug Team. Reorders using the E2212 Drug Request 
Form should be emailed to the ECOG-ACRIN Drug Team at 
900.drugorder@jimmy.harvard.edu. 
Each shipment will contain a 3-month supply of everolimus/placebo. 
Study drug is provided in blister packs. Each blister pack contains 10 
5 mg tablets. 
Once approved by the ECOG-ACRIN Drug Team, the drug will be 
received on site within 4 business days. Shipments will be made from 
UVI, Inc. Shipments will be made from UVI Monday through Thursday 
for delivery onsite Tuesday through Friday. 
There will be no weekend or holiday delivery of drugs. 
8.1.2 
Drug Inventory Records 
Investigational Product Records at Investigational Site(s): It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried and disposed. Records or 
logs must comply with applicable regulations and guidelines. 
8.1.3 
Drug Destruction 
At the completion of the patient’s treatment at your institution, all 
unused drugs, partially used, or empty blister packs must be 
destroyed at the site according to the institution’s policy for drug 
destruction. Please maintain appropriate records of the disposal, 
including dates and quantities. 
8.1.4 
Emergency Unblinding 
The information provided below is for the use by a physician, 
nurse, CRA or pharmacist treating the patient. These contact 
numbers should not be used by patients.  Patients should be 
instructed to call their doctor’s office in the event of an 
emergency or adverse event that may result in the need to 
unblind the patient. 
In the event of an emergency or severe adverse reaction 
necessitating identification of the medication for the welfare of the 
patient, please contact the Study Chair, Dr. Steven Libutti M.D.,- at 
718-920-4231 or Email slibutti@montefiore.org, first to ensure the 
reason for unblinding is valid. Then call a member of the ECOG-
ACRIN Operations Office – Boston drug team at (617) 632-3610 
Monday through Friday between 9:00 AM and 5:00 PM Eastern Time. 
For unblinding outside of these hours, contact AnswerConnect at 1-
866-296-8940. This service will request the reason for unblinding and 
then page the on-call ECOG-ACRIN staff who will return your call and 
provide the unblinded treatment assignment if applicable. Remember, 
AnswerConnect should only be contacted outside of normal business 
hours and only in the event of an emergency.  The ECOG-ACRIN 
Operations Office – Boston or AnswerConnect will require the protocol 


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number (i.e., “E2212”), the patient ID number (e.g., “44444”), and the 
patient initials (e.g., “FL”) to unblind the patient.  Note that if a patient 
is unblinded, he/she must discontinue protocol treatment. 
8.1.5 
Other Names  
Afinitor 
8.1.6 
Classification  
mTOR inhibitor 
8.1.7 
Mode of Action  
Everolimus acts as an inhibitor of cytokine and growth-factor-
dependent proliferation of cells. Currently, the only known target of 
everolimus is mTOR, a key regulatory protein affecting various cell 
functions including cell proliferation(22). Everolimus exerts its activity 
through high affinity interaction with FKBP12. The FKBP12/everolimus 
complex subsequently interacts with the mTOR protein kinase, 
inhibiting downstream signaling events involved in regulation of the 
G1 to S-phase transition. 
8.1.8 
Storage and Stability  
Store everolimus/placebo tablets at 25°C (77°F); excursions permitted 
between 15° – 30°C (59° – 86°F). See USP Controlled Room 
Temperature. Store in the original container, protect from light and 
moisture. Keep this and all drugs out of the reach of children.  
Procedures for proper handling and disposal of anticancer drugs 
should be considered. Several guidelines on this subject have been 
published. 
Everolimus/placebo tablets should not be crushed. Do not take tablets 
which are crushed or broken. 
Medication labels will comply with US legal requirements and be 
printed in English. They will supply no information about the patient. 
The storage conditions for everolimus/placebo will be described on 
the medication label. 
Tablets are blister-packed under aluminum foil, which should be 
opened only at the time of administration as drug is both hygroscopic 
and light-sensitive. 
8.1.9 
Dose Specifics  
The recommended dose of everolimus/placebo for treatment of 
advanced PNET is 10 mg, to be taken once daily. 
8.1.10 
Preparation  
Everolimus/placebo tablets should be swallowed whole with a glass of 
water. The tablets should not be chewed or crushed. For patients 
unable to swallow tablets, everolimus/placebo tablet(s) should be 
dispersed completely in a glass of water (containing approximately 30 
mL) by gently stirring, immediately prior to drinking. The glass should 
be rinsed with the same volume of water and the rinse should be 
completely swallowed to ensure that the entire dose is administered. 


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8.1.11 
Route of Administration  
Everolimus/placebo should be administered orally once daily at the 
same time every day, either consistently with food or consistently 
without food. 
8.1.12 
Incompatibilities  
Agents that may Increase Everolimus/Placebo Blood Concentrations: 
CYP3A4 Inhibitors and PgP Inhibitors: See Appendix V for a list of 
CYP3A4 inhibitors.  
In healthy subjects, compared to everolimus treatment alone there 
were significant increases in everolimus/placebo exposure when 
everolimus/placebo was coadministered with: 
• 
ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - 
Cmax and AUC increased by 3.9- and 15.0-fold, respectively. 
• 
erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - 
Cmax and AUC increased by 2.0- and 4.4-fold, respectively. 
• 
verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - 
Cmax and AUC increased by 2.3- and 3.5-fold, respectively. 
Concomitant strong inhibitors of CYP3A4 should not be used  
Use caution when everolimus is used in combination with moderate 
CYP3A4 and/or PgP inhibitors.  
Agents that may Decrease Everolimus/Placebo Blood Concentrations: 
CYP3A4 Inducers: 
In healthy subjects, co-administration of everolimus/placebo with 
rifampin, a strong inducer of CYP3A4, decreased everolimus/placebo 
AUC and Cmax by 63% and 58% respectively, compared to 
everolimus/placebo treatment alone. Consider a dose increase of 
everolimus/placebo when co-administered with strong CYP3A4 
inducers if alternative treatment cannot be administered. St. John’s 
Wort may decrease everolimus/placebo exposure unpredictably and 
should be avoided. See Appendix V for a list of CYP3A4 inhibitors. 
Agents whose Plasma Concentrations may be Altered by 
Everolimus/Placebo: 
Studies in healthy subjects indicate that there are no clinically 
significant pharmacokinetic interactions between everolimus/placebo 
and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 
substrate) and pravastatin (a non-CYP3A4 substrate) and population 
pharmacokinetic analyses also detected no influence of simvastatin (a 
CYP3A4 substrate) on the clearance of everolimus. 
Coadministration of everolimus/placebo and depot octreotide 
increased octreotide Cmin by approximately 50%. 
Immunosuppressants may affect the response to vaccination and 
vaccination during treatment with everolimus may therefore be less 
effective. The use of live vaccines should be avoided during treatment 


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with Everolimus. Examples of live vaccines are: intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and 
TY21a typhoid vaccines. 
8.1.13 
Side Effects  
Information about common side effects already known about the 
investigational drug can be found in the Investigators’ Brochure. 
8.1.13.1 
Gastrointestinal disorders: 
• 
Stomatitis  
• 
Diarrhea 
• 
Abdominal pain 
• 
Nausea 
• 
Vomiting 
• 
Constipation 
• 
Dry mouth 
8.1.13.2 
General disorders and administration site conditions: 
• 
Fatigue/malaise 
• 
Edema (general and peripheral) 
• 
Fever 
• 
Asthenia 
8.1.13.3 
Infections and infestations 
• 
Nasopharyngitis/rhinitis/URI 
• 
Urinary tract infection 
8.1.13.4 
Investigations 
• 
Weight decreased 
8.1.13.5 
Metabolism and nutrition disorders 
• 
Decreased appetite 
• 
Diabetes mellitus 
8.1.13.6 
Musculoskeletal and connective tissue disorders 
• 
Arthralgia 
• 
Back pain 
• 
Pain in extremity 
• 
Muscle spasms 
8.1.13.7 
Nervous system disorders 
• 
Headache/migraine 
• 
Dysgeusia 
• 
Dizziness 
8.1.13.8 
Psychiatric disorders 
• 
Insomnia 


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8.1.13.9 
Respiratory, thoracic and mediastinal disorders 
• 
Cough/productive cough 
• 
Epistaxis 
• 
Dyspnea/dyspnea exertional 
• 
Pneumonitis  
• 
Oropharyngeal pain 
8.1.13.10 Skin and subcutaneous disorders 
• 
Rash 
• 
Nail disorders 
• 
Pruritus/pruritus generalized 
• 
Dry skin/xeroderma 
8.1.13.11 Vascular disorders 
• 
Hypertension 
8.1.13.12 Laboratory abnormalities 
• 
Anemia 
• 
Thrombocytopenia 
• 
Lymphopenia 
• 
Neutropenia 
• 
LFT derangement 
• 
Renal function abnormality 
• 
Hypercholesterolemia 
8.1.14 
Nursing/Patient Implications  
• 
Non-infectious Pneumonitis 
Warn patients of the possibility of developing non-infectious 
pneumonitis. In clinical studies, some non-infectious pneumonitis 
cases have been severe and occasionally fatal. Advise patients to 
report promptly any new or worsening respiratory symptoms. 
• 
Infections 
Inform patients that they are more susceptible to infections while 
being treated with everolimus/placebo and that cases of hepatitis 
B reactivation have been associated with everolimus/placebo 
treatment. In clinical studies, some of these infections have been 
severe (e.g., leading to respiratory or hepatic failure) and 
occasionally fatal. Patients should be aware of the signs and 
symptoms of infection and should report any such signs or 
symptoms promptly to their physician. 
• 
Oral Ulceration 
Inform patients of the possibility of developing mouth ulcers, 
stomatitis, and oral mucositis. In such cases, mouthwashes and/or 
topical treatments are recommended, but these should not contain 
alcohol or peroxide. 


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• 
Renal Failure Events 
Inform patients of the possibility of developing kidney failure. In 
some cases kidney failure has been severe and occasionally fatal. 
Inform patients of the need for the healthcare provider to monitor 
kidney function, especially in patients with risk factors that may 
impair kidney function. 
• 
Laboratory Tests and Monitoring 
Inform patients of the need to monitor blood chemistry and 
hematology prior to the start of everolimus/placebo therapy and 
periodically thereafter. 
• 
Drug-drug interactions  
Advise patients to inform their healthcare providers of all 
concomitant medications, including over-the-counter medications 
and dietary supplements. Avoid concurrent treatment with strong 
CYP3A4 inhibitors. Use caution if everolimus/placebo must be co-
administered with moderate CYP3A4 and/or PgP inhibitors; 
reduce the dose and carefully monitor the patient for undesirable 
effects. Avoid concurrent treatment with strong CYP3A4 inducers. 
If everolimus/placebo must be co-administered with strong 
CYP3A4 inducers, consider a dose increase and carefully monitor 
the patient for clinical response. 
Patients should avoid eating grapefruit and citrus fruits or drinking 
their juices while in the study. The juices in these fruits can 
change the way the body treats or breaks down everolimus 
(Afinitor®). 
• 
Hepatic Impairment 
Advise patients that everolimus/placebo is not recommended in 
patients with severe hepatic impairment (Child-Pugh class C). For 
advanced PNET and advanced RCC patients with moderate 
hepatic impairment (Child-Pugh class B), prescribe a reduced 
dose of 5 mg everolimus per day.  For SEGA patients with 
moderate hepatic impairment (Child-Pugh class B), adjustment to 
the starting dose may not be needed. However, subsequent 
dosing should be individualized based on therapeutic drug 
monitoring. 
• 
Vaccinations 
Advise patients to avoid the use of live vaccines and close contact 
with those who have received live vaccines. 
• 
Pregnancy 
Advise female patients of childbearing potential and sexually 
active males that everolimus/placebo may cause fetal harm and 
that a highly effective method of contraception or abstinence must 
be used during therapy with everolimus/placebo and for 8 weeks 
after ending treatment. 
Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, must use highly 
effective contraception during the study and for 8 weeks after 


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stopping treatment. Highly effective contraception is defined as 
either: 
• 
Total abstinence: When this is in line with the preferred and 
usual lifestyle of the subject. [Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception] 
• 
Sterilization: have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks 
before taking study treatment. In case of oophorectomy alone, 
only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment 
• 
Male partner sterilization (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate). [For 
female subjects on the study, the vasectomised male partner 
should be the sole partner for that subject]. 
• 
Use of a combination of any two of the following (a+b or a+c or 
b+c): 
a. Use of oral, injected, implanted or other hormonal methods 
of contraception 
b. Placement of an intrauterine device (IUD) or intrauterine 
system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive 
cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository 
In case of use of oral contraception, women should have been 
stable on the oral agent before taking study treatment. 
Sexually active males must use a condom during intercourse 
while taking the drug and for 8 weeks after stopping treatment and 
should not father a child in this period. 
A condom is required to be used also by vasectomised men in 
order to prevent delivery of the drug via seminal fluid. 
Female partners of male patients should also be advised to use 
one of the following contraception methods: Use of (1) oral, 
injected, implanted or other hormonal methods of contraception, 
or (2) intrauterine device (IUD) or intrauterine system (IUS), or (3) 
prior male/female sterilization. 
• 
Dosing Instructions 
Inform patients to take everolimus/placebo orally once daily at the 
same time every day, either consistently with food or consistently 
without food. The tablets should not be crushed or chewed. 
Everolimus/placebo should be swallowed whole with a glass of 
water. For patients unable to swallow tablets, everolimus/placebo 
tablet(s) should be dispersed completely in a glass of water 
(containing approximately 30 mL) by gently stirring, immediately 
prior to drinking. The glass should be rinsed with the same volume 
of water and the rinse should be completely swallowed to ensure 
that the entire dose is administered. 


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If vomiting occurs, no attempt should be made to replace the 
vomited dose. 
Instruct patients that if they miss a dose of everolimus/placebo, 
they may still take it up to 6 hours after the time they would 
normally take it. If more than 6 hours have elapsed, they should 
be instructed to skip the dose for that day. The next day, they 
should take everolimus/placebo at the usual time. Warn patients 
to not take 2 doses to make up for the one that they missed. 
8.1.15 
References 
22. Boulay A, Lane HA.  The mammalian target of rapamycin kinase 
and tumor growth inhibition. Recent Results Cancer Res. 
2007;172:99-124. 


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9. 
Statistical Considerations 
 
Endpoints 
Primary endpoint: Disease free survival 
Secondary endpoints: Overall survival 
The definitions of primary and secondary endpoints are described in Section 9.3.  
 
Sample size with power justification 
The trial will be a randomized double-blinded, placebo-controlled Phase II design 
with patients equally randomized between everolimus (Arm A) or placebo (arm 
B.) Randomization will be stratified on the factors outlined in Section 4. A total of 
150 patients will be needed to accrue 144 randomized eligible cases. The study 
seeks to establish an improvement in the primary endpoint, which is defined as 
an 80% increase in median disease-free survival (DFS) from 15 months in the 
control arm (Arm B) to 27 months in the experimental arm (Arm A). The study is 
designed to have 90% power for a 44% reduction in the hazard rate with 144 
eligible patients and 82 DFS events (as total information) which are expected to 
occur with 38 months of accrual at 4 patients per month and 7 additional months 
of follow-up, using a log-rank test at a one–sided significance level of 0.10. Under 
exponential distributions the hypothesized reduction corresponds to the 
improvement in median DFS from 15 months to 27 months and 3-year disease-
free survival of 39.7% in Arm A versus 18.9% in Arm B. The sample size was 
computed using seqopr6 (part of the study design library at the ECOG-ACRIN 
Statistical Office). 
 
Analysis plan including plans for formal interim analysis 
The primary analysis set will include all randomized eligible patients. Disease-
free survival (DFS) is defined as time from randomization to the earlier of 
documented recurrence (a return of tumor imaged by CT or MRI, new invasive 
primary cancer, or death without recurrence). Patients alive without documented 
recurrence or secondary primary reported will be censored at the time of the last 
documented disease evaluation. Tumor recurrence will be evaluated using 
evaluation criteria defined in Section 6 for a return of tumor imaged by CT or 
MRI. In the secondary analyses, overall survival (OS) is defined as time from 
randomization to death from any cause, censoring cases who are alive at the 
date of last contact. Kaplan-Meier estimates will be used for event-time 
distributions. DFS and OS by arm will be compared using one-sided stratified 
log-rank tests. Cox’s proportional hazards models will be used to estimate hazard 
ratios. Toxicity will be assessed through summaries of adverse events by arm. 
Formal comparison of toxicity rates between the arms is not a goal of this trial 
and the sample size will provide sufficient power for detecting only relative large 
difference in adverse events. With 75 patients per arm, the study will have 
sufficient precision to provide 90% confidence interval on toxicity that will be no 
wider than 20%. For rare toxicities with 2% true probability, there will be 78% 
probability of observing one or more toxicities in either treatment arm. For rare 
toxicities with 3% true probability, there will be 90% probability of observing one 
or more toxicities on either treatment arm. Patient demographics and disease 
characteristics will be compared using two-sample t-tests or Fisher’s exact tests 


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with a two-sided significance level of 0.10 as appropriate. Stratification will be 
used to ensure balance between groups and not for subset analysis.  
The study will be monitored for potential efficacy stopping using an early look at 
DFS after approximately 50% of the planned full information (41/82 DFS events) 
has been observed. A one-sided log-rank test for DFS will be performed for the 
monitoring analysis. To preserve the overall type I error rate at 0.10, a critical 
value at the interim analysis will be determined using the O’Brien-Fleming 
boundary. Under the planned accrual schedule with four patients per month (3.8 
eligible patients/ month), the monitoring analysis is projected to occur at 28.3 
months following the start of accrual. If the true control median DFS is 15 months 
and the true experimental median DFS is 27 months, there will be 42% 
probability of crossing the upper efficacy boundary (2.05).  
This study will also be monitored for futility using a rule that the study will be 
stopped early for lack of benefit if the estimated hazard ratio for 
experimental/control ≥ 1 at 50% of the planned full information. There will be 50% 
probability of early termination under the null hazard ratio of 1.0 
(experimental/control) and 3.6% probability of early termination under the target 
alternative hazard ratio of 0.56 (experimental/control).  
 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Reports of these analyses are sent to the ECOG-ACRIN Principal 
Investigator or Senior Investigator at the participating institutions. Expedited 
reporting of certain adverse events is required, as described in Section 5.2.  
 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office - Boston. 


