Conditions: Resectable Cholangiocarcinoma Stage IB Intrahepatic Cholangiocarcinoma AJCC v8 Stage II Intrahepatic Cholangiocarcinoma AJCC v8 Stage III Intrahepatic Cholangiocarcinoma AJCC v8 Stage IIIA Intrahepatic Cholangiocarcinoma AJCC v8 Stage IIIB Intrahepatic Cholangiocarcinoma AJCC v8
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
This phase II trial studies how well gemcitabine, cisplatin, and nab-paclitaxel work before surgery in treating participants with high-risk bile duct cancer in the liver (intrahepatic cholangiocarcinoma). Drugs used in chemotherapy, such as nab-paclitaxel, cisplatin, and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed description:
PRIMARY OBJECTIVE:

To assess the feasibility of therapeutic approach that includes neoadjuvant chemotherapy including gemcitabine hydrochloride (gemcitabine), cisplatin, and nab-paclitaxel for high-risk but technically resectable intrahepatic cholangiocarcinoma and is completed with surgical resection.

SECONDARY OBJECTIVES:

I. To assess the radiological response rate to neoadjuvant systemic chemotherapy according to the Response Evaluation Criteria in Solid Tumors (RECIST).

II. To determine the R0 resection rate.

III. To determine patient recurrence-free survival (RFS).

IV. To identify patient overall survival (OS) rate.

OUTLINE:

Participants receive nab-paclitaxel intravenously (IV) over 30 minutes, cisplatin IV over 60 minutes, and gemcitabine IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Participants with stable disease (SD), partial response (PR), or complete response (CR) then undergo standard of care hepatectomy with portal lymphadenectomy.

After completion of study treatment, participants are followed up every 4 months for 3 years.

Arms:
arm 1: Participants receive nab-paclitaxel IV over 30 minutes, cisplatin IV over 60 minutes, and gemcitabine IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Participants with stable disease (SD), partial response (PR), or complete response (CR) then undergo standard of care hepatectomy with portal lymphadenectomy.

Interventions: intervention 1: Cisplatin intervention 2: Gemcitabine intervention 3: Nab-paclitaxel
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV

Protocol document:
ICF_000.pdf: 
 
 
 
 
 
Informed Consent Form 
 
 
A Single-arm Feasibility Study of Gemcitabine, Cisplatin, and Nab-Paclitaxel as 
Neoadjuvant Therapy for Resectable Oncologically High-Risk Intrahepatic 
Cholangiocarcinoma 
 
NCT Number: NCT03579771 
 
 
Document IRB Approval Date: 5/19/2021 


Study No.: «ID»
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IRB use only
Document Approved On: «ApproveDate»
   
PI: Shishir Maithel, MD                                             Page 1 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017
You Are Being Asked to Be in a Research Study
What Is a Research Study?
The main purpose of research studies is to gain knowledge that may be used to help others. Although it is 
possible to directly benefit you by participating in a research study, these research studies are not intended to 
necessarily benefit the patients that participate in them.
Do I Have to Do This?
No. Being in this study is entirely your choice.  If you decide to join this study, you can change your 
mind later on and withdraw from the research study. 
Taking part in a study is separate from medical care. The decision to join or not join the research study will not 
affect your status as a patient.  
What Is This Document?
This form is an informed consent document. It will describe the study risks, procedures, and any costs to you.
This form is also a HIPAA Authorization document. It will describe how your health information will be used and 
by whom.
Signing this form indicates you are willing to take part in the study and allow your health information to be 
used.
What Should I Do Next?
1.
Read this form, or have it read to you.
2.
Make sure the study doctor or study staff explains the study to you.
3.
Ask questions (e.g., time commitment, unfamiliar words, specific procedures, etc.) 
4.
If there will be medical treatment, know which parts are research and which are standard care.
5.
Take time to consider this, and talk about it with your family and friends.
IRB00104175
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PI: Shishir Maithel, MD                                             Page 2 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017
Emory University and Saint Joseph’s Hospital
Consent to be a Research Subject / HIPAA Authorization 
Title: A Single-arm Feasibility Study of Gemcitabine, Cisplatin, and Nab-Paclitaxel as Neoadjuvant Therapy for 
Resectable Oncologically High-Risk Intrahepatic Cholangiocarcinoma
Principal Investigator:  Shishir K. Maithel, MD
Study-Supporter:  Celgene
Introduction
You are being asked to be in a medical research study. This form is designed to tell you everything you need 
to think about before you decide if you want to be a part of the study.  It is entirely your choice.  If you 
decide to take part, you can change your mind later on and withdraw from the research study. The 
decision to join or not join the research study will not cause you to lose any medical benefits.  If you decide not 
to take part in this study, your doctor will continue to treat you.
Before making your decision:

Please carefully read this form or have it read to you

Please listen to the study doctor or study staff explain the study to you 

Please ask questions about anything that is not clear
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether you 
would like to participate. You may wish to discuss your decision with family or friends. Do not sign this consent 
form unless you have had a chance to ask questions and get answers that make sense to you.  By signing this 
form you will not give up any legal rights.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This 
Web site will not include information that can identify you. At most the Web site will include a summary of the 
results. You can search this Web site at any time.
What is the purpose of this study?
The purpose of this study is to examine the ability to give a novel chemotherapy regimen prior to attempted 
resection of an intrahepatic cholangiocarcinoma that has characteristics that make it very high risk for not 
being able to be removed or for coming back after it has been removed. The purpose is also to study the effect 
of the chemotherapy on the tumor and its ability to come back after being removed. The chemotherapy drugs 
used in this regimen are all FDA approved for treating patients.  The application of this regimen for this specific 
indication in the preoperative setting is investigational. We expect to enroll about 34 patients in this study. 
Emory will enroll about 12 patients.
What will I be asked to do? 
You are being invited to participate in this study because you have recently been diagnosed with intrahepatic 
cholangiocarcinoma, or bile duct cancer inside the liver. The standard recommendation is to undergo surgery 
where part of your liver is removed and the lymph nodes around your liver are removed as well.  There are 
IRB00104175
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PI: Shishir Maithel, MD                                             Page 3 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017
features of your tumor which make it high-risk for coming back after surgery. In this study, we are studying the 
ability of a patient to receive and tolerate 3 months of chemotherapy prior to undergoing surgery. You will 
receive 3 months of chemotherapy prior to undergoing surgery.  The chemotherapy will consist of 3 different 
drugs, namely gemcitabine, cisplatin, and nab-Paclitaxel. The gemcitabine / cisplatin / nab-Paclitaxel are given 
as part of a 3-week cycle, where you receive chemotherapy on day 1 and day 8 of the 21-day cycle.  This will 
continue for 4 cycles, which equals a total of 12 weeks. After the chemotherapy is done and you have 
recovered, you will be re-evaluated for surgery with imaging scans. If the cancer is stable or improved, you will 
undergo surgery to remove your tumor. If the cancer has spread to other parts of your body, then you may not 
undergo surgery. After all the treatment is done, you will continue to undergo imaging studies (CT and/or MRI) 
every 4 months for 3 years after surgery or until the cancer has returned, whichever comes first. If you are a 
woman of child-bearing potential, you will be asked to have a pregnancy test.  You will also undergo a physical 
examination and undergo baseline laboratory tests to ensure that you are eligible for this study.
CT Scan: A CT scan allows your doctor to see inside your body to look at the size of your tumor(s). For the CT 
scan, you may be given a contrast liquid to drink. Or, an IV (intravenous) line may be started by a needle stick 
in the arm so a contrast liquid can be injected through the line. The IV contrast liquid is a special dye used to 
get clearer pictures of your body. You will lie flat on a table that will move you into the CT scanner, which is a 
large, tunnel-shaped machine. You will be asked to lie still and may be asked to hold your breath for a few 
seconds. The CT scan takes about 30 to 60 minutes and is considered a part of your standard medical care.
MRI Scan: An MRI scan also allows your doctor to see inside your body to see the size of your tumor(s). You 
may be given gadolinium (a contrast liquid) through a vein in your arm. Gadolinium is a liquid that causes some 
tumors to appear much brighter than normal tissue on MRI scans. Before gadolinium is injected, the tumor may 
not be visible. An intravenous (IV) catheter (a tiny tube) may be placed in your arm to inject the contrast liquid. 
You will then lie on a table that will move into a large tunnel-shaped machine (similar to a CT scan). The MRI 
scan uses radio frequency waves (like those in an AM/FM radio) and a strong magnet to create a picture of 
your tumor(s). The MRI scan takes about 60 minutes and is considered a part of your standard medical care.
Who owns my study information and samples?
If you join this study, you will be donating your samples and study information.  You will not receive any 
compensation if your samples or information are used to make a new product. If you withdraw from the study, 
data and samples that were already collected may be still be used for this study.  
What are the possible risks and discomforts?
There may be side effects from the study drugs that are not known at this time.  
Gemcitabine
The most common risks and discomforts (>20% of patients):

Flu-like symptoms of muscle pain, fever, headache, chills and fatigue

Nausea, vomiting

Rash

Hair loss

Infection, especially when white blood cell count is low

Bruising, bleeding

Anemia which may require a blood transfusion
IRB00104175
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Protocol #: EU4339-18                                                                                                                    IRB Form 12152017

Muscle weakness

Blood in urine

Feeling of "pins and needles" in arms and legs

Numbness and tingling of the arms and legs

Tiredness

Difficulty sleeping

Hearing loss

Swelling of arms, legs
The less common risks and discomforts (4-20%):

Diarrhea, constipation

Sores in mouth which may cause difficulty swallowing

Shortness of breath

Fluid in the organs which may cause low blood pressure, shortness of breath, swelling of ankles

Brain damage, Reversible Posterior Leukoencephalopathy Syndrome, which may cause headache, 
seizure, blindness
Rare but possible risks (<4%):

Abnormal heartbeat

Heart failure or heart attack which may cause shortness of breath, swelling of ankles, and tiredness

Blisters on the skin

Sores on the skin

Blood clot

Liver damage which may cause yellowing of eyes and skin, swelling

Damage to organs which may cause shortness of breath

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of 
the face or throat

Kidney damage which may require dialysis

Scarring of the lungs

Fluid around lungs

Blockage of the airway which may cause cough
Cisplatin
The most common risks and discomforts (>20% of patients):
•
Nausea, vomiting
•
Infection, especially when white blood cell count is low
•
Anemia, which may cause tiredness, or may require blood transfusions
•
Bruising, bleeding
•
Kidney damage, which may cause swelling
•
Hearing decrease,
•
Ringing in ears
•
Change in taste
The less common risks and discomforts (4-20%):
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PI: Shishir Maithel, MD                                             Page 5 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017

Allergic reaction, which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of 
the face or throat

Confusion

Difficulty with balance

Numbness in the fingers and toes

Low blood pressure

Low magnesium, which may cause heart beat irregularities that are possible life threatening
Rare but possible risks (<4%):

Cancer of bone marrow later in life caused by chemotherapy

Seizure
nab-Paclitaxel
The most common risks and discomforts (>20% of patients):
•
Anemia, which may cause tiredness, or may require blood transfusions

Infection, especially when white blood cell count is low

Diarrhea, nausea

Pain

Numbness and tingling of the arms and legs

Tiredness

Hair loss
The less common risks and discomforts (4-20%):

Abnormal heartbeat

Heart stops beating

Cloudiness of the eye, visual disturbances

Vomiting

Swelling of the body

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of 
the face or throat

Mini stroke

Paralysis, weakness, headache

Stroke

Blood clot which may cause swelling, pain, shortness of breath

Hoarseness
Rare but possible risks (<4%):

Bruising, bleeding

Lung collapse which may cause chest pain
If you are a woman: Women of child-bearing potential (defined as a sexually mature woman who (1) has not 
undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy [the surgical removal of 
both ovaries] or (2) has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had 
IRB00104175
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PI: Shishir Maithel, MD                                             Page 6 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017
menses at any time during the preceding 24 consecutive months]) must commit to true abstinence from 
heterosexual contact (which must be reviewed on a monthly basis), or agree to use, and be able to comply 
with, effective contraception without interruption for 28 days prior to starting gemcitabine/cisplatin/nab- 
paclitaxel (including dose interruptions) until treatment with gemcitabine/cisplatin/nab-paclitaxel is complete.
If you are a man: Male subjects must practice true abstinence or agree to use a condom during sexual contact 
with a female of childbearing potential or a pregnant female while on treatment (including during dose 
interruptions) with gemcitabine/cisplatin/nab-paclitaxel and for 6 months following  gemcitabine/cisplatin/nab- 
paclitaxel discontinuation, even if he has undergone a successful vasectomy.
Contrast Agent
Your CT or MRI procedure will require the use of a “contrast agent.” The contrast agent is a substance that 
helps the radiologist interpret the images. The contrast agent will be injected by either a hand‐held needle or a 
machine that does the injection. Most contrast agents stay in your body for only a few minutes, but some of 
them can remain for a few hours or days without any harm to you or anyone near you. Contrast agents are 
generally quite safe, but any injection involves some risks. The injection could harm a nerve, artery or vein, or 
cause infection. The contrast agent could affect kidney function or cause an allergic reaction, though these 
outcomes are rare. The contrast agent could also leak from your veins a little causing swelling and discomfort, 
that is typically treated with ice packs.
MRI
MRI exams use powerful magnets to create images of the body. In addition to the possible reactions to 
contrast materials, you may feel claustrophobic while in the magnet, and will hear loud beeping or hammering 
noises. If you have tattoos or any metal items in your body such as implants, pacemakers, clips or shrapnel, 
we will do special screening to make sure your MRI scan is done safely.
Radiation-Related Risks
You will be exposed to radiation from CT scans. These procedures are necessary for your medical care and 
will occur even if you do not participate in this study. The radiation dose estimate that you will receive is equal 
to or less than the radiation exposure allowed to be received by a radiation worker for 4 years.  The principal 
risk associated with a radiation dose is the possibility of developing a radiation-induced cancer later in life.  
Although the risk from radiation is cumulative it is not expected to adversely affect your condition or treatment.  
The Emory University Radiation Safety Committee has reviewed and approved the use of radiation in this 
research study. 
Will I benefit directly from the study? 
This study is not designed to benefit you directly.  Your disease may improve while you are in this study but it 
may not, and it may even get worse.  This study is designed to learn more about whether receiving this 
chemotherapy regimen before undergoing surgery for intrahepatic cholangiocarcinoma is feasible. The study 
results may be used to help others in the future.
Will I be compensated for my time and effort?
You will not be offered compensation for being in this study.  
What are my other options?
IRB00104175
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PI: Shishir Maithel, MD                                             Page 7 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017
If you decide not to enter this study, there is care available to you outside of this research study.  The study 
doctor will discuss these with you.  You do not have to be in this study to be treated for intrahepatic 
cholangiocarcinoma.
Taking part in this study, however, may make you unable to participate in some other research studies, if they 
exclude people who have taken certain treatments.  You should discuss this with the researchers if you have 
concerns. You may wish to research other study options at websites like clinicaltrials.gov and 
ResearchMatch.org.
How will you protect my private information that you collect in this study?
Whenever possible, a study number, rather than your name, will be used on study records.  Your name and 
other identifying information will not appear when we present or publish the study results.
Study records can be opened by court order.  They also may be provided in response to a subpoena or a 
request for the production of documents. 
Storing and Sharing your Information
De-identified data from this study, including your de-identified genetic information, may be shared with the 
research community at large to advance science and health. Data from this study may be placed into public 
databases where, in addition to having no direct identifiers, researchers will need to sign data use agreements 
before accessing the data. We will remove or code any personal information that could identify you before your 
information is shared. This will ensure that, by current scientific standards and known methods, it is extremely 
unlikely that anyone would be able to identify you from the information we share. Despite these measures, we 
cannot guarantee anonymity of your personal data.
Medical Record
If you have been an Emory and Saint Joseph’s Hospital patient before, then you already have an Emory and 
Saint Joseph’s Hospital medical record.  If you have never been an Emory and Saint Joseph’s Hospital patient, 
you do not have one.   An Emory and Saint Joseph’s Hospital medical record will be made for you if an Emory 
and Saint Joseph’s Hospital provider or facility gives you any services or procedures for this study.  
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory and Saint Joseph’s 
Hospital medical record you have now or any time during the study.  
Emory and Saint Joseph’s Hospital may create study information about you that can help with your care.  For 
example, the results of study tests or procedures.  These study results will be put in your Emory and Saint 
Joseph’s Hospital medical record. Anyone who has access to your medical records will be able to have access 
to all the study information placed there.  The confidentiality of the study information in your medical record will 
be protected by laws like the HIPAA privacy rule.  State and federal laws may not protect the research 
information from disclosure. 
Tests and procedures done at non-Emory and Saint Joseph’s Hospital places may not become part of your 
Emory and Saint Joseph’s Hospital medical record. Also, if you decide to be in this study, it is up to you to let 
your other health providers know. 
IRB00104175
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PI: Shishir Maithel, MD                                             Page 8 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017
In Case of Injury
If you get ill or injured from being in the study, Emory and Saint Joseph’s Hospital will help you get medical 
treatment.   Emory and Saint Joseph’s Hospital and the study supporter have not, however, set aside any 
money to pay you or to pay for this medical treatment. The only exception is if it is proven that your injury or 
illness is directly caused by the negligence of an Emory and Saint Joseph’s Hospital or study supporter 
employee.  “Negligence” is the failure to follow a standard duty of care. 
If you become ill or injured from being in this study, your insurer will be billed for your treatment costs.  If you 
do not have insurance, or if your insurer does not pay, then you will have to pay these costs.  
If you believe you have become ill or injured from this research, you should contact Dr. Maithel at telephone 
number 
. You should also let any health care provider who treats you know that you are in a 
research study. 
Costs
The study supporter will pay for certain items and services that you may receive if you take part in this study.  
You will have to pay for the items or services for which the study supporter does not pay. The study supporter 
will not pay for your regular medical care. If you have insurance, Emory and Saint Joseph’s Hospital will submit 
claims to your insurance for items and services that the study supporter does not cover.  Emory and Saint 
Joseph’s Hospital will send in only those claims for items and services that it reasonably believes your 
insurance will pay and that the study supporter has not paid. 
The actual amount that you have to pay depends on whether or not you have health insurance and whether or 
not that insurance will pay for any research study costs. Generally, insurance companies will not pay for items 
and services that are required just for a research study. Some insurance companies will not pay for regular 
medical treatment or treatment for complications if you are in a study.  How much you will have to pay for any 
co-payments, deductibles or co-insurance depends on your plan.  Emory and Saint Joseph’s Hospital and the 
study supporter will not pay for these costs. 
It is a good idea to contact your insurance provider and tell them you want to be in this research study.  Ask 
them what they will pay for and what they will not pay for.  You can also ask the study team for help in figuring 
out what you will have to pay. 
If you do not have insurance, Emory and Saint Joseph’s Hospital will review your case as part of its program 
for low-income patient care.  The standard policies of that program will apply.  The program will figure out if you 
have to pay any costs for taking part in the study and what those costs will be.
Withdrawal from the Study
You have the right to leave a study at any time without penalty.  
For your safety, however, you should consider the study doctor’s advice about how to go off the study 
treatment.  If you leave the study before the final planned study visit, the researchers may ask you to have 
some of the final steps done.  
The researchers also have the right to stop your participation in this study without your consent for any reason, 
especially if they believe it is in your best interest or if you were to object to any future changes that may be made 
in the study plan.
IRB00104175
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5/19/2021


Study No.: «ID»
Emory University IRB
IRB use only
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PI: Shishir Maithel, MD                                             Page 9 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017
Authorization to Use and Disclose Protected Health Information
The privacy of your health information is important to us.  We call your health information that identifies you, 
your “protected health information” or “PHI.”  To protect your PHI, we will follow federal and state privacy laws, 
including the Health Insurance Portability and Accountability Act and regulations (HIPAA).  We refer to all of 
these laws as the “Privacy Rules.”  Here we let you know how we will use and disclose your PHI for the study 
in which you may choose to participate.
PHI that Will be Used/Disclosed:  
The PHI that we will use or share for the research study includes:

Medical information about you including your medical history and present/past medications.

Results of exams, procedures and tests you have before and during the study.

Laboratory test results.
Purposes for Which Your PHI Will be Used/Disclosed:
We will use and share your PHI for the conduct and oversight of the research study.  We will use and share 
your PHI to provide you with study related treatment and for payment for such treatment.  We will also use and 
share your PHI to conduct normal business operations.  We may share your PHI with other people and places 
that help us conduct or carry out the study, such as laboratories, data management centers, data monitors, 
contract research organizations, Institutional Review Boards (IRBs) and other study sites. If you leave the 
study, we may use your PHI to determine your health, vital status or contact information. We will use and 
disclose your PHI for the administration and payment of any costs relating to subject injury from the study. 
Use and Disclosure of Your Information That is Required by Law:  
We will use and disclose your PHI when we are required to do so by law. This includes laws that require us to 
report child abuse or abuse of elderly or disabled adults. We will also comply with legal requests or orders that 
require us to disclose your PHI. These include subpoenas or court orders.  
Authorization to Use PHI is Required to Participate:
By signing this form, you give us permission to use and share your PHI as described in this document. You do 
not have to sign this form to authorize the use and disclosure of your PHI.  If you do not sign this form, then 
you may not participate in the research study or receive research-related treatment.  You may still receive non-
research related treatment.  
People Who will Use/Disclose Your PHI:
The following people and groups will use and disclose your PHI in connection with the research study:

The Principal Investigator and the research staff will use and disclose your PHI to conduct the 
study and give you study related treatment.

Emory may use and disclose your PHI to get payment for study related treatment and to run 
normal business operations. 

The Principal Investigator and research staff will share your PHI with other people and groups to 
help conduct the study or to provide oversight for the study.
IRB00104175
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PI: Shishir Maithel, MD                                             Page 10 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017

Winship Cancer Institute is the lead institution of the study.  They may use and disclose your 
PHI to make sure the research is done correctly and to collect and analyze the results of the 
research.  They may disclose your PHI to other people and groups like study monitors to help 
conduct the study or to provide oversight for the study.  

The research team and the Study supporter may use and disclose your PHI, including 
disclosure to insurance carriers to administer payment for subject injury. 

The following people and groups will use your PHI to make sure the research is done correctly 
and safely:
o
Emory offices that are part of the Human Research Participant Protection Program and 
those that are involved in study administration and billing.  These include the Emory IRB, 
the Emory Research and Healthcare Compliance Offices, and the Emory Office for 
Clinical Research. 
o
Government agencies that regulate the research including: Food and Drug 
Administration.
o
Public health agencies.
o
Research monitors and reviewer.
o
Accreditation agencies.
o
Study supporter: Celgene

Sometimes a Principal Investigator or other researcher moves to a different institution. If this 
happens, your PHI may be shared with that new institution and their oversight offices. PHI will 
be shared securely and under a legal agreement to ensure it continues to be used under the 
terms of this consent and HIPAA authorization.
Expiration of Your Authorization
Your PHI will be used until this research study ends.
Revoking Your Authorization
If you sign this form, at any time later you may revoke (take back) your permission to use your information.  If 
you want to do this, you must contact the study team at:  
Shishir K. Maithel, MD
Winship Cancer Institute, Emory University
1365-C Clifton Road NE
Atlanta, GA 30322
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose the 
information you already gave them so they can follow the law, protect your safety, or make sure that the study 
was done properly and the data is correct.  If you revoke your authorization you will not be able to stay in the 
study. 
Other Items You Should Know about Your Privacy
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care providers, 
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covered by the Privacy Rules, including HIPAA, then your information won’t be protected by the Privacy Rules.  
People who do not have to follow the Privacy rules can use or disclose your information with others without 
IRB00104175
IRB Approved
5/19/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
   
PI: Shishir Maithel, MD                                             Page 11 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017
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use and disclose your information as described in this Consent and Authorization. 
To maintain the integrity of this research study, you generally will not have access to your PHI related to this 
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organizations for purposes besides this study.  
Contact Information
Contact Dr. Shishir Maithel at 
:

if you have any questions about this study or your part in it,  

if you feel you have had a research-related injury or a bad reaction to the study drug, or

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Contact the Emory Institutional Review Board at 
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
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
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
You may also let the IRB know about your experience as a research participant through our Research 
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IRB00104175
IRB Approved
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Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
   
PI: Shishir Maithel, MD                                             Page 12 of 12                                          Version Date: 09/24/2019
Protocol #: EU4339-18                                                                                                                    IRB Form 12152017
Consent and Authorization
TO BE FILLED OUT BY SUBJECT ONLY
Please print your name, sign, and date below if you agree to be in the main study. By signing this consent and 
authorization form, you will not give up any of your legal rights. We will give you a copy of the signed form to keep.
Name of Subject 
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IRB00104175
IRB Approved
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Prot_SAP_002.pdf: 
Protocol 
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1
A Single-arm Feasibility Study of Gemcitabine, Cisplatin, and Nab-Paclitaxel as 
Neoadjuvant Therapy for Resectable Oncologically High-Risk Intrahepatic 
Cholangiocarcinoma
Protocol #: EU4339-18
NCT#:
Main Study Site:
Emory University
201 Dowman Dr
Atlanta, GA 30322
Additional Study Site:
MD Anderson Cancer Center
1515 Holcombe Blvd
Houston, TX, 77030
Mayo Clinic Rochester
200 First St., SW
Rochester, MN 55901
Virginia Mason Hospital
1100 9th Ave
Seattle, WA 98101
Oregon Health and Science University
3181 SW Sam Jackson Park Road
Portland, OR 97239
Principal Investigator:
Shishir Maithel, MD
Department of Surgery, Division of Surgical Oncology, 
Emory University School of Medicine
Telephone: 404-778-5777
Email: smaithe@emory.edu
Emory Biostatistician:
Jeffrey M. Switchenko, Ph.D.


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2
Research Assistant Professor 
Biostatistics & Bioinformatics Shared Resource at Winship 
Cancer Institute 
Department of Hematology & Medical Oncology, 
Department of Radiology and Imaging Sciences, School of 
Medicine 
Department of Biostatistics & Bioinformatics, Rollins 
School of Public Health, Emory University 
1518 Clifton Road NE
Atlanta, Georgia 30322, USA
Tel: 404-778-4157  Fax: 404-778-5016.
Co-Investigators: 
MD Anderson Cancer Center Collaborators:
Milind Javle, MD
J. Nicolas Vauthey, MD
Mayo Clinic Rochester Collaborators:
Rory Smoot, MD
Virginia Mason Hospital Collaborators:
Bruce Lin, MD
Oregon Health and Science University Collaborators:
Skye Mayo, MD
Charles Lopez, MD, PhD
Multi-site Coordinator:  Quin Boynes
Qboynes@emory.edu


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TABLE OF CONTENTS
1.0
Synopsis
2.0
Background
3.0
Drug Information
4.0
Objectives
5.0
Patient Eligibility
6.0
Treatment Plan
7.0
Evaluation During Study
8.0
Criteria for Removal from the Study
9.0
Response Evaluation
10.0
Statistical Methods
11.0     Registration Process
12.0     Data and Protocol Management
13.0 
Safety Reporting of Adverse Events
14.0     References
APPENDICES
Appendix 1 – ECOG Performance Status
Appendix 2 – Nab-Paclitaxel- Additional Information
Appendix 3 – Registration Process for Participating Sites
Appendix 4 – Multicenter Data Management Process


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1.
SYNOPSIS
Institution/Affiliation:
Department of Surgery, Division of Surgical Oncology, 
Emory University School of Medicine
Protocol Title:
A Single-arm Feasibility Study of Gemcitabine, 
Cisplatin, and Nab-Paclitaxel as Neoadjuvant Therapy 
for Resectable Oncologically High-Risk Intrahepatic 
Cholangiocarcinoma
Phase of Development:
II
Trial Locations:
1) MD Anderson Cancer Center
2) Mayo Clinic Rochester
3) Virginia Mason Hospital
4) Emory University
Number of sites:
4
Patient Population:
Resectable 
Oncologically 
High-Risk 
Intrahepatic 
Cholangiocarcinoma
Estimated Number of Patients:
37 patients
Primary Objective:
To assess the feasibility of neoadjuvant chemotherapy 
including gemcitabine, cisplatin, and nab-paclitaxel for 
resectable oncologically high-risk intrahepatic 
cholangiocarcinoma that is treated with surgical 
resection. Thus, the primary aim will be completion of all 
treatment including neoadjuvant therapy and resection, 
while assessing safety and tolerability of the preoperative 
chemotherapy regimen prior to surgery.
Secondary Objectives:
1) To assess the radiological response rate according to 
Response Evaluation Criteria in Solid Tumors 
(RECIST)
2) To determine the R0 resection rate
3) To determine recurrence-free survival (RFS)
4) To identify patients’ overall survival (OS) rate. 
Study Design:
1) Phase II
2) 37 patients
Select Inclusion Criteria:
1) Diagnosis of intrahepatic cholangiocarcinoma
2) Oncologic high-risk disease at the time of enrollment 
defined as(must meet at least one of the criteria 
below)
T-stage ≥ Ib (Ib – IV)
Solitary lesion > 5 cm
Multifocal tumors or satellite lesions present 
confined to the same lobe of the liver as the 
dominant lesion but still technically resectable


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Presence of major vascular invasion but still 
technically resectable
Suspicious or involved regional lymph nodes 
(N1)
3) High-quality cross-sectional imaging (CT or MRI) 
performed within 6 weeks prior to enrollment
4) No distant extrahepatic disease (M0)
5) Adults >18 years of age
6) Able to give informed consent
7) Able to adhere to study visit schedule and other 
protocol requirements
8) ECOG performance status of 0-1
9) Absolute neutrophil count ≥ 1500/mm3
10) Platelet count ≥ 100,000/mm3
11) Albumin ≥3 g/dl
Select Exclusion Criteria
1) Serum creatinine > 1.5x upper limit of normal
2) Serum total bilirubin > 1.5x upper limit of normal
3) Presence of active infection
4) Pregnant and/or breastfeeding
5) Active other primary malignancy
6) Concurrent severe and/or uncontrolled medication 
conditions which could compromise participation in 
study such as unstable angina, MI within 6 months, 
unstable symptomatic arrhythmia, symptomatic CHF, 
serious active or uncontrolled infection after 
inadequate biliary drainage if tumor obstructing bile 
duct.
Length of Study:
Our plan is to enroll 37 resectable oncologically high-
risk intrahepatic cholangiocarcinoma patients over an 18 
month period starting from May 1st 2018 in order to have 
30 evaluable patients. Last study participant will be 
enrolled 6 months prior to study completion. All patients 
will be followed for recurrence free survival and overall 
survival as part of routine care.
Additional Therapies 
1) Gemcitabine
2) Cisplatin
3) nab-paclitaxel


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Scheme
Surgery
Biopsy-proven, oncologically high-risk, but technically resectable, intrahepatic 
cholangiocarcinoma
Initial staging as per standard of care of participating institution
Signed informed consent
Gemcitabine 800 mg/m2 + Cisplatin 25 mg/m2 + nab-paclitaxel 100 mg/m2
D 1 and D8 every 21 days (a total of 4 cycles)
Restaging 
Stable or 
Responding Disease
Disease progression
Safety Follow up Visit
Long Term Follow up
Patient off protocol and will 
receive other treatment 
approaches according to each 
institution


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7
2.
BACKGROUND
Intrahepatic cholangiocarcinoma (IHCCA) is the second most common primary liver 
cancer, with a rising incidence but without parallel advances in treatment or patient 
outcome.  Surgical resection is the only potentially curative treatment for IHCCA and is 
associated with 5-year survival rates between 15% and 40%.  Up to two-thirds of patients 
are not resectable at presentation and of those who undergo curative-intent resection, 
two-thirds suffer postoperative disease recurrence, most commonly in the remnant liver, 
followed by the peritoneum and abdominal lymph nodes.  Risk factors for disease 
recurrence include vascular invasion, multiple tumors, lymph node metastases, increased 
tumor size, and periductal infiltrating tumor morphology.1,2  
Neoadjuvant chemotherapy for intrahepatic cholangiocarcinoma 
The potential benefits of neoadjuvant therapy in IHCCA are early treatment of 
micrometastases, downsizing of tumors to increase margin-negative resection rates, 
eradication of disease from regional lymph nodes, and improved selection of patients for 
complex liver resection.  To date, a prospective study on neoadjuvant therapy for 
resectable IHCCA has not been conducted.  
A retrospective study by Le Roy et al investigated the efficacy of neoadjuvant 
chemotherapy in locally advanced IHCCA. They enrolled 170 IHCCA including 74 
locally advanced and 96 resectable tumors. Out of 74 patients, 51 were treated with 
gemcitabine based regimens and 19 received 5-fluorouracil, oxaliplatin and irinotecan. In 
their study, 39 (53%) out of 74 locally advanced IHCCA patients became resectable after 
receiving 6 months of systemic chemotherapy. There was no statistically significant 
difference in the median overall survival (OS) of locally advanced IHCCA patients’ who 
received neoadjuvant chemotherapy as compared to patients who had surgery alone for 
resectable disease. These data suggested that the survival of patients with locally 
advanced disease treated with neoadjuvant therapy may be similar to those who received 
primary resection.3  
Stromal interactions in biliary cancers and the role of Nab-Paclitaxel
Tumor progression and growth has been previously linked to dynamic interactions 
between tumor cells and the surrounding stromal tissue. Cancers with a “reactive” stroma 
are associated with a high density of alpha-smooth muscle actin (α-SMA)-positive 
fibroblasts, hypovascularity, and activated stellate cells.4-7 The presence of α-SMA-
positive fibroblasts within the cholangiocarcinoma stroma has been associated with a 
poor prognosis.6-8
IHCCA is characterized by fibroinflammatory desmoplasia and hypoperfused stroma.  In 
preclinical studies of pancreatic cancer, which incites a similarly dense desmoplastic 
reaction, nab-paclitaxel, an FDA-approved chemotherapy for treatment of metastatic 
pancreatic cancer, induced stromal collapse and increased intratumoral delivery of 
gemcitabine.9 In a study of potentially resectable pancreatic cancer patients treated with 
Nab-Paclitaxel and gemcitabine, surgical specimens of patients with a marked pathologic 


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8
response demonstrated stromal disruption, characterized by collagen disorganization, and 
a lower density of α-SMA-positive fibroblasts suggesting a role for this combination in 
other stromal-rich malignancies like biliary tracts cancers (BTC).10 Therefore, both 
preclinical and clinical data support the use of neoadjuvant nab-paclitaxel, gemcitabine, 
and cisplatin for IHCCA.
Currently, the standard of care regimen for unresectable IHCCA is gemcitabine and 
cisplatin, which is associated with a median progression-free survival (PFS) of 8 months 
and overall survival (OS) of 11.7 months.11 
Safety of combining gemcitabine, cisplatin, and Nab-Paclitaxel
The safety of combining gemcitabine and cisplatin and gemcitabine and Nab-Paclitaxel 
has been previously described in BTC and pancreatic cancers, respectively.11,12 A recent 
phase II study of 51 patients was completed at MD Anderson Cancer Center with 
unresectable BTC treated with gemcitabine, cisplatin, and nab-paclitaxel (GAP). Patients 
treated initially with cisplatin 25mg/m2, nab-paclitaxel 125mg/m2 and gemcitabine 
1000mg/m2 experienced grade 3/4 hematological toxicity including neutropenia, febrile 
neutropenia, anemia, and thrombocytopenia leading to treatment discontinuation in 6 out 
of 30 patients.  Nab-paclitaxel was reduced to 100mg/m2 and gemcitabine to 800mg/m2. 
After dose reduction, treatment was better tolerated and only 3 patients experienced grade 
4 hematological toxicity. Moreover, grade 3 non-hematological toxicities developed in 19 
patients including nausea, vomiting, diarrhea, thromboembolic event, cardiovascular 
arrhythmia, hypokalemia, constipation, cystitis, and elevations of liver transaminases. 
The median PFS = 11.4 mos (95% CI: 6.1, 16.1) with median OS = 19.2 (95%CI: 13.6, 
NA) and 1-year survival rate 67.6%. The disease control rate was demonstrated in 84.3% 
of patients and 12 initially unresectable cases were operated on post treatment with 1 
patient having had a complete pathologic response.13 
3.
DRUG INFORMATION
3.1
Nab-Paclitaxel
3.1.1
The Product
NAB-PACLITAXEL for Injectable Suspension (also known as ABI-007, nab-paclitaxel, 
paclitaxel protein-bound particles for injectable suspension) is an albumin-bound form of 
paclitaxel with a mean particle size of approximately 130 nanometers. Paclitaxel exists in 
the particles in a non-crystalline, amorphous state. NAB-PACLITAXEL is supplied as a 
white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% 
Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial 
contains 100 mg of paclitaxel and approximately 900 mg of human albumin. Each 
milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. NAB-
PACLITAXEL is free of solvents.   The active agent in NAB-PACLITAXEL is 
paclitaxel. 


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9
3.1.2
Indication
In the United States, NAB-PACLITAXEL for Injectable Suspension (paclitaxel protein-
bound particles for injectable suspension) is indicated for the treatment of metastatic 
adenocarcinoma of the pancreas as first-line treatment, in combination with gemcitabine.
3.1.3
Introduction
NAB-PACLITAXEL is a biologically interactive albumin-bound paclitaxel combining a 
protein with a chemotherapeutic agent in the particle form. This composition provides a 
novel approach of increasing intra-tumoral concentrations of the drug by a receptor-
mediated transport process allowing transcytosis across the endothelial cell. This 
albumin-specific receptor mediated process involves the binding of albumin to a specific 
receptor (gp60) on the intraluminal endothelial cell membrane, resulting in activation of a 
protein (caveolin-1), which initiates an internalization process in the endothelial cell 
through the formation of caveolae, with transport of the intact albumin-bound 
chemotherapeutic complex via these caveolae to the underlying tumor interstitium.14  
Other postulated mechanisms of action for the combination of gemcitabine with nab-
paclitaxel include downregulation of cytidine deaminase by paclitaxel resulting in 
higher/sustained concentrations of gemcitabine, macropinocytosis of proteins such as 
albumin by Ras-transformed cells which would allow for enhanced uptake of paclitaxel 
loaded albumin nanoparticles into pancreatic cancer tumor cells.15,16
3.1.4
Preclinical Studies with NAB-PACLITAXEL 
Preclinical studies comparing NAB-PACLITAXEL to Taxol® (paclitaxel Cremophor® 
EL solvent-based, BMS) demonstrated lower toxicities, with an MTD approximately 
50% higher for NAB-PACLITAXEL compared to Taxol.  At equal doses there was less 
myelosuppression and improved efficacy in a xenograft tumor model of human 
mammary adenocarcinoma.  At equitoxic doses of paclitaxel, NAB-PACLITAXEL 
treated groups showed more complete regressions, longer time to recurrence, longer 
doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the 
curve was 33% higher for NAB-PACLITAXEL versus solvent based paclitaxel, 
indicating more effective intratumoral accumulation of NAB-PACLITAXEL.14 
3.1.6
Clinical Studies with NAB-PACLITAXEL
A multicenter, multinational, randomized, open-label study was conducted in 861 
patients comparing NAB-PACLITAXEL plus gemcitabine versus gemcitabine 
monotherapy as first-line treatment of metastatic adenocarcinoma of the pancreas. Key 
eligibility criteria were Karnofsky Performance Status (KPS) ≥70, normal bilirubin level, 
transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 5 times the ULN 
for patients with liver metastasis, no prior cytotoxic chemotherapy in the adjuvant setting 
or for metastatic disease, no ongoing active infection requiring systemic therapy, and no 
history of interstitial lung disease. Patients with rapid decline in KPS (≥10%) or serum 
albumin (≥20%) during the 14 day screening period prior to study randomization were 
ineligible.