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Gender and Ethnicity  
Based on data from E6201 the anticipated accrual in subgroups defined by 
gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
3 
6 
Not Hispanic or Latino 
66 
78 
144 
Ethnic Category: Total of all subjects 
69 
81 
150 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
1 
2 
Black or African American 
5 
5 
10 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
63 
75 
138 
Racial Category: Total of all subjects 
69 
81 
150 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
 


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10. 
Specimen Submissions 
Fixed paraffin-embedded metastatic tumor from core biopsy or surgery must be 
submitted for central diagnostic review and classification. Primary tumor tissue, if 
available, is also requested. Blood specimens and frozen tissue, if available, are to be 
submitted for use in research from consenting patients. Descriptions of the diagnostic 
review and examples of potential research studies are in Section 11.   
SAMPLE TRACKING SYSTEM (STS): All specimens submitted on this trial must be 
entered and tracked using the ECOG-ACRIN Sample Tracking System.  Any case 
reimbursements associated with specimen submissions to ECOG-ACRIN–designated 
laboratories will be determined only from data contained in STS. 
LABELING: Specimens are to be labeled clearly with the ECOG-ACRIN protocol 
number “E2212”, patient initials, date and time of collection, and sample type. All sample 
submissions are to be accompanied with an STS shipping manifest. 
SHIPPING ACCOUNT: Samples shipped to the ECOG-ACRIN PCORL or Libutti 
Laboratory are to be shipped using the PCORL’s FedEx account using the FedEx On-
Line Services. Access to the shipping account for specimen shipments to the ECOG-
ACRIN PCORL at Northwestern University can now only be obtained by logging into 
fedex.com with an account issued by the ECOG-ACRIN PCORL. For security reasons, 
the account number will no longer be given out in protocols, over the phone, or via email. 
If your site needs to have an account created, please contact the ECOG-ACRIN PCO by 
email at ecogpcorl@northwestern.edu 
 
Submissions to the (PCORL) - MANDATORY 
The ECOG-ACRIN Pathology Coordinating Office-Reference Laboratory 
(PCORL) is the receiving laboratory for all specimens submitted from patients 
participating in this trial. 
10.1.1 
Pathology Materials - MANDATORY 
Submission of pathology materials from all patients is mandatory. 
The submitting pathologist and clinical research associate should 
refer to Appendix I (Pathology Submission Guidelines) for guidelines 
and summary of submission requirements. Failure to submit the 
required materials may render the patient’s data unevaluable. 
The required materials are to be submitted within four (4) weeks 
following randomization. 
If these criteria cannot be met, please contact the ECOG-ACRIN 
Pathology Coordinating Office (PCO) (ecogpcorl@northwestern.edu) 
to obtain alternative submission requirements. 
A. FFPE TUMOR TISSUE 
All of the following materials are to be submitted. If unavailable, 
please contact the PCORL and provide justification in STS.  
• 
All original stained diagnostic slides. 
NOTE: 
These slides will be returned to the site upon 
completion of the review which is retrospective 
and will be performed in batches. If the return of 
Rev. 5/14 


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these slides is to be expedited, please indicate as 
such in the appropriate comment field in STS.   
• 
One representative diagnostic-fixed paraffin-embedded 
metastatic liver tumor block, core biopsy or surgical 
specimen. 
• 
One representative diagnostic fixed paraffin-embedded 
primary tumor block, core biopsy or surgical specimen, if 
available. 
NOTE: 
If blocks are not available for submission, submit 
the following: 
• 
Two (2) H&E slides.  
• 
Twenty (20) unstained charged slides 4 or 5 
µm thick 
• 
Two (2) 4mm cores. 
B. FORMS 
• 
Pathology Material Submission Form (#638 v04.2), Parts A & 
B completed. Please identify the clinical status of the 
submitted materials 
• 
A copy of the surgical (if appropriate) and pathology reports 
• 
Immunologic studies, if available 
• 
Sample Tracking System Shipping Manifest 
10.1.2 
Specimens from Consenting Patients 
Specimens are to be submitted from patients who answered “yes” to “I 
agree to provide additional samples for research.” 
Blood specimens are to be collected prior to start of treatment and 
upon completion/end of treatment.  The pretreatment samples, ideally, 
are to be drawn at 6-8 WEEKS POST-SURGERY, prior to start of 
protocol therapy. If protocol treatment will begin prior to the sixth week 
post-surgery, still collect prior to start of treatment. 
Institution supplies are to be used for the collection and shipment of 
blood and frozen tissue specimens. No kits are available. 
Blood samples are to be frozen (at < -70ºC) as quickly as possible 
after draw. If samples are frozen in a standard freezer (approximately 
-20ºC), it is asked that samples be shipped within a month of 
collection. 
Questions are to be directed to the ECOG-ACRIN PCORL 
(ecogpcorl@northwestern.edu), Dr. Steven Libutti, Phone: (718) 920-
4231, FAX: (718) 798-0309, E-mail: slibutti@montefiore.org. 


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A. Frozen Surgical Tumor Tissue Specimens 
Specimens are to be shipped overnight with the blood specimens 
on dry ice. 
The site’s pathology ID for submitted frozen tissue samples must 
be provided in STS. If samples are not available, indicate as such 
in the STS as well. This information will reduce unnecessary 
follow-up with the site by the laboratory. 
B. Peripheral Blood, ACD vacutainer 
Draw prior to start of protocol therapy, ideally 6-8 weeks post-
surgery. 
• 
Draw blood into a 10 mL ACD vacutainer (EDTA tube may 
substitute). Invert gently eight to ten times to thoroughly mix 
the blood and anti-coagulant.  
• 
Specimens collected in glass vacutainers must be transferred 
to sterile cryovials prior to freezing. Plastic vacutainers may be 
frozen directly. Freeze at ≤ -70ºC until shipped 
C. Plasma, EDTA (purple top) 
Draw prior to start of protocol therapy, ideally 6-8 weeks post-
surgery. 
• 
Draw peripheral blood into vacutainer and gently invert 8-10 
times.  
• 
Within 20 minutes of collection, centrifuge at 1500xg (2700-
3000 rpm) for 15 minutes.  
• 
Pipette the plasma into 4 cryotubes (approximately 1 mL 
each) and store frozen, below –20oC (-70 oC preferred), until 
shipped 
• 
Remaining Cells: If the vacutainer is plastic, replace the 
stopper on the EDTA tube containing the cells and ship with 
the plasma samples. 
10.1.3 
Shipping Guidelines 
The receiving laboratory is not available to receive shipments over 
holidays or weekends. Therefore, samples are only to be shipped via 
overnight courier Sunday through Thursdays (excluding a day before 
a holiday). 
The required initial diagnostic tumor tissue materials, reports and 
forms are to be submitted within four (4) weeks following patient 
randomization. 
Frozen samples are to be shipped on dry ice (5 lbs. minimum). 
Samples batched in a regular freezer are to be shipped within a 
month following the draw. Samples stored at < -70ºC may be shipped 
on a quarterly basis. 
Samples from multiple patients may be batched and shipped together. 
All samples must be adequately labeled with protocol number, ECOG-
ACRIN patient case number, and date of collection. 


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Shipping Address 
ECOG-ACRIN Pathology Coordinating Office 
Robert H. Lurie Comprehensive Cancer Center  
of Northwestern University Medical School 
Olson Pavilion - Room 8421 
710 North Fairbanks Court 
Chicago, IL 60611 
Tel: (312) 503-3384 
FAX: (312) 503-3385 
Tissue specimens shipped standard mail must utilize a “trackable” 
mechanism. For shipments utilizing FedEx, access to the shipping 
account for specimen shipments requires logging into fedex.com with 
an account issued by the ECOG-ACRIN PCORL. 
 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important:  Any case reimbursements associated with specimen submissions 
will not be credited if specimens are not logged into STS. Additionally, please 
note that the STS software creates pop-up windows, so you will need to enable 
pop-ups within your web browser while using the software.  A user manual and 
interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated shipping manifest should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to .  
Study Specific Notes 
Generic Specimen Submission Form (#2981v2) will be required only if STS is 
unavailable at time of sample submission. Include site contact information on the 
form. Notify the laboratory of the shipment by faxing a copy of the completed 
form to the laboratory the day of shipping. Indicate the shipping tracking number 
and the appropriate Lab ID# on the submission form: 
• 
0001 = ECOG-ACRIN PCORL 
Retroactively enter all specimen collection and shipping information when STS is 
available. 


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Use of Specimens in Research 
Tissue specimens will be processed and distributed to investigators for the 
central diagnostic review. 
Specimens from patients who consented to allow their specimens to be used for 
research studies will be retained in an ECOG-ACRIN-designated central 
repository. For this trial, specimens will be retained at the ECOG-ACRIN 
Pathology Coordinating Office. 
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Processing may include, but not limited to, extraction of 
DNA and RNA and construction of tissue microassays (TMAs). DNA and plasma 
(if appropriate) will be isolated from the submitted peripheral blood samples. 
Any residual blocks will be available for purposes of individual patient 
management on specific written request.  
Request for the use of archived specimens requires submission of a correlative 
science proposal detailing the scientific hypothesis, research plan, assay 
methods for use of the biospecimens, and a complete statistical section (with 
adequate power justification and analysis plan) will be submitted and reviewed by 
CTEP in accordance with the NCI National Clinical Trials Network (NCTN) review 
policies. 
If future use is denied or withdrawn by the patient, the samples will be removed 
from consideration for use in any future study. Bloods and other products may be 
destroyed per protocol of the given lab, or they could be anonymized (stripped of 
all identifiers) and used for instrument calibration or other quality control 
measures which are not published or linked to the clinical trial. Tissue will be 
returned or stored indefinitely in for return to the site upon request.  
 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory. 
Inventories of specimens forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office – Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office – Boston. 


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11. 
Laboratory Research Studies  
 
Diagnostic Review and Classification (MANDATORY) 
Central pathological review will include Ki-67 and mitotic index, NANETS grading 
system will be employed (19, 20). The review will be performed by Dr. Guang-Yu 
Yang at Northwestern University. The analysis will be retrospective and will be 
used for determination of patient evaluability. The results of the review will not 
impact patient participation in the trial. 
 
Research Studies 
Blood and tumor specimens are requested from consenting patients for future 
research studies. Request for the use of archived specimens, via a protocol 
amendment or a separate correlative science proposal, will be in accordance 
with the ECOG-ACRIN and NCI National Clinical Trials Network (NCTN) policies. 
The background supporting the following potential research studies is presented 
in the introduction of this protocol. These studies, if performed, will be performed 
under the direction of Drs. Steven Libutti, Montefiore Medical Center, and Luis 
Diaz, Johns Hopkins University. 
11.2.1 
Predictive value of PIK3CA, PTEN, and TSC Mutations 
We hypothesize that patients with tumors that are mutant for PIK3CA, 
PTEN or TSC will benefit in terms of DFS and OS as compared to 
patients with tumors without mutations in these genes. 
DNA from tumor tissue and germline DNA from peripheral blood will 
be used for these studies. 
Sequencing will be performed following PCR amplification of the 
regions of interest. Mutations detected will be confirmed using the 
tumor and matched normal DNA (obtained from whole blood). 
Mutations identified in the tumor will be used to design primers and 
probes to detect circulating tumor DNA (ctDNA) fragments that 
contain these mutations using highly sensitive PCR-based 
methodologies (i.e. BEAMing or SafeSeqs) (see below). 
11.2.2 
Analysis of post-operative circulating tumor DNA to detect minimal 
residual disease and predict disease recurrence  
We hypothesize that the post-operative detection of ctDNA is 
consistent with the presence of minimal residual disease and signifies 
a population of patients that will suffer with disease recurrence. 
DNA extracted from plasma from each time point collected will be 
interrogated for the presence of ctDNA using probes designed from 
mutations detected in the tumor tissue (see above). At this time, the 
proposed genomic method to detect and quantify the 
ctDNA,“BEAMing”, is described in the introduction to the protocol. 


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11.2.3 
Mutations in Chromatin Remodeling Genes 
We hypothesize that tumors with defect in chromatin remodeling will 
confer a survival benefit to patients with metastatic pancreatic tumors.  
Sequencing of DAXX, ATRX and MEN1 will be performed following 
PCR amplification of the regions of interest.  Mutations detected will 
be confirmed using the tumor and matched normal DNA (obtained 
from whole blood). 
 
Lab Data Transfer Guidelines  
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office – Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. The quarterly 
cut-off dates are March 31, June 30, September 30, and December 31. Data is 
due at the ECOG-ACRIN Operations Office – Boston 1 week after these cut-off 
dates. 
 


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12. 
Electronic Data Capture 
Please refer to the E2212 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. Reports are due January 31, April 30, 
July 31 and October 31st. 
 
Records Retention  
This study is being conducted under an IND exemption and is not intended to 
support any FDA-related filings. However, ECOG-ACRIN requires clinical 
investigators to retain all trial-related documentation, including source 
documents, for at least one year from the posting of the final clinical study report 
of the outcome of this trial to support any publication of the data. Please contact 
the ECOG-ACRIN Operations Office – Boston prior to destroying any source 
documents. 
 


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13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
1. Mayo SC, de Jong MC, Pulitano C et al. Surgical management of hepatic 
neuroendocrine tumors metastasis: results from an international multi-institutional 
analysis. Ann Surg Oncol 2010;17:3129-3136. PMID: 20585879 
2. Ballian N, Loeffler AG, Rajamanickam V, et al.  A simplified prognostic system for 
resected pancreatic neuroendocrine neoplasms.  HBP 2009;11:422-8. PMID 
19768147 
3. Yao JC, Hassan M, Phan A,et al. One hundred years after "carcinoid": epidemiology 
of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United 
States. J Clin Oncol. 2008 Jun 20;26(18):3063-72. Review. PubMed PMID: 
18565894 
4. Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-
fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl 
J Med. 1992 Feb 20;326(8):519-23. PubMed PMID: 1310159 
5. Cheng PNM, Saltz LB.  Failure to confirm major objective antitumor activity for 
streptozocin and doxorubicin in the treatment of patients with advanced islet cell 
carcinoma.  Cancer 1999;86:944-8. PMID: 10491519 
6. McCollum DA, Kulke MH, Ryan DP, et al.  Lack of efficacy of streptozocin and 
doxorubicin in patients with advanced pancreatic endocrine tumors.  Am J Clin Onc 
2004;27:485-8. PMID: 15596916 
7. Raymond E, Dahan L, Raoul JL, et al.  Sunitinib maleate for the treatment of 
pancreatic neuroendorcine tumors.  NEJM 2011;364:501-13. PMID: 21306237 
8. Missiaglia E, Dalia I, Barbi S, et al.  Pancreatic endocrine tumors: expression 
profiling evidences a role for AKT-mTOR pathway.  J Clin Onc 2010;28:245-55. 
PMID: 19917848 
9. Yao JC, Shah MH, Ito T, et al.  Everolimus for advanced pancreatic neuroendocrine 
tumors. NEJM 2011;364:514-23. PMID: 21306238 
10. Elias D, Lasser P, Ducreux M, et al.  Liver resection and associated extra-hepatic 
resections for metastatic well-differentiated endocrine tumors: a 15-year single 
center prospective study.  Surgery 2003;133:375-82. PMID: 12717354 
11. Knigge U, Hansen CP, Stadil F.  Interventional treatment of neuroendocrine liver 
metastases. Surgeon 2008;6:232-9. PMID: 18697366 
12. Yao KA, Talamonti MS, Nemcek A, et al. Indications and results of liver resection 
and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine 
tumors.  Surgery 2001;130:677-85. PMID: 11602899 
13. Gaujoux S, Gonen M, Tang L, Klimstra D, Brennan MF, D'Angelica M, Dematteo R, 
Allen PJ, Jarnagin W, Fong Y. Synchronous Resection of Primary and Liver 
Metastases for Neuroendocrine Tumors. Ann Surg Oncol. 2012 Jul 3. [Epub ahead 
of print] PMID: 22752376. 


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14. Glazer ES, Tseng JF, Al-Refaie W, Solorzano CC, Liu P, Willborn KA, Abdalla EK, 
Vauthey JN, Curley SA. Long-term survival after surgical management of 
neuroendocrine hepatic metastases. HPB (Oxford). 2010 Aug;12(6):427-33. PubMed 
PMID: 20662794; PubMed Central PMCID: PMC3028584. 
15. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after 
resection of localised, primary gastrointestinal stromal tumour: a randomised, 
double-blind, placebo-controlled trial. Lancet 2009;373:1097-104.  PMID 19303137. 
16. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib 
for operable gastrointestinal stromal tumor: a randomized trial. JAMA : the journal of 
the American Medical Association 2012;307:1265-72.  PMID: 22453568. 
17. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are 
frequently altered in pancreatic neuroendocrine tumors. Science 2011;331:1199-203.  
PMID: 21252315. 
18. Snoeren N, Voest EE, Bergman AM, Dalesio O, Verheul HM, Tollenaar RA, van der 
Sijp JR, Schouten SB, Rinkes IH, van Hillegersberg R. A randomized two arm phase 
III study in patients post radical resection of liver metastases of colorectal cancer to 
investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) 
vs CAPOX alone as adjuvant treatment. BMC Cancer. 2010 Oct 11;10:545. PMID: 
20937118. 
19. Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine 
tumors: application of the Delphic consensus process to the development of a 
minimum pathology data set. The American journal of surgical pathology 
2010;34:300-13.  PMID: 20118772. 
20. Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification 
of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. 
Pancreas 2010; 39:707-12. PMID: 20664470. 
21. Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, 
Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz Jr LA.  Circulating mutant DNA 
to assess tumor dynamics. Nat Med. 2008: 14(9): 985-90. Epub 2007 Jul 31. PMID 
18670422. 
22. Boulay A, Lane HA.  The mammalian target of rapamycin kinase and tumor growth 
inhibition. Recent Results Cancer Res. 2007;172:99-124. 
 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. List of Required Materials for E2212 
4. Pathology Submission Form (#638 v04.2) 
 


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Guidelines for Submission of Pathology Materials 
E2212: A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine 
Tumors to the Liver 
The following materials are to be submitted within one month of randomizing patient to the trial 
1. Pathology materials required for pathology review and, per patient consent, research 
• 
REQUIRED FOR CENTRAL DIAGNOSTIC REVIEW 
• 
One representative diagnostic-fixed paraffin-embedded metastatic tumor block, 
core biopsy or surgical specimen. 
• 
One representative diagnostic fixed paraffin-embedded primary tumor block, core 
biopsy or surgical specimen, if available  
• 
Original stained diagnostic slides 
NOTE: 
These slides will be returned to the site upon completion of the review 
which is retrospective and will be performed in batches. If the return of 
these slides is to be expedited, please indicate as such in the appropriate 
comment field in STS.   
• 
If available, frozen surgical tumor tissue 
2. Forms and reports: 
The following items are to be included with every submission of pathology materials. 
• 
Institutional Surgical Pathology Report 
• 
Pathology Material Submission Form (#638 v04.2) – Parts A & B completed 
• 
ECOG-ACRIN Sample Tracking System (STS) manifest 
NOTE: 
Adequate patient identifying information must be included with every submission. 
It is strongly recommended that full patient names be provided. The information 
will be used only to identify patient materials, will expedite any required 
communications with the institution (including site pathologists).   
3. Mail pathology materials to: 
ECOG-ACRIN Pathology Coordinating Office 
Robert H. Lurie Comprehensive Cancer Ctr  
of Northwestern University Medical School 
Olson Pavilion - Room 8421 
710 North Fairbanks Court 
Chicago, IL  60611 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact the 
Pathology Coordinator at the ECOG-ACRIN Pathology Coordinating Office at (312) 503-
3384 or FAX (312) 503-3385 or ecogpcorl@northwestern.edu. 
 


 
63 
MEMORANDUM 
TO:  
(Submitting Pathologist) 
 
 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Pathology Committee 
DATE:  
 
SUBJECT: 
Submission of Pathology Materials for E2212: A Randomized, Double-
Blinded, Placebo-Controlled Phase II Study of Adjuvant Everolimus 
Following the Resection of Metastatic Pancreatic Neuroendocrine 
Tumors to the Liver  
 
 
The patient named on the attached Pathology Material Submission Form (#638 v04.2) 
has been entered onto an ECOG-ACRIN protocol by 
_____________________________ (ECOG-ACRIN Investigator). This protocol requires 
the submission of pathology materials for diagnostic review and research studies. 
Please complete PART B of the Submission Form. Keep a copy for your records and 
return the completed Submission Form, the surgical pathology report(s), the slides 
and/or blocks and any other required material (see List of Required Material) to the 
Clinical Research Associate (CRA). The CRA will forward all required pathology material 
to the appropriate laboratory. 
Pathology materials submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies per patient consent.  Paraffin blocks will be returned upon 
request for purposes of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
Results of the diagnostic review will be distributed to you upon completion of the review. 
This review will be retrospective and will not impact patient participation in E2212.  
If you have any questions regarding this request, please contact the Pathology 
Coordinating Office at (312) 503-3384 or FAX (312) 503-3385. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 


Form No. 638 v04.2 
ECOG DIAGNOSTIC PATHOLOGY MATERIAL SUBMISSION FORM 
64 
Instructions: 
This form is a required part of pathology submission.  Please complete and submit along with 
all pathology material and corresponding pathology reports requested by the protocol.  See list of 
required materials as specified in EACH protocol. 
ECOG PCO-RL IS FULLY- COMPLIANT WITH DHHS, HIPAA, AND OHRP REGULATIONSTel. 
312-503-3384
 
Fax 312-503-3385 
PART A:  To Be Completed By Data Manager/CRA 
DO NOT USE INITIALS – Submit Patient’s FULL Name 
 
(The Patient has authorized the use of PHI.) 
Date sample sent to ECOG ______/______/_______ (M,D,Y) 
 
Patient’s Name: 
Data Manager _______________________________________  
 
Last _______________________ 
First ____________________  
Address  ___________________________________________  
 
ECOG Prot. No. _________  ECOG Patient Seq. No. ________  
 __________________________________________________  
 
Participating Group 
Prot. No. _______________  
Participating Group 
Patient ID No. ________________  
Telephone No. (          ) _______________________________  
 
Group __________ 
Institution _________ 
PI _____________  
Fax No. (          ) _____________________________________  
 
Step No. ________ 
Affiliate _________  
Email address  ______________________________________  
 
ECOG Parent Prot. No. ________  
Seq. No. ______________  
PART B: 
TO BE COMPLETED BY DATA MANAGER/CRA AND SUBMITTING PATHOLOGIST 
 
 
 
 
 
 
 
PCO-RL Use Only 
Complete for 
Slides/Vials 
Status* 
(See Below) 
Date Specimen 
Collected (M/D/Y) Disease Site 
Number of 
Slides/Vials 
Specimen ID  
Numbers 
Type of 
Stain 
PCO ID 
Numbers 
 
 
/        / 
 
 
 
 
 
 
 
/        / 
 
 
 
 
 
Complete for 
Blocks/Punch 
Status* 
(See Below) 
Date Specimen 
Collected (M/D/Y) Disease Site 
Number of 
Blocks/Punch 
Specimen ID  
Numbers 
Fixative 
PCO ID 
Numbers 
 
 
/        / 
 
 
 
 
 
 
 
/        / 
 
 
 
 
 
*Status: Please identify the clinical status of the sample.  
List all that apply: 
 
 
1. Original diagnostic material 
5. Post-surgery biopsy/tissue 
 
Submitting Pathologist _____________________ 
2. AML/MDS diagnosis 
6. Relapse/recurrence 
 
Telephone No. (          ) ____________________ 
3. Pre-protocol treatment 
biopsy/tissue 
7. Remission/response 
 
 
Address  ________________________________ 
4. Post-protocol treatment 
biopsy/tissue 
8. Other, specify: ______________  
 
  _________________________  
 
 _______________________________________ 
Did the patient consent to participate in the storage of samples for future research? 
Yes 
No 
MATERIAL RETURN (All materials will be retained by the ECOG PCO unless return is requested here.) 
Does the submitting institution’s policy require the return of any submitted material (blocks, H&E slides, etc.)? 
Yes 
No 
If so, please indicate which materials must be returned ______________________________________________________________  
All materials will be returned to the submitting pathologist unless an alternate address is indicated here ______________________  
If materials were not able to be submitted for this protocol and its correlative studies, please circle the 
reason for non-submission. Attach a formal letter referencing regulations, policy, and/or other explanation. If 
possible, include a copy of the policy.  
Federal/State Regulations ____  Hospital/Institutional Policy _____ Insufficient Tissue _____  Other ______  (Specify) _________  
Pathologist of Investigator’s Signature ______________________________________________ 
(PCO-RL Use Only) 
PV  _________________________  
PART C: 
ECOG PATHOLOGY COORDINATING OFFICE USE ONLY 
Date Sample Received at PCO ____/____/____ 
Date Sent to Reviewer ____/____/____ 
Date Sent to PI/Central Lab ____/____/_____ 
Site Compliance % _____________ 
Name of Reviewer __________________ PI/Central Lab _________________________  
PCO Comments: _____________________________________________________________________  
Staff Init. _____________  
Investigator:  Keep a copy for your files and submit original form to the destination specified in protocol. 
2/05 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions 
remain unanswered in cancer.  With the participation of people like you in clinical trials, 
we will improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care.  I and my research staff will 
maintain very close contact with you.  This will allow me to provide you with the best 
care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, with the 
participation of people like you in clinical trials, we thank you again. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix III 
 
Patient Tablet Calendar 
Tablet Calendar Directions 
1. Take your scheduled dose of each tablet as instructed by your doctor. 
2. If you forget, the missed tablets will not be taken if more than six hours late. 
3. Note the time and number of tablets you take each day. If you develop any side 
effects or symptoms, please record them in the appropriate spot on your calendar. If 
you take any medications other than everolimus/placebo, note them in the 
appropriate spot on your calendar. 
4. Please bring the bottle, any leftover tablets, and your  
tablet calendar to your next clinic visit. 
 


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Patient Tablet Calendar 
Patient ID #:  _______________________   
 
Drug Name: Everolimus/Placebo 
Dose: _____________________________  
 
Cycle#: ______________________ 
 
DAY 
Date 
 
Month   Day   Year 
Time 
tablets 
taken 
Number 
of tablets 
taken 
Use the space below to make notes about things you 
would like to tell the doctor (including unusual symptoms 
you experience, other medicine you have taken and 
anything else you think would be of interest.) 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
 
 
 
 
 
 
30 
 
 
 
 
 
 
Additional Notes: 
 
 
 
Patient signature:  ________________________   
Date: ______________________ 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
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the Liver 
 
Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled.  Cannot carry on any self-care. Totally confined to bed or 
chair. 
 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix V 
 
Drugs Which May Affect Everolimus Metabolism 
 
The following is a list of common CYP3A4 inducers and inhibitors which may impact 
everolimus metabolism. This is NOT a complete list of medications potentially incompatible 
with everolimus; therefore patient medications must be evaluated closely to determine 
patient eligibility for this trial. 
 
List of CYP3A4 Inducing Agents: 
Carbamazepine 
Phenytoin 
Dexamethasone 
Primidone 
Ethosuximide 
Progesterone 
Glucocorticoids 
Rifabutin 
Griseofulvin 
Rifampin 
Modafinil 
Rifapentine 
Naficillin 
Rofecoxib 
Nelfinavir 
St. John’s Wort 
Nevirapine 
Sulfadimidine 
Oxcarbazepine 
Sulfinpyrazone 
Phenobarbitol 
Tipranavir 
Phenylbutazone 
Troglitazone 
 
List of CYP3A4 Inhibitors: 
Amiodarone 
 
Mifepristone 
Cimetidine 
 
Nefazodone 
Ciprofloxacin 
 
Nelfinavir 
Clarithromycin 
 
Norfloxacin 
Delavirdine 
 
Norfluoxetine 
Diethyl-dithiocarbamate 
 
Ritonavir 
Diltiazem 
 
Roxithromycin 
Erythromycin 
 
Saquinavir 
Fluconazole 
 
Troleandomycin 
Fluvoxamine 
 
Voriconazole 
Gestodene 
 
Warfarin 
Grapefruit or Grapefruit juice 
 
Amprenavir 
Indanvir 
 
Atazanavir 
Itraconazole 
 
Miconazole 
Ketoconazole 
 
Telithromycin 
Mibefradil 
 
Verapamil 


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the Liver 
Appendix VI 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy test 
regardless of age or disease state) of a female patient while she is on Everolimus/placebo, or 
within 28 days of the patient’s last dose of Everolimus/placebo must be reported in an 
expeditious manner.  The outcome of the pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be reported 
via CTEP’s Adverse Event Reporting System (CTEP-AERS) 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, followed 
by a complete expedited CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERS report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium and 
perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
• 
The start date of the pregnancy should be reported as the calculated date of conception.   
• 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the CTEP-AERS 
report.  
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female patient until completion of the pregnancy and must 
report the outcome of the pregnancy and neonatal status via CTEP-AERS.  
• 
The decision on whether an individual female patient can continue protocol treatment will be 
made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office – Boston.  Please contact the ECOG-ACRIN Operations Office – Boston 
to ask for a conference call to be set up with the appropriate individuals. 
• 
It is recommended the female subject be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
Rev. 5/14 


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How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERS 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  However, if 
the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-AERS report 
should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the CTEP AEMD 
Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed on a case 
by case basis. 
Reporting a Fetal Death 
A fetal death is defined in CTCAE as “A disorder characterized by death in utero; failure of the 
product of conception to show evidence of respiration, heartbeat, or definite movement of a 
voluntary muscle after expulsion from the uterus, without possibility of resuscitation.” 
It must be reported via CTEP-AERS as Grade 4 “Pregnancy, puerperium and perinatal 
conditions - Other (pregnancy loss)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions”.   
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERS recognizes 
this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A disorder characterized by cessation of life occurring 
during the first 28 days of life” that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention. However, for this protocol, any neonatal death that occurs 
within 28 days of birth, without regard to causality, must be reported via CTEP-AERS AND any 
infant death after 28 days that is suspected of being related to the in utero exposure to 
Everolimus/placebo  must also be reported via CTEP-AERs . 
It must be reported via CTEP-AERS as Grade 4 “General disorders and administration - Other 
(neonatal loss)”under the System Organ Class (SOC) “General disorder and administration”.  
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERS reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any additional 
medical information to CTEP (301-230-0159). This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportFor
m.pdf)  
 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix VII 
 
E2212 Drug Request Form 
E2212 EVEROLIMUS/PLACEBO DRUG REQUEST FORM 
Section I (To be completed by the institution) 
CTEP NCI ID#: 
      
Principal Investigator: 
      
Institution Name: 
      
Institution Pharmacy 
Delivery Address: 
      
Pharmacy Contact: 
      
Pharmacy Contact 
Telephone Number: 
      
Pharmacy Contact email: 
      
Pharmacy Contact fax: 
      
Shipment Must Reach 
Destination By (Please allow 
4 business days for delivery): 
      
ECOG-ACRIN Patient 
Sequence Number: 
      
Blinded Drug ID#: 
      
Initial Order or Resupply: 
      
Quantity of Blister Packs 
      
 
Order placed by: (print name) 
      
Signature:  
Date:  
 
Section II  (To be completed by ECOG-ACRIN Drug Team) 
IRB Approval:  
Blinded Drug ID Confirmed: 
Personnel Name: 
 
 
 
        Signature:          
 
             Date: 
PLEASE EMAIL THIS DRUG REQUEST FORM AS AN ATTACHMENT TO 
900.drugorder@jimmy.harvard.edu or by FAX: 617-632-2063 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix VIII 
 
Hepatitis Screening 
Screening for hepatitis B 
Prior to randomization, 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. 
• 
Additional patients at the discretion of the investigator 
Screening for hepatitis C 
Prior to randomization, 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. 

Prot_000.pdf: 
E2212 
 
1 
A Randomized, Double-Blinded, Placebo-Controlled 
Phase II Study of Adjuvant Everolimus Following the 
Resection of Metastatic Pancreatic Neuroendocrine 
Tumors to the Liver 
STUDY CHAIR: 
Steven K. Libutti, M.D.  
STUDY CO-CHAIR: 
Pamela L. Kunz, M.D. 
STUDY STATISTICIAN: 
Paul Catalano, Sc.D. 
PATHOLOGY CO-CHAIR: 
Guang-Yu Yang, M.D., Ph.D. 
SURGICAL CO-CHAIR: 
Steven K. Libutti, M.D.  
LABORATORY STUDIES CO-CHAIR: 
Steven K. Libutti, M.D. 
Luis A. Diaz, M.D. 
GASTROINTESTINAL COMMITTEE CO-CHAIRS: 
Peter O’Dwyer, M.D. 
Terence Z. Wong, M.D., Ph.D. 
 
 
Version Date:  April 21, 2014 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
United States Only 
 
 
January 17, 2014 
ALLIANCE / Alliance for Clinical Trials in Oncology 
NRG / NRG Oncology Foundation, Inc 
SWOG / SWOG 
 
 
 
 
PRE-ACTIVATION DATE 
NOTE: This study is supported by the NCI Cancer 
Trials Support Unit (CTSU). Institutions not 
aligned with ECOG-ACRIN will participate 
through the CTSU mechanism. 
 
December 23, 2013 
 
Addendum #1 –3/14 
Addendum #2 – 5/14 
 
 
Addendum #3 – 5/14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agents 
IND# 
NSC# 
Supply 
IND Sponsor 
Everolimus/Placebo 
N/A 
NSC 733504 
Novartis 
IND Exempt 
Rev. 5/14 


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Table of Contents 
Schema ...................................................................................................................... 5 
1. Introduction ........................................................................................................ 6 
1.1 Trial Design ................................................................................................ 6 
1.2 Background For Potential Laboratory Research Studies ........................... 7 
2. Objectives ........................................................................................................... 9 
2.1 Primary objective: ..................................................................................... 9 
2.2 Secondary objectives: ............................................................................... 9 
3. Selection of Patients ......................................................................................... 10 
3.1 Eligibility: Criteria .................................................................................... 10 
4. Randomization Procedures ............................................................................... 15 
4.1 Randomization ........................................................................................ 17 
4.2 Eligibility Verification .............................................................................. 17 
4.3 Stratification Factors ............................................................................... 17 
4.4 Additional Requirements ........................................................................ 18 
4.5 Investigator’s Drug Brochure and Safety Alerts ...................................... 18 
4.6 IND Status ................................................................................................ 19 
4.7 Emergency Unblinding ............................................................................ 19 
4.8 Instructions for Patients Who Do Not Start Assigned Protocol Treatment19 
5. Treatment Plan ................................................................................................. 20 
5.1 Administration Schedule ......................................................................... 20 
5.2 Adverse Event Reporting Requirements ................................................. 20 
5.3 Dose Modifications ................................................................................. 27 
5.4 Supportive Care ....................................................................................... 34 
5.5 Duration of Therapy ................................................................................ 35 
5.6 Duration of Follow-up ............................................................................. 35 
6. Measurement of Effect ..................................................................................... 36 
6.1 Local, Regional Disease ........................................................................... 36 
6.2 Distant Disease ........................................................................................ 36 
6.3 Disease-Free Survival .............................................................................. 36 
6.4 Survival .................................................................................................... 36 
6.5 Second primary cancer............................................................................ 36 
7. Study Parameters .............................................................................................. 37 
8. Drug Formulation and Procurement ................................................................. 39 
8.1 Everolimus/Placebo ................................................................................ 39 
9. Statistical Considerations .................................................................................. 48 
9.1 Endpoints ................................................................................................ 48 
9.2 Sample size with power justification ...................................................... 48 
9.3 Analysis plan including plans for formal interim analysis ....................... 48 
9.4 Safety Monitoring ................................................................................... 49 
9.5 Study Monitoring .................................................................................... 49 


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9.6 Gender and Ethnicity .............................................................................. 50 
10. Specimen Submissions ...................................................................................... 51 
10.1 Submissions to the (PCORL) - MANDATORY ........................................... 51 
10.2 ECOG-ACRIN Sample Tracking System .................................................... 54 
10.3 Use of Specimens in Research ................................................................ 55 
10.4 Sample Inventory Submission Guidelines ............................................... 55 
11. Laboratory Research Studies ............................................................................ 56 
11.1 Diagnostic Review and Classification (MANDATORY) ............................. 56 
11.2 Research Studies ..................................................................................... 56 
11.3 Lab Data Transfer Guidelines .................................................................. 57 
12. Electronic Data Capture .................................................................................... 58 
12.1 Records Retention ................................................................................... 58 
13. Patient Consent and Peer Judgment ................................................................ 59 
14. References ........................................................................................................ 59 
Appendix I  Pathology Submission Guidelines ........................................................ 61 
Appendix II  Patient Thank You Letter ..................................................................... 65 
Appendix III  Patient Tablet Calendar ...................................................................... 66 
Appendix IV  ECOG Performance Status.................................................................. 68 
Appendix V  Drugs Which May Affect Everolimus Metabolism .............................. 69 
Appendix VI  Instructions for Reporting Pregnancies on a Clinical Trial ................. 70 
Appendix VII  E2212 Drug Request Form ................................................................ 72 
Appendix VIII  Hepatitis Screening .......................................................................... 73 
 


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STUDY CHAIR 
STUDY CO-CHAIR 
Steven K. Libutti, M.D. 
Montefiore Medical 
3400 Bainbridge Avenue 
Map Building, Fourth Floor 
Bronx, NY 10467 
Phone: 718-920-4231 
Fax: 718-798-0309 
Email: slibutti@montefiore.org  
 
Pamela L. Kunz, M.D. 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305-5826 
Phone: 650-725-8738 
Fax: 650-498-4696 
Email: pkunz@stanford.edu 
 
STUDY CHAIR LIAISON (SCL) 
Monique White 
Montefiore Medical 
3400 Bainbridge Avenue 
Map Building, Fourth Floor 
Bronx, NY 10467 
Phone: 718-862-8840 
Fax: 718-862-8854 
Email: mnwhite@montefiore.org  
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Data collection will be performed 
exclusively in Medidata Rave: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Please refer to the patient 
enrollment section for 
instructions on using the 
OPEN system. 
Please refer to the Forms 
Completion Guidelines for the Forms 
Submission Schedule.  
The study protocol and all related forms and documents must be downloaded from the protocol-
specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Sites must use the 
current form version and adhere to the instructions and submission schedule outlined in the protocol. 
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, 
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
For patient eligibility or treatment-related questions Contact the Study PI of the Coordinating Group. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU 
Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org 
The CTSU Web site is located at   https://www.ctsu.org 
 
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Schema 
 
Accrual Goal: 150 patients
Cycle = 4 week (28 days)
R
A
N
D
O
M
I
Z 
E
Stratification
• R0 versus R1 resection
• Primary tumor resection with 
metastasectomy versus primary 
tumor resection prior to 
metastasectomy 
• RF or microwave ablation plus 
resection versus resection alone
Everolimus 10 mg
PO daily
Placebo 10 mg 
PO daily
Long-term Follow-up
Arm A1
Arm B1
1. Treatment will continue for up to 12 cycles (approximately 1 year).
Long-term Follow-up
 
 


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1. 
Introduction 
Pancreatic neuroendocrine tumors (PNETs) have a spectrum of behavior from indolent 
to quite aggressive with the liver being the most common site of metastases. Patients 
with metastatic disease have a median survival of 24 months (1-3). To date, medical 
treatment options have been limited and include: chemotherapy-based streptozocin and 
doxorubicin, which has debated efficacy; sunitinib, a tyrosine-kinase inhibitor that 
appears to have antitumor activity (4-7). More recently, studies of the mammalian target 
of rapamycin (mTOR), a serine-threonine kinase, demonstrates its role in tumor growth 
(8).  Everolimus, an oral inhibitor of mTOR, appears to confer a statistically significant 6-
month prolongation in median disease free survival over placebo in patients with 
advanced PNETs (4.6 vs. 11.0 months) with a reasonable side effect profile (9). 
Despite advances in the medical treatment options for advanced PNETs, only 
cytoreductive strategies, by way of hepatic resection or ablation, have been shown to 
significantly improve overall survival or to provide an opportunity for cure (10-12).  While 
the majority of patients recur (94% by 5 years), and while it is difficult to obtain an R0 
resection, the morbidity and mortality rates are acceptably low, and surgical resection of 
liver metastases seems to increase median survival to 125 months (1, 10), more if the 
patients undergo further hepatectomy following recurrence. For patients undergoing an 
R0 or R1 resection of liver metastases from a PNET, the median recurrence free survival 
is 15 months in the largest series and comparable in others (1, 13, 14). Given this 
knowledge of the survival benefit from surgical metastasectomy and the antiproliferative 
effect of everolimus, we propose to study a combined medical and surgical approach, to 
evaluate this combined strategy on both recurrence free survival and overall survival.   
Additionally, there is precedent for using targeted agents in the adjuvant setting – 
specifically imatinib following resection of gastrointestinal stromal tumors (GISTs), which 
improves recurrence free survival (15, 16). GISTs harbor mutations in the KIT proto-
oncogene (85%) and platelet-derived growth factor alpha receptor (3-5%). Imatinib 
specifically targets these pathways involved in GIST carcinogenesis including KIT, 
PDGFR A, and other ABL and BCR-ABL tyrosine kinases. Everolimus likewise targets a 
relevant pathway in NET carcinogenesis as PNETs are known to have mutations in 
mTOR (17).  The concept of adjuvant therapy following surgical metastasectomy as a 
means of improving time to recurrence has also been validated in the treatment of stage 
IV colorectal cancer (18). 
 