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A total of 861 patients were randomized (1:1) to the NAB-PACLITAXEL/gemcitabine 
arm (N=431) or to the gemcitabine arm (N=430). Randomization was stratified by 
geographic region (Australia, Western Europe, Eastern Europe, or North America), KPS 
(70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no). Patients 
randomized to NAB-PACLITAXEL/gemcitabine received NAB-PACLITAXEL 125 
mg/m2 as an intravenous infusion over 30-40 minutes followed by gemcitabine 1000 
mg/m2 as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-
day cycle. Patients randomized to gemcitabine received 1000 mg/m2 as an intravenous 
infusion over 30-40 minutes weekly for 7 weeks followed by a 1-week rest period in 
Cycle 1 then as 1000 mg/m2 on Days 1, 8 and 15 of each subsequent 28-day cycle. 
Patients in both arms received treatment until disease progression or unacceptable 
toxicity. The major efficacy outcome measure was overall survival (OS). Additional 
outcome measures were progression-free survival (PFS) and overall response rate (ORR), 
both assessed by independent, central, blinded radiological review using RECIST 
(version 1.0).
In the intent to treat (all randomized) population, the median age was 63 years (range 27-
88 years) with 42% ≥ 65 years of age; 58% were men; 93% were White and KPS was 90-
100 in 60%. Disease characteristics included 46% of patients with 3 or more metastatic 
sites; 84% of patients had liver metastasis; and the location of the primary pancreatic 
lesion was in the head of pancreas (43%), body (31%), or tail (25%).
The median overall survival of the NAB-PACLITAXEL/gemcitabine group was 8.5 
months compared to 6.7 months in the gemcitabine alone group (HR 0.72, p<0.0001). 
PFS was similarly improved in the combination arm (5.5 vs. 3.7 months, HR 0.69, 
p<0.0001). Overall response rate by central review was 23% with NAB-
PACLITAXEL/gemcitabine and 7% with gemcitabine alone (p<0.0001).
3.1.6
Potential Risks of NAB-PACLITAXEL Toxicities 
As of 06 Oct 2014, approximately 11,867 subjects have been treated with nab-paclitaxel 
in clinical studies, with 3,905 in the Celgene development program worldwide and an 
estimated 7,962 in non-Celgene-sponsored studies globally.  It is estimated that 
cumulative exposure to nab-paclitaxel during marketing experience is approximately 
296,427 patients.  Therefore, overall estimated cumulative exposure to nab-paclitaxel 
during clinical trials and commercial experience is approximately 308,294 patients. 
Clinically significant adverse drug reactions identified during clinical trials or post-
marketing surveillance, considered by Celgene to be at least possibly associated with 
nab-paclitaxel, are provided below. 
Very common (≥ 10%):
 
• anemia, red blood cell count decreased
• febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombocytopenia 
• constipation  
• diarrhea 


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• nausea  
• vomiting 
• abdominal pain, abdominal pain upper
• stomatitis, mucosal inflammation 
• SMQ peripheral neuropathy 
• dizziness  
• headache 
• asthenia, fatigue 
• arthralgia, back pain, bone pain, chest pain, musculoskeletal pain, myalgia, pain in  
extremity 
• edema, edema peripheral 
• pyrexia 
• chills  
• decreased appetite  
• dysgeusia 
• weight decreased  
• insomnia 
• depression 
• cough 
• dyspnea 
• alopecia 
• rash, generalized rash, maculopapular rash  
• pruritus 
• nail disorder, nail discoloration, onycholysis  
• alanine aminotransferase increased, aspartate aminotransferase increased 
• dehydration 
• epistaxis
• hypokalemia 
Common (≥ 1% to < 10% ):
 
• bone marrow depression (failure), pancytopenia  
• candidiasis, cholangiitis,folliculitis, lower respiratory infection, nail infection, oral 
candidiasis, pneumonia, upper respiratory tract infection, urinary tract infection 
• neutropenic sepsis, sepsis 
• bronchitis 
• pneumonitis
• colitis, intestinal obstruction, small intestinal obstruction
• dysphagia 
• dyspepsia
• hyperbilirubinaemia, blood alkaline phosphatase increased, blood bilirubin increased, 
blood creatinine increased 
• acute renal failure 
• hematuria 
• ataxia 


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• muscle weakness 
• anxiety  
• nasal congestion  
• oropharyngeal pain 
• dry mouth, dry throat, nasal dryness 
• hemoptysis
• pulmonary embolism, deep vein thrombosis 
• pleural effusion 
• flushing, erythema 
• dry skin  
• palmar-plantar erythrodysaethesia syndrome
• hypertension 
• hypotension 
• tachycardia, cardiac failure congestive, palpitations 
• increased lacrimation
• visual disturbance, visual Impairment vision blurred 
• infusion site extravasation, infusion site inflammation, infusion site rash, infusion site 
reaction, injection site reactions, injection site infection, extravasation 
• lymphedema
Uncommon (0.1% < 1.0%):
• arrhythmia, sinus bradycardia, atrioventricular block, supraventricular tachycardia  
• cardiac arrest 
• drug hypersensitivity, hypersensitivity, dermatitis allergic 
• thrombotic thrombocytopenic purpura, hemolytic uremic syndrome 
• cystoid macular edema, maculopathy 
• conjunctivitis 
• keratitis 
• fluid retention 
• malaise 
• lethargy 
• skin exfoliation 
• urticaria
• erythema multiforme
• facial palsy, VIIth nerve paralysis
Elderly
In subjects ≥ 65 years old with metastatic breast cancer who received nab-paclitaxel 
monotherapy, a higher incidence of epistaxis, diarrhea, dehydration, fatigue and 
peripheral edema has been reported.
nab-Paclitaxel in combination with gemcitabine 


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In subjects with metastatic pancreatic cancer, who received the combination of nab-
paclitaxel and gemcitabine, there may be an increase of sepsis.  Pneumonitis appears to 
occur more often (4%) when the two drugs are given together.  This requires early 
detection and treatment as it may be life-threatening or even fatal.  In addition, acute 
renal or kidney failure and hemolytic uremic syndrome have been reported commonly 
and uncommonly, respectively, in combination of nab-paclitaxel with gemcitabine.
A very rare condition known as Posterior Reversible Encephalopathy Syndrome has 
occurred when gemcitabine is given alone or in combination with other chemotherapy 
medications.
A very rare condition known as Capillary Leak Syndrome that causes leaking of fluid 
outside of blood vessels has occurred when gemcitabine is given alone or in combination 
with other chemotherapy medications.
Additional side effects observed during post-marketing surveillance of gemcitabine, not
otherwise noted above include:
•
vasculitis 
•
gangrene
Additional side effects observed during post-marketing surveillance of nab-paclitaxel, not 
otherwise noted above include: 
•
cranial nerve palsies and vocal cord paresis 
•
palmar-plantar erythrodysethesia syndrome
•
photosensitivity reaction 
•
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme  
radiation pneumonitis, radiation recall phenomenon
Elderly
In subjects ≥ 65 years old, who received nab-paclitaxel and gemcitabine, a higher 
incidence of diarrhea, decreased appetite, dehydration, and epistaxis has been reported 
compared to subjects < 65 years old.  In subjects ≥ 75 years old, a higher incidence of 
serious adverse reactions and adverse reactions leading to treatment discontinuation has 
been reported. 
 
Adverse drug reactions reported from post-marketing experience, even though their 
frequency is unknown, have been similar in type and severity to those reported in nab-
paclitaxel clinical trials. 
nab-Paclitaxel in combination with carboplatin
Concomitant use of yellow fever vaccine is contraindicated and concomitant use of live 
attenuated vaccines (except yellow fever) is not recommended in subjects receiving 


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carboplatin due to the risk of potentially life-threatening, systemic complications.
Although uncommon, subjects receiving carboplatin have an increased risk of bleeding in 
their cancer tumor(s). 
Additional clinically important side effects for carboplatin, not already stated above for 
nabpaclitaxel and /or stated with a different frequency or severity include:
Very common (≥ 10%):
•
Myelosuppression
•
Decreased levels of certain minerals in the blood (sodium, potassium, calcium, 
and magnesium) 
•
Decreased hearing
- Pediatric patients: clinically significant hearing loss has been reported to occur in 
pediatric patients administered at higher than recommended doses in
           combination with other ototoxic agents. Cases of hearing loss with a delayed
           onset have been reported in pediatric patients. A long-term audiometric
           follow-up in this population is recommended.
            - Elderly patients: Ototoxicity is more likely seen in patients older than 65 years
           old and/or previously treated with other platinum treatments and other
           ototoxic agents.
Common (≥ 1% to < 10% ):
•
Ringing sensation in the ear
•
Abnormal kidney function (defined as a decrease in creatinine clearance below 60 
ml/min)
Uncommon (0.1% < 1.0%):
•
Taste changes
Elderly
In subjects ≥ 65 years old, who received nab-paclitaxel and carboplatin, a higher 
frequency of bone marrow depression, SMQ peripheral neuropathy, and arthralgia have 
been reported compared to patients < 65 years old.
3.1.7
Further Information
See Appendix 2, Nab paclitaxel (Nab-PaclitaxelTM) Prescribing Information (Updated 
7/2015) – Accessed via Nab-Paclitaxel Website: http://www.Nab-
Paclitaxel.com/docs/Nab-   Paclitaxel_PrescribingInformation.pdf
3.2
Gemcitabine
3.2.1
The Product
Gemcitabine for injection, USP (GEMZAR®) is available in sterile single-use vials 
individually packaged in a carton containing: 200 mg white to off-white, lyophilized 


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powder in a 10-mL size sterile single-use vial – NDC 0002-7501-01 (No.7501) or 1g 
white to off-white, lyophilized powder in a 50-mL size sterile single-use vial – NDC 
0002-7502-01 (No. 7502). Unopened vials of gemcitabine are stable until the expiration 
date indicated on the package when stored at controlled room temperature 20° to 25°C 
(68° to 77°F) and that allows for excursions between 15° and 30°C (59° and 86°F). Do 
not refrigerate as crystallization can occur.
3.2.2
Potential Risks of Gemcitabine Toxicities 
The most common toxicities reported for gemcitabine include myelosuppression, 
transient elevations in serum transaminases (approximately 70%), nausea and vomiting 
(69%), fever (41%), rash (30%), diarrhea (19%), flu syndrome, (19%), infection (16%), 
alopecia (15%), edema (13%), stomatitis (11%),) neurotoxicity (mild 10%, severe <1%), 
mild proteinuria and hematuria; Hemolytic Uremia Syndrome (HUS) reported rarely 
(0.25%), dyspnea (0.2%) and serious pulmonary toxicity (0.06%). Also reported include 
constipation and pruritus.
Myelosuppression with Gemcitabine
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with 
gemcitabine as a single agent and the risks are increased when gemcitabine is combined 
with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and 
thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-
agent gemcitabine. The frequencies of Grade 3-4 neutropenia, anemia, and 
thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in 
patients receiving gemcitabine in combination with another drug.
Pulmonary Toxicity and Respiratory Failure with Gemcitabine
Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary 
edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, 
these pulmonary events can lead to fatal respiratory failure despite discontinuation of 
therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of 
gemcitabine. Discontinue gemcitabine in patients who develop unexplained dyspnea, with 
or without bronchospasm, or have any evidence of pulmonary toxicity.
 
Hemolytic Uremic Syndrome with Gemcitabine
Hemolytic uremic syndrome, including fatalities from renal failure or the requirement for 
dialysis, can occur in patients treated with gemcitabine. In clinical trials, HUS was reported 
in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS Assess 
renal function prior to initiation of gemcitabine and periodically during treatment. Consider 
the diagnosis of HUS in patients who develops anemia with evidence of microangiopathic 
hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or 
evidence of renal failure (elevation of serum creatinine or BUN) Permanently discontinue 
gemcitabine in patients with HUS or severe renal impairment. Renal failure may not be 
reversible even with discontinuation of therapy.


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Hepatic Toxicity with Gemcitabine
Drug-induced liver injury, including liver failure and death, has been reported in patients 
receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs. 
Transient elevation in serum transaminases occurs in approximately 70% of patients. 
Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing 
medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the 
underlying hepatic insufficiency. Assess hepatic function prior to initiation of gemcitabine 
and periodically during treatment. Discontinue gemcitabine in patients that develop severe 
liver injury.
Embryo and Fetal Toxicity with Gemcitabine 
Gemcitabine can cause fetal harm when administered to a pregnant woman, based on its 
mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice 
and rabbits. If this drug is used during pregnancy, or if a woman becomes pregnant while 
taking gemcitabine, the patient should be apprised of the potential hazard to a fetus. 
Capillary Leak Syndrome with Gemcitabine
Capillary leak syndrome (CLS) with severe consequences has been reported in patients 
receiving Gemcitabine as a single agent or in combination with other chemotherapeutic 
agents. Immediate discontinuation of Gemcitabine should be done if CLS develops during 
therapy.
Posterior Reversible Encephalopathy Syndrome with Gemcitabine
Posterior reversible encephalopathy syndrome (PRES) has been reported in patients 
receiving Gemcitabine as a single agent or in combination with other chemotherapeutic 
agents. PRES can present with headache, seizure, lethargy, hypertension, confusion, 
blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES 
with MRI and discontinue Gemcitabine immediately if PRES develops during therapy.
3.2.3
Further Information
Gemcitabine (GemzarTM) Prescribing Information (Updated 2/2011) – Accessed via 
Gemzar Website: http://pi.lilly.com/us/gemzar.pdf
3.3
Cisplatin
3.3.1
The Product
Cisplatin for injection, USP (CISPLATIN®) is available in a sterile, multiple dose vial 
without preservatives. Cisplatin Injection (1 mg/mL) is supplied as follows: NDC No. Fill 
Volume 16729-288-11 for 50 mL and 16729-288-38 for 100 mL. Do not refrigerate. 
Protect unopened container from light. The cisplatin remaining in the amber vial following 
initial entry is stable for 28 days protected from light or for 7 days under fluorescent room 
light. HOW SUPPLIED: Store at 20° to 25°C (68° to 77°F). This container closure is not 
made with natural rubber latex. Needles or intravenous sets containing aluminum parts that 


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may come in contact with cisplatin should not be used for preparation or administration. 
Aluminum reacts with cisplatin, causing precipitate formation and a loss of potency.
3.3.2
Potential Risks of Cisplatin Toxicities 
The most common toxicities of cisplatin include nephrotoxicity (28-36%; acute renal 
failure and chronic renal insufficiency), peripheral neuropathy (dose and duration 
dependent), nausea and vomiting (76% to 100%), myelosuppression (25% to 30%; nadir: 
day 18-23; recovery: by day 39; mild with moderate doses, mild-to-moderate with high-
dose therapy), liver enzymes increased (especially SGOT and bilirubin), ototoxicity (10% 
to 30%; manifested as high frequency hearing loss; ototoxicity is especially pronounced in 
children), tissue irritation (extravasation).
Other toxicities (<1%) include alopecia (mild), anaphylactic reaction, arrhythmias, 
arterial vasospasm (acute), blurred vision, bradycardia, diarrhea, heart block, heart 
failure, hemolytic anemia (acute), hemolytic uremic syndrome, hypercholesterolemia, 
hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, limb 
ischemia (acute), mesenteric ischemia (acute), myocardial infarction, myocardial 
ischemia, mouth sores, neutropenic typhlitis, optic neuritis, orthostatic hypotension, 
pancreatitis, papilledema, phlebitis, reversible posterior leukoencephalopathy syndrome 
(RPLS), SIADH, stroke, thrombophlebitis, thrombotic thrombocytopenic purpura.
Nephrotoxicity with Cisplatin
Dose-related and cumulative renal insufficiency, including acute renal failure, is the major 
dose limiting toxicity of cisplatin. Renal toxicity has been noted in 28% to 36% of patients 
treated with a single dose of 50 mg/m. It is first noted during the second week after a dose 
and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease 
in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated 
courses of the drug. Renal function must return to normal before another dose of cisplatin 
can be given. Elderly patients may be more susceptible to nephrotoxicity. Impairment of 
renal function has been associated with renal tubular damage. The administration of 
cisplatin using a 6- to 8-hour infusion with intravenous hydration, and mannitol has been 
used to reduce nephrotoxicity. However, renal toxicity still can occur after utilization of 
these procedures.
Ototoxicity with Cisplatin
Ototoxicity has been observed in up to 31% of patients treated with a single dose of 
cisplatin 50 mg/m, and is manifested by tinnitus and/or hearing loss in the high frequency 
range (4000 to 8000 Hz). Decreased ability to hear normal conversational tones may occur. 
Deafness after the initial dose of cisplatin has been reported. Hearing loss can be unilateral 
or bilateral and tends to become more frequent and severe with repeated cisplatin doses. It 
is unclear whether cisplatin-induced ototoxicity is reversible. Vestibular toxicity has also 
been reported. Ototoxic effects may be related to the peak plasma concentration of 
cisplatin. Ototoxicity can occur during treatment or be delayed. Audiometric monitoring 
should be performed prior to initiation of therapy, prior to each subsequent dose, and for 
several years post therapy. The risk of ototoxicity may be increased by prior or 


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simultaneous cranial irradiation, and may be more severe in patients being treated with 
other ototoxic drugs (e.g., aminoglycosides and vancomycin), and in patients with renal 
impairment. 
Hematological toxicity with Cisplatin
Myelosuppression occurs in 25% to 30% of patients treated with cisplatin. The nadirs in 
circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with 
most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia 
are more pronounced at higher doses (>50 mg/m). Anemia (decrease of 2 g 
hemoglobin/100 mL) occurs at approximately the same frequency and with the same 
timing as leukopenia and thrombocytopenia. Fever and infection have also been reported 
in patients with neutropenia. Potential fatalities due to infection (secondary to 
myelosuppression) have been reported. Elderly patients may be more susceptible to 
myelosuppression. In addition to anemia secondary to myelosuppression, a Coombs’ 
positive hemolytic anemia has been reported. In the presence of cisplatin hemolytic 
anemia, a further course of treatment may be accompanied by increased hemolysis and this 
risk should be weighed by the treating physician. The development of acute leukemia 
coincident with the use of cisplatin has been reported. In these reports, cisplatin was 
generally given in combination with other leukemogenic agents.
Gastrointestinal toxicity with Cisplatin
Marked nausea and vomiting occur in almost all patients treated with cisplatin, and may be 
so severe that the drug must be discontinued. Nausea and vomiting may begin within 1 to 
4 hours after treatment and last up to 24 hours. Various degrees of vomiting, nausea and/or 
anorexia may persist for up to 1 week after treatment. Delayed nausea and vomiting (begins 
or persists 24 hours or more after chemotherapy) has occurred in patients attaining 
complete emetic control on the day of cisplatin therapy. Diarrhea has also been reported.
Serum Electrolytes disturbance with Cisplatin
Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia 
have been reported to occur in patients treated with cisplatin and are probably related to 
renal tubular damage. Tetany has been reported in those patients with hypocalcemia and 
hypomagnesemia. Generally, normal serum electrolyte levels are restored by administering 
supplemental electrolytes and discontinuing cisplatin. Inappropriate antidiuretic hormone 
syndrome has also been reported.
Hyperuricemia with Cisplatin
Hyperuricemia has been reported to occur at approximately the same frequency as the 
increases in BUN and serum creatinine. It is more pronounced after doses greater than 50 
mg/m, and peak levels of uric acid generally occur between 3 to 5 days after the dose. 
Allopurinol therapy for hyperuricemia effectively reduces uric acid levels.