Trial Design 
The trial design would be a prospective, randomized placebo controlled study of 
adjuvant everolimus (orally at 10 mg per day) versus placebo after surgical 
resection (with or without ablation) of liver metastases from a PNET to an R0 or 
R1 resection. Patients will be randomized after surgery. Patients will receive 
study drug (ARM A) or placebo (ARM B) for approximately 12 months following 
resection or until recurrence whichever comes first. The current standard of care 
following resection is no treatment; therefore, placebo is an acceptable control 
arm in this patient population. The primary endpoint will be recurrence free 
survival with overall survival as a secondary endpoint. Given that everolimus in 
patients with advanced PNET improves progression free survival from 4.6 to 11.0 
months as seen in the RADIANT-3 study (a > 50% improvement), we would 
predict that the addition of everolimus to surgical metastasectomy would improve 
disease free survival from 15 to 27 months (conservatively < 50% improvement). 


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A prospective randomized double-blinded study is necessary in order to assess 
impact on disease free survival.  
 
Background For Potential Laboratory Research Studies 
Genes are frequently mutated in pancreatic neuroendocrine tumors.  
Genes 
Frequency Mutated (n=68) 
MEN1 
44% (30) 
DAXX 
25% (17) 
ATRX 
18% (12) 
PTEN 
7% (2) 
TSC2 
9% (6) 
PIK3CA 
1% (1) 
The mutations in the PTEN/PIK3CA/MROT pathway suggests that tumors with 
activating mutations in this pathway may be preferentially sensitive to treatment 
with mTOR inhibitors, these patients with tumors that are mutant for PIK3CA, 
PTEN or TSC may benefit in terms of DFS and OS. Further characterization of 
the tumors by exploring genes such as MEN1, DAXX, ATRX and mutations in 
chromatin remodeling may give insight to patient outcome. Mutations in 
chromatic remodeling have been demonstrated to confer a survival benefit in 
patients with metastatic neuroendocrine tumors (mOS of 5 years vs. 13 years; 
HR 0.14; p=0.02). 
Small fragments of DNA (165 bp) are released by tumors into the circulation and 
can be distinguished from DNA fragments released by normal cells using the 
mutations found in the tumor. Circulating tumor DNA (ctDNA) is only detectable 
when there is tumor present and quickly disappears from the circulation (half-life 
~ 2 hours) after tumor resection. A recent study by our laboratory, applied a 
digital genomic method to detect and quantify ctDNA in patients with colorectal 
cancer (21). This approach termed “BEAMing”, which was named after 
components of this method (Beads, Emulsification, Amplification and Magnetics). 
This method uses standard laboratory tools and reagents to create a water-in-oil 
emulsion wherein each aqueous microdroplet houses an individual fragment of 
DNA bound to a bead. This setting allows billions of compartmentalized 
polymerase chain reactions (PCR) to be performed in parallel in a single test 
tube. The products of these reactions coat each bead with thousands of copies of 
DNA fragments that are identical to the single DNA molecule originally present. 
In this case, the result is millions of beads coated entirely with either mutant or 
wild-type DNA. To distinguish mutant from wild-type coated beads, allele-specific 
fluorescent probes complementary to the known wild-type or mutant sequences 
are simultaneously added to the beads for hybridization. The beads are then 
accessed via flow cytometry to detect rare mutant DNA molecules among a 
much larger number of normal DNA molecules. BEAMing is a digital assay and is 
able to count the frequency of individual DNA fragments in a sample.  
In a cohort of patients with colorectal cancer, tumor response and progression 
was tracked in patients using ctDNA as a biomarker of tumor burden. For each 
patient, the mutation profile for his or her tumor was identified from 
microdissected paraffin embedded tissue.  BEAMing assay was used to quantify 


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ctDNA over time in each patient undergoing multi-modality treatment for 
colorectal cancer over the course of 1-2 years. The results from this study 
demonstrated that ctDNA could be used a biomarker of tumor burden and that 
dynamic changes in ctDNA levels correlated with tumor response and 
progression (Figure, below). Of note, ctDNA was detected in 100% of patients 
evaluated. In addition, ctDNA was significantly more sensitive than the standard 
protein biomarker used in colorectal cancer monitoring (CEA – Carcinoembryonic 
Antigen). One of the most promising aspects of this study was showing that 
ctDNA was sufficiently sensitive to detect minimal residual disease after surgical 
resection with curative-intent (Figures, below), thereby detecting micrometastatic 
disease and recurrence before it was evident with traditional protein biomarkers 
or imaging.  
 
 


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2. 
Objectives 
 
Primary objective:  
2.1.1 
To evaluate if the addition of adjuvant everolimus to the R0 or R1 
surgical resection of pancreatic neuroendocrine tumor metastases to 
the liver will result in an improvement in disease free survival. 
 
Secondary objectives: 
2.2.1 
To evaluate if the addition of adjuvant everolimus to the R0 or R1 
surgical resection of pancreatic neuroendocrine tumor metastases to 
the liver will result in an improvement in overall survival. 
2.2.2 
To evaluate the toxicity associated with adjuvant everolimus following 
resection in patients with metastatic pancreatic neuroendocrine 
tumors to the liver. 


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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
 
Eligibility: Criteria 
3.1.1 
Patients must have histologically or pathologically confirmed 
metastatic low or intermediate grade pancreatic neuroendocrine 
tumor(s) to the liver as per the Klimstra guidelines (20). 
3.1.2 
Patients must have recovered from an R0 or R1 resection of all 
disease (including resection of a primary PNET if present). Patients 
may have had resection plus microwave or radiofrequency ablation, 
provided that no ablated lesion was ≥ 5 cm prior to ablation. 
3.1.3 
Patients must be within 4 to 8 weeks from the completion of surgery at 
time of randomization.  
3.1.4 
Patients must have paraffin-embedded fixed metastatic tumor tissue 
available for submission for central review per Sections 10 and 11. 
Core biopsy or surgical specimens required. 
3.1.5 
 Patients must have post-operative CT or MRI to confirm no evidence 
of disease within 4 weeks prior to randomization. Patients must be 
able to tolerate CT or MRI imaging including contrast agents as 
required for the protocol. 
3.1.6 
Patients must NOT have either clinically apparent central nervous 
system metastases or carcinomatous meningitis ≤ 6 months prior to 
randomization. 
3.1.7 
Women must NOT be pregnant or breast-feeding due to possible risk 
involved in taking everolimus. 
All females of childbearing potential must have a blood test within 2 
weeks prior to randomization to rule out pregnancy. A female of 
childbearing potential is any female, regardless of sexual orientation 
or whether they have undergone tubal ligation, who meets the 
following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy or 2) has not been naturally postmenopausal for at 
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least 24 consecutive months (i.e. has had menses at any time in the 
preceding 24 consecutive months). 
Female? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.8 
Women of child-bearing potential and sexually active males must be 
strongly advised to use an accepted and highly effective method of 
contraception or abstain from sexual intercourse for the duration of 
their treatment through 8 weeks after their last dose of protocol 
therapy. Women of child-bearing potential, sexually active males, and 
the female partners of male participants should be advised of the risk 
or becoming pregnant or fathering a child while receiving protocol 
treatment. Should a woman become pregnant while participating in 
this study, she should inform her treating physician immediately. If a 
man impregnates a woman while participating in this study, he should 
inform his treating physician immediately. See Section 8.1.14 for 
information on methods of contraception. 
3.1.9 
Prior treatment with sunitinib and/or cytotoxic chemotherapy are 
allowed provided last dose was > 30 days prior to randomization. 
3.1.10 
Prior chemoembolization is allowed provided last dose was > 30 days 
prior to randomization. 
3.1.11 
Patients must NOT have received prior everolimus.  
3.1.12 
Patients may not be receiving any other investigational agents while 
on study treatment. Prior treatment with other investigational agent is 
allowed provided last dose was > 30 day prior to randomization. 
3.1.13 
Patients must have normal organ and marrow function as defined 
below within ≤ 4 weeks prior to randomization: 
3.1.13.1 
Total bilirubin ≤ 1.5 X institutional upper limit of normal 
(ULN)  
ULN: _________ Bilirubin:_________ Date:________ 
3.1.13.2 
AST(SGOT)/ALT(SGPT) ≤ 5 X institutional ULN  
ULN: _________ AST_________ Date:________ 
ULN: _________ ALT_________ Date:________ 
3.1.13.3 
Serum creatinine ≤ 1.5 X institutional ULN or creatinine 
clearance ≥ 60 mL/min for patients with creatinine levels 
above 1.5 X institutional normal. 
ULN: _________ Creatinine: ________ Date:________ 
Creatinine clearance: ________ Date:________ 
3.1.13.4 
Fasting serum total cholesterol ≤ 300 mg/dL OR ≤ 7.75 
mmol/L AND fasting triglycerides ≤ 2.5x ULN.  
NOTE: 
If one or both of these thresholds are exceeded, 
the patient can only be randomized after 
initiation of appropriate lipid lowering 
medication 
_____
_____


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Fasting serum cholesterol: ________ Date:________ 
Fasting triglycerides: ________ Date:________ 
Lipid lowering medication: ______ (Yes or No) 
3.1.13.5 
 Absolute neutrophil count ≥ 1,500/mm3 
Neutrophil count: _______ Date:________ 
3.1.13.6 
Leukocytes ≥ 3,000/mm3 
Leukocytes: _______ Date:________ 
3.1.13.7 
 Platelets ≥ 100,000/mm3 
Platelets: _________ Date:________ 
3.1.13.8 
Hemoglobin ≥ 9 g/dL 
Hemoglobin: _________ Date: ________ 
3.1.14 
Patients must NOT have ongoing cardiac dysrhythmia of NCI CTCAE 
v4.0 Grade ≥ 2, uncontrolled atrial fibrillation of any grade, or QTc 
interval > 470 msec. 
3.1.15 
Patients with a history of the following within ≤ 12 months of 
randomization are not eligible. 
• 
Arterial thromboembolic events: Yes____ Date:______ No:_____ 
• 
Unstable angina: Yes_____ Date:_____ No:_____ 
• 
Myocardial Infarction: Yes_____ Date:______ No:______ 
3.1.16 
Patients must NOT have experienced thrombotic events (deep vein 
thrombosis, pulmonary embolism) ≤ 3 months prior to randomization.  
3.1.17 
Patients must NOT have liver disease such as cirrhosis, chronic 
active hepatitis, or chronic persistent hepatitis at randomization. 
Patients at increased risk for hepatitis B or hepatitis C per Appendix 
VIII must be screened for hepatitis prior to randomization. 
3.1.18 
Patients must NOT have history of severely impaired pulmonary 
function for their age due to the risk of noninfectious pneumonitis. 
Patients with known history of abnormal pulmonary function must 
have documentation of DLCO of  > 50% predicted and SaO2 of > 87% 
at rest on room air ≤ 4 weeks prior to randomization. 
3.1.19 
Patients with unexplained pulmonary infiltrates must have pulmonary 
function tests within the institutional limits of normal ≤ 4 weeks prior to 
randomization. 
3.1.20 
Patients with known history of HIV seropositivity are ineligible due to 
lack of safety data on combining antiretroviral therapy, the 
immunosuppressive effects of everolimus and the risk of opportunistic 
infection.  
3.1.21 
Patients with poorly controlled diabetes mellitus as defined by HbA1c 
> 8% despite adequate therapy are ineligible. Patients with a known 
history of impaired fasting glucose or diabetes mellitus must have 
blood glucose and antidiabetic treatment monitored closely throughout 
the trial and adjusted as necessary. 
_____
_____


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3.1.22 
Patients must NOT have any severe and/or uncontrolled medical 
conditions such as: 
a. unstable angina pectoris, symptomatic congestive heart failure, 
myocardial infarction ≤ 6 months prior to randomization, serious 
uncontrolled cardiac arrhythmia, or any other clinically significant 
cardiac disease 
b. Symptomatic congestive heart failure of New York Heart 
Association Class III or IV 
c. active (acute or chronic) or uncontrolled severe infection, liver 
disease such as cirrhosis, decompensated liver disease, and 
chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive 
HbsAg, quantifiable HCV-RNA) 
d. active, bleeding diathesis 
3.1.23 
Patients must NOT have previous or concurrent malignancy. 
Exceptions are made for patients who meet any of the following 
conditions: 
• 
Non-melanoma skin cancer, in situ cervical cancer, breast cancer 
in situ, or superficial bladder cancer (noninvasive papillary 
carcinoma or carcinoma in situ). 
OR 
• 
Prior malignancy completely excised or removed and patient has 
been continuously disease free for > 5 years. 
Date of last evidence of disease: ___________ 
3.1.24 
Patients may not be receiving any other investigational agents while 
on study treatment. Prior treatment with other investigational agent is 
allowed provided last dose was ≥ 30 days prior to randomization.  
3.1.25 
Patients must NOT have received live attenuated vaccines ≤ 1 week 
prior to randomization. Patients should also be advised not to receive 
live attenuated vaccines during the study and to 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. 
3.1.26 
Patients must NOT be on chronic treatment with corticosteroids or 
other immunosuppressive agents. Topical or inhaled corticosteroids 
are allowed. 
3.1.27 
Patients should be advised to avoid drugs or foods that are known 
potent CYP3A4 inhibitors or inducers, included but not limited to those 
outlined in Appendix V. 
3.1.28 
Patients must NOT have history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to everolimus. 
3.1.29 
Patients must NOT have known intolerance or hypersensitivity to 
everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus). 
_____
_____
_____
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3.1.30 
Patients must NOT have absorption issues that would limit the ability 
to absorb everolimus.  
3.1.31 
Patients must NOT have a history of non-compliance to medical 
regimens or who are considered potentially unreliable or will not be 
able to complete the entire study.  
3.1.32 
Patients must be at least ≥ 18 years of age. 
3.1.33 
Patients must have ECOG performance status ≤ 1. (Refer to 
Appendix IV) 
3.1.34 
Patients must have life expectancy ≥ 12 weeks. 
 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to use 
the eligibility checklist as source documentation. 
 
_____
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4. 
Randomization Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group. Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet (FDA Form 1572 with original 
signature, current CV, Supplemental Investigator Data Form with signature, and 
Financial Disclosure Form with original signature) to the Pharmaceutical Management 
Branch, CTEP, DCTD, NCI. These forms are available on the CTSU Web site (enter 
credentials at https://www.ctsu.org; then click on the Register tab) or by calling the PMB 
at 240-276-6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org. 
Requirements for E2212 site registration: 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
Submitting Regulatory Documents 
Before an ECOG-ACRIN Institution may enter patients, protocol specific regulatory 
documents must be submitted to the CTSU Regulatory Office at the following address:   
 
CTSU Regulatory Office 
 
Coalition of National Cancer Cooperative Groups 
 
1818 Market Street, Suite 1100 
 
Philadelphia, PA 19103 
 
FAX: (215) 569-0206 
Required Protocol Specific Regulatory Documents 
1. CTSU Regulatory Transmittal Form. 
2. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
3. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter. 
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NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
The CTSU encourages you to link to the following RSS2.0 webpage so that more 
information on RSS2.0 as well as the submission forms can be accessed. Log in to 
http://www.ctsu.org and click on the Regulatory tab to access the RSS web page. If you 
have questions regarding regulatory document submission, please telephone the CTSU 
Help Desk at 1-888-823-5923 or E-mail CTSUContact@westat.com.   
Patients must not start protocol treatment prior to randomization. 
Treatment must start within five working days after randomization. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to this study.  
OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool 
to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
Access requirements for OPEN:  
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for the CTSU 
members' web site.  
• 
To perform registrations, the site user must have been assigned the 'Registrar' role 
on the relevant Group or CTSU roster.  
• 
To perform registrations on protocols for which you are a member of the Lead Group, 
you must have an equivalent 'Registrar' role on the Lead Group roster. Role 
assignments are handled through the Groups in which you are a member. 
• 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead 
Group registrations) you must have the role of Registrar on the CTSU roster. Site 
and/or Data Administrators can manage CTSU roster roles via the new Site Roles 
maintenance feature under RSS on the CTSU members' web site. This will allow 
them to assign staff the "Registrar" role. 
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NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
Randomization  
Please note that no blinded starter supplies will be available for this study. At the 
time of patient randomization each patient will be assigned a specific blinded 
drug ID number (e.g. DR117). This blinded drug ID number should be included 
on the drug request form that is submitted to the ECOG-ACRIN Drug Team. (See 
Section 8 for complete details.) 
Please note that when a patient has been successfully randomized, the 
confirmation of randomization will indicate that the patient is on arm X. The 
patient will actually be randomized to arm A or B, but as this is a double-
blind trial, that information cannot be displayed. 
At time of randomization, the following information will be requested:  
4.1.1 
Protocol Number 
4.1.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
4.1.3 
Patient Identification 
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
 
Stratification Factors 
Stratification will only be used to ensure balance between groups, not for subset 
analysis. There are three stratification factors as follows: 
4.3.1 
R0 versus R1 resection 
4.3.2 
Primary tumor resection  
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4.3.2.1 
Primary tumor resection with metastasectomy 
4.3.2.2 
Primary tumor resection prior to metastasectomy 
4.3.3 
Resection ± ablation 
4.3.3.1 
RF or microwave ablation plus resection 
4.3.3.2 
Resection alone 
 
Additional Requirements  
4.4.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston.  
4.4.2 
Pathological samples are required to be submitted for central 
diagnostic review as indicated in Section 10.  
4.4.3 
Biological samples to be submitted for research as outlined in Section 
10. 
4.4.4 
Data collection for this study will be done exclusively through 
Medidata Rave. Access to the trial in Rave is granted through the 
iMedidata application to all persons with the appropriate roles in RSS. 
To access iMedidata/Rave the site user must have an active CTEP 
IAM account (https://eapps-ctep.nci.nih.gov/iam). In addition, site 
users that are a member of ECOG-ACRIN must have the mapped 
ECOG-ACRIN roles or explicit Rave roles (Rave CRA, Read-Only, 
Site Investigator) in RSS at the enrolling site. Site users that are not 
members of ECOG-ACRIN must have the Rave roles on the CTSU 
roster at the enrolling sites. The Site Administrator or Data 
Administrator at the enrolling site may assign the appropriate roles 
from the Site Roles tab on the CTSU website. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be listed in the upper right pane of the iMedidata screen. 
Users that have not previously activated their iMedidata/Rave 
accounts will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on 
the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on the CTSU 
website under the Rave tab at http://www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.5 
Investigator’s Drug Brochure and Safety Alerts 


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The Investigator Drug Brochure (IDB) for everolimus is available for download 
from the ECOG-ACRIN webpage. The IDB provides relevant and current 
scientific information about the investigational product. The IDB should be 
submitted to your IRB/EC according to GCP regulations. The IDB and any 
correspondence to the Institutional Review Board (IRB)/Ethics Committee (EC) 
should be kept in the E2212 regulatory files.  
Should any SAE report on this study qualify as a safety alert report requiring 
expedited reporting, the SAE report will be sent by the respective pharmaceutical 
company to regulatory authorities globally (including the FDA) and ECOG-
ACRIN. If applicable, ECOG-ACRIN will disseminate these safety alert reports to 
all ECOG-ACRIN investigators in the bimonthly group mailings. These reports 
should be forwarded to your IRB/EC within 90 days of receipt for review. 
Reporting instructions are provided with each safety alert. These safety alerts 
and any correspondence to your IRB/EC should be maintained in your E2212 
study files. 
 
IND Status  
When used in this protocol. Everolimus/placebo are each classified as an 
“unapproved use of an approved agent” and by definition considered 
investigational agents. However, while it is not an indication currently approved 
by the FDA, the use of everolimus/placebo in this protocol is exempt from the 
requirements of an IND and described under Title 21 CFR 312.2(b). 
 
Emergency Unblinding 
The information provided below is for the use by a physician, nurse, CRA 
or pharmacist treating the patient. These contact numbers should not be 
used by patients. Patients should be instructed to call their doctor’s office 
in the event of an emergency or adverse event that may result in the need 
to unblind the patient. 
In the event of an emergency or severe adverse reaction necessitating 
identification of the medication for the welfare of the patient, please contact the 
Study Chair, Dr. Steven Libutti M.D., at 718-920-4231 or Email 
slibutti@montefiore.org, first to ensure the reason for unblinding is valid. Then 
call a member of the ECOG-ACRIN Operations Office – Boston drug team at 
(617) 632-3610 Monday through Friday between 9:00 AM and 5:00 PM Eastern 
Time. For unblinding outside of these hours, contact AnswerConnect at 1-866-
296-8940. This service will request the reason for unblinding and then page the 
on-call ECOG-ACRIN staff who will return your call and provide the unblinded 
treatment assignment if applicable. Remember, AnswerConnect should only be 
contacted outside of normal business hours and only in the event of an 
emergency. The ECOG-ACRIN Operations Office – Boston or AnswerConnect 
will require the protocol number (i.e., “E2212”), the patient ID number (e.g., 
“44444”), and the patient initials (e.g., “FL”) to unblind the patient.  Note that if a 
patient is unblinded, he/she must discontinue protocol treatment. 
 
Instructions for Patients Who Do Not Start Assigned Protocol Treatment 
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the E2212 Forms Completion Guidelines. 


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5. 
Treatment Plan 
 
Administration Schedule 
One cycle = 28 days. 
NOTE: 
Everolimus/placbo is packaged in blister cards of ten 5 mg tablets; 
patients should receive 6 blister cards (30 doses) for each 28 day 
cycle. The start of each treatment cycle may be scheduled up to 2 
days later than the expected Day 1 of that cycle. 
Patients should take everolimus/placebo, 10 mg, orally once daily at the same 
time every day, either consistently with food or consistently without food.  
A missed dose may still be taken up to 6 hours after the normally scheduled time. 
If more than 6 hours have elapsed, patient should be instructed to skip the dose 
for that day. The next day, they should take everolimus/placebo at the usual time. 
Patients should not take 2 doses to make up for the one that they missed. 
If vomiting occurs, no attempt should be made to replace the vomited dose. 
Everolimus/placebo tablets should not be crushed or chewed. Tablets should be 
swallowed whole with a glass of water. For patients unable to swallow tablets, 
everolimus/placebo tablets should be dispersed completely in a glass of water 
(containing approximately 30 mL) by gently stirring, immediately prior to drinking. 
The glass should be rinsed with the same volume of water and the rinse should 
be completely swallowed to ensure that the entire dose is administered. 
5.1.1 
Treatment/ARM A 
Everolimus 10 mg PO daily 
Repeat cycles every 28 days for a maximum duration of 12 cycles. 
5.1.2 
Treatment/ARM B 
Placebo PO daily 
Repeat cycles every 28 days for a maximum duration of 12 cycles. 
 
Adverse Event Reporting Requirements 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
• 
Routine reporting:  Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave.   
• 
Expedited reporting:  In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
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5.2.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution:  An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
• 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred.   
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 


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CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to 
• 
the AE Team at ECOG-ACRIN (617-632-3610)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours.  
NCI Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both  
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade  
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
• 
when the adverse event occurred (within 30 days of the last 
administration of everolimus/placebo vs. ≥ 30 days after the last 
administration of everolimus/placebo) 
• 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E2212 and outline 
the specific expedited adverse event reporting requirements for 
study E2212. 


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5.2.5 
Steps to determine if an adverse event is to be reported in an 
expedited manner 
5.2.5.1 
Guidelines for adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the 
last administration of the everolimus/placebo. 
 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the 
table below in Section 5.2.6. 
Yes 
No 
Identify the type and 
grade of the event 
using CTCAE v4.0. 
Determine if the patient 
was hospitalized for ≥ 
24 hours for the event. 
With this information, review 
the chart in Section 5.2.6 to 
determine if event is 
reportable via CTEP-AERS. 
Refer to Section 5.2.7 to 
determine if the event 
meets the protocol specific 
reporting requirements for 
this study. If so, report the 
event via CTEP-AERS. 
Refer to Section 5.2.7 to determine 
if the event meets the protocol 
specific reporting requirements for 
this study.  If so, report the event 
via CTEP-AERS. 
Is the event 
reportable? 
No 
Yes 
Report the event via 
CTEP-AERS. 


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5.2.5.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
everolimus/placebo. 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.5.2, AND has 
an attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 4 and 5 adverse events  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported via CTEP-AERS even if the patient 
is off study. 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
• 
Grade 3 adverse events 
5.2.6 
Expedited Reporting Requirements for Arm X (Arm A or B) on 
Protocol E2212 
Investigational Agents:  Everolimus/Placebo 
Commercial Agents:  None 
NOTE: 
Although the agents used on this protocol are IND exempt, 
the adverse event investigational reporting requirements 
will be used on this protocol. 
Late Phase 2 and Phase 3 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
of investigational agent/intervention. 
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REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
• “24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
• “10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
5.2.7 
Additional instructions, requirements and exceptions for 
protocol E2212 
Additional Instructions: 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
birth defect events via CTEP-AERS, please contact the AEMD Help 
Desk at aemd@tech-res.com or 301-897-7497. This will need to be 
discussed on a case-by-case basis. 
 
E2212 specific expedited reporting requirements: 
• 
Pregnancy 
Pregnancies and suspected pregnancies (including a positive or 
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occurring while the subject is on Everolimus/Placebo, or within 
28 days of the subject’s last dose of Everolimus/Placebo, are 
considered immediately reportable events. The pregnancy, 
suspected pregnancy, or positive/inconclusive pregnancy 
test must be reported via CTEP-AERS within 24 hours of 
the Investigator’s knowledge.   
Please refer to Appendix VI for detailed instructions on how 
to the occurrence of a pregnancy as well as the outcome of 
all pregnancies. 
5.2.8 
Other recipients of adverse event reports and supplemental data 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and Novartis within 24 hours of receipt. 
A drug supporter representative may call a site for additional or 
supplemental information regarding a serious adverse event. Any 
additional written AE information requested by the drug supporter 
MUST be submitted to BOTH ECOG-ACRIN and the drug supporter. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.9 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol). Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 


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• 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or  
c.) treatment related secondary malignancy. 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even if 
ECOG-ACRIN was not the patient's most recent trial. 
NOTE: Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should be 
submitted via CTEP-AERS or by the Second Primary Form. 
 
Dose Modifications  
5.3.1 
General 
If dose reduction is required, reduction is permanent. Missed doses 
may be taken up to 6 hours after normally scheduled time. If more 
than 6 hours have elapsed, patient should be instructed to skip the 
dose for that day. The next day, they should take everolimus/placebo 
at the usual time. Patients should not take 2 doses to make up for the 
one that they missed. 
If multiple toxicities are seen, the dose administered in a subsequent 
cycle should be based on the most severe toxicity experienced in the 
current cycle.  
AEs determined to be unrelated to study treatment will not require 
dose reduction.  
If everolimus/placebo is held for > 4 weeks (28 days), patient 
must discontinue protocol treatment. 
All toxicities should be graded according to the Common 
Terminology Criteria for Adverse Events (version 4.0).  
All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov).  
5.3.2 
Everolimus/Placebo Dose Modifications  
• 
For individual subjects, dose modifications will be based on 
hematologic or non-hematologic toxicity, laboratory test results, 


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and clinical assessment on the day of treatment and during the 
previous cycle. 
• 
If dose delays are required, weekly evaluation with laboratory 
tests and clinical assessments, if applicable, should be performed 
until recovery to the specified grade or until the subject is 
discontinued from the study. 
• 
If toxicities have not resolved within ≤ 4 weeks (28 days), patient 
must discontinue protocol treatment. 
• 
The study chair or study chair liaison should be contacted for dose 
delays and modifications for all other toxicities not listed in this 
section. 
• 
One dose reduction is permitted before everolimus/placebo will be 
discontinued. Patients who require further dose reductions beyond 
the -1 dose level must be discontinued from study treatment.  
Everolimus/Placebo Dose Level Table 
Dose Level 
Dose in mg 
0 
10 mg daily 
-1 
5 mg daily 
5.3.2.1 
Management of Hematologic Toxicity 
Toxicity 
Action 
Grade 2 Platelet count decreased  
No action 
Grade 3 Platelet count decreased 
Interrupt everolimus/placebo until resolution to grade ≤ 1  
If resolution occurs ≤ 7 days, reintroduce everolimus/placebo at 
the dose level prior to interruption. 
If resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce everolimus/placebo at one dose level lower, if 
available. 
Grade 4 Platelet count decreased 
Interrupt everolimus/placebo until recovery to grade ≤ 1. Then 
reintroduce everolimus/placebo at one dose level lower, if 
available.  
Grade 3 Neutrophil count 
decreased 
Interrupt everolimus/placebo until resolution to grade ≤ 1 or 
baseline value 
If AE resolution occurs ≤ 7 days, reintroduce everolimus/placebo 
at the same dose level. 
If AE resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce everolimus/placebo at one dose level lower, if 
available. 
Grade 4 Neutrophil count 
decreased or grade 4 Anemia 
Interrupt everolimus/placebo until recovery to grade ≤ 1 or 
baseline value. Reintroduce everolimus/placebo at one dose level 
lower, if available. 
Febrile neutropenia 
Interrupt everolimus/placebo until resolution to grade ≤ 1 (or 
baseline value) and no fever. Reintroduce everolimus/placebo at 
one dose level lower, if available. 
Recurrence of grade 3 hematologic 
toxicity after dose reduction 
Reduce dose to the next lower dose level, if available. 


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Recurrence of grade 4 
hematologic toxicity (including 
febrile neutropenia) after dose 
reduction 
Discontinue protocol treatment. 
Any hematologic toxicity 
requiring everolimus/placebo 
interruption for > 28 days 
Discontinue protocol treatment. 


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5.3.2.2 
Non-Hematologic Toxicity  
Toxicity 
Action 
AST or ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain current dose level 
AST or ALT elevation 
Grade 3 (> 5.0 - 20.0 ULN) 
Interrupt everolimus/placebo administration until resolution to ≤ 
grade 1 (or ≤ grade 2 if baseline values were within the range of 
grade 2). If resolution occurs ≤ 7 days, everolimus/placebo should 
be re-started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, hold 
everolimus/placebo until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce everolimus/placebo at one dose level lower, 
if available. 
AST or ALT elevation 
Grade 4 (> 20 x ULN) 
Interrupt everolimus/placebo administration until resolution to ≤ 
grade 1 (or ≤ grade 2 if baseline values were within the range of 
grade 2). If resolution occurs ≤ 7 days, everolimus/placebo should 
be re-started at one dose level lower. If resolution takes > 7 days, 
discontinue everolimus/placebo. 
Intolerable grade 3 AE, except 
hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia 
Interrupt everolimus/placebo administration until resolution to ≤ 
grade 1 or baseline grade / value. 
If resolution occurs within ≤ 7 days, everolimus/placebo should be 
re-started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, hold 
everolimus/placebo until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce everolimus/placebo at one dose level lower, 
if available. 
Patients will be withdrawn from the study if they fail to recover to ≤ 
grade 1 or baseline grade / value within 28 days. 
Any other grade 4 non-
hematologic 
Hold everolimus/placebo until recovery to grade ≤ 1 or baseline 
value 
Reintroduce everolimus/placebo at one dose level lower, if 
available. 
Grade 3 or 4 clinical liver failure 
(asterixis or 
encephalopathy/coma) 
Discontinue everolimus/placebo 
Recurrence of intolerable grade 
2 mucositis or grade 3 event 
after dose reduction 
Reduce dose to the next lower dose level, if available. 
Recurrence of grade 4 non-
hematologic toxicity after 
dose reduction 
Discontinue protocol treatment. 
Any non-hematologic toxicity 
requiring Everolimus/Placebo 
interruption for > 28 days 
Discontinue protocol treatment. 
 


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5.3.2.2.1 
Mucositis1 
Category 
Grade 
Everolimus/placebo dose 
modification 
Mucositis oral 
Grades 1 
No dose modification. 
Grades 2-4 
Hold until ≤ grade 1 then 
reduce by one dose level. 
1 
Please refer to Section 5.4.2 for mucositis and stomatitis 
supportive care information. 
5.3.2.2.2 
Stomatitis1 
Adverse Drug Reaction 
Severity 
Everolimus/Placebo Dose Adjustment and 
Management Recommendations 
Stomatitis 
Grade 1 
No dose adjustment required. 
Grade 2 
Hold until grade ≤1. 
Re-initiate everolimus/placebo at same dose. 
If stomatitis recurs at grade 2, hold until ≤ grade 1 then 
reduce by one dose level. 
Grade 3 
Hold until ≤ grade 1 then reduce by one dose level. 
Grade 4 
Discontinue protocol therapy and treat with appropriate 
medical therapy. 
1. Please refer to Section 5.4.2 for mucositis and stomatitis supportive care information. 
5.3.2.2.3 
Diarrhea 
Appearance of grade 1-2 diarrhea attributed 
to study drug toxicity may be treated with 
supportive care such as loperamide, 
initiated at the earliest onset (for example 4 
mg orally followed by 2 mg orally every 2 
hours until resolution of diarrhea). 
5.3.2.2.4 
Metabolic Events: Hyperlipidemia and 
Hyperglycemia 
Hyperglycemia has been reported in clinical 
trials. Monitoring of fasting serum glucose is 
recommended prior to the start of 
everolimus/placebo and periodically 
thereafter. Optimal glycemic control should 
be achieved before starting a patient on 
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Category 
Grade 
Everolimus/Placebo Dose Adjustment and 
Management Recommendations 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia) 
Grade 1 
No dose adjustment required. 
Initiate appropriate medical therapy and monitor. 
Grade 2 
No dose adjustment required. 
Manage with appropriate medical therapy and 
monitor. 
Grade 3 
Hold until ≤ grade 1 then reduce by one dose level. 
Manage with appropriate medical therapy and 
monitor. 
Grade 4 
Discontinue protocol therapy and treat with 
appropriate medical therapy. 
5.3.2.2.5 
Pulmonary Toxicity 
Category 
Grade 
Everolimus/placebo dose modification 
Vital 
Capacity 
Abnormal 
Grades 1 
Obtain CT scan with lung windows. Continue previous dose of treatment. 
Grade 2 
Obtain CT scan with lung windows. Obtain pulmonary function testing 
including spirometry, DLCO, and room air O2 saturation at rest. Hold protocol 
treatment until toxicity improves to ≤ grade 1, then resume with one dose 
level reduction of treatment. Steroids may be used at the discretion of the 
treating physician for relief of symptoms associated with pulmonary toxicity. 
Grade 3 
Obtain CT scan with lung windows and pulmonary function testing including 
spirometry, DLCO, room air O2 saturation at rest, and bronchoscopy. Hold 
protocol treatment until recovery to ≤ grade 1, then resume treatment with 
one dose level reduction. Steroids may be used at the discretion of the 
treating physician for relief of symptoms associated with pulmonary toxicity. 
Grade 4 
Obtain CT scan with lung windows and pulmonary function testing including 
spirometry, DLCO, room air O2 saturation at rest, and bronchoscopy. 
Discontinue protocol treatment. Steroids may be used at the discretion of the 
treating physician for relief of symptoms associated with pulmonary toxicity. 
5.3.2.2.6 
Non-Infectious Pneumonitis 
Non-infectious pneumonitis is a class effect 
of rapamycin derivatives. Cases of non-
infectious pneumonitis (including interstitial 
lung disease) have also been described in 
patients taking Everolimus. Some of these 
have been severe and on rare occasions, a 
fatal outcome was observed. 
A diagnosis of non-infectious pneumonitis 
should be considered in patients presenting 
with non-specific respiratory signs and 
symptoms such as hypoxia, pleural effusion, 
cough or dyspnea, and in whom infectious, 
neoplastic and other non-medicinal causes 
have been excluded by means of 
appropriate investigations. Patients should 


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be advised to report promptly any new or 
worsening respiratory symptoms. 
Consultation with a pulmonologist is 
recommended for any case of pneumonitis 
that develops during the study. 
Worst grade 
pneumonitis 
Suggested investigations 
Management of 
pneumonitis 
Everolimus/placebo dose 
adjustment 
Grade 1 
CT scans with lung windows. 
No specific 
therapy is required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
CT scan with lung windows. 
Consider pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy 
and/or BAL. Monitoring at each 
visit until return to ≤ grade 1. 
Return to initial monitoring 
frequency if no recurrence. 
Symptomatic only. 
Consider 
corticosteroids 
and/or other 
supportive therapy 
if symptoms are 
troublesome. 
Rule out infection and consider 
interruption of 
Everolimus/placebo until 
symptoms improve to Grade ≤ 
1. 
Re-initiate Everolimus/placebo 
at one dose level lower.  
Discontinue 
Everolimus/placebo if failure to 
recover within ≤ 28 days. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing 
includes: spirometry, DLCO, 
and room air O2 saturation at 
rest. Monitoring at each visit 
until return to ≤ grade 1. Return 
to initial monitoring frequency if 
no recurrence. Bronchoscopy 
with biopsy and/or BAL is 
recommended. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Rule out infection and interrupt 
Everolimus/placebo until 
symptoms improve to Grade ≤ 
1. 
Consider re-initiating 
Everolimus/placebo at one 
dose level lower. 
Discontinue protocol therapy if 
failure to recover within ≤ 28 
days. 
Grade 4 
CT scan with lung windows and 
required pulmonary function 
testing, if possible, includes: 
spirometry, DLCO, and room air 
O2 saturation at rest. 
Monitoring at each visit until 
return to ≤ grade 1. Return to 
initial monitoring frequency if no 
recurrence. Bronchoscopy with 
biopsy and/or BAL is 
recommended if possible. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Rule out infection and 
discontinue protocol 
ttreatment. 


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5.3.2.2.7 
Infections 
Everolimus has immunosuppressive 
properties and may predispose patients to 
bacterial, fungal, viral or protozoal 
infections, including infections with 
opportunistic pathogens. Localized and 
systemic infections, including pneumonia, 
other bacterial infections, invasive fungal 
infections, such as aspergillosis or 
candidiasis and viral infections including 
reactivation of hepatitis B virus, have been 
described in patients taking Everolimus 
Some of these infections have been severe 
(e.g. leading to respiratory or hepatic failure) 
and occasionally have had a fatal outcome. 
Physicians and patients should be aware of 
the increased risk of infection with 
Everolimus/placebo. Treat pre-existing 
infections prior to starting treatment with 
Everolimus/placebo. While taking 
Everolimus/placebo, be vigilant for 
symptoms and signs of infection; if a 
diagnosis of infection is made, institute 
appropriate treatment promptly and 
consider interruption or discontinuation of 
protocol treatment. 
If a diagnosis of invasive systemic fungal 
infection is made, discontinue protocol 
treatment and treat with appropriate 
antifungal therapy. 
 