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Neurotoxicity with Cisplatin
Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The 
neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic 
symptoms have been reported to occur after a single dose. Although symptoms and signs 
of cisplatin neuropathy usually develop during treatment, symptoms of neuropathy may 
begin 3 to 8 weeks after the last dose of cisplatin. Cisplatin therapy should be discontinued 
when the symptoms are first observed. The neuropathy, however, may progress further 
even after stopping treatment. Preliminary evidence suggests peripheral neuropathy may 
be irreversible in some patients. Elderly patients may be more susceptible to peripheral 
neuropathy. Lhermitte’s sign, dorsal column myelopathy, and autonomic neuropathy have 
also been reported. Loss of taste, seizures, leukoencephalopathy, and reversible posterior 
leukoencephalopathy syndrome (RPLS) have also been reported. Muscle cramps, defined 
as localized, painful, involuntary skeletal muscle contractions of sudden onset and short 
duration, have been reported and were usually associated in patients receiving a relatively 
high cumulative dose of cisplatin and with a relatively advanced symptomatic stage of 
peripheral neuropathy. 
Ocular Toxicity with Cisplatin
Optic neuritis, papilledema, and cerebral blindness have been reported in patients receiving 
standard recommended doses of cisplatin. Improvement and/or total recovery usually 
occurs after discontinuing cisplatin. Steroids with or without mannitol have been used; 
however, efficacy has not been established. Blurred vision and altered color perception 
have been reported after the use of regimens with higher doses of cisplatin or greater dose 
frequencies than recommended in the package insert. The altered color perception 
manifests as a loss of color discrimination, particularly in the blue-yellow axis. The only 
finding on funduscopic exam is irregular retinal pigmentation of the macular area. 
Anaphylactic-Like Reactions with Cisplatin
Anaphylactic-like reactions have been reported in patients previously exposed to cisplatin. 
The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a 
few minutes of drug administration. Reactions may be controlled by intravenous 
epinephrine with corticosteroids and/or antihistamines as indicated. Patients receiving 
cisplatin should be observed carefully for possible anaphylactic-like reactions and 
supportive equipment and medication should be available to treat such a complication. 
Hepatotoxicity with Cisplatin
Transient elevations of liver enzymes, especially AST, as well as bilirubin, have been 
reported to be associated with cisplatin administration at the recommended doses.
 
3.3.3
Further Information
Cisplatin Prescribing Information (updated 2012) – Accessed via Daily Med (National 
Library of Medicine) http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a440f077-
46f6-4688-a209- 65bce38d1c92


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4.
OBJECTIVES
4.1
Primary endpoint
To assess the feasibility of therapeutic approach that includes neoadjuvant chemotherapy 
including gemcitabine, cisplatin, and nab-paclitaxel for high-risk but technically resectable 
intrahepatic cholangiocarcinoma and is completed with surgical resection. Thus, the 
primary aim will assess completion of all treatment including neoadjuvant therapy and 
resection, while assessing safety and tolerability of the preoperative chemotherapy regimen 
as well.
4.2
Secondary endpoints
1.
To assess the radiological response rate to neoadjuvant systemic chemotherapy 
according to the Response Evaluation Criteria in Solid Tumors (RECIST)
2.
To determine the R0 resection rate
3.
To determine patients’ recurrence-free survival (RFS)
4.
To identify patients’ overall survival (OS) rate.
5.
PATIENT ELIGIBILITY
Patients will be included in the study based on the following inclusion and exclusion 
criteria.   
5.1
INCLUSION CRITERIA

Diagnosis of intrahepatic cholangiocarcinoma

High-quality cross-sectional imaging by computerized tomography (CT) or magnetic 
resonant imaging (MRI) performed within 6 weeks prior to enrollment and showed a 
resectable, but high-risk, IHCCA confined to the liver, bile duct, and /or regional lymph 
nodes. Tumors will be considered high-risk if the high-quality, contrast-enhanced CT 
and/or MRI +/- positron emission tomography (PET) scan showed: (must meet at least 
one of the criteria below)
1. T-stage ≥ Ib (Ib – IV)
2. Solitary lesion > 5 cm
3. Multifocal tumors or satellite lesions present confined to the same lobe of the liver 
as the dominant lesion but still technically resectable
4. Presence of major vascular invasion but still technically resectable
5. Suspicious or involved regional lymph nodes (N1)

No distant extrahepatic disease (M0) 

Adults >18 years of age

Able to give informed consent

Able to adhere to study visit schedule and other protocol requirements


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
ECOG performance status of 0-1

Adequate bone marrow reserves as evidenced by:
a) ANC ≥1,500 cells/μl; and
b) Platelet count ≥100,000 cells/μl; and
c) Hemoglobin ≥9 g/dL 

Adequate hepatic function as evidenced by:
a) Serum total bilirubin ≤1.5 x ULN; and
b) AST and ALT ≤2.5 x ULN; and
c) Albumin ≥3 g/dl

Adequate renal function as evidenced by creatinine ≤1.5 x ULN.

Male, or a non-pregnant and non-lactating female.

Women of child-bearing potential (defined as a sexually mature woman who (1) has 
not undergone hysterectomy [the surgical removal of the uterus] or bilateral 
oophorectomy [the surgical removal of both ovaries] or (2) has not been naturally 
postmenopausal for at least 24 consecutive months [i.e., has had menses at any time 
during the preceding 24 consecutive months]) must commit to true abstinence from 
heterosexual contact, or agree to use, and be able to comply with, effective 
contraception 
without 
interruption 
for 
28 
days 
prior 
to 
starting 
gemcitabine/cisplatin/nab- paclitaxel (including dose interruptions) until treatment 
with gemcitabine/cisplatin/nab-paclitaxel is complete.

Male subjects must practice true abstinence or agree to use a condom during sexual 
contact with a female of childbearing potential or a pregnant female while on treatment 
(including during dose interruptions) with gemcitabine/cisplatin/nab-paclitaxel and for 
6 months following  gemcitabine/cisplatin/nab- paclitaxel discontinuation, even if he 
has undergone a successful vasectomy.
5.2
EXCLUSION CRITERIA

Peripheral neuropathy of grade 2 or greater by Common Terminology Criteria for 
Adverse Events (CTCAE) 4.0. In CTCAE version 4.0 grade 2 sensory neuropathy is 
defined as “moderate symptoms; limiting instrumental activities of daily living 
(ADLs)”.

Concurrent severe and/or uncontrolled medical conditions which could compromise 
participation in the study such as unstable angina, myocardial infarction within 6 
months, unstable symptomatic arrhythmia, symptomatic congestive heart failure, 
uncontrolled diabetes, serious active, uncontrolled infection after inadequate biliary 
drainage if tumor obstructing bile duct, or psychiatric illness/social situations.

Pregnancy (positive pregnancy test) or lactation. 


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
Known CNS disease, except for treated brain metastasis.  Treated brain metastases are 
defined as having no evidence of progression or hemorrhage after treatment and no 
ongoing requirement for dexamethasone, as ascertained by clinical examination and 
brain imaging (MRI or CT) during the screening period.  Anticonvulsants (stable dose) 
are allowed.  Treatment for brain metastases may include whole brain radiotherapy 
(WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as 
deemed appropriate by the treating physician.  Patients with CNS metastases treated by 
neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will 
be excluded.

Previous (within the past 5 years) or concurrent presence of other cancer, except non-
melanoma skin cancer and in situ carcinomas.

History of allergy or hypersensitivity to any of the study drugs. 

Current abuse of alcohol or illicit drugs.

Inability or unwillingness to sign the informed consent form.
6.
TREATMENT PLAN
This is a multi-institution, open label phase II study designed to investigate the feasibility 
of gemcitabine/cisplatin/nab-paclitaxel as a neoadjuvant systemic chemotherapy for 
patients with reseactable oncologically high-risk IHCCA. This study will enroll up to 37 
patients from all participating institutions with an accrual rate of 2 patients per month in 
order to have 30 evaluable patients.
This will be an open-label, single arm study with each cycle equal to 21 days. All three 
drugs will be administered intravenously on day 1 and day 8 of each cycle. Dosing will 
be calculated using body surface area (BSA) based on the actual weight of the patient at 
each visit. Nab-Paclitaxel will be given at 100 mg/m2, followed by cisplatin at 25 mg/m2 
and then gemcitabine at 800 mg/m2 for 2 weeks in a row followed by a week of rest. 
Patients will receive 4 cycles of neoadjuvant systemic chemotherapy. Restaging will be 
done after 4 cycles (+/- 1 week) by radiological imaging. If radiological scans 
demonstrate stable disease or partial or complete tumor response and the tumor remains 
resectable, surgery will be performed. For patients with radiological scans that document 
disease progression during the study, treatment will be discontinued off the protocol and 
will not be evaluable for other secondary endpoints. Resection will be performed per 
standard of care and will include a portal lymphadenectomy for all cases. Objective 
evidence of recurrent disease after resection will be recorded at the time of recurrence. 
Patients will be followed for overall survival endpoint as well.
Table 1: Starting Dose Level
Drug
Dose
Infusion Time
Schedule (in 21-day 
cycle)
IV Nab-Paclitaxel
100 mg/m2
30 min (+/- 5 min)
Day 1 and 8
IV Cisplatin
25 mg/m2
60 min (+/- 5 min)
Day 1 and 8


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IV Gemcitabine
800 mg/m2
30 min (+/- 5 min)
Day 1 and 8
Dosing and Administration
The study drugs will be stored according to package inserts. Local institutional guidelines 
and administration protocols for anti-emetics, pre-hydration, and supportive care will be 
utilized for administration of the chemotherapy medications. Suggested guidelines 
include the following specified pre-medications and hydration:

Pre-cisplatin hydration: 0.9% Sodium Chloride Injection 1000 mL with Mannitol 18.5 
grams and Magnesium Sulfate 2 grams IV infusion over 2 hours on days 1 and 8 
repeated every 21 days. 

Aloxi (palonosetron) 0.25 mg IV, Emend (fosaprepitant) 150 mg IV and 
dexamethasone 12 mg IV within 30 minutes prior to treatment on days 1 and 8, repeated 
every 21 days. Patients will continue oral antiemetic prophylaxis at home with 
dexamethasone 4 mg bid for 2 days after chemotherapy. 

Nab-paclitaxel 100mg/m2 in NS dilute to a total concentration of 5 mg/mL (DO NOT 
FILTER) over 30 minute IV infusion on days 1 and 8 repeated every 21 days, followed 
by: 

Cisplatin 25mg/m2 in 500 mL of NS over 60 minute IV infusion on days 1 and 8 
repeated every 21 days, followed by: 

Gemcitabine 800 mg/m2 in 500ml over 30 minute IV infusion on days 1 and 8 repeated 
every 21 days 

Post-cisplatin hydration: 0.9% Sodium Chloride Injection 1000 mL IV infusion over 3 
hours on days 1 and 8 repeated every 21 days. May start at the same time as the 
gemcitabine infusion. 
Dose Modifications and Toxicity Management
Dose modifications and treatment delays based on observed drug-related toxicity will be 
performed as described below. Any toxicity associated or possibly associated with 
gemcitabine, cisplatin, and Nab-Paclitaxel treatment should be managed according to 
standard medical practice.
A cycle of therapy may be delayed up to 3 weeks to allow for weather events, patient’s 
personal emergencies, observation of holidays, or other unforeseen delays that the 
Investigator deems to be in the best interest of the patient. For any dose interruptions, re-
initiation of therapy may be delayed for a maximum of 21 days to allow recovery from 
any toxicity. In exceptional cases where subjects are responding, re-initiation of therapy 
after missing > 21 consecutive days of treatment may be done on a case-by-case basis 
after confirmation with the Primary Investigator. Day 8 of cycle can be delayed up to 2 
weeks or a treating physician’s discretion.
Toxicity will be graded according to the NCI CTCAE, Version 4.0 (which is available at: 
http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/ctc.htm). For any 


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event which is apparent at baseline, the dose modification will apply according to the 
corresponding shift in toxicity grade if the investigator feels this is appropriate, (e.g. if a 
patient has grade 1 asthenia at baseline which increases to grade 2 during treatment, this 
will be considered as a shift of 1 grade and treated as a grade 1 toxicity for dose 
modification purposes).  
Dose modifications of gemcitabine and Nab-Paclitaxel will be done based on the specific 
toxicity. Once a dose of any study drug has been reduced, it should not be increased at a 
later time.  Reasons for dose modifications or delays, the supportive measures taken, and 
the outcome will be documented in progress notes. Growth factors may be used to treat 
hematologic toxicity and will not constitute a dose reduction. A maximum of a 3-week 
treatment delay is permitted to allow recovery of toxicities.
Table 2: Dose Levels
Dose Level
Nab-Paclitaxel (mg/m2)
Cisplatin (mg/m2)
Gemcitabine (mg/m2)
0 – baseline
100
25
800
-1
75
25
600
-2
50
25
600
-3
50
20
600
Hematologic Toxicity
In the event dose modifications are required at the beginning of a cycle or within a cycle 
due to hematologic toxicities, doses of nab-paclitaxel, cisplatin, and gemcitabine may be 
adjusted as detailed below. In the event that patients must have treatment delayed within 
a treatment cycle due to hematologic toxicities, those doses held during a cycle will not 
be made up. 
Table 3: Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity)
ANC
Platelets
Timing
≥ 1,500 cells/mm3
AND
≥ 100,000/uL
Treat on time
< 1,500 cells/mm3
OR
< 100,000/uL
Delay by 1 week 
intervals until 
recovery
Table 4: Dose Modifications for Day 8 of Each Cycle (Hematologic Toxicity)*
Day 8 
Laboratory 
Results
Day 8 Nab-Paclitaxel
Day 8 
Cisplatin
Day 8 Gemcitabine
ANC > 1000 
and Platelets ≥ 
100,000
100%
100%
100%


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ANC 500-1000a 
or Platelets 
50,000-99,000
Decrease dose by 1 level 
(treat on time)
100%
Decrease dose by 1 level 
(treat on time)
ANC < 500 or 
Platelets < 
50,000
HOLD
HOLD
HOLD
Febrile 
Neutropenia 
(Grade 3 or 4)b
HOLD. Upon resuming 
dosing, decrease to next 
lower dose level and do 
not re-escalate 
throughout the rest of 
treatment.
HOLD
HOLD. Upon resuming 
dosing, decrease to next 
lower dose level and do not 
re-escalate throughout the 
rest of treatment.
Recurrent
Febrile 
Neutropenia
(Grade 3 or 4)
Decrease 2 dose levels 
(to 75 mg/m2) and do not 
re-escalate throughout 
the rest of treatment.
HOLD
Decrease 2 dose levels (to 
600 mg/m2) and do not re-
escalate throughout the rest 
of treatment.
* See Table 3 for dose reductions guidelines.
a If patients do not experience resolution of neutropenia within 21 days, despite
uninterrupted G-CSF treatment, study treatment will be discontinued. 
b Febrile neutropenic should have their chemotherapy treatment interrupted. A full sepsis 
diagnostic work-up should be performed while continuing broad spectrum antibiotics. If 
cultures are positive, the antibiotic may or may not be changed, depending on the sensitivity 
profile of the isolated organism. Patients with persisting fever after 3 weeks, despite 
uninterrupted antibiotic treatment, will discontinue study treatment. Patients can also receive 
G-CSF, in addition to antibiotic treatment, to hasten the resolution of their febrile neutropenia 
(following current institutional guidelines). In all cases, blood counts must have returned to 
non-neutropenic levels before resuming chemotherapy treatment. 
Special Instructions Regarding Treatment of Chemotherapy-related Toxicity
Dose modification or delay may occur in the setting of lower Grade toxicity if the 
treating physician believes that it is in the interest of a subject’s safety.  Alopecia and 
nausea and/or vomiting that can be controlled by antiemetics do not require dose 
modification or interruption.  No dose reduction or interruption will be required for 
anemia as it can be satisfactorily managed by transfusions. Dose reductions for non-
hematologic toxicity should be as below. Nab-Paclitaxel and Gemcitabine and specific 
exceptions are listed separately below Tables 6 and 7.
Table 5: Dose Modifications for Nab-Paclitaxel and Gemcitabine on Day 1 of Each 
Cycle (Non-Hematologic Toxicity)*
Toxicity/Dose Held
Nab-Paclitaxel+Gemcitabine dose this cycle
Grade 0-2 toxicity
Same as Day 1 previous cycle (except for Grade 2 cutaneous 
toxicity where doses of nab-paclitaxel and gemcitabine should 
be reduced to next lower dose level – see below)
Grade 3 toxicitya,c
Decrease Nab-Paclitaxel and gemcitabine
to next lower dose levela


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Grade 4 toxicityb
Off protocol treatmentb
Dose held in 2 
previous consecutive 
cycles
Decrease Nab-Paclitaxel and gemcitabine to next lower dose 
level and continue throughout the rest of treatment
   *Except peripheral neuropathy and nephrotoxicity (see below)
aIf the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced (see below).
bPulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will be 
exempt from this requirement (see below). 
cExcluding electrolyte abnormalities per judgment of the physician/investigator. 
Table 6: Dose Modifications for Nab-Paclitaxel and Gemcitabine on Day 8 of Each 
Cycle (Non-Hematologic Toxicity)
CTC Grade
% of Day 1 Nab-Paclitaxel+Gemcitabine Dose
0-2
100%a
3+
Hold treatment until resolution to ≤
Grade 1b,c
   aExcept for cutaneous toxicity (see below). 
   bPulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will be 
exempt from this requirement.
   cExcluding electrolyte abnormalities per judgment of the physician/investigator. 
6.1
G-CSF Administration
The exact dosage amount and schedule for G-CSF support will be left to the treating 
physician’s discretion.  A recommended approach would be to administer G-CSF 5 
mcg/kg/day (rounded to the nearest vial size per investigator’s standard of care) 24 hours 
after chemotherapy until recovery to the predetermined neutrophil count.
6.2
Sensory Neuropathy
Cisplatin and nab-paclitaxel treatment should be withheld in patients who experience ≥ 
Grade 3 peripheral neuropathy. Gemcitabine administration can continue during this 
period. Cisplatin may be resumed at the same dose and nab-paclitaxel treatment may be 
resumed at the next lower dose level in subsequent cycles after the peripheral neuropathy 
improves to ≤ Grade 2. Patients experiencing peripheral neuropathy that requires a delay 
in scheduled cisplatin and nab-paclitaxel dosing for ≥ 21 days will discontinue study 
treatment. The time to resolution to Grade ≤ 2 should be the adverse event duration used 
for adverse event reporting. In those patients who experience Grade 4 sensory neuropathy, 
both drugs should be withheld, and treatment resumed at a reduction of 2 dose levels (Dose 
Level -2) in subsequent cycles after the sensory neuropathy improves to  Grade 2.  Note: 
the investigator may elect to dose modify for Grade 2 sensory neuropathy.
6.3
Nephrotoxicity
Cisplatin (cisplatin injection) produces cumulative nephrotoxicity. The serum creatinine, 
BUN, creatinine clearance, and magnesium, sodium, potassium, and calcium levels should 
be measured prior to initiating therapy, and prior to each subsequent course. Cisplatin 


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should not be given unless adequate renal function is confirmed with a calculated creatinine 
clearance of  ≥ 45 mL/min.
6.4
Cutaneous Toxicity
Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose reduced to 
the next lower dose level as per Table 3. If the patient continues to experience these 
reactions, despite dose reduction, treatment should be discontinued. Patients who develop 
Grade 4 cutaneous toxicity should have treatment discontinued.
6.5
Gastrointestinal Toxicity
If Grade 3 mucositis or diarrhea occurs, all 3 study drugs should be withheld until 
resolution to ≤ Grade 1, then reinstituted at the next lower dose level as per Table 3. Patients 
who develop Grade 4 mucositis or diarrhea should have treatment discontinued.
6.6
Pulmonary Embolism 
Asymptomatic or clinically mild pulmonary embolism can be treated with low-molecular 
weight heparin without interruption of therapy. Moderate to severe pulmonary embolism 
will require permanent discontinuation of treatment. 
6.7
Interstitial Pneumonitis
Pulmonary toxicity has been reported for both gemcitabine and paclitaxel. Epidemiology 
reports show that gemcitabine monotherapy is weakly associated with lung toxicity. A 
retrospective review of pooled clinical trial data of 4,448 patients with mixed cancer 
indications reported an incidence of dyspnea of 0.2% and serious pulmonary toxicity of 
0.06%. 
During study participation, patients should be carefully monitored for signs and 
symptoms of pneumonitis (i.e. episodes of transient or repeated dyspnea with 
unproductive persistent cough or fever) and, if observed, immediate clinical evaluation 
and timely institution of appropriate management (emphasizing the need for 
corticosteroids if an infectious process has been ruled out as well as appropriate 
ventilation and oxygen support when required). Administration of study drugs will be 
permanently discontinued upon making a diagnosis of interstitial pneumonitis.
Prevention, Surveillance and Management of Interstitial Pneumonitis

During study treatment, episodes of transient or repeated dyspnea with unproductive 
persistent cough or fever should be paid attention to. Radiographic evaluation with 
chest X-rays and CT scans (normal or high resolution) may be indicated to look for 
infiltrates, ground-glass opacities or honeycombing patterns. Pulse oximetry and 
pulmonary function tests can show respiratory and ventilation compromise.