Supportive Care  
5.4.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.4.2 
Mucositis, Stomatitis, and Mouth Ulcers 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and 
those with gastrointestinal morbidity associated with mouth/dental 
infections, irritation of esophageal mucosa e.g. gastroesophageal 
reflux disease (GERD) and pre-existing stomatitis/mucositis must be 
monitored closely. Patients should be instructed to report the first 
onset of buccal mucosa irritation/reddening to their study physician 
immediately. 
Stomatitis/oral mucositis/mouth ulcers due to Everolimus/placebo 
should be treated using local supportive care. Please note that 
investigators in earlier trials have described the oral toxicities 
associated with Everolimus/placebo as mouth ulcers, rather than 
mucositis or stomatitis. If your examination reveals mouth ulcers 
rather than a more general inflammation of the mouth, please classify 


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the adverse event as such. The suggested paradigm for treatment of 
stomatitis/oral mucositis/mouth ulcers is as follows: 
1. For mild toxicity (grade 1), no dose adjustment required. Manage 
with non-alcoholic mouth wash or salt water (0.9%) mouth wash 
several times a day until resolution. 
2. 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®). 
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme 
derivatives may tend to worsen mouth ulcers.  These agents 
should be avoided. 
4. Antifungal agents should 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/placebo 
metabolism, therefore leading to higher Everolimus/placebo 
exposures. Therefore, topical antifungal agents are preferred if an 
infection is diagnosed. 
 
Duration of Therapy  
Patients will receive protocol therapy unless: 
5.5.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E2212 Forms Completion Guidelines.  
5.5.2 
Patient withdraws consent. 
5.5.3 
Patient experiences unacceptable toxicity.  
5.5.4 
Non-protocol cancer therapies are administered.  
5.5.5 
Disease recurrence per protocol criteria, development of new primary 
cancer, or death. 
5.5.6 
Patient completes 12 cycles of therapy.  
5.5.7 
Patient is unblinded.  
 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until disease recurrence, even if non-protocol 
therapy is initiated, and for survival for 5 years from the date of randomization. All 
patients must also be followed through completion of all protocol therapy.  
 


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6. 
Measurement of Effect 
 
Local, Regional Disease  
The development of a local or regional pancreatic neuroendocrine cancer. 
 
Distant Disease  
The development of a distant recurrence of pancreatic neuroendocrine cancer. 
 
Disease-Free Survival  
Date of randomization to the date of documented recurrence (a return of tumor 
imaged by CT or MRI), new invasive primary cancer, or death without recurrence 
 
Survival  
Date of randomization to date of death. 
 
Second primary cancer 
The diagnosis of a second primary cancer must be confirmed histologically 
whenever possible. 
 


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7. 
Study Parameters 
1. Prestudy CT scan or MRI must be done after surgery and ≤ 4 weeks before randomization. 
2. Prestudy CBC (with differential and platelet count) must be done ≤ 4 weeks before randomization.  
3. All required prestudy chemistries and hepatitis antibody lab panels must be performed ≤ 4 weeks randomization unless 
otherwise specified in Section 3. 
 
Prior to 
Randomization 
Day 1 of 
each cycle 
Every 3 cycles 
(every 12 weeks) 
End of 
Treatment13 
At 
recurrence8 
Follow-
up7 
History and Progress Notes 
X 
X 
 
X 
 
X 
Physical Exam 
X 
X 
 
X 
 
X 
Vital Signs 
X 
X 
 
X 
 
 
Weight/BSA 
X 
X 
 
X 
 
 
ECOG Performance Status 
X 
X 
 
X 
 
 
Adverse Event Assessment11 
 
X 
 
X 
 
X11 
CBC with Differential1 
X 
X 
 
X 
 
 
Serum Chemistry and Electrolytes2 
X 
X 
 
X 
 
 
Lipid Panel2 
X 
X 
 
 
 
 
Blood/Urine Pregnancy Test3,4 
X 
 X4 
 
X 
 
 
Hepatitis Antibody Lab Panels12 
X 
 
 
 
 
 
Patient table calendar 
 
X 
 
X 
 
 
Multiphasic CT Scan (Chest, Abdomen and Pelvis) or MRI of 
Abdomen and Pelvis with CT Scan of Chest 9 
X 
 
X 
X 
X 
X 
CgA, NSE level and hemoglobin A1c10  
X 
 
X 
X 
X 
X 
Tumor Measurement 
 
 
 
 
X 
 
Pathology and surgery reports 
X 
 
 
 
X 
 
Specimen Submissions: Specimens to be submitted within 4 weeks following randomization. See Section 10. 
 
MANDATORY: Pre-trial FFPE tumor5 
X 
 
 
 
 
 
Frozen Surgical Tumor Tissue6 
X 
 
 
 
 
 
Peripheral Blood, ACD vacutainer6 
 
Prior to start 
of treatment 
 
X 
 
 
Plasma from EDTA6 
 
 
X 
 
 
1. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be done ≤ 24 
hours prior to Cycle 1 Day 1, ≤ 72 hours prior to Day 1 of all subsequent cycles.  
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2. Serum electrolytes: Glucose, Na+, K+, bicarbonate, BUN, Cl, creatinine. Other serum chemistries: Albumin, total protein, alkaline phosphatase, 
SGOT(AST), SGPT(ALT), total bilirubin; Ca++. Lipid Panel: Serum fasting cholesterol and serum triglycerides. Serum electrolytes, chemistries, 
and lipid panel must be done ≤ 72 hours prior to each treatment cycle. 
3. Women of childbearing potential only. Serum pregnancy test must be performed ≤ 14 days prior to randomization and at the end of study 
treatment. Urine pregnancy testing should be performed prior to each treatment cycle at the physician’s discretion.  
4. Urine pregnancy testing should be performed prior to each treatment cycle at the physician’s discretion. 
5. Diagnostic metastatic tumor tissue (core biopsy or surgical specimen, liver mets, and diagnostic slides) must be submitted for central diagnostic 
review and classification and for optional laboratory research studies within 4 weeks following randomization as outlined in Section 10. Failure 
to submit the required materials may render the case unevaluable. 
6. Research samples are to be submitted from patients who consent to allow the samples to be submitted for research as outlined in Section 10. It 
is requested that the “prior to start of treatment” blood draws occur 6-8 weeks after surgery, prior to start of protocol therapy. Please indicate 
date of surgery in STS.  
7. Every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2-5 years from study entry. Once there is confirmation of 
recurrence, follow-up scans, CgA, NSE level, and hemoglobin A1c no longer have to be performed; patient must continue to be followed for 
survival. 
8. It is strongly encouraged that disease recurrence documented by scans also be confirmed by biopsy. If there is a recurrence, it is also strongly 
encouraged that patients be fully restaged, including a CT scan of the thorax and abdomen, imaging (preferably MRI, but CT is acceptable) of 
the brain. 
9. Baseline CT or MRI scans must be done after surgery and ≤ 4 weeks prior to randomization. After randomization, the CT Scan or MRI may be 
scheduled with a ± 2 week leeway. The scheduling of the last on-treatment scan may be moved up or delayed up to 6 weeks to also meet the 
end of treatment time frame. 
10. Chromogranin A (CgA), neuron-specific enolase (NSE) level and hemoglobin A1c should be performed at the same time scans are performed. 
If other tumor markers (i.e., glucagon, insulin, VIP, pancreatic polypeptide, gastrin) are obtained at baseline and found to be elevated, it is 
suggested to continue to follow those markers at the time points at which CgA, NSE and hemoglobin A1c are also being followed. 
11. Adverse events should be assessed 30 days after the last dose of study drug. 
12. Patients with increased risk or history of hepatitis only. See Appendix VIII. 
13. End of treatment assessments should be performed ≤ 14 days after going off treatment. 
 
Rev. 
5/14, 5/14 


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8. 
Drug Formulation and Procurement 
 
Everolimus/Placebo 
8.1.1 
Drug Orders 
Everolimus and matching placebo are being provided free of charge 
by Novartis and will be distributed by UVI. The 5 mg tablets of 
everolimus/placebo will be packaged in 10 tablets per blister pack. 
IND Status  
When used in this protocol, everolimus/placebo are each classified as 
an “unapproved use of an approved agent” and by definition 
considered investigational agents. However, while it is not an 
indication currently approved by the FDA, the use of 
everolimus/placebo in this protocol is exempt from the requirements of 
an IND and described under Title 21 CFR 312.2(b). 
Initial Orders: Following submission of the required regulatory 
documents and patient randomization, a supply of everolimus/placebo 
may be ordered. Institutions must electronically submit the completed 
E2212 Drug Request Form to the ECOG-ACRIN Drug Team at 
900.drugorder@jimmy.harvard.edu. The drug order form can be found 
in Appendix VI and is also available for download on the ECOG Web 
Site. If email is not available, the completed form may be faxed to 
ATTN: ECOG-ACRIN Drug Team at 617-632-2063. No blinded starter 
supplies are available for this protocol. 
Important information for drug orders: 
At the time of randomization each patient will be assigned a patient 
specific Blinded Drug ID number, example DR1117. The Blinded Drug 
ID number will appear on the patient’s Confirmation of Registration 
Form. 
The E2212 Drug Request Form must include the patient specific 
Blinded Drug ID number with each drug request in order for the drug 
order to be processed.  Failure to provide this information on the drug 
order form will result in a delay of the drug order being processed and 
shipped. 
This study is a double-blinded treatment protocol. Blinded blister 
packs of everolimus and matching placebo MAY NOT be 
transferred from one patient to another patient. 
Each shipment will contain a 3-month supply of everolimus/placebo. 
Study drug is provided in blister packs. Each blister pack contains 10 
5 mg tablets.  
Institutions should allow 4 business days for receipt of the 
everolimus/placebo from the date the drug request is received by UVI.  
Shipments will be made from UVI Monday through Thursday for 
delivery onsite Tuesday through Friday. 
There will be no weekend or holiday delivery of drugs. 


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Reorders: Institutions should keep in mind that shipments take 4 
business days from the date the drug request is received by the 
ECOG-ACRIN Drug Team. Reorders using the E2212 Drug Request 
Form should be emailed to the ECOG-ACRIN Drug Team at 
900.drugorder@jimmy.harvard.edu. 
Each shipment will contain a 3-month supply of everolimus/placebo. 
Study drug is provided in blister packs. Each blister pack contains 10 
5 mg tablets. 
Once approved by the ECOG-ACRIN Drug Team, the drug will be 
received on site within 4 business days. Shipments will be made from 
UVI, Inc. Shipments will be made from UVI Monday through Thursday 
for delivery onsite Tuesday through Friday. 
There will be no weekend or holiday delivery of drugs. 
8.1.2 
Drug Inventory Records 
Investigational Product Records at Investigational Site(s): It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried and disposed. Records or 
logs must comply with applicable regulations and guidelines. 
8.1.3 
Drug Destruction 
At the completion of the patient’s treatment at your institution, all 
unused drugs, partially used, or empty blister packs must be 
destroyed at the site according to the institution’s policy for drug 
destruction. Please maintain appropriate records of the disposal, 
including dates and quantities. 
8.1.4 
Emergency Unblinding 
The information provided below is for the use by a physician, 
nurse, CRA or pharmacist treating the patient. These contact 
numbers should not be used by patients.  Patients should be 
instructed to call their doctor’s office in the event of an 
emergency or adverse event that may result in the need to 
unblind the patient. 
In the event of an emergency or severe adverse reaction 
necessitating identification of the medication for the welfare of the 
patient, please contact the Study Chair, Dr. Steven Libutti M.D.,- at 
718-920-4231 or Email slibutti@montefiore.org, first to ensure the 
reason for unblinding is valid. Then call a member of the ECOG-
ACRIN Operations Office – Boston drug team at (617) 632-3610 
Monday through Friday between 9:00 AM and 5:00 PM Eastern Time. 
For unblinding outside of these hours, contact AnswerConnect at 1-
866-296-8940. This service will request the reason for unblinding and 
then page the on-call ECOG-ACRIN staff who will return your call and 
provide the unblinded treatment assignment if applicable. Remember, 
AnswerConnect should only be contacted outside of normal business 
hours and only in the event of an emergency.  The ECOG-ACRIN 
Operations Office – Boston or AnswerConnect will require the protocol 


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number (i.e., “E2212”), the patient ID number (e.g., “44444”), and the 
patient initials (e.g., “FL”) to unblind the patient.  Note that if a patient 
is unblinded, he/she must discontinue protocol treatment. 
8.1.5 
Other Names  
Afinitor 
8.1.6 
Classification  
mTOR inhibitor 
8.1.7 
Mode of Action  
Everolimus acts as an inhibitor of cytokine and growth-factor-
dependent proliferation of cells. Currently, the only known target of 
everolimus is mTOR, a key regulatory protein affecting various cell 
functions including cell proliferation(22). Everolimus exerts its activity 
through high affinity interaction with FKBP12. The FKBP12/everolimus 
complex subsequently interacts with the mTOR protein kinase, 
inhibiting downstream signaling events involved in regulation of the 
G1 to S-phase transition. 
8.1.8 
Storage and Stability  
Store everolimus/placebo tablets at 25°C (77°F); excursions permitted 
between 15° – 30°C (59° – 86°F). See USP Controlled Room 
Temperature. Store in the original container, protect from light and 
moisture. Keep this and all drugs out of the reach of children.  
Procedures for proper handling and disposal of anticancer drugs 
should be considered. Several guidelines on this subject have been 
published. 
Everolimus/placebo tablets should not be crushed. Do not take tablets 
which are crushed or broken. 
Medication labels will comply with US legal requirements and be 
printed in English. They will supply no information about the patient. 
The storage conditions for everolimus/placebo will be described on 
the medication label. 
Tablets are blister-packed under aluminum foil, which should be 
opened only at the time of administration as drug is both hygroscopic 
and light-sensitive. 
8.1.9 
Dose Specifics  
The recommended dose of everolimus/placebo for treatment of 
advanced PNET is 10 mg, to be taken once daily. 
8.1.10 
Preparation  
Everolimus/placebo tablets should be swallowed whole with a glass of 
water. The tablets should not be chewed or crushed. For patients 
unable to swallow tablets, everolimus/placebo tablet(s) should be 
dispersed completely in a glass of water (containing approximately 30 
mL) by gently stirring, immediately prior to drinking. The glass should 
be rinsed with the same volume of water and the rinse should be 
completely swallowed to ensure that the entire dose is administered. 


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8.1.11 
Route of Administration  
Everolimus/placebo should be administered orally once daily at the 
same time every day, either consistently with food or consistently 
without food. 
8.1.12 
Incompatibilities  
Agents that may Increase Everolimus/Placebo Blood Concentrations: 
CYP3A4 Inhibitors and PgP Inhibitors: See Appendix V for a list of 
CYP3A4 inhibitors.  
In healthy subjects, compared to everolimus treatment alone there 
were significant increases in everolimus/placebo exposure when 
everolimus/placebo was coadministered with: 
• 
ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - 
Cmax and AUC increased by 3.9- and 15.0-fold, respectively. 
• 
erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - 
Cmax and AUC increased by 2.0- and 4.4-fold, respectively. 
• 
verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - 
Cmax and AUC increased by 2.3- and 3.5-fold, respectively. 
Concomitant strong inhibitors of CYP3A4 should not be used  
Use caution when everolimus is used in combination with moderate 
CYP3A4 and/or PgP inhibitors.  
Agents that may Decrease Everolimus/Placebo Blood Concentrations: 
CYP3A4 Inducers: 
In healthy subjects, co-administration of everolimus/placebo with 
rifampin, a strong inducer of CYP3A4, decreased everolimus/placebo 
AUC and Cmax by 63% and 58% respectively, compared to 
everolimus/placebo treatment alone. Consider a dose increase of 
everolimus/placebo when co-administered with strong CYP3A4 
inducers if alternative treatment cannot be administered. St. John’s 
Wort may decrease everolimus/placebo exposure unpredictably and 
should be avoided. See Appendix V for a list of CYP3A4 inhibitors. 
Agents whose Plasma Concentrations may be Altered by 
Everolimus/Placebo: 
Studies in healthy subjects indicate that there are no clinically 
significant pharmacokinetic interactions between everolimus/placebo 
and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 
substrate) and pravastatin (a non-CYP3A4 substrate) and population 
pharmacokinetic analyses also detected no influence of simvastatin (a 
CYP3A4 substrate) on the clearance of everolimus. 
Coadministration of everolimus/placebo and depot octreotide 
increased octreotide Cmin by approximately 50%. 
Immunosuppressants may affect the response to vaccination and 
vaccination during treatment with everolimus may therefore be less 
effective. The use of live vaccines should be avoided during treatment 


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with Everolimus. Examples of live vaccines are: intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and 
TY21a typhoid vaccines. 
8.1.13 
Side Effects  
Information about common side effects already known about the 
investigational drug can be found in the Investigators’ Brochure. 
8.1.13.1 
Gastrointestinal disorders: 
• 
Stomatitis  
• 
Diarrhea 
• 
Abdominal pain 
• 
Nausea 
• 
Vomiting 
• 
Constipation 
• 
Dry mouth 
8.1.13.2 
General disorders and administration site conditions: 
• 
Fatigue/malaise 
• 
Edema (general and peripheral) 
• 
Fever 
• 
Asthenia 
8.1.13.3 
Infections and infestations 
• 
Nasopharyngitis/rhinitis/URI 
• 
Urinary tract infection 
8.1.13.4 
Investigations 
• 
Weight decreased 
8.1.13.5 
Metabolism and nutrition disorders 
• 
Decreased appetite 
• 
Diabetes mellitus 
8.1.13.6 
Musculoskeletal and connective tissue disorders 
• 
Arthralgia 
• 
Back pain 
• 
Pain in extremity 
• 
Muscle spasms 
8.1.13.7 
Nervous system disorders 
• 
Headache/migraine 
• 
Dysgeusia 
• 
Dizziness 
8.1.13.8 
Psychiatric disorders 
• 
Insomnia 


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8.1.13.9 
Respiratory, thoracic and mediastinal disorders 
• 
Cough/productive cough 
• 
Epistaxis 
• 
Dyspnea/dyspnea exertional 
• 
Pneumonitis  
• 
Oropharyngeal pain 
8.1.13.10 Skin and subcutaneous disorders 
• 
Rash 
• 
Nail disorders 
• 
Pruritus/pruritus generalized 
• 
Dry skin/xeroderma 
8.1.13.11 Vascular disorders 
• 
Hypertension 
8.1.13.12 Laboratory abnormalities 
• 
Anemia 
• 
Thrombocytopenia 
• 
Lymphopenia 
• 
Neutropenia 
• 
LFT derangement 
• 
Renal function abnormality 
• 
Hypercholesterolemia 
8.1.14 
Nursing/Patient Implications  
• 
Non-infectious Pneumonitis 
Warn patients of the possibility of developing non-infectious 
pneumonitis. In clinical studies, some non-infectious pneumonitis 
cases have been severe and occasionally fatal. Advise patients to 
report promptly any new or worsening respiratory symptoms. 
• 
Infections 
Inform patients that they are more susceptible to infections while 
being treated with everolimus/placebo and that cases of hepatitis 
B reactivation have been associated with everolimus/placebo 
treatment. In clinical studies, some of these infections have been 
severe (e.g., leading to respiratory or hepatic failure) and 
occasionally fatal. Patients should be aware of the signs and 
symptoms of infection and should report any such signs or 
symptoms promptly to their physician. 
• 
Oral Ulceration 
Inform patients of the possibility of developing mouth ulcers, 
stomatitis, and oral mucositis. In such cases, mouthwashes and/or 
topical treatments are recommended, but these should not contain 
alcohol or peroxide. 