Infections should be ruled out with routine immunological/ microbiological 
methods. Transbronchial lung biopsy is not recommended, given its limited value 
and risk of pneumothorax and hemorrhage, and should be reserved for cases with 
unclear etiology. 

Study drug administration should be interrupted upon diagnosis of interstitial 
pneumonitis and patients permanently discontinued from further study drug 


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treatment. After ruling out an infectious etiology, intravenous high-dose 
corticosteroid therapy and secondary pathogen coverage should be instituted 
without delay. Patients with an added immunological component may also require 
immune modulation with azathioprine or cyclophosphamide. Appropriate 
ventilation and oxygen support should be used when required. 
6.8
Sepsis
Sepsis has been reported in less than 1% during Nab-Paclitaxel monotherapy and 
fatalities attributed to these events have been rare. However, the risk was appreciably 
higher in patients with advanced or metastatic pancreatic cancer receiving Nab-Paclitaxel 
in combination with gemcitabine with a rate of 5% in patients in patients with or without 
neutropenia receiving Nab-Paclitaxel/gemcitabine. Complications due to the underlying 
pancreatic cancer, especially biliary obstruction or presence of biliary stent, were 
identified as significant contributing factors. The increased risk of sepsis in the setting of 
advanced or metastatic cancer in combination with gemcitabine could be managed with 
prophylactic antibiotic treatment in febrile patients (regardless of neutrophil count) and 
dose reduction, and with G-CSF treatment in neutropenic patients. If a patient becomes 
febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. 
For febrile neutropenia, withhold Nab-Paclitaxel and gemcitabine until fever resolves and 
ANC ≥ 1500, then resume treatment at reduced dose levels.
Prophylaxis Against Sepsis
Due to the incidences of non-neutropenic sepsis, at the first occurrence of fever ≥ 38.5°C 
(regardless of neutrophil count), institution of ciprofloxacin (500 mg orally, twice daily) 
or amoxicillin/clavulanate (500 mg orally, 2-3 times daily) in patients with allergy to 
fluoroquinolones should be initiated. On their first visit, patients should be provided with 
enough ciprofloxacin (or the alternative antibiotic) for use at home, and they should be 
instructed to begin taking it when they first record a temperature of ≥ 38.5 °C (or if they 
feel they are developing a fever and a thermometer is not available). They should also 
immediately contact their physician for guidance on where to go for blood counts and to 
be evaluated for sepsis as soon as possible. Hospitalization or evaluation in the 
emergency room may be required depending on the clinical presentation. If 
hospitalization is required, this should be reported as a Serious Adverse Event (SAE).
6.9
Hypersensitivity Reactions
Hypersensitivity reactions rarely occur.  If they do occur, minor symptoms such as 
flushing, skin reactions, dyspnea, lower back pain, hypotension, or tachycardia may require 
temporary interruption of the infusion.  However, severe reactions, such as hypotension 
requiring treatment, dyspnea requiring bronchodilators, angioedema or generalized 
urticaria require immediate discontinuation of study drug administration and aggressive 
symptomatic therapy.  Patients who experience severe hypersensitivity reactions to Nab-
Paclitaxel should not be re-challenged.  It is not recommended to administer Nab-Paclitaxel 
to patients with prior hypersensitivity to a taxane. If mild to moderate cisplatin 
hypersensitivity develops (per NCI CTCAE), the patient may be desensitized using the 


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standard desensitization protocol of the institution. In the setting of a severe 
hypersensitivity reaction, cisplatin should be discontinued.
Nab-Paclitaxel Premedication
Patients do not require premedication prior to Nab-Paclitaxel administration, as 
hypersensitivity reactions are rare. Although the solubilizing agents Cremophor® EL and 
Tween® 80 have long been implicated in adverse events including hypersensitivity 
reactions due to their detergent-like nature and known ability to induce histamine release 
(Ten Tije et al, 2003), the administration of solvent-based taxanes (Taxol and 
Taxotere) requires premedication with corticosteroids and histamine receptor blocking 
agents to prevent the occurrence of hypersensitivity reactions. However, the 
hypersensitizing role of the taxane molecules themselves cannot be ruled out.  
In the unlikely event of a mild hypersensitivity reaction, premedication may be 
administered using the premedication regimen the institution typically uses for solvent 
based paclitaxel.  In the rare event of a severe hypersensitivity reaction, discontinue Nab-
Paclitaxel.
Concomitant Medications
Supportive care, including but not limited to anti-emetic medications, may be 
administered at the discretion of the Investigator.  Erythropoietin and G-CSF may be 
administered at the discretion of the investigator, consistent with institutional guidelines. 
7.
EVALUATION DURING STUDY
Patients must begin Cycle 1 within 30 days of signing the informed consent document 
and after the screening assessments. Treatment will be administered by qualified and 
trained site personnel in a hospital, clinic, or other out-patient setting appropriate for 
chemotherapeutic infusions. All assessments should be performed within 48 hours of 
each specified time parameter, with the exception of Cycle 1 in which physical and 
laboratory assessments must be conducted within 7 days and radiological assessment 
within 6 weeks. 
Day 1 of each cycle (except where noted)

Inclusion/exclusion review (Cycle 1 only) 

Directed physical exam with neuropathy assessment

Vital Signs 

Measurement of weight (kg) and BSA calculation prior to dosing  

ECOG Performance Status (see Appendix 1) 

Hematology: CBC with differential and platelet count 

Serum chemistries: BUN, creatinine, total bilirubin, aspartate transaminase (AST), alanine 
transaminase (ALT), total protein, albumin, serum glucose, lactic dehydrogenase (LDH), 
and electrolytes (sodium, potassium, phosphorus, chloride, C02, magnesium, calcium). In 
patients with known Gilbert’s syndrome, it is recommended to perform a direct bilirubin 
and indirect bilirubin. Calculate creatinine clearance. 

Tumor markers: CA 19-9 and CEA

Serum Pregnancy (at Screening only)

AEs using the NCI CTCAE (http://ctep.info.nih.gov)

Concomitant medication notation  


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Day 8 of each cycle  

Directed physical exam with neuropathy assessment

Vital Signs

Measurement of weight (kg) 

ECOG Performance Status (see Appendix 1) 

Hematology: CBC with differential and platelet count 

Serum chemistries

AEs using the NCI CTCAE (http://ctep.info.nih.gov)  

Concomitant medication notation
 
After Cycles 4 

Reassessment of the extent of tumor should be made by the same imaging methods used to 
establish baseline tumor measurements. 

In order to more precisely determine the tumor response, the investigator is encouraged to 
obtain radiological assessments earlier if there is a strong clinical suspicion of disease 
progression, in order to either confirm or refute the clinical impression. 


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Table 7: Study Assessments 
Gemcitabine/Cisplatin/Nab- paclitaxel cycles
(21 day cycle, x 4cycles)a
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Procedure
Screening 
Visit
(within 
7 days unless 
otherwise 
noted)b
Day 1
Day 8
Day 1
Day 8
Day 1
Day 8
Day 1
Day 8
Surgical 
resection 
evaluation
4 weeks
 (± 1 week) 
following last 
dose
End of 
Treatment 
Visit
4 weeks
(± 1 week) 
following last 
dose or post-
surgery
Long Term 
Survival 
Follow-up 
(every 4 
months for 
3 years)
Informed consent
x
Medical history & 
Demographics
x
Concomitant meds
x
x
x
x
x
x
x
x
x
x
x
Examination
Physical Exam
x
x
x
x
x
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
Height
x
Weight
x
x
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
x
x
x
x
x
x
x
Laboratory
CBC total/differential
x
x
x
x
x
x
x
x
x
x
x
Serum chemistryc
x
x
x
x
x
x
x
x
x
x
x
Tumor markersd
x
x
x
x
x
x
x
x
Pregnancy teste
x
Radiology 
CT chest, abdomen, and 
pelvisf
x
x
x
x
Toxicity assessment 
x
x
x
x
x
x
x
x
x
x
Recurrence, and overall 
survival reporting
x
aEach cycle of therapy may be delayed up to 3 weeks to allow for weather events, patient’s personal emergencies, observation of holidays, or other 
unforeseen delays that the Investigator deems to be in the best interest of the patient. For any dose interruptions, re-initiation of therapy may be delayed for a 
maximum of 21 days to allow recovery from any toxicity. In exceptional cases where subjects are responding, re-initiation of therapy after missing > 21 
consecutive days of treatment may be done on a case-by-case basis after confirmation with the Primary Investigator. Day 8 of cycle can be delayed up to 2 
weeks or a treating physician’s discretion.
bAll screening procedures must be done within 7 days from treatment start date except patient height can be done at any time during the screening window 
and baseline diagnostic imaging must be done within 6 weeks prior to first day of study treatment.
cSerum chemistry includes urea, creatinine, total bilirubin, AST, ALT, total protein, albumin, and electrolytes (sodium, potassium, phosphorus, chloride, C02, 
magnesium, calcium), glucose, and LDH
dTumor markers include carcinoembryonic antigen (CEA) and Cancer antigen 19-9 (CA19-9)
eFor females of childbearing potential only. May be repeated any time during the study at investigator discretion.


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fRadiological imaging will be performed during the screening window, approximately within 6 weeks before starting chemotherapy to identify patients’ 
eligibility for study enrollment, then within 2 weeks  (+/- 1 week) after administration and completion of  4 cycles of chemotherapy (12 weeks) to assess 
response to therapy according to RECIST criteria 1.1. If radiological scans demonstrates a stable, partial or complete tumor response and tumor still 
resectable, surgery will be performed. Surveillance imaging after surgery will be performed every 4 months. If radiological scans demonstrated disease 
progression, treatment will be discontinued off the protocol and will not be evaluable for other secondary endpoints. 


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1.
Informed consent must be obtained before any evaluations are initiated.  Diagnostic imaging 
studies must be completed within 6 weeks prior to first day of study treatment. All other baseline 
evaluations, except for height (which can be obtained at any time prior to enrollment), must be 
completed within 7 days prior to first dose of study drug.
2.
For Cycle 1, baseline evaluations will be sufficient if they are performed within 7 days prior to 
first dose of study drug (except for imaging studies which are performed within 6 weeks prior).
3.
For all other chemotherapy cycles except for Cycle 1, baseline physical and laboratory 
assessment must be done within 48 hours prior to start of day 1 and day 8.
4.
Imaging should be obtained within 2 weeks (+/- 1 week) after completion of 4 cycles of 
chemotherapy.  If radiological scans demonstrates stable disease or partial or complete tumor 
response and the tumor remains resectable, surgery will be performed. Patients with 
radiologically documented disease progression at any point during the study treatment with study 
drugs under this protocol will be discontinue. Objective evidence of recurrent disease after 
resection will be recorded at the time of recurrence. Earlier radiological evaluations are allowed 
if, in the investigator’s opinion, this evaluation is in the patient’s best interest.   
5.
Surgical resection will be performed per standard of care and will include a portal 
lymphadenectomy for all cases.
6.
CT of the chest, abdomen, and pelvis with contrast will be used. MRI may be used in cases where 
it is felt to be unsafe to perform CT secondary to patient's history of dye allergy, or if the tumor is 
not adequately seen on CT for the purposes of this study. Positron emission tomography (PET) 
scan may be done to exclude the presence of any suspicious metastatic lesion.
7.
Treatment-related adverse events occurring during study treatment or within 30 days (window of 
28-35 days allowed) after the last administration of study drug(s) will be followed until resolution 
or stabilization. If the patient is unable or unwilling to return to the participating treating center 
for this assessment, the patient will be contacted by phone for this assessment.   
7.1
End of treatment evaluations 
The investigator will evaluate the results of the following clinical and laboratory 
assessments to be conducted at the time the patient discontinues study treatment. This 
will be done within 4 weeks post-surgery or after the last dose of systemic therapy in 
patient who have disease progression and will not undergo surgery. 

Physical examination with neuropathy assessment

ECOG Performance Status

Weight

Vital signs (blood pressure)

Hematology: CBC with differential and platelet count 

Serum chemistries: BUN, creatinine, total bilirubin, aspartate transaminase (AST), 
alanine transaminase (ALT), total protein, albumin, serum glucose, lactic 
dehydrogenase (LDH), and electrolytes (sodium, potassium, phosphorus, chloride, 
C02, magnesium, calcium). In patients with known Gilbert’s syndrome, it is 
recommended to perform a direct bilirubin and indirect bilirubin. Calculate creatinine 
clearance. 

Tumor markers: CA 19-9 and CEA

Concomitant medication notation


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
Toxicity (adverse events) assessment (including neurologic toxicities) using 
NCTCTCAE Version 4.0

Tumor evaluations including CT scan or MRI of the chest, abdomen, and pelvis 
7.2
Long-term follow-up
All patients will be followed for survival and/or recurrence status. All study enrolled patients 
who will undergo tumor resection will be followed every 4 months (+/- 1 month) post-
surgery for up to 3 years to assess recurrence free survival. Survival status may be obtained 
by checking the electronic medical record or by telephone call.  If radiological scans 
demonstrated disease progression after neoadjuvant chemotherapy that prohibits surgery, 
treatment will be discontinued off the protocol but the patient will be still be followed for the 
secondary endpoint of overall survival. After a patient completes all intended therapy, 
including neoadjuvant chemotherapy and surgery, the patient will be followed for secondary 
endpoints of recurrence and overall survival.  If a patient recurs during postoperative 
surveillance, they will still be followed for overall survival. During long term follow-up, 
there is no specific requirement for labs or toxicity recording as the patient will not be 
receiving any therapy on protocol.
8.
CRITERIA FOR REMOVAL FROM THE STUDY 
      Subjects who meet the following criteria should be discontinued from the study: 

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s) as determined by the treating physician

Patient decides to withdraw from the study 

General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator.  
9.
RESPONSE EVALUATION
9.1
Measurement of effect 
Response, progression, and recurrence will be evaluated in this study using the new international 
RECIST criteria (version 1.1, 2009) proposed by the RECIST committee.17 All patients who 
have measurable disease according to the RECIST criteria and who have their disease re-
evaluated will be evaluable for response.  For the purposes of this study, patients should be 
reevaluated for response after 4 cycles of neoadjuvant chemotherapy.  Note:  Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional meaning or 
accuracy.
9.2
Definitions
All sites of disease should be followed as either target or non-target lesions, as categorized at 
baseline.  All measurable lesions up to a maximum of 2 lesions per organ or 5 lesions in total, 
representative of all involved organs should be identified as target lesions, while all other lesions 
(either additional measurable lesions or non-measurable lesions) should be classified as non-
target lesions. In cases where a target lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned. To ensure comparability, the 


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baseline radiology/scans and subsequent radiology/scans to assess response should be performed 
using identical techniques (eg, scans performed immediately following bolus contrast 
administration should be made with a standard volume of contrast, the identical contrast agent, 
and preferably the same scanner). The same method, radiological or physical, should be 
employed and assessed by the same individual on each occasion, when possible. 
9.3
Measurable disease
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >10 mm with CT scan (with minimum slice 
thickness no greater than 5mm, or 10mm caliper measurement by clinical exam, or 20mm by 
chest X-ray).  All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters).
Pathological lymph nodes may also be considered as target or non-target lesions.  To be 
considered pathologically enlarged and measurable (target lesion), a lymph node must be ≥ 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). Lymph nodes with a short axis ≥ 10 mm but < 15 mm should be considered 
non-target lesions. Lymph nodes that have a short axis < 10 mm are considered non-pathologic 
and should not be recorded. The short axis measurement of any lymph node that is considered a 
target lesion should continue to be recorded regardless if the node progresses to below 10 mm. 
This may prevent the sum of lesions from being zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm.  In rare circumstances, 
when a target lymph node is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned. 
9.4
Non-measurable disease
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15mm short axis) as well as truly non-measurable 
lesions.  Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI).  For bone and cystic lesions, please refer to the 
RECIST criteria (version 1.1, 2009).
9.5
Target lesions
All measurable lesions up to a maximum of five lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  A sum of the diameters for all target lesions (longest for non-
nodal lesions, short axis for nodal lesions) will be calculated and reported as the baseline sum 
diameters (LD).  The baseline sum diameters will be used as reference by which to characterize 
the objective tumor response.
9.6
Non-target lesions
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline.  Non-target lesions include measurable lesions that exceed the maximum 
numbers per organ or total of all involved organs as well as non-measurable lesions. It is possible 


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to record multiple non-target lesions involving the same organ as a single item on the case record 
form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).   
Measurements of these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up. 
9.7
Guidelines for evaluation of measurable disease
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 6 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment.
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable. 
Conventional CT and Magnetic Resonance Imaging.  Conventional CT and MRI should be 
performed to obtain images of 5 mm or less slice thickness.
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.
Cytology, Histology.  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
9.8
Response Criteria
9.8.1
Evaluation of target lesions 

Complete Response (CR): Disappearance of all target and non-target lesions including 
normalization of elevated tumor marker level. Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to < 10 mm. All non-target lymph nodes must be non-
pathological in size (< 10 mm short axis). Complete response must be confirmed at a second tumor 
assessment not less than 4 weeks apart from the assessment at which CR was observed.

Partial Response (PR): At least a 30% decrease in the sum of LD of target lesions taking as 
reference the baseline sum LD. 

Progressive Disease (PD): At least a 20% increase (and an absolute increase of at least 5 
mm) in the sum of LD of measured lesions taking as references the smallest sum LD 
recorded since the treatment started. Appearance of new lesions will also constitute PD. In 
exceptional circumstances, unequivocal progression of non-target lesions may be accepted as 
evidence of disease progression.


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
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started

Non-CR/Non-PD: Persistence of 1 or more non-target lesions and/or maintenance of tumor 
marker level above the normal limits.
9.8.2
Evaluation of non-target lesions

Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level

Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits

Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions

Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail, and the progression status 
should be confirmed at a later time by the study PI (Maithel).

Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
9.9
Time point evaluation
At each protocol specified time point, a response assessment occurs. Table 8 provides a summary 
of this for patients who have measurable disease at baseline. Table 9 provides a summary of this 
for patients with non-measurable (therefore non-target) disease.
Table 8: Response for Measurable Disease
Target 
Lesions
Non-target Lesions 
New Lesions 
Overall 
Response 
Best Response for this Category 
also Requires 
CR
CR
No
CR
≥ 4 weeks Confirmation
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
≥ 4 weeks Confirmation
SD
Non-PD or not all 
evaluated
No
SD
Documented at least once ≥ 6 
weeks from baseline
Not All 
Evaluated
Non-PD
No
NE
NE
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
No prior SD, PR or CR
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. NE = inevaluable Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 


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Table 9: Response for Non-measurable Disease
Non-target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
NE = inevaluable a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised. 
9.10
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
Table 10: Response Assignment
Overall Response First Time 
Point
Overall Response Subsequent 
Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR
CR
SD
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for 
SD duration met, otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for 
SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for 
SD duration met, otherwise, NE
NE
NE
NE
NE = inevaluable.  If a CR is truly met at first time point, then any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR).  Best response would depend on whether minimum duration for SD was met. However, 
sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in 
fact, the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 


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“symptomatic deterioration.”  Every effort should be made to document the objective 
progression, even after discontinuation of treatment.
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete 
response status.
9.11
Confirmation
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessment at a minimum follow-up interval of 6 weeks after the criteria for response are 
first met.  In the case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval of 6 weeks.
9.12
Duration of overall response
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
9.13
Duration of stable disease
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
10.
STATISTICAL METHODS
This is a phase II open-label, non-randomized, multicenter clinical trial. Our primary objective is 
to assess the feasibility of therapeutic strategy that begins with neoadjuvant therapy with 
gemcitabine, cisplatin, and nab-paclitaxel for resectable oncologically high-risk IHCCA patients 
prior to complete surgical resection. Anticipating maximum 20% dropout rate due to screen 
failures or withdrawals, our planned sample size for this trial will be 37 subjects to have 30 
evaluable patients. The primary endpoint will be completion of all preoperative and operative 
therapy.  Secondary endpoints will include radiological response according to Response 
Evaluation Criteria in Solid Tumor (RECIST), RFS, and OS.
The analysis will be performed for all patients registered to the trial who receive at least one dose 
of study drug. Patients who are registered to the study but do not receive study treatment will be 
summarized separately. The method of Thall, Simon and Estey will be used for futility and 
toxicity monitoring in this study. The design software Multc Lean Desktop (version 2.1) 
developed by the Department of Biostatistics at M D Anderson Cancer Center (MDACC) was 
used to generate the stopping boundaries and the operating characteristics table for futility and 
toxicity monitoring. This is free software accessible through 
https://biostatistics.mdanderson.org/softwaredownload/.
10.1 Power estimation
The primary endpoint is completion of all therapy. We hypothesize that the new treatment will 
improve this rate to 70%. A sample size of 30 evaluable patients will provide approximately 73% 
power for detecting an increase from 50% to 70% in this study at 1-sided type I error of 0.05. The 


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power estimation is based on the exact binomial test. To account for up to 20% dropout rate due 
to screen failures or withdrawals, the maximum study accrual will be 37 participants to have 30 
evaluable patients.
10.2 Futility monitoring 
We assume a target rate of 70% and a rate of 50% or lower will be considered not desirable. The 
study will be stopped early if the data suggest that: 
Pr(PE > PH + 0.20 | data)<0.025
where PE and PH are the  rates for this combination and historical treatment, respectively. That is, 
if at any time during the study we determine that there is less than 2.5% chance that the rate 
improves over historical rate by more than 20%, the trial will be stopped due to futility. PE and 
PH are assumed to follow a prior of Beta (1, 1) and Beta (50, 50), respectively. We will apply 
these stopping boundaries in cohort sizes of 5. The stopping boundaries for futility based on 
these assumptions and monitoring conditions are provided in Table 11. 
Table 11.  Stopping boundaries for futility monitoring
# of evaluable patients 
Stop the trial if # of patients completing therapy is: 
5
0-1
10
0-3
15
0-6
20
0-9
25
0-12
30
0-15
10.3 Toxicity monitoring
Unacceptable toxicities are defined as any Grade 3 or higher toxicities by CTCAE criteria or a 
treatment delay of >4weeks. Denote the probability of toxicity by PT. We assume as a priori, PT ~ 
beta (1, 1). Our stopping rule is given by the following probability statement: 
Pr(PT > 0.50 | data)>0.90.
That is, we will stop the trial for new patient enrollment if at any time during the study, we 
determine that there is more than 90% chance that the unacceptable toxicity rate is more than 
50%. This toxicity monitoring rule will be applied after the first 5 patients have been enrolled 
and evaluated, and then in cohort size of 5. Stopping boundaries corresponding to this stopping 
rule are listed in Table 12. The operating characteristics for futility and toxicity monitoring are 
summarized in Table 13.
Table 12.  Early stopping boundaries for toxicity monitoring
# of evaluable patients ( in cohort size of 5, 
starting from the 5th  patient)
Stop the trial if there are this many patients 
with unacceptable toxicities: 
5
5
10
8-10
15
11-15


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20
13-20
25
16-25
30
19-30
Table 13. Operating characteristics for futility and toxicity monitoring
True resectability rate
True toxicity rate
Prob(stop the trial 
early)
Average number of 
patients treated
0.6
0.40
0.2701
25.5
0.50
0.3841
23.8
0.60
0.6345
19.9
0.7
0.40
0.0931
28.3
0.50
0.2347
26.3
0.60
0.5458
21.7
0.8
0.40
0.0470
29.2
0.50
0.1958
27.1
0.60
0.5227
22.3
10.4 Statistical analysis plan
For the primary analysis, all enrolled patients who received at least one dose of study treatment 
will be included in the statistical analysis. We will record the completion of all therapy rate, along 
with the 95% credible interval. Safety and tolerability will be assessed in terms of adverse events 
(AEs), and serious adverse events (SAEs). Summary of these events will be tabulated by the 
maximum reported Common Terminology Criteria for Adverse Events (CTCAE) grade and by it 
is relation to study treatment. Both AEs and SAEs will be tabulated using frequencies and 
percentages. For secondary endpoint of radiological response rate it will be defined as the 
percentage of patients who will have complete response (CR), partial response (PR) or stable 
disease (SD) after the neoadjuvant therapy. We will estimate the radiological response rate, along 
with the 95% confidence interval.
RFS (Recurrence-free survival) is defined as the time between the date of surgery and the date of 
disease recurrence or death, whichever occurred first. If a patient did not have an event (i.e. disease 
recurrence or death) by the time of final analysis, patient will be censored at the last disease 
evaluation time. Overall survival (OS) is defined as the time from date of neoadjuvant treatment 
start to the date of death from any cause or to the date of last follow-up if patients are alive. If a 
patient is alive by the time of final analysis, the patient will be censored at the last follow-up date. 
The Kaplan-Meier method will be used to estimate RFS or OS. The two-sided log-rank tests will 
be used to assess the differences of RFS or OS between groups.
11.
REGISTRATION PROCESS
Please see Appendix 3 for a detailed description of the registration process for all sites.


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12.
DATA AND PROTOCOL MANAGEMENT
Designated research personnel must enter the information required by the protocol onto 
electronic Case Report Forms (CRFs). The Emory University Clinical Oncology Research 
(OnCore) system will be used for this study.  The clinical management system being used for 
this study is The Online Collaborative Research Environment (OnCore). OnCore will be used to 
record all study related information for all registered subjects, including their assigned patient ID 
and assigned dose cohort. All data must be entered no later than 30 days following registration 
and each visit completion. All queries are to be resolved within 4 weeks of issue. The MSC will 
provide OnCore training and request access to the appropriate staff at the participating site.
OnCore is a clinical research information management system. The OnCore CRF is an electronic 
document designed to record all the protocol-required information to be reported on each trial 
subject.
OnCore provides data entry templates as defined in the protocol. Users must have clearance 
through the Emory University Information Services Security Department in order to access 
OnCore. OnCore login is password protected. The Investigator is responsible for verifying and 
providing source documentation for all adverse events and assigning attribution for each event 
for all subjects enrolled on the trial. 
For details regarding the process for data collection among all participating centers involved in 
the study, please see Appendix 4.
13.
SAFETY REPORTING OF ADVERSE EVENTS
13.1
Adverse Event Reporting and Definitions 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy.
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate.  Adverse events will be 
collected from the signing of the informed consent until 30 days after the last dose of study drug, 
or any time after that if the PI determines the event is related to the study drug.
The occurrence of adverse events should be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when volunteered by the patient 
during or between visits or through physical examination, laboratory test, or other assessments. 
As far as possible, each adverse event should be evaluated to determine:

The severity grade (mild, moderate, severe or grade 1-5)

Its relationship to the study drug(s) (suspected/not suspected)

Its duration (start and end dates or if continuing at final exam)

Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization)


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
Whether it constitutes a serious adverse event (SAE)
All adverse events should be treated appropriately. Such treatment may include changes in study 
drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about drug can be found in the 
Investigators’ Brochure or will be communicated between IB updates in the form of Investigator 
Notifications. This information will be included in the patient informed consent and should be 
discussed with the patient during the study as needed.
13.2
Adverse event attribution
Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
Adverse events for this protocol will be recorded using the Recommended Adverse Event 
Recording Guidelines for phase II protocols.  
Recommended Adverse Event Recording Guidelines 
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Unrelated
Phase II
Phase II
Phase II
Unlikely
Phase II
Phase II
Phase II
Possible
Phase II
Phase II
Phase II
Phase II
Phase II
Probable
Phase II
Phase II
Phase II
Phase II
Phase II
Definitive
Phase II
Phase II
Phase II
Phase II
Phase II
The Investigator is responsible for verifying and providing source documentation for all adverse 
events and assigning attribution for each event for all subjects enrolled on the trial.
13.3
Serious adverse event (SAE) reporting 
A serious adverse event is one that at any dose (including overdose):
Results in death
Is life-threatening
1
Requires inpatient hospitalization or prolongation of existing hospitalization
Results in persistent or significant disability or incapacity
2


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Is a congenital anomaly or birth defect
Is an important medical event
3
1“Life-threatening” means that the subject was at immediate risk of death at the time of the 
serious adverse event; it does not refer to a serious adverse event that hypothetically might have 
caused death if it were more severe.
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of 
a person’s ability to carry out normal life functions.
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred.  Important medical 
events that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes listed in 
the definition above should also usually be considered serious.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.  A new diagnosis of cancer during the course of a treatment 
should be considered as medically important.  
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting.  A 
copy of the CTCAE Version 4.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov).  All appropriate treatment areas should have access to a copy of the 
CTCAE Version 4.0.  All adverse clinical experiences, whether observed by the investigator or 
reported by the patient, must be recorded, with details about the duration and intensity of each 
episode, the action taken with respect to the test drug, and the patient’s outcome.  The 
investigator must evaluate each adverse experience for its relationship to the test drug and for its 
seriousness.
Pregnancies
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 28 days, are 
considered immediately reportable events.  IP is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form. The female subject may be referred to an obstetrician-gynecologist 
(not necessarily one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form. 
IF THE OUTCOME OF THE PREGNANCY WAS ABNORMAL (E.G., SPONTANEOUS OR 
THERAPEUTIC ABORTION), THE INVESTIGATOR SHOULD REPORT THE 
ABNORMAL OUTCOME AS AN AE.  IF THE ABNORMAL OUTCOME MEETS ANY OF 
THE SERIOUS CRITERIA, IT MUST BE REPORTED AS AN SAE TO CELGENE DRUG 
SAFETY IMMEDIATELY BY FACSIMILE, OR OTHERAPPROPRIATE METHOD, 


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WITHIN 24 HOURS OF THE INVESTIGATOR’S KNOWLEDGE OF THE EVENT USING 
THE SAE REPORT FORM, OR APPROVED EQUIVALENT FORM.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form.
Male Subjects
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. Male patients treated with nab-paclitaxel 
are advised not to father a child during and up to 6 months after treatment.
Overdose
Overdose, as defined for this protocol, refers to nab-paclitaxel, gemcitabine, and cisplatin dosing 
only.  
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of nab-paclitaxel, gemcitabine, and cisplatin assigned to a given patient, regardless of any 
associated adverse events or sequelae.
PO
any amount over the protocol-specified dose
IV
10% over the protocol-specified dose 
SC
10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.  
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified 
rate.  For nab-paclitaxel, an infusion completed in less than 25 minutes may increase Cmax by 
approximately 20%, therefore a nab-paclitaxel infusion completed in less than 25 minutes will 
meet the infusion rate criterion for an overdose.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.   
Drug Safety Contact Information:
Celgene Corporation     
Global Drug Safety and Risk Management   
86 Morris Avenue
Summit, New Jersey 07901
Fax: (908) 673-9115


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E-mail: drugsafety@celgene.com
Telephone: 1-908-673-9667
Toll Free:    1-800-640-7854               
Investigator Reporting Responsibilities
The conduct of the study will comply with all FDA safety reporting requirements.  
All adverse experience reports must include the patient number, age, sex, weight, severity of 
reaction (mild, moderate, severe), relationship to drug (probably related, unknown relationship, 
definitely not related), date and time of administration of test medications and all concomitant 
medications, and medical treatment provided.   The investigator is responsible for evaluating all 
adverse events to determine whether criteria for “serious” and as defined above are present.  The 
investigator is responsible for reporting adverse events to Celgene as described below.
Expedited reporting by investigator to Celgene
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events of being related to ABRAXANE® based on the Investigator Brochure.  In the United 
States, all suspected unexpected serious adverse reactions (SUSARs) will be reported in an 
expedited manner in accordance with 21 CFR 312.32.
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of 
being aware of the event.  The written report must be completed and supplied to Celgene by 
facsimile within 24 hours.  The initial report must be as complete as possible, including an 
assessment of the causal relationship between the event and the investigational product.  
Information not available at the time of the initial report (e.g., an end date for the adverse event 
or laboratory values received after the report) must be documented on a follow-up report.  A 
final report to document resolution of the SAE is required.  The Celgene tracking number (AX- 
CL-CHOL-PI-13255) and the institutional protocol number should be included on SAE reports 
(or on the fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the 
SAE report to Celgene should be attached to the SAE and retained with the patient records. 
Participating study sites must report SAEs to Celgene as described and within 24 hours of 
awareness.  Participating sites should also report SAEs to Emory University, the primary study 
site within 48 hours of awareness.
Report of Adverse Events to the Institutional Review Board
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a 
serious adverse event according to institutional policy.  
Investigator Reporting to the FDA
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly associated 
to the drug, and that have not previously been reported in the Investigators brochure, or 
reference safety information document should be reported promptly to the Food and Drug 
Administration (FDA) by telephone or by fax.  Fatal or life threatening SAEs that meet the 


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criteria for reporting to the FDA must be reported to the FDA within 7 calendar days after 
awareness of the event.  All other SAEs that meet the criteria for reporting to the FDA must be 
reported to the FDA within 15 calendar days after awareness of the event.  A clear description of 
the suspected reaction should be provided along with an assessment as to whether the event is 
drug or disease related.   
Adverse event updates/IND safety reports
Celgene shall notify the Investigator via an IND Safety Report of the following information:

Any AE associated with the use of drug in this study or in other studies that is both 
serious and unexpected.

Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected 
AE(s) or significant risks to subjects. The Investigator must keep copies of all AE information, 
including correspondence with Celgene and the IRB/EC, on file.
14.
REFERENCES
1.
Spolverato G, Vitale A, Cucchetti A, et al. Can hepatic resection provide a long-term cure 
for patients with intrahepatic cholangiocarcinoma? Cancer. 2015;121(22):3998-4006.
2.
Weber SM, Ribero D, O'Reilly EM, Kokudo N, Miyazaki M, Pawlik TM. Intrahepatic 
cholangiocarcinoma: expert consensus statement. HPB : the official journal of the 
International Hepato Pancreato Biliary Association. 2015;17(8):669-680.
3.
Le Roy B, Gelli M, Pittau G, et al. Neoadjuvant chemotherapy for initially unresectable 
intrahepatic cholangiocarcinoma. The British journal of surgery. 2017.
4.
Claperon A, Mergey M, Aoudjehane L, et al. Hepatic myofibroblasts promote the 
progression of human cholangiocarcinoma through activation of epidermal growth factor 
receptor. Hepatology (Baltimore, Md). 2013;58(6):2001-2011.
5.
Coulouarn C, Clement B. Stellate cells and the development of liver cancer: therapeutic 
potential of targeting the stroma. Journal of hepatology. 2014;60(6):1306-1309.
6.
Sirica AE, Gores GJ. Desmoplastic stroma and cholangiocarcinoma: clinical implications 
and therapeutic targeting. Hepatology (Baltimore, Md). 2014;59(6):2397-2402.
7.
Sulpice L, Rayar M, Desille M, et al. Molecular profiling of stroma identifies osteopontin 
as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma. 
Hepatology (Baltimore, Md). 2013;58(6):1992-2000.
8.
Sirica AE. The role of cancer-associated myofibroblasts in intrahepatic 
cholangiocarcinoma. Nature reviews Gastroenterology & hepatology. 2011;9(1):44-54.
9.
Ma WW, Hidalgo M. The winning formulation: the development of paclitaxel in 
pancreatic cancer. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2013;19(20):5572-5579.
10.
Alvarez R, Musteanu M, Garcia-Garcia E, et al. Stromal disrupting effects of nab-
paclitaxel in pancreatic cancer. British journal of cancer. 2013;109(4):926-933.
11.
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for 
biliary tract cancer. The New England journal of medicine. 2010;362(14):1273-1281.


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12.
Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-
paclitaxel plus gemcitabine. The New England journal of medicine. 2013;369(18):1691-
1703.
13.
Shroff RT, Borad MJ, Xiao L, et al. A phase II trial of gemcitabine (G), cisplatin (C), and 
nab-paclitaxel (N) in advanced biliary tract cancers (aBTCs). Journal of Clinical 
Oncology. 2017;35(15_suppl):4018-4018.
14.
Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel 
concentrations, and endothelial cell transport of cremophor-free, albumin-bound 
paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clinical Cancer 
Research. 2006;12(4):1317-1324.
15.
Commisso C, Davidson SM, Soydaner-Azeloglu RG, et al. Macropinocytosis of protein 
is an amino acid supply route in Ras-transformed cells. Nature. 2013;497(7451):633-637.
16.
Frese KK, Neesse A, Cook N, et al. nab-Paclitaxel potentiates gemcitabine activity by 
reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer 
discovery. 2012;2(3):260-269.
17.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer (Oxford, 
England : 1990). 2009;45(2):228-247.


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Data and Safety Monitoring Language Guidelines for Investigator-Initiated Studies
A sensible data safety monitoring plan (DSMP) for a particular clinical trial must be 
based on the medical or health-related context of the particular study and in particular 
the degree of risk to which participants in the trial are exposed. (NCI Data and Safety 
Monitoring Guidelines, 2005)
I.
Standard language for Investigator-Initiated studies under purview of 
Winship DSMC:
The Data and Safety Monitoring Committee (DSMC) of the 
Winship Cancer Institute will provide oversight for the conduct of 
this study.  The DSMC functions independently within Winship 
Cancer Institute to conduct internal monitoring functions to ensure 
that research being conducted by Winship Cancer Institute 
Investigators produces high-quality scientific data in a manner 
consistent with good clinical practice (GCP) and appropriate 
regulations that govern clinical research.    Depending on the risk 
level of the protocol, the DSMC review may occur every 6 months 
or annually.  For studies deemed High Risk, initial study 
monitoring will occur within 6 months from the date of the first 
subject accrued, with 2 of the first 5 subjects being reviewed.  For 
studies deemed Moderate Risk, initial study monitoring will occur 
within 1 year from the date of the first subject accrued, with 2 of the 
first 5 subjects being reviewed.  Subsequent monitoring will occur 
in routine intervals per the Winship Data and Safety Monitoring 
Plan (DSMP). 
The DSMC will review pertinent aspects of the study to assess 
subject safety, compliance with the protocol, data collection, and 
risk-benefit ratio. Specifically, the Winship Cancer Institute Internal 
Monitors assigned to the DSMC may verify informed consent, 
eligibility, data entry, accuracy and availability of source 
documents, AEs/SAEs, and essential regulatory documents.  
Following the monitoring review, monitors will provide a 
preliminary report of monitoring findings to the PI and other 
pertinent individuals involved in the conduct of the study.  The PI 
is required to address and respond to all the deficiencies noted in 
the preliminary report.  Prior to the completion of the final 
summary report, monitors will discuss the preliminary report 


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responses with the PI and other team members (when appropriate).  
A final monitoring summary report will then be prepared by the 
monitor.  Final DSMC review will include the final monitoring 
summary report with corresponding PI response, submitted CAPA 
(when applicable), PI Summary statement, and available aggregate 
toxicity and safety data.  
The DSMC will render a recommendation and rating based on the 
overall trial conduct.  The PI is responsible for ensuring that 
instances of egregious data insufficiencies are reported to the IRB.  
Continuing Review submissions will include the DSMC 
recommendation letter.  Should any revisions be made to the 
protocol-specific monitoring plan after initial DSMC approval, the 
PI will be responsible for notifying the DSMC of such changes.  The 
Committee reserves the right to conduct additional audits if 
necessary. 
The data safety monitoring plan will be implemented by Dr Maithel, the 
Principal Investigator (P.I.) of this study.  The plan is based on weekly-
monitoring by the GI Working Group, and monitoring via Winship Cancer 
Institute Data Safety Monitoring Committee (DSMC) as per Winship DSMP. Dr. 
Maithel and the investigators, the clinical research coordinator and the 
regulatory affairs coordinator will meet at least on a monthly basis to review and 
discuss study data to ensure subject safety. The research coordinators will 
maintain one spread sheet which will summarize all the patient data for patients 
actively being treated on the trial as well as a roadmap detailing pending 
tests/treatments for each individual patient. During weekly meetings of the GI 
Oncology Working Group, the group will review the eligibility criteria for each 
new patient. In addition, during these meeting the group will review all the 
toxicity (AE/SAE) logs, case report form completion and roadmap for each 
patient on the trial. Decisions to continue treating subjects and/or if the trial 
accrual should continue, along with the recruitment methods and the insurance 
of confidentiality are also discussed during these meetings. Documentation of 
the discussions during these meetings are completed and filed. The P.I. and the 
study investigators will discuss any required modifications to this study at the 
weekly meetings. No modifications to this study are implemented until they are 
submitted for review and approved by the Emory University IRB. The comments 
from the Winship Cancer Institute DSMC are forwarded to the IRB at the time of 
the annual renewal of this study or sooner if warranted and requested by the 
Winship Cancer Institute DSMC.   