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• 
Renal Failure Events 
Inform patients of the possibility of developing kidney failure. In 
some cases kidney failure has been severe and occasionally fatal. 
Inform patients of the need for the healthcare provider to monitor 
kidney function, especially in patients with risk factors that may 
impair kidney function. 
• 
Laboratory Tests and Monitoring 
Inform patients of the need to monitor blood chemistry and 
hematology prior to the start of everolimus/placebo therapy and 
periodically thereafter. 
• 
Drug-drug interactions  
Advise patients to inform their healthcare providers of all 
concomitant medications, including over-the-counter medications 
and dietary supplements. Avoid concurrent treatment with strong 
CYP3A4 inhibitors. Use caution if everolimus/placebo must be co-
administered with moderate CYP3A4 and/or PgP inhibitors; 
reduce the dose and carefully monitor the patient for undesirable 
effects. Avoid concurrent treatment with strong CYP3A4 inducers. 
If everolimus/placebo must be co-administered with strong 
CYP3A4 inducers, consider a dose increase and carefully monitor 
the patient for clinical response. 
Patients should avoid eating grapefruit and citrus fruits or drinking 
their juices while in the study. The juices in these fruits can 
change the way the body treats or breaks down everolimus 
(Afinitor®). 
• 
Hepatic Impairment 
Advise patients that everolimus/placebo is not recommended in 
patients with severe hepatic impairment (Child-Pugh class C). For 
advanced PNET and advanced RCC patients with moderate 
hepatic impairment (Child-Pugh class B), prescribe a reduced 
dose of 5 mg everolimus per day.  For SEGA patients with 
moderate hepatic impairment (Child-Pugh class B), adjustment to 
the starting dose may not be needed. However, subsequent 
dosing should be individualized based on therapeutic drug 
monitoring. 
• 
Vaccinations 
Advise patients to avoid the use of live vaccines and close contact 
with those who have received live vaccines. 
• 
Pregnancy 
Advise female patients of childbearing potential and sexually 
active males that everolimus/placebo may cause fetal harm and 
that a highly effective method of contraception or abstinence must 
be used during therapy with everolimus/placebo and for 8 weeks 
after ending treatment. 
Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, must use highly 
effective contraception during the study and for 8 weeks after 


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stopping treatment. Highly effective contraception is defined as 
either: 
• 
Total abstinence: When this is in line with the preferred and 
usual lifestyle of the subject. [Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception] 
• 
Sterilization: have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks 
before taking study treatment. In case of oophorectomy alone, 
only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment 
• 
Male partner sterilization (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate). [For 
female subjects on the study, the vasectomised male partner 
should be the sole partner for that subject]. 
• 
Use of a combination of any two of the following (a+b or a+c or 
b+c): 
a. Use of oral, injected, implanted or other hormonal methods 
of contraception 
b. Placement of an intrauterine device (IUD) or intrauterine 
system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive 
cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository 
In case of use of oral contraception, women should have been 
stable on the oral agent before taking study treatment. 
Sexually active males must use a condom during intercourse 
while taking the drug and for 8 weeks after stopping treatment and 
should not father a child in this period. 
A condom is required to be used also by vasectomised men in 
order to prevent delivery of the drug via seminal fluid. 
Female partners of male patients should also be advised to use 
one of the following contraception methods: Use of (1) oral, 
injected, implanted or other hormonal methods of contraception, 
or (2) intrauterine device (IUD) or intrauterine system (IUS), or (3) 
prior male/female sterilization. 
• 
Dosing Instructions 
Inform patients to take everolimus/placebo orally once daily at the 
same time every day, either consistently with food or consistently 
without food. The tablets should not be crushed or chewed. 
Everolimus/placebo should be swallowed whole with a glass of 
water. For patients unable to swallow tablets, everolimus/placebo 
tablet(s) should be dispersed completely in a glass of water 
(containing approximately 30 mL) by gently stirring, immediately 
prior to drinking. The glass should be rinsed with the same volume 
of water and the rinse should be completely swallowed to ensure 
that the entire dose is administered. 


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If vomiting occurs, no attempt should be made to replace the 
vomited dose. 
Instruct patients that if they miss a dose of everolimus/placebo, 
they may still take it up to 6 hours after the time they would 
normally take it. If more than 6 hours have elapsed, they should 
be instructed to skip the dose for that day. The next day, they 
should take everolimus/placebo at the usual time. Warn patients 
to not take 2 doses to make up for the one that they missed. 
8.1.15 
References 
22. Boulay A, Lane HA.  The mammalian target of rapamycin kinase 
and tumor growth inhibition. Recent Results Cancer Res. 
2007;172:99-124. 


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9. 
Statistical Considerations 
 
Endpoints 
Primary endpoint: Disease free survival 
Secondary endpoints: Overall survival 
The definitions of primary and secondary endpoints are described in Section 9.3.  
 
Sample size with power justification 
The trial will be a randomized double-blinded, placebo-controlled Phase II design 
with patients equally randomized between everolimus (Arm A) or placebo (arm 
B.) Randomization will be stratified on the factors outlined in Section 4. A total of 
150 patients will be needed to accrue 144 randomized eligible cases. The study 
seeks to establish an improvement in the primary endpoint, which is defined as 
an 80% increase in median disease-free survival (DFS) from 15 months in the 
control arm (Arm B) to 27 months in the experimental arm (Arm A). The study is 
designed to have 90% power for a 44% reduction in the hazard rate with 144 
eligible patients and 82 DFS events (as total information) which are expected to 
occur with 38 months of accrual at 4 patients per month and 7 additional months 
of follow-up, using a log-rank test at a one–sided significance level of 0.10. Under 
exponential distributions the hypothesized reduction corresponds to the 
improvement in median DFS from 15 months to 27 months and 3-year disease-
free survival of 39.7% in Arm A versus 18.9% in Arm B. The sample size was 
computed using seqopr6 (part of the study design library at the ECOG-ACRIN 
Statistical Office). 
 
Analysis plan including plans for formal interim analysis 
The primary analysis set will include all randomized eligible patients. Disease-
free survival (DFS) is defined as time from randomization to the earlier of 
documented recurrence (a return of tumor imaged by CT or MRI, new invasive 
primary cancer, or death without recurrence). Patients alive without documented 
recurrence or secondary primary reported will be censored at the time of the last 
documented disease evaluation. Tumor recurrence will be evaluated using 
evaluation criteria defined in Section 6 for a return of tumor imaged by CT or 
MRI. In the secondary analyses, overall survival (OS) is defined as time from 
randomization to death from any cause, censoring cases who are alive at the 
date of last contact. Kaplan-Meier estimates will be used for event-time 
distributions. DFS and OS by arm will be compared using one-sided stratified 
log-rank tests. Cox’s proportional hazards models will be used to estimate hazard 
ratios. Toxicity will be assessed through summaries of adverse events by arm. 
Formal comparison of toxicity rates between the arms is not a goal of this trial 
and the sample size will provide sufficient power for detecting only relative large 
difference in adverse events. With 75 patients per arm, the study will have 
sufficient precision to provide 90% confidence interval on toxicity that will be no 
wider than 20%. For rare toxicities with 2% true probability, there will be 78% 
probability of observing one or more toxicities in either treatment arm. For rare 
toxicities with 3% true probability, there will be 90% probability of observing one 
or more toxicities on either treatment arm. Patient demographics and disease 
characteristics will be compared using two-sample t-tests or Fisher’s exact tests 


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with a two-sided significance level of 0.10 as appropriate. Stratification will be 
used to ensure balance between groups and not for subset analysis.  
The study will be monitored for potential efficacy stopping using an early look at 
DFS after approximately 50% of the planned full information (41/82 DFS events) 
has been observed. A one-sided log-rank test for DFS will be performed for the 
monitoring analysis. To preserve the overall type I error rate at 0.10, a critical 
value at the interim analysis will be determined using the O’Brien-Fleming 
boundary. Under the planned accrual schedule with four patients per month (3.8 
eligible patients/ month), the monitoring analysis is projected to occur at 28.3 
months following the start of accrual. If the true control median DFS is 15 months 
and the true experimental median DFS is 27 months, there will be 42% 
probability of crossing the upper efficacy boundary (2.05).  
This study will also be monitored for futility using a rule that the study will be 
stopped early for lack of benefit if the estimated hazard ratio for 
experimental/control ≥ 1 at 50% of the planned full information. There will be 50% 
probability of early termination under the null hazard ratio of 1.0 
(experimental/control) and 3.6% probability of early termination under the target 
alternative hazard ratio of 0.56 (experimental/control).  
 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Reports of these analyses are sent to the ECOG-ACRIN Principal 
Investigator or Senior Investigator at the participating institutions. Expedited 
reporting of certain adverse events is required, as described in Section 5.2.  
 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office - Boston. 


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Gender and Ethnicity  
Based on data from E6201 the anticipated accrual in subgroups defined by 
gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
3 
6 
Not Hispanic or Latino 
66 
78 
144 
Ethnic Category: Total of all subjects 
69 
81 
150 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
1 
2 
Black or African American 
5 
5 
10 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
63 
75 
138 
Racial Category: Total of all subjects 
69 
81 
150 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
 


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10. 
Specimen Submissions 
Fixed paraffin-embedded metastatic tumor from core biopsy or surgery must be 
submitted for central diagnostic review and classification. Primary tumor tissue, if 
available, is also requested. Blood specimens and frozen tissue, if available, are to be 
submitted for use in research from consenting patients. Descriptions of the diagnostic 
review and examples of potential research studies are in Section 11.   
SAMPLE TRACKING SYSTEM (STS): All specimens submitted on this trial must be 
entered and tracked using the ECOG-ACRIN Sample Tracking System.  Any case 
reimbursements associated with specimen submissions to ECOG-ACRIN–designated 
laboratories will be determined only from data contained in STS. 
LABELING: Specimens are to be labeled clearly with the ECOG-ACRIN protocol 
number “E2212”, patient initials, date and time of collection, and sample type. All sample 
submissions are to be accompanied with an STS shipping manifest. 
SHIPPING ACCOUNT: Samples shipped to the ECOG-ACRIN PCORL or Libutti 
Laboratory are to be shipped using the PCORL’s FedEx account using the FedEx On-
Line Services. Access to the shipping account for specimen shipments to the ECOG-
ACRIN PCORL at Northwestern University can now only be obtained by logging into 
fedex.com with an account issued by the ECOG-ACRIN PCORL. For security reasons, 
the account number will no longer be given out in protocols, over the phone, or via email. 
If your site needs to have an account created, please contact the ECOG-ACRIN PCO by 
email at ecogpcorl@northwestern.edu 
 
Submissions to the (PCORL) - MANDATORY 
The ECOG-ACRIN Pathology Coordinating Office-Reference Laboratory 
(PCORL) is the receiving laboratory for all specimens submitted from patients 
participating in this trial. 
10.1.1 
Pathology Materials - MANDATORY 
Submission of pathology materials from all patients is mandatory. 
The submitting pathologist and clinical research associate should 
refer to Appendix I (Pathology Submission Guidelines) for guidelines 
and summary of submission requirements. Failure to submit the 
required materials may render the patient’s data unevaluable. 
The required materials are to be submitted within four (4) weeks 
following randomization. 
If these criteria cannot be met, please contact the ECOG-ACRIN 
Pathology Coordinating Office (PCO) (ecogpcorl@northwestern.edu) 
to obtain alternative submission requirements. 
A. FFPE TUMOR TISSUE 
All of the following materials are to be submitted. If unavailable, 
please contact the PCORL and provide justification in STS.  
• 
All original stained diagnostic slides. 
NOTE: 
These slides will be returned to the site upon 
completion of the review which is retrospective 
and will be performed in batches. If the return of 
Rev. 5/14 


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these slides is to be expedited, please indicate as 
such in the appropriate comment field in STS.   
• 
One representative diagnostic-fixed paraffin-embedded 
metastatic liver tumor block, core biopsy or surgical 
specimen. 
• 
One representative diagnostic fixed paraffin-embedded 
primary tumor block, core biopsy or surgical specimen, if 
available. 
NOTE: 
If blocks are not available for submission, submit 
the following: 
• 
Two (2) H&E slides.  
• 
Twenty (20) unstained charged slides 4 or 5 
µm thick 
• 
Two (2) 4mm cores. 
B. FORMS 
• 
Pathology Material Submission Form (#638 v04.2), Parts A & 
B completed. Please identify the clinical status of the 
submitted materials 
• 
A copy of the surgical (if appropriate) and pathology reports 
• 
Immunologic studies, if available 
• 
Sample Tracking System Shipping Manifest 
10.1.2 
Specimens from Consenting Patients 
Specimens are to be submitted from patients who answered “yes” to “I 
agree to provide additional samples for research.” 
Blood specimens are to be collected prior to start of treatment and 
upon completion/end of treatment.  The pretreatment samples, ideally, 
are to be drawn at 6-8 WEEKS POST-SURGERY, prior to start of 
protocol therapy. If protocol treatment will begin prior to the sixth week 
post-surgery, still collect prior to start of treatment. 
Institution supplies are to be used for the collection and shipment of 
blood and frozen tissue specimens. No kits are available. 
Blood samples are to be frozen (at < -70ºC) as quickly as possible 
after draw. If samples are frozen in a standard freezer (approximately 
-20ºC), it is asked that samples be shipped within a month of 
collection. 
Questions are to be directed to the ECOG-ACRIN PCORL 
(ecogpcorl@northwestern.edu), Dr. Steven Libutti, Phone: (718) 920-
4231, FAX: (718) 798-0309, E-mail: slibutti@montefiore.org. 


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A. Frozen Surgical Tumor Tissue Specimens 
Specimens are to be shipped overnight with the blood specimens 
on dry ice. 
The site’s pathology ID for submitted frozen tissue samples must 
be provided in STS. If samples are not available, indicate as such 
in the STS as well. This information will reduce unnecessary 
follow-up with the site by the laboratory. 
B. Peripheral Blood, ACD vacutainer 
Draw prior to start of protocol therapy, ideally 6-8 weeks post-
surgery. 
• 
Draw blood into a 10 mL ACD vacutainer (EDTA tube may 
substitute). Invert gently eight to ten times to thoroughly mix 
the blood and anti-coagulant.  
• 
Specimens collected in glass vacutainers must be transferred 
to sterile cryovials prior to freezing. Plastic vacutainers may be 
frozen directly. Freeze at ≤ -70ºC until shipped 
C. Plasma, EDTA (purple top) 
Draw prior to start of protocol therapy, ideally 6-8 weeks post-
surgery. 
• 
Draw peripheral blood into vacutainer and gently invert 8-10 
times.  
• 
Within 20 minutes of collection, centrifuge at 1500xg (2700-
3000 rpm) for 15 minutes.  
• 
Pipette the plasma into 4 cryotubes (approximately 1 mL 
each) and store frozen, below –20oC (-70 oC preferred), until 
shipped 
• 
Remaining Cells: If the vacutainer is plastic, replace the 
stopper on the EDTA tube containing the cells and ship with 
the plasma samples. 
10.1.3 
Shipping Guidelines 
The receiving laboratory is not available to receive shipments over 
holidays or weekends. Therefore, samples are only to be shipped via 
overnight courier Sunday through Thursdays (excluding a day before 
a holiday). 
The required initial diagnostic tumor tissue materials, reports and 
forms are to be submitted within four (4) weeks following patient 
randomization. 
Frozen samples are to be shipped on dry ice (5 lbs. minimum). 
Samples batched in a regular freezer are to be shipped within a 
month following the draw. Samples stored at < -70ºC may be shipped 
on a quarterly basis. 
Samples from multiple patients may be batched and shipped together. 
All samples must be adequately labeled with protocol number, ECOG-
ACRIN patient case number, and date of collection. 


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Shipping Address 
ECOG-ACRIN Pathology Coordinating Office 
Robert H. Lurie Comprehensive Cancer Center  
of Northwestern University Medical School 
Olson Pavilion - Room 8421 
710 North Fairbanks Court 
Chicago, IL 60611 
Tel: (312) 503-3384 
FAX: (312) 503-3385 
Tissue specimens shipped standard mail must utilize a “trackable” 
mechanism. For shipments utilizing FedEx, access to the shipping 
account for specimen shipments requires logging into fedex.com with 
an account issued by the ECOG-ACRIN PCORL. 
 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important:  Any case reimbursements associated with specimen submissions 
will not be credited if specimens are not logged into STS. Additionally, please 
note that the STS software creates pop-up windows, so you will need to enable 
pop-ups within your web browser while using the software.  A user manual and 
interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated shipping manifest should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to .  
Study Specific Notes 
Generic Specimen Submission Form (#2981v2) will be required only if STS is 
unavailable at time of sample submission. Include site contact information on the 
form. Notify the laboratory of the shipment by faxing a copy of the completed 
form to the laboratory the day of shipping. Indicate the shipping tracking number 
and the appropriate Lab ID# on the submission form: 
• 
0001 = ECOG-ACRIN PCORL 
Retroactively enter all specimen collection and shipping information when STS is 
available. 


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Use of Specimens in Research 
Tissue specimens will be processed and distributed to investigators for the 
central diagnostic review. 
Specimens from patients who consented to allow their specimens to be used for 
research studies will be retained in an ECOG-ACRIN-designated central 
repository. For this trial, specimens will be retained at the ECOG-ACRIN 
Pathology Coordinating Office. 
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Processing may include, but not limited to, extraction of 
DNA and RNA and construction of tissue microassays (TMAs). DNA and plasma 
(if appropriate) will be isolated from the submitted peripheral blood samples. 
Any residual blocks will be available for purposes of individual patient 
management on specific written request.  
Request for the use of archived specimens requires submission of a correlative 
science proposal detailing the scientific hypothesis, research plan, assay 
methods for use of the biospecimens, and a complete statistical section (with 
adequate power justification and analysis plan) will be submitted and reviewed by 
CTEP in accordance with the NCI National Clinical Trials Network (NCTN) review 
policies. 
If future use is denied or withdrawn by the patient, the samples will be removed 
from consideration for use in any future study. Bloods and other products may be 
destroyed per protocol of the given lab, or they could be anonymized (stripped of 
all identifiers) and used for instrument calibration or other quality control 
measures which are not published or linked to the clinical trial. Tissue will be 
returned or stored indefinitely in for return to the site upon request.  
 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory. 
Inventories of specimens forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office – Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office – Boston. 


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11. 
Laboratory Research Studies  
 
Diagnostic Review and Classification (MANDATORY) 
Central pathological review will include Ki-67 and mitotic index, NANETS grading 
system will be employed (19, 20). The review will be performed by Dr. Guang-Yu 
Yang at Northwestern University. The analysis will be retrospective and will be 
used for determination of patient evaluability. The results of the review will not 
impact patient participation in the trial. 
 
Research Studies 
Blood and tumor specimens are requested from consenting patients for future 
research studies. Request for the use of archived specimens, via a protocol 
amendment or a separate correlative science proposal, will be in accordance 
with the ECOG-ACRIN and NCI National Clinical Trials Network (NCTN) policies. 
The background supporting the following potential research studies is presented 
in the introduction of this protocol. These studies, if performed, will be performed 
under the direction of Drs. Steven Libutti, Montefiore Medical Center, and Luis 
Diaz, Johns Hopkins University. 
11.2.1 
Predictive value of PIK3CA, PTEN, and TSC Mutations 
We hypothesize that patients with tumors that are mutant for PIK3CA, 
PTEN or TSC will benefit in terms of DFS and OS as compared to 
patients with tumors without mutations in these genes. 
DNA from tumor tissue and germline DNA from peripheral blood will 
be used for these studies. 
Sequencing will be performed following PCR amplification of the 
regions of interest. Mutations detected will be confirmed using the 
tumor and matched normal DNA (obtained from whole blood). 
Mutations identified in the tumor will be used to design primers and 
probes to detect circulating tumor DNA (ctDNA) fragments that 
contain these mutations using highly sensitive PCR-based 
methodologies (i.e. BEAMing or SafeSeqs) (see below). 
11.2.2 
Analysis of post-operative circulating tumor DNA to detect minimal 
residual disease and predict disease recurrence  
We hypothesize that the post-operative detection of ctDNA is 
consistent with the presence of minimal residual disease and signifies 
a population of patients that will suffer with disease recurrence. 
DNA extracted from plasma from each time point collected will be 
interrogated for the presence of ctDNA using probes designed from 
mutations detected in the tumor tissue (see above). At this time, the 
proposed genomic method to detect and quantify the 
ctDNA,“BEAMing”, is described in the introduction to the protocol. 


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11.2.3 
Mutations in Chromatin Remodeling Genes 
We hypothesize that tumors with defect in chromatin remodeling will 
confer a survival benefit to patients with metastatic pancreatic tumors.  
Sequencing of DAXX, ATRX and MEN1 will be performed following 
PCR amplification of the regions of interest.  Mutations detected will 
be confirmed using the tumor and matched normal DNA (obtained 
from whole blood). 
 