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The Winship Cancer Institute DMSC does not tolerate protocol deviations, but 
does recognize that they occur unintentionally. Any protocol violations are 
reviewed and reported to the Winship Cancer Institute DSMC, IRB, and all other 
designated regulatory agencies as required by the study protocol, IRB policy or 
regulations.


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Appendix 1 – Eastern Cooperative Oncology Group Performance Status
ECOG PERFORMANCE STATUS*
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.


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Appendix 2 - Nab-Paclitaxel – Additional Information
 
Contacts:     
For Celgene International Sàrl
Investors:
+41 32 729 8303 ir@celgene.com
Media:
+41 32 729 8304 media@celgene.com
NAB-PACLITAXEL® DEMONSTRATES STATISTICALLY SIGNIFICANT 
IMPROVEMENT IN OVERALL SURVIVAL FOR PATIENTS WITH ADVANCED 
PANCREATIC CANCER IN PHASE III STUDY 
BOUDRY, Switzerland – (November 9, 2012) – Celgene International Sàrl, a subsidiary of 
Celgene Corporation (NASDAQ: CELG) today announced that its phase III study of NAB-
PACLITAXEL® (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 
in combination with gemcitabine in treatment-naïve patients with advanced pancreatic cancer 
met its primary endpoint of overall survival. In the study, NAB-PACLITAXEL in combination 
with gemcitabine demonstrated a statistically significant improvement in overall survival 
compared to patients receiving gemcitabine alone.  
In the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, a Celgene-
sponsored, open-label, randomized, international study 861 metastatic pancreatic cancer patients 
were randomized to receive either NAB-PACLITAXEL plus gemcitabine (125 mg/m2 followed 
by 1000 mg/m2 gemcitabine for 3 weeks followed by a week of rest) or gemcitabine alone (1000 
mg/m2 administered weekly for 7 weeks followed by a week of rest followed by cycles of 
weekly administration for 3 weeks followed by one week of rest). 
The primary endpoint for the study is improvement in overall survival. Secondary endpoints 
include evaluation of progression-free survival, objective tumor response and the safety and 
tolerability of this combination in this patient population.
The safety profile of NAB-PACLITAXEL in combination with gemcitabine observed in the 
study is comparable with other NAB-PACLITAXEL clinical trials in pancreatic cancer. A late-
breaker placeholder abstract for this study has been submitted to the American Society of 
Clinical Oncology’s (ASCO) 2013 Gastrointestinal Cancers Symposium being held in San 
Francisco on January 24-26, 2013. 


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Based on the results of the MPACT study, the company plans to submit dossiers for registration 
in the US, Europe and other markets. 
Abraxane is now indicated for the first-line treatment of patients with metastatic adenocarcinoma 
of the pancreas, in combination with gemcitabine.
About Advanced Pancreatic Cancer
Advanced pancreatic cancer is a difficult-to-treat cancer with the lowest survival rates among all 
cancer types.  Across all patients with pancreatic cancer, relative 5-year survival is 5.5%.  There 
are two main types of pancreatic cancer - adenocarcinomas, which accounts for approximately 
95% of all pancreatic cancer, and neuroendocrine tumors.  Pancreatic cancer is relatively 
uncommon with new cases accounting for only 2.1% of all newly diagnosed cancers. However, 
pancreatic cancer is the fourth most common cause of cancer death in the United States and 
throughout the world. 
About NAB-PACLITAXEL®   
NAB-PACLITAXEL is an albumin-bound form of paclitaxel that is manufactured using patented 
nab® technology.  NAB-PACLITAXEL is formulated with albumin, a human protein, and is free 
of solvents.
In the United States, NAB-PACLITAXEL was first approved in January 2005 for the treatment of 
breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 
months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless 
clinically contraindicated.  NAB-PACLITAXEL is also available in Europe, Canada, Russia, 
Australia, New Zealand, India, Japan, South Korea, Bhutan, Nepal, United Arab Emirates and 
China for the treatment of metastatic breast cancer.
In October 2012, NAB-PACLITAXEL was approved by the U.S. Food and Drug Administration 
for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in 
combination with carboplatin, in patients who are not candidates for curative surgery or radiation 
therapy.
For the full prescribing information for NAB-PACLITAXEL please visit http://www.Nab-
Paclitaxel.com. 
NAB-PACLITAXEL is currently in various stages of investigation for the treatment of the 
following cancers: pancreatic, metastatic melanoma, bladder, ovarian, and expanded applications 
for breast cancer.
NAB-PACLITAXEL® for Injectable Suspension (paclitaxel protein-bound particles for 
injectable suspension) (albumin bound) is indicated for the treatment of breast cancer after 
failure of combination chemotherapy for metastatic disease or relapse within 6 months of 
adjuvant chemotherapy. Prior therapy should have included an anthracycline unless 
clinically contraindicated.  
NAB-PACLITAXEL is indicated for the first-line treatment of locally advanced or 
metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are 


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not candidates for curative surgery or radiation therapy. Other indications include 
metastatic breast cancer and pancreas adenocarcinoma.
Important Safety Information
WARNING - NEUTROPENIA

Do not administer NAB-PACLITAXEL therapy to patients who have baseline 
neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of 
bone marrow suppression, primarily neutropenia, which may be severe and result in 
infection, it is recommended that frequent peripheral blood cell counts be performed on 
all patients receiving NAB-PACLITAXEL

Note: An albumin form of paclitaxel may substantially affect a drug’s functional 
properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR 
WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS
Neutrophil Counts

NAB-PACLITAXEL should not be used in patients who have baseline neutrophil counts of < 
1,500 cells/mm3 
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to NAB-PACLITAXEL should 
not be rechallenged with the drug
WARNINGS AND PRECAUTIONS
Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting 
toxicity of NAB-PACLITAXEL

Monitor for myelotoxicity by performing complete blood cell counts frequently, including 
prior to dosing on Day 1 for metastatic breast cancer (MBC) and Days 1, 8, and 15 for non-
small cell lung cancer (NSCLC)

Do not administer NAB-PACLITAXEL to patients with baseline absolute neutrophil counts 
(ANC) of less than 1,500 cells/mm3

In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of 
NAB-PACLITAXEL therapy, reduce the dose of NAB-PACLITAXEL in subsequent courses 
in patients with either MBC or NSCLC

In patients with MBC, resume treatment with every-3-week cycles of NAB-PACLITAXEL 
after ANC recovers to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3

In patients with NSCLC, resume treatment if recommended at permanently reduced doses for 
both weekly NAB-PACLITAXEL and every-3-week carboplatin after ANC recovers to at 
least 1,500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC 
of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of 
the cycle
Nervous System


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
Sensory neuropathy is dose- and schedule-dependent

The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose 
modification

If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to 
Grade 1 or 2 for MBC or until resolution to ≤ Grade1 for NSCLC followed by a dose 
reduction for all subsequent courses of NAB-PACLITAXEL
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have 
been reported

Patients who experience a severe hypersensitivity reaction to NAB-PACLITAXEL should 
not be re-challenged with this drug
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, 
administration of NAB-PACLITAXEL in patients with hepatic impairment should be 
performed with caution

The starting dose should be reduced for patients with moderate or severe hepatic impairment
Albumin (Human)

NAB-PACLITAXEL contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

NAB-PACLITAXEL can cause fetal harm when administered to a pregnant woman 

If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this 
drug, the patient should be apprised of the potential hazard to the fetus

Women of childbearing potential should be advised to avoid becoming pregnant while 
receiving NAB-PACLITAXEL
Use in Men

Men should be advised not to father a child while receiving NAB-PACLITAXEL
ADVERSE REACTIONS 
Randomized Metastatic Breast Cancer (MBC) Study

The most common adverse reactions (≥20%) with single-agent use of NAB-PACLITAXEL 
in the MBC study  were alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory 
neuropathy (any symptoms 71%; severe 10%), abnormal ECG (all patients 60%; patients 
with normal baseline 35%), fatigue/asthenia (any 47%; severe 8%), myalgia/arthralgia (any 
44%; severe 8%), AST elevation (any 39%), alkaline phosphatase elevation (any 36%), 
anemia (all cases 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe 
<1%) and infections (24%) 

Sensory neuropathy was the cause of NAB-PACLITAXEL discontinuation in 7/229 (3%) 
patients 

Other adverse reactions of note included vomiting (any 18%; severe 4%), renal dysfunction 
(any 11%; severe 1%), fluid retention (any 10%; severe 0%); mucositis (any 7%; severe 


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<1%), hepatic dysfunction (elevations in bilirubin 7%), hypersensitivity reactions (any 4%; 
severe 0%), thrombocytopenia (any 2%; severe <1%), and injection site reactions (<1%). In 
all NAB-PACLITAXEL treated patients (n=366) ocular/visual disturbances were reported 
(any 13%; severe 1%). Dehydration and pyrexia were also reported

Severe cardiovascular events possibly related to single-agent NAB-PACLITAXEL occurred 
in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac 
arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, 
pulmonary emboli, and hypertension 

Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported 
Non-Small Cell Lung (NSCLC) Cancer Study

Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of 
NAB-PACLITAXEL and carboplatin in NSCLC were: anemia (28%); neutropenia (47%); 
thrombocytopenia (18%), and peripheral neuropathy (3%)

The most common adverse reactions (≥ 20%) of NAB-PACLITAXEL in combination with 
carboplatin for NSCLC were anemia, neutropenia, thrombocytopenia, alopecia, peripheral 
neuropathy, nausea, and fatigue

The most common serious adverse reactions of NAB-PACLITAXEL in combination with 
carboplatin for NSCLC were anemia (4%) and pneumonia (3%)

The most common adverse reactions resulting in permanent discontinuation of NAB-
PACLITAXEL were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy 
(1%)

The most common adverse reactions resulting in dose reduction of NAB-PACLITAXEL 
were neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

The most common adverse reactions leading to withholding or delay in NAB-PACLITAXEL 
dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%)

The following common (≥10% incidence) adverse reactions were observed at a similar 
incidence in NAB-PACLITAXEL plus carboplatin-treated and paclitaxel injection plus 
carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 
17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 
10% (incidence rates are for the NAB-PACLITAXEL plus carboplatin treatment group)
Post-Marketing Experience with NAB-PACLITAXEL and other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with NAB-
PACLITAXEL. The use of NAB-PACLITAXEL in patients previously exhibiting 
hypersensitivity to paclitaxel injection or to human albumin has not been studied

There have been reports of congestive heart failure and left ventricular dysfunction with 
NAB-PACLITAXEL, primarily among individuals with underlying cardiac history or prior 
exposure to cardiotoxic drugs

There have been reports of extravasation of NAB-PACLITAXEL. Given the possibility of 
extravasation, it is advisable to monitor closely the NAB-PACLITAXEL infusion site for 
possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering NAB-PACLITAXEL concomitantly with 
medicines known to inhibit or induce either CYP2C8 or CYP3A4


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USE IN SPECIFIC POPULATIONS
Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are 
excreted in human milk and because of the potential for serious adverse reactions in nursing 
infants, a decision should be made to discontinue nursing or to discontinue the drug, taking 
into account the importance of the drug to the mother
Pediatric

The safety and efficacy of NAB-PACLITAXEL in pediatric patients have not been evaluated
Geriatric

No toxicities occurred notably more frequently among patients ≥ 65 years of age who 
received NAB-PACLITAXEL for MBC

Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 
years of age treated with NAB-PACLITAXEL and carboplatin in NSCLC
Renal Impairment

The use of NAB-PACLITAXEL has not been studied in patients with renal impairment
DOSAGE AND ADMINISTRATION

Dose adjustment is recommended for patients with moderate and severe hepatic impairment 
and patients who experience severe neutropenia or severe sensory neuropathy during 
treatment with NAB-PACLITAXEL 

Withhold NAB-PACLITAXEL if AST >10 x ULN or bilirubin > 5 x ULN

Dose reductions or discontinuation may be needed based on severe hematologic or 
neurologic toxicities 

Monitor patients closely
Please see full Prescribing Information, including Boxed WARNING, 
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE 
REACTIONS.
About Celgene International Sàrl
Celgene International Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a 
wholly owned subsidiary and international headquarters of Celgene Corporation. Celgene 
Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical 
company engaged primarily in the discovery, development and commercialization of innovative 
therapies for the treatment of cancer and inflammatory diseases through gene and protein 
regulation. For more information, please visit the Company's website at www.celgene.com.
Forward-Looking Statements
This press release contains forward-looking statements, which are generally statements that are 
not historical facts. Forward-looking statements can be identified by the words "expects," 
"anticipates," "believes," "intends," "estimates," "plans," "will," “outlook” and similar 


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expressions. Forward-looking statements are based on management’s current plans, estimates, 
assumptions and projections, and speak only as of the date they are made. We undertake no 
obligation to update any forward-looking statement in light of new information or future events, 
except as otherwise required by law. Forward-looking statements involve inherent risks and 
uncertainties, most of which are difficult to predict and are generally beyond our control. Actual 
results or outcomes may differ materially from those implied by the forward-looking statements 
as a result of the impact of a number of factors, many of which are discussed in more detail in 
our Annual Report on Form 10-K and our other reports filed with the Securities and Exchange 
Commission. 


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Appendix 3 - Registration Process for Participating Sites
Centralized Registrations 
A centralized registration procedure will be used. Subjects who are considered candidates for the 
study will be evaluated for eligibility by the participating investigators. There will be a 2-part 
registration procedure: 
1) Participating Institutions Registration 
Subjects at participating institutions should be registered with their institutional central 
registration following each institution’s established policies. 
2) Emory University Registration 
Participating institutions must register subjects with Emory University in accordance with project 
specific procedures. After each subject signs consent, the Central Subject Registration form is to 
be completed and sent to Winship within 24 hours of consent. This form, along with the valid, 
signed informed consent form/HIPAA authorization form, is to be faxed or emailed to Winship’s 
Central Subject Registrar per instructions on the form. Once a subject is registered, each 
participating site will be notified via e-mail. All participating institution subjects must be registered 
with Emory University before protocol treatment is initiated. Late registrations will not be 
accepted. 
Registrations will be completed by Emory University within 1 business day after the date the 
registration is received from the participating site. 
Subject ID Number 
At the time of registration, the participating institution’s subject will be assigned an Emory 
University subject number. This number is unique to the subject and must be used for 
registrations onto subsequent protocols and written on all data and correspondence for that 
subject prior to submission to Emory University. 
Emory University subjects will be registered using their Emory University subject number. 
Registration Verification Letter 
A Registration Verification Letter will be created by Emory University and then faxed or 
emailed to the participating institutions after the registration is completed. 
Initiation of Therapy 
Subjects must be registered with Emory University before receiving study treatment. Treatment 
may not be initiated until the participating institutions receive the subject’s Registration 
Verification Letter from Emory University. 
Confidentiality 
All documents, investigative reports, or information relating to the subject are strictly 
confidential. Any subject specific data or reports (i.e. Pathology Reports, MRI Reports, 


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Operative Reports, etc.) that the site submits to Emory University will adhere to a policy of strict 
confidentiality.
Patient registration process flowchart below.
Patient Registration Process Flowchart
Consent
Eligibility Checklist
Source Documents
Participating Sites
Send by e-mail to:
lmoor25@emory.edu
Verify Eligibility
Emory University
Patient not Eligible
Inform site that 
participation has 
been registered 
“or” is ineligible
Patient Eligible
CRSC
(Coordinating Center)
Register in 
OnCore
Send registration 
documents
A protocol email 
address makes it 
easy for the site to 
register as well as 
send messages
The email group 
includes everyone 
involved with the 
management of the 
protocol including 
the PI


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APPENDIX 4
DATA QUALITY MANAGEMENT PLAN
Multicenter Project
TABLE OF CONTENTS
1.
   Introduction
2.
General Roles and Responsibilities
2.1
Protocol Principal Investigator
2.2
Coordinating Center
2.3
Participating Institution Principal Investigator
3.
Coordinating Center
3.1
Correspondence Information
3.2
Hours of Operation
4.
Protocol Management
4.1
Protocol Distribution
4.2
Protocol Revisions and Closures
4.3
Informed Consent Requirements
4.4
Regulatory Documents
4.5
Participating Institution Site Initiation
4.6
IRB Annual Review
4.7
Participant Confidentiality and Authorization Statement
4.8
Patient Registration
4.9
Schedule of Data Entry and Source Document Submission
4.10 Data Form and Source Document Review
4.11 Missing and Deficient Memorandum
5.
Study Drug Requisition
6.
Safety Assessments and Toxicity Monitoring
6.1
Serious Adverse Events
6.2
Oversight for Safety Assessment and Toxicity Monitoring
6.3
Reporting Serious Adverse Events
7.
Protocol Deviations and Unanticipated Problems


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7.1
Definitions
7.2
Reporting Procedures
8.
Quality Assurance
8.1
Ongoing Monitoring of Protocol Compliance
8.2
Verification of Study Data
    
8.3
On-Site Audit
    
9.
Evaluation of Participating Institution Performance                                                                                          
9.1
Sub-Standard Performance                                                                                                       
9.2
Corrective Actions                                                                                                                                 
 


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1.
INTRODUCTION
The purpose of the Data Quality Management Plan (DQMP) is to establish standards 
which will ensure that the conduct of an Emory University multicenter protocol complies 
with institutional guidelines, Federal regulations (21 CFR Part 11), Good Clinical 
Practice (GCP) Guidelines, and Health Insurance Portability and Accountability Act 
(HIPAA) requirements.
The DQMP outlines the procedures required for participating institutions in the conduct 
of an Emory University multicenter protocol.
2.
GENERAL ROLES AND RESPONSIBILITIES
Each participating site is responsible for the coordination, development, submission, and 
approval of a protocol as well as its subsequent amendments.  Each site-PI will assume 
the same responsibility at their own respective site.
The Emory University Protocol Principal Investigator, Coordinating Center, and the 
Participating Institution Principal Investigator will all agree to the general responsibilities 
as follows:
2.1
Protocol Principal Investigator (Protocol PI)
Being charged with the administrative responsibilities of the Emory University 
multicenter protocol, the Protocol PI will accept the following:
 

Obtain initial approval of the protocol and approval of any subsequent 
amendments from the Emory University IRB, and/or sponsor or supporting entity 
(if applicable).

Identify participating institutions and investigators, and obtain accrual 
commitments.

Include the list of participating institutions and responsible investigators in the 
abstract or protocol appendix.

Coordinate contractual agreements with sponsor or supporters (when applicable), 
and with each participating institution.  

Assure that all participating institutions are using the correct version of the 
protocol.

Assure that all participating institutions obtain IRB (or equivalent) approval of the 
protocol prior to performing any study related activities with potential subjects.

Participating sites will promptly provide the coordinating investigator/site with 
copies of adverse event reports that require expedited reporting to their local IRBs

Coordinating investigator/site will forward adverse events reports requiring 
expedited reporting to participating sites

Coordinating/Lead investigator will review data summary reports of adverse 
events on a regular basis, at least annually

Coordinating/ Lead investigator will submit data summary reports to the Data 
Safety Monitoring Committee for review as per their guidelines.