Lab Data Transfer Guidelines  
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office – Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. The quarterly 
cut-off dates are March 31, June 30, September 30, and December 31. Data is 
due at the ECOG-ACRIN Operations Office – Boston 1 week after these cut-off 
dates. 
 


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12. 
Electronic Data Capture 
Please refer to the E2212 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. Reports are due January 31, April 30, 
July 31 and October 31st. 
 
Records Retention  
This study is being conducted under an IND exemption and is not intended to 
support any FDA-related filings. However, ECOG-ACRIN requires clinical 
investigators to retain all trial-related documentation, including source 
documents, for at least one year from the posting of the final clinical study report 
of the outcome of this trial to support any publication of the data. Please contact 
the ECOG-ACRIN Operations Office – Boston prior to destroying any source 
documents. 
 


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13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
1. Mayo SC, de Jong MC, Pulitano C et al. Surgical management of hepatic 
neuroendocrine tumors metastasis: results from an international multi-institutional 
analysis. Ann Surg Oncol 2010;17:3129-3136. PMID: 20585879 
2. Ballian N, Loeffler AG, Rajamanickam V, et al.  A simplified prognostic system for 
resected pancreatic neuroendocrine neoplasms.  HBP 2009;11:422-8. PMID 
19768147 
3. Yao JC, Hassan M, Phan A,et al. One hundred years after "carcinoid": epidemiology 
of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United 
States. J Clin Oncol. 2008 Jun 20;26(18):3063-72. Review. PubMed PMID: 
18565894 
4. Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-
fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl 
J Med. 1992 Feb 20;326(8):519-23. PubMed PMID: 1310159 
5. Cheng PNM, Saltz LB.  Failure to confirm major objective antitumor activity for 
streptozocin and doxorubicin in the treatment of patients with advanced islet cell 
carcinoma.  Cancer 1999;86:944-8. PMID: 10491519 
6. McCollum DA, Kulke MH, Ryan DP, et al.  Lack of efficacy of streptozocin and 
doxorubicin in patients with advanced pancreatic endocrine tumors.  Am J Clin Onc 
2004;27:485-8. PMID: 15596916 
7. Raymond E, Dahan L, Raoul JL, et al.  Sunitinib maleate for the treatment of 
pancreatic neuroendorcine tumors.  NEJM 2011;364:501-13. PMID: 21306237 
8. Missiaglia E, Dalia I, Barbi S, et al.  Pancreatic endocrine tumors: expression 
profiling evidences a role for AKT-mTOR pathway.  J Clin Onc 2010;28:245-55. 
PMID: 19917848 
9. Yao JC, Shah MH, Ito T, et al.  Everolimus for advanced pancreatic neuroendocrine 
tumors. NEJM 2011;364:514-23. PMID: 21306238 
10. Elias D, Lasser P, Ducreux M, et al.  Liver resection and associated extra-hepatic 
resections for metastatic well-differentiated endocrine tumors: a 15-year single 
center prospective study.  Surgery 2003;133:375-82. PMID: 12717354 
11. Knigge U, Hansen CP, Stadil F.  Interventional treatment of neuroendocrine liver 
metastases. Surgeon 2008;6:232-9. PMID: 18697366 
12. Yao KA, Talamonti MS, Nemcek A, et al. Indications and results of liver resection 
and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine 
tumors.  Surgery 2001;130:677-85. PMID: 11602899 
13. Gaujoux S, Gonen M, Tang L, Klimstra D, Brennan MF, D'Angelica M, Dematteo R, 
Allen PJ, Jarnagin W, Fong Y. Synchronous Resection of Primary and Liver 
Metastases for Neuroendocrine Tumors. Ann Surg Oncol. 2012 Jul 3. [Epub ahead 
of print] PMID: 22752376. 


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14. Glazer ES, Tseng JF, Al-Refaie W, Solorzano CC, Liu P, Willborn KA, Abdalla EK, 
Vauthey JN, Curley SA. Long-term survival after surgical management of 
neuroendocrine hepatic metastases. HPB (Oxford). 2010 Aug;12(6):427-33. PubMed 
PMID: 20662794; PubMed Central PMCID: PMC3028584. 
15. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after 
resection of localised, primary gastrointestinal stromal tumour: a randomised, 
double-blind, placebo-controlled trial. Lancet 2009;373:1097-104.  PMID 19303137. 
16. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib 
for operable gastrointestinal stromal tumor: a randomized trial. JAMA : the journal of 
the American Medical Association 2012;307:1265-72.  PMID: 22453568. 
17. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are 
frequently altered in pancreatic neuroendocrine tumors. Science 2011;331:1199-203.  
PMID: 21252315. 
18. Snoeren N, Voest EE, Bergman AM, Dalesio O, Verheul HM, Tollenaar RA, van der 
Sijp JR, Schouten SB, Rinkes IH, van Hillegersberg R. A randomized two arm phase 
III study in patients post radical resection of liver metastases of colorectal cancer to 
investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) 
vs CAPOX alone as adjuvant treatment. BMC Cancer. 2010 Oct 11;10:545. PMID: 
20937118. 
19. Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine 
tumors: application of the Delphic consensus process to the development of a 
minimum pathology data set. The American journal of surgical pathology 
2010;34:300-13.  PMID: 20118772. 
20. Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification 
of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. 
Pancreas 2010; 39:707-12. PMID: 20664470. 
21. Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, 
Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz Jr LA.  Circulating mutant DNA 
to assess tumor dynamics. Nat Med. 2008: 14(9): 985-90. Epub 2007 Jul 31. PMID 
18670422. 
22. Boulay A, Lane HA.  The mammalian target of rapamycin kinase and tumor growth 
inhibition. Recent Results Cancer Res. 2007;172:99-124. 
 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. List of Required Materials for E2212 
4. Pathology Submission Form (#638 v04.2) 
 


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Guidelines for Submission of Pathology Materials 
E2212: A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine 
Tumors to the Liver 
The following materials are to be submitted within one month of randomizing patient to the trial 
1. Pathology materials required for pathology review and, per patient consent, research 
• 
REQUIRED FOR CENTRAL DIAGNOSTIC REVIEW 
• 
One representative diagnostic-fixed paraffin-embedded metastatic tumor block, 
core biopsy or surgical specimen. 
• 
One representative diagnostic fixed paraffin-embedded primary tumor block, core 
biopsy or surgical specimen, if available  
• 
Original stained diagnostic slides 
NOTE: 
These slides will be returned to the site upon completion of the review 
which is retrospective and will be performed in batches. If the return of 
these slides is to be expedited, please indicate as such in the appropriate 
comment field in STS.   
• 
If available, frozen surgical tumor tissue 
2. Forms and reports: 
The following items are to be included with every submission of pathology materials. 
• 
Institutional Surgical Pathology Report 
• 
Pathology Material Submission Form (#638 v04.2) – Parts A & B completed 
• 
ECOG-ACRIN Sample Tracking System (STS) manifest 
NOTE: 
Adequate patient identifying information must be included with every submission. 
It is strongly recommended that full patient names be provided. The information 
will be used only to identify patient materials, will expedite any required 
communications with the institution (including site pathologists).   
3. Mail pathology materials to: 
ECOG-ACRIN Pathology Coordinating Office 
Robert H. Lurie Comprehensive Cancer Ctr  
of Northwestern University Medical School 
Olson Pavilion - Room 8421 
710 North Fairbanks Court 
Chicago, IL  60611 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact the 
Pathology Coordinator at the ECOG-ACRIN Pathology Coordinating Office at (312) 503-
3384 or FAX (312) 503-3385 or ecogpcorl@northwestern.edu. 
 


 
63 
MEMORANDUM 
TO:  
(Submitting Pathologist) 
 
 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Pathology Committee 
DATE:  
 
SUBJECT: 
Submission of Pathology Materials for E2212: A Randomized, Double-
Blinded, Placebo-Controlled Phase II Study of Adjuvant Everolimus 
Following the Resection of Metastatic Pancreatic Neuroendocrine 
Tumors to the Liver  
 
 
The patient named on the attached Pathology Material Submission Form (#638 v04.2) 
has been entered onto an ECOG-ACRIN protocol by 
_____________________________ (ECOG-ACRIN Investigator). This protocol requires 
the submission of pathology materials for diagnostic review and research studies. 
Please complete PART B of the Submission Form. Keep a copy for your records and 
return the completed Submission Form, the surgical pathology report(s), the slides 
and/or blocks and any other required material (see List of Required Material) to the 
Clinical Research Associate (CRA). The CRA will forward all required pathology material 
to the appropriate laboratory. 
Pathology materials submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies per patient consent.  Paraffin blocks will be returned upon 
request for purposes of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
Results of the diagnostic review will be distributed to you upon completion of the review. 
This review will be retrospective and will not impact patient participation in E2212.  
If you have any questions regarding this request, please contact the Pathology 
Coordinating Office at (312) 503-3384 or FAX (312) 503-3385. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 


Form No. 638 v04.2 
ECOG DIAGNOSTIC PATHOLOGY MATERIAL SUBMISSION FORM 
64 
Instructions: 
This form is a required part of pathology submission.  Please complete and submit along with 
all pathology material and corresponding pathology reports requested by the protocol.  See list of 
required materials as specified in EACH protocol. 
ECOG PCO-RL IS FULLY- COMPLIANT WITH DHHS, HIPAA, AND OHRP REGULATIONSTel. 
312-503-3384
 
Fax 312-503-3385 
PART A:  To Be Completed By Data Manager/CRA 
DO NOT USE INITIALS – Submit Patient’s FULL Name 
 
(The Patient has authorized the use of PHI.) 
Date sample sent to ECOG ______/______/_______ (M,D,Y) 
 
Patient’s Name: 
Data Manager _______________________________________  
 
Last _______________________ 
First ____________________  
Address  ___________________________________________  
 
ECOG Prot. No. _________  ECOG Patient Seq. No. ________  
 __________________________________________________  
 
Participating Group 
Prot. No. _______________  
Participating Group 
Patient ID No. ________________  
Telephone No. (          ) _______________________________  
 
Group __________ 
Institution _________ 
PI _____________  
Fax No. (          ) _____________________________________  
 
Step No. ________ 
Affiliate _________  
Email address  ______________________________________  
 
ECOG Parent Prot. No. ________  
Seq. No. ______________  
PART B: 
TO BE COMPLETED BY DATA MANAGER/CRA AND SUBMITTING PATHOLOGIST 
 
 
 
 
 
 
 
PCO-RL Use Only 
Complete for 
Slides/Vials 
Status* 
(See Below) 
Date Specimen 
Collected (M/D/Y) Disease Site 
Number of 
Slides/Vials 
Specimen ID  
Numbers 
Type of 
Stain 
PCO ID 
Numbers 
 
 
/        / 
 
 
 
 
 
 
 
/        / 
 
 
 
 
 
Complete for 
Blocks/Punch 
Status* 
(See Below) 
Date Specimen 
Collected (M/D/Y) Disease Site 
Number of 
Blocks/Punch 
Specimen ID  
Numbers 
Fixative 
PCO ID 
Numbers 
 
 
/        / 
 
 
 
 
 
 
 
/        / 
 
 
 
 
 
*Status: Please identify the clinical status of the sample.  
List all that apply: 
 
 
1. Original diagnostic material 
5. Post-surgery biopsy/tissue 
 
Submitting Pathologist _____________________ 
2. AML/MDS diagnosis 
6. Relapse/recurrence 
 
Telephone No. (          ) ____________________ 
3. Pre-protocol treatment 
biopsy/tissue 
7. Remission/response 
 
 
Address  ________________________________ 
4. Post-protocol treatment 
biopsy/tissue 
8. Other, specify: ______________  
 
  _________________________  
 
 _______________________________________ 
Did the patient consent to participate in the storage of samples for future research? 
Yes 
No 
MATERIAL RETURN (All materials will be retained by the ECOG PCO unless return is requested here.) 
Does the submitting institution’s policy require the return of any submitted material (blocks, H&E slides, etc.)? 
Yes 
No 
If so, please indicate which materials must be returned ______________________________________________________________  
All materials will be returned to the submitting pathologist unless an alternate address is indicated here ______________________  
If materials were not able to be submitted for this protocol and its correlative studies, please circle the 
reason for non-submission. Attach a formal letter referencing regulations, policy, and/or other explanation. If 
possible, include a copy of the policy.  
Federal/State Regulations ____  Hospital/Institutional Policy _____ Insufficient Tissue _____  Other ______  (Specify) _________  
Pathologist of Investigator’s Signature ______________________________________________ 
(PCO-RL Use Only) 
PV  _________________________  
PART C: 
ECOG PATHOLOGY COORDINATING OFFICE USE ONLY 
Date Sample Received at PCO ____/____/____ 
Date Sent to Reviewer ____/____/____ 
Date Sent to PI/Central Lab ____/____/_____ 
Site Compliance % _____________ 
Name of Reviewer __________________ PI/Central Lab _________________________  
PCO Comments: _____________________________________________________________________  
Staff Init. _____________  
Investigator:  Keep a copy for your files and submit original form to the destination specified in protocol. 
2/05 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions 
remain unanswered in cancer.  With the participation of people like you in clinical trials, 
we will improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care.  I and my research staff will 
maintain very close contact with you.  This will allow me to provide you with the best 
care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, with the 
participation of people like you in clinical trials, we thank you again. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix III 
 
Patient Tablet Calendar 
Tablet Calendar Directions 
1. Take your scheduled dose of each tablet as instructed by your doctor. 
2. If you forget, the missed tablets will not be taken if more than six hours late. 
3. Note the time and number of tablets you take each day. If you develop any side 
effects or symptoms, please record them in the appropriate spot on your calendar. If 
you take any medications other than everolimus/placebo, note them in the 
appropriate spot on your calendar. 
4. Please bring the bottle, any leftover tablets, and your  
tablet calendar to your next clinic visit. 
 


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Patient Tablet Calendar 
Patient ID #:  _______________________   
 
Drug Name: Everolimus/Placebo 
Dose: _____________________________  
 
Cycle#: ______________________ 
 
DAY 
Date 
 
Month   Day   Year 
Time 
tablets 
taken 
Number 
of tablets 
taken 
Use the space below to make notes about things you 
would like to tell the doctor (including unusual symptoms 
you experience, other medicine you have taken and 
anything else you think would be of interest.) 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
 
 
 
 
 
 
30 
 
 
 
 
 
 
Additional Notes: 
 
 
 
Patient signature:  ________________________   
Date: ______________________ 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
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the Liver 
 
Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled.  Cannot carry on any self-care. Totally confined to bed or 
chair. 
 


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A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix V 
 
Drugs Which May Affect Everolimus Metabolism 
 
The following is a list of common CYP3A4 inducers and inhibitors which may impact 
everolimus metabolism. This is NOT a complete list of medications potentially incompatible 
with everolimus; therefore patient medications must be evaluated closely to determine 
patient eligibility for this trial. 
 
List of CYP3A4 Inducing Agents: 
Carbamazepine 
Phenytoin 
Dexamethasone 
Primidone 
Ethosuximide 
Progesterone 
Glucocorticoids 
Rifabutin 
Griseofulvin 
Rifampin 
Modafinil 
Rifapentine 
Naficillin 
Rofecoxib 
Nelfinavir 
St. John’s Wort 
Nevirapine 
Sulfadimidine 
Oxcarbazepine 
Sulfinpyrazone 
Phenobarbitol 
Tipranavir 
Phenylbutazone 
Troglitazone 
 
List of CYP3A4 Inhibitors: 
Amiodarone 
 
Mifepristone 
Cimetidine 
 
Nefazodone 
Ciprofloxacin 
 
Nelfinavir 
Clarithromycin 
 
Norfloxacin 
Delavirdine 
 
Norfluoxetine 
Diethyl-dithiocarbamate 
 
Ritonavir 
Diltiazem 
 
Roxithromycin 
Erythromycin 
 
Saquinavir 
Fluconazole 
 
Troleandomycin 
Fluvoxamine 
 
Voriconazole 
Gestodene 
 
Warfarin 
Grapefruit or Grapefruit juice 
 
Amprenavir 
Indanvir 
 
Atazanavir 
Itraconazole 
 
Miconazole 
Ketoconazole 
 
Telithromycin 
Mibefradil 
 
Verapamil 


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the Liver 
Appendix VI 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy test 
regardless of age or disease state) of a female patient while she is on Everolimus/placebo, or 
within 28 days of the patient’s last dose of Everolimus/placebo must be reported in an 
expeditious manner.  The outcome of the pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be reported 
via CTEP’s Adverse Event Reporting System (CTEP-AERS) 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, followed 
by a complete expedited CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERS report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium and 
perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
• 
The start date of the pregnancy should be reported as the calculated date of conception.   
• 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the CTEP-AERS 
report.  
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female patient until completion of the pregnancy and must 
report the outcome of the pregnancy and neonatal status via CTEP-AERS.  
• 
The decision on whether an individual female patient can continue protocol treatment will be 
made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office – Boston.  Please contact the ECOG-ACRIN Operations Office – Boston 
to ask for a conference call to be set up with the appropriate individuals. 
• 
It is recommended the female subject be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
Rev. 5/14 


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Version Date: April 21, 2014 
71 
How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERS 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  However, if 
the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-AERS report 
should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the CTEP AEMD 
Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed on a case 
by case basis. 
Reporting a Fetal Death 
A fetal death is defined in CTCAE as “A disorder characterized by death in utero; failure of the 
product of conception to show evidence of respiration, heartbeat, or definite movement of a 
voluntary muscle after expulsion from the uterus, without possibility of resuscitation.” 
It must be reported via CTEP-AERS as Grade 4 “Pregnancy, puerperium and perinatal 
conditions - Other (pregnancy loss)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions”.   
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERS recognizes 
this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A disorder characterized by cessation of life occurring 
during the first 28 days of life” that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention. However, for this protocol, any neonatal death that occurs 
within 28 days of birth, without regard to causality, must be reported via CTEP-AERS AND any 
infant death after 28 days that is suspected of being related to the in utero exposure to 
Everolimus/placebo  must also be reported via CTEP-AERs . 
It must be reported via CTEP-AERS as Grade 4 “General disorders and administration - Other 
(neonatal loss)”under the System Organ Class (SOC) “General disorder and administration”.  
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERS reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any additional 
medical information to CTEP (301-230-0159). This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportFor
m.pdf)  
 


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Version Date: April 21, 2014 
72 
A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix VII 
 
E2212 Drug Request Form 
E2212 EVEROLIMUS/PLACEBO DRUG REQUEST FORM 
Section I (To be completed by the institution) 
CTEP NCI ID#: 
      
Principal Investigator: 
      
Institution Name: 
      
Institution Pharmacy 
Delivery Address: 
      
Pharmacy Contact: 
      
Pharmacy Contact 
Telephone Number: 
      
Pharmacy Contact email: 
      
Pharmacy Contact fax: 
      
Shipment Must Reach 
Destination By (Please allow 
4 business days for delivery): 
      
ECOG-ACRIN Patient 
Sequence Number: 
      
Blinded Drug ID#: 
      
Initial Order or Resupply: 
      
Quantity of Blister Packs 
      
 
Order placed by: (print name) 
      
Signature:  
Date:  
 
Section II  (To be completed by ECOG-ACRIN Drug Team) 
IRB Approval:  
Blinded Drug ID Confirmed: 
Personnel Name: 
 
 
 
        Signature:          
 
             Date: 
PLEASE EMAIL THIS DRUG REQUEST FORM AS AN ATTACHMENT TO 
900.drugorder@jimmy.harvard.edu or by FAX: 617-632-2063 


ECOG-ACRIN 
E2212 
Cancer Research Group  
Version Date: April 21, 2014 
73 
A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant 
Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to 
the Liver 
 
Appendix VIII 
 
Hepatitis Screening 
Screening for hepatitis B 
Prior to randomization, 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. 
• 
Additional patients at the discretion of the investigator 
Screening for hepatitis C 
Prior to randomization, 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.