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
Ensure timely submission of protocol data from all participating institutions.

Review and assess protocol data from all participating institutions for study 
analysis in a timely fashion.

Submit all required reports to Emory University, IRB, Sponsor or Supporter, and 
any other relevant regulatory agencies.

Monitor the overall conduct and progress of the study at all participating 
institutions.
2.2
Coordinating Center 
To assist the Protocol PI in fulfilling these responsibilities, the study teams in the 
Division of Surgical Oncology, Department of Surgery, at Emory University School of 
Medicine and the Multi-site coordinator / regulatory specialist at Emory University, will 
provide the administrative support and assume the following responsibilities to ensure 
data quality and protocol compliance at all participating institutions.

Act as liaison between Emory University and the participating institutions. 

Implement quality assurance and quality control systems to ensure quality data 
and protocol compliance.

Distribute Emory University IRB approved protocol and its amendments to all 
participating institutions.    

Collect and maintain documentation of IRB approval for all participating 
institutions. 

Collaborate with the Division of Surgical Oncology, Department of Surgery, at 
Emory University School of Medicine in providing protocol and database 
trainings to ensure that all investigators and staff are given instructions on 
following the protocol, on complying with a uniform set of standards for the 
assessment of clinical and laboratory findings, and on completing the 
CRFs/eCRFs. 

Review, process, and maintain records of Adverse Events/Serious Adverse Events 
from all participating institutions on a timely basis to assure participant safety. 

Review, process, and maintain records of Deviations or Unanticipated problems 
that are reported from all participating institutions on a timely basis to assure 
participant safety and protocol integrity. 

Distribute Safety Reports (External Adverse Events), if applicable, to all 
participating institutions.

Ensure timely submission and accuracy of protocol data from all participating 
institutions. 

Assist in the submission of all required reports to the Protocol PI, Emory 
University IRB and any other relevant regulatory agencies. 
2.3
Participating Institution Principal Investigator (Participating PI)

Commit to accrual to the Emory University protocol.

Submit the Emory University IRB approved protocol and its amendments to the 
institution’s local or central IRB (or equivalent) for approval prior to performing 
any study related activities with potential subjects. 

Assume overall responsibility for the trial at his/her institution. 


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
Oversee the conduct of the clinical trial at his/her institution. 

Identify study collaborators from that institution who agree to participate. 

Assure that all involved research personnel are aware of the effort required to 
oversee and conduct the trial. 

Balance the trial needs with other commitments. 

Assure adequate staff with adequate research and protocol training. 

Assure adequate facilities to conduct the trial. 

Provide, and update as needed, a list of contact information of involved staff and 
Delegation Authority Log for the protocol to the Coordinating Center. 

Ensure that the multicenter trial procedures are performed at his/her institution in 
compliance with the protocol and the DQMP.
3.
   COORDINATING CENTER
3.1
Correspondence Information  
Division of Surgical Oncology, Department of Surgery, at Emory University 
School of Medicine 
(Patient Registrations to be performed by the Central Subject Registrar

Phone: 404-778-5471
Fax: 404-778-5071
Email: winshipcsr@emory.edu

Mailing address: for all U.S. Mail excluding express mail:
Winship Cancer Institute, Emory University
Clinical Trials Office
1365-C Clifton Road NE, Suite C3012
Atlanta, GA 30322

Mailing address for Federal Express, Airborne, and UPS:
Winship Cancer Institute, Emory University
Clinical Trials Office
1365-C Clifton Road NE, Suite C3012
Atlanta, GA 30322
Clinical Research Support Center at Emory University
(Regulatory oversight, study monitoring and auditing, and general correspondence)
  
Mailing address: for all U.S. Mail excluding express mail:
1784 North Decatur Rd., Ste 402
Atlanta, GA 30322
Mailing address for Federal Express, Airborne, and UPS: 
Winship Cancer Institute, Emory University
Clinical Trials Office
1365-C Clifton Road NE, Suite C3012
Atlanta, GA 30322
Email:  lmoor25@emory.edu


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3.2
Hours of Operation
The staff at both the Division of Surgical Oncology, Department of Surgery, at Emory 
University School of Medicine and Clinical research Support Center (Coordinating Center) 
at Emory University are available between the hours of 8:00 a.m. and 5:00 p.m. Eastern 
Standard Time, Monday through Friday, excluding holidays. On designated Emory 
University holidays, the office will be closed.
Transactions (i.e. participant registration, correspondences) will not take place on holidays.  
Occasionally, the Coordinating Center may close due to hurricanes or other inclement 
weather conditions.  Each participating institution will be notified of office closures by 
phone, fax, or e-mail.
Night, Weekend, and Holiday Emergencies: 
If participant-related emergencies or questions arise when the Coordinating Center is closed, 
please email the Protocol PI and confirm receipt by contacting the PI the next business day 
at the telephone number listed in the protocol.
4.
PROTOCOL MANAGEMENT
The Coordinating Center will maintain copies of all IRB approvals from each participating 
institution. 
4.1
Protocol Distribution
The Coordinating Center will distribute the final Emory University IRB approved protocol 
and any subsequent amended protocols to all participating institutions within thirty (30) days 
of approval. 
4.2
Protocol Revisions and Closures 
The Participating Institutions will receive fax or e-mail notification of protocol revisions 
from the Coordinating Center.  Protocol revisions will be submitted in pdf format to 
participating institutions. It is the responsibility of each participating institution to notify its 
IRB of these revisions within the timeline set forth below. 
Major Amendment: A substantive change in the study which may increase or decrease the 
risk to study subjects.  Major revisions require full IRB approval.  
Participating institutions shall provide its IRB approval of the revision within 90 days after 
notice.  If more than 90 days, participant enrollment shall be temporarily suspended at 
participating institution until its IRB approval is submitted to the Coordinating Center. 
The following are examples of major amendments:

Change of eligibility (inclusion/exclusion) criteria 

Change in design of protocol 

Change in statistical section 

Change in sample size/accrual (e.g., doubling the sample size) 

Change in informed consent 

Change of estimated dropout rate 

Change of treatment or intervention 


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
Change of device 

Change in primary objective evaluation process 
Non-life-threatening Revisions: Participating institutions will receive written (faxed or 
emailed) notification of revisions regarding non-life-threatening events from the 
Coordinating Center. Non-life-threatening revisions must be submitted to the participating 
institution’s IRB within fourteen (14) days from the date of notification. 
Revisions for Life-threatening Causes: Participating institutions will receive a phone 
notification followed by the written (faxed or emailed) notification from the Coordinating 
Center concerning protocol revisions required to protect lives.  Life-threatening protocol 
revisions must be submitted to the local IRB within one business day from date of 
notification.   Immediate closure of the protocol will be required until the protocol 
amendment is approved.
Once the participating institution’s IRB has approved the amendment, notification of IRB 
approval should be sent to the Coordinating Center within fourteen (14) business days of 
approval.
Protocol Closures and Temporary Holds: Participating institutions will receive written 
(fax or e-mail) notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately.  In addition, the Coordinating 
Center will update the Participating institutions on an ongoing basis about protocol accrual 
data so that they will be aware of imminent protocol closures. 
4.3
Informed Consent Requirements 
The Protocol PI or designee will ensure review and approval of the participating institution’s 
Informed Consent Document (ICD) prior to its submission to the institution’s IRB.
 The Participating PI will identify members of the study team who will be obtaining 
participants’ signed ICD for protocols, as per the delegation of authority log and the 
institution’s Informed Consent Policy.
4.4
Regulatory Documents 
The following must be on file with the Coordinating Center prior to participant registration: 
Participating Institution

Participating institution's IRB approval memo/letter of the protocol and ICD

IRB approval for all amendments within the predetermined timelines

CLIA, CAP, and Normal Lab Values (if applicable)
Participating Institution Research Personnel

Certification of Human Subjects Protection Training

Current Medical License (Participating PI and co-investigators)

Curriculum Vitae

Delegation of Authority Log


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4.5
Participating Institution Site Initiation
Before an institution begins participating in an Emory University multicenter protocol, the 
following steps must be completed: 

Submit all required regulatory documents to the Coordinating Center 

Participate in a site initiation visit, webcast, or conference call 

Receive training regarding study specific CRFs/eCRFs

Execute all required contractual agreements
After these requirements have been fulfilled, the participating institution will receive a 
written Site Activation Notification by fax or e-mail.  Once the Site Activation Notification 
has been received, the participating institution may begin to register patients to the protocol. 
4.6
IRB Annual Review
Continuing IRB approval from the participating institution is required in order to register 
participants onto a protocol.  There is no grace period for annual reviews. 
Protocol registrations will be suspended if an annual review letter is not received by the 
Coordinating Center from the participating institutions within thirty (30) days of the 
anniversary of the previous approval date.   
4.7
Participant Confidentiality and Authorization Statement
In order for covered entities to use or disclose protected health information during the course 
of this trial, the participant in the trial must sign an authorization. This authorization may or 
may not be separate from the Informed Consent. 
Emory University will attempt to limit its use of protected health information in its 
Multicenter Project trials.  However, portions of a participant’s protected health information 
may be collected. In order for Emory University to collect this information on any 
participant enrolled, the participant must have signed an informed consent document, which 
includes an authorization for the release of protected personal health information (IC/A). 
The authorization that each institution obtains to use and disclose protected health 
information must include Emory University as an entity with whom they will share data.  
Each institution should also list study sponsor or supporter in their authorization form.  
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Any participant specific reports (i.e. Pathology Reports, MRI Reports,  etc.) 
submitted to the Coordinating Center must have the participant’s full name & social security 
number de-identified and the assigned Emory University participant ID number , accession 
number and protocol number written in. Participant initials need to be included or retained 
for cross verification of identification. 
The de-identification process can be waived only when the following criteria are met:
1) The participating institution provides the Coordinating Center an IRB policy or a 
written statement that the de-identification process is not required on all documents 
submitted to Emory University.


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2) The study participants give their authorization to Emory University for the use and 
disclosure of their Protected Health Information in either the protocol specific 
Informed Consent or HIPAA Authorization Form. 
4.8
Patient Registration 
The Division of Surgical Oncology, Department of Surgery, at Emory University School of 
Medicine is responsible for central patient registration and randomization. 
All participants must be registered centrally before a protocol treatment is initiated. Late 
registrations will not be accepted.  
Fax:   404-778-5071
Phone: 404-778-5471
Email: winshipcsr@emory.edu
Registration hours are 8:00 a.m. to 5:00 p.m. Eastern Standard Time, Monday through 
Friday, except holidays.
4.8.1
Registration Information
The following are required for registration. All subject related information sent via fax or 
email must be encrypted.

Copy of the signed ICD and HIPAA authorization

Completed and signed Eligibility Checklist

Source documents supporting each eligibility requirement
4.8.2
Multicenter Project Participant Number
Once eligibility has been established, non Emory University patients will be assigned a ten 
character patient number. This number is unique to the patient and must be written on all 
correspondence related to the patient.
4.8.3
Eligibility Exceptions:  There will be no eligibility exceptions. 
All documents submitted to Emory University must be identified with:
1. Emory University protocol number
2. Assigned multicenter protocol participant ID number
3. Participant initials
All participants must be registered in the OnCore system at Emory University with the 
correct corresponding institution and investigator.
4.9
Schedule of Data Entry and Source Document Submission
All documents, except for those sent at the time of registration, are to be forwarded to the 
Division of Surgical Oncology, Department of Surgery, at Emory University School of 
Medicine via OnCore. Case Report Form/s (CRF), will be used for data collection for this 
protocol. The schedule for data submission (CRF) and submission of source documents into 
OnCore as agreed is specified in this document. 


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COMMON FORMS & DOCUMENTS
Signed Informed Consent/Patient Authorization for the Release of Personal Health 
Information
Eligibility Checklist
Baseline Medical History 
Treatment Data (Chemotherapy documentation -  Medication Administration Record, 
Laboratory Results, administration of any blood products)
Evaluation Data (Protocol Response) 
Adverse Events 
Off-Treatment Update 
Follow-Up Update Off Study Update 
Source Documents (e.g. Pathology, Radiology, Operative, Laboratory Reports; History 
and Physical, Progress Notes)
PROTOCOL [EU4339-18] DATA AND SOURCE SUBMISSION SCHEDULE (See table 
below)
DATA
CASE REPORT 
FORM
SOURCE
DOCUMENT
EVENT 
INTERVAL
SUBMISSION 
SCHEDULE
1.
 Informed 
Consent with 
HIPAA 
Authorization
N/A
Copy of 
signed/initialled
Informed Consent 
w/HIPAA 
Authorization
Baseline 
On or before 
registration 
date.
2.
Demographics 
Pre-registration 
Form
Baseline History & 
Physical Note or 
Demographic Form
Baseline 
On or before 
registration 
date.
3.
Eligibility 
Checklist 
Inclusion-
Exclusion Form
History and Physical 
Progress Note that 
includes prior 
treatment history 
(medical/surgical/ and 
other treatments such 
us chemotherapy, 
radiotherapy), 
pathology report, and 
laboratory report (to 
include tumor 
markers).
Baseline
On or before 
registration 
date.


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4.
Baseline History 
and Evaluation 
Data
Medical History 
Form, Physical 
Exam Form, Vital 
Signs Form, 
Concomitant 
Medication Form, 
Laboratory 
Results Form, 
Other Data 
Submission Form, 
Research 
Specimen Status 
Form
History and Physical 
Progress Note that 
includes prior 
treatment history 
(medical/surgical/ and 
other treatments such 
us chemotherapy, 
radiotherapy), 
pathology report, and 
laboratory report (to 
include tumor 
markers).
Baseline
On or before 
registration 
date.
5.
Disease Evaluation 
Data 
 
Disease 
Evaluation Form 
(Target and Non 
Target Tumor 
Measurements), 
Other Data 
Submission Form
CT (or MRI) Scan 
Report of the chest, 
abdomen and pelvis. 
Baseline
On or before 
registration 
date.
6.
Treatment Data
Treatment Form, 
Physical Exam 
Form, Vital Signs 
Form, 
Concomitant 
Medication Form, 
Laboratory 
Results Form, 
Adverse Event 
Form, Multicenter 
SAE Form (if 
applicable). 
Serious Adverse 
Event source (if 
applicable), physician 
treatment orders, and 
chemotherapy 
MAR/infusion 
records.
Treatment 
Phase
Within 14 days 
after end of 
each of cycle.
7.
Disease Evaluation 
Data
Disease 
Evaluation Form 
(Target and Non 
Target Tumor 
Measurements), 
Other Data 
Submission Form
To include clinical 
evaluations to 
determine response 
(CT or MRI reports of 
the chest, abdomen 
and pelvis after cycle 
4 and 6). 
Continue to submit 
report until first 
Progressive Disease 
(PD) event.
Treatment 
Phase
Within 14 days 
after event 
date.
8.
End of Treatment 
Summary Data
End of Treatment 
Form, Physical 
Exam Form, Vital 
N/A
Off-
treatment 
Phase
Within 4 weeks 
after the end of 


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Signs Form, 
Concomitant 
Medication Form, 
Laboratory 
Results Form, 
Adverse Event 
Form, Disease 
Evaluation/Target 
and Non Target 
Tumor 
Measurements 
Form, Other Data 
Submission Form, 
Research 
Specimen Status 
Form.
last dose or 
post-surgery.
9.
Disease Evaluation
Data 
N/A
CT scan or MRI 
report of the chest, 
abdomen and pelvis 
(off treatment patients  
who met first PD at 
this interval)
Off 
Treatment 
Phase
Within 14 days 
after event 
date.
10. Follow-Up 
Off Treatment 
Data
Survival Status  
Data (Long term 
follow-up)
Survival Follow-
up Form, Adverse 
Event Form 
N/A
Follow-up 
Phase
Within 59 days 
after end of 
treatment 
protocol date.
11. Off Study Data
 
Off Study Form
Off Study Note
Off Study 
Phase
Within 14 days 
after off study 
date.
4.10
Data Form and Source Document Review
The data entered in the CRFs and source document submitted via OnCore as agreed are 
reviewed by the Coordinating Center for: 

Timeliness: Did the form arrive on time as specified in the protocol?

Completeness: Is all the information provided as required per protocol?

Patient Eligibility: Does the patient meet the eligibility requirements for the study?

Treatment Compliance: Are the body surface area (BSA) and drug dosage 
calculations correct? The dose must be within 10% of the calculated protocol dose.

Adverse Events: Did the patient experience adverse events attributed to protocol 
treatment? Was the treatment delayed due to an adverse event? What were the 
maximum grade, duration, and attribution of the event? Notations concerning adverse 
events will contain grade, start and stop date, and attribution.


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
Response:  Response will be assessed using the RECIST Criteria (version 1.1, 2009).  
Responses must be verified, documented, and signed in the local medical record by 
the local PI.
4.11
Missing and Deficient Memorandum
Data submissions are monitored for timeliness and completeness of submission.  
Participating institutions are notified of their data submission delinquencies in accordance 
with the following policies and procedures:
Incomplete or Questionable Data
If data entered in the CRFs is incomplete, or if there is a conflict between data entered and 
source documents reviewed, queries will be generated. Responses to any queries generated 
are due within 14 days.  Source documents are also expected to be available within 14 days 
of occurrence.
Missing Source Documents
If source documents are not submitted or available for viewing on schedule, the participating 
institution will receive a “Missing and Deficient Report” from the coordinating center noting 
the missing source document (s). These reports are distributed on a monthly basis. If source 
documents are 30 or more days late, the site will be contacted by telephone for assistance in 
obtaining delinquent forms. If forms are > 60 days late, the Protocol PI (Maithel) will 
contact the participating institution’s Principal Investigator for assistance.  
Missing Query Responses:
If replies to Queries are not received on schedule, the institution will receive a “Missing and 
Deficient Query Report” from the coordinating center noting the missing Query.  These 
reports are compiled and distributed on a monthly basis. If responses are 30 or more days 
late, the coordinating center will communicate with the participating institution’s Research 
staff for assistance in obtaining the forms.  If responses are 60 or more days late, the 
Protocol PI and the Participating PI will be notified via email.  All delinquencies will also be 
discussed in the monthly consortia meetings.
5.
STUDY DRUG REQUISITION
Gemcitabine and Cisplatin are FDA approved and commercially available drugs for the 
treatment of biliary cancer.   The study will not provide these 2 study agents and the patient 
and/or insurance will be charged for the drugs. 
Nab-Paclitaxel is provided by Celgene. No supplies will be shipped to any site until regulatory 
approval has been obtained. Investigational sites will be supplied with nab-paclitaxel upon 
identification and screening of a potential trial subject. 
Upon identification of a potential subject and for re-supply of drug, sites must email a completed 
Drug Request Form to Celgene Corporation (NonIMIDUSOrders@celgene.com). Allow at least 
5 working days for drug shipment. There are no shipments on Fridays or holidays.  To order 
study supplied drugs contact:
Ralph F. Petruzzi


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6.
SAFETY ASSESSMENTS AND TOXICITY MONITORING
6.1
Serious Adverse Events
A serious adverse event (SAE) is any adverse drug experience at any dose that results in 
any of the following outcomes: Death, a life-threatening adverse drug experience, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant disability/incapacity, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions in a 
participant who has never had seizure activity in the past that do not result in inpatient 
hospitalization, or the development of drug dependency or abuse (21 CFR 312.32).
6.2
Oversight for Safety Assessments and Toxicity Monitoring
6.2.1
Participating Institution
The Emory University multicenter protocol which outlines the methods to be used for 
data safety monitoring will be submitted by the participating institution to its own IRB.  
The participating institution IRB will be responsible for reviewing and approving the 
protocol, as well as, monitoring the conduct of the study at its institution.  Data and 
safety monitoring at the participating institution must be consistent with the data and 
safety monitoring guidelines delineated in the Emory University protocol.  The 
participating institution will ensure that all safety information related to their study site 
has been forwarded to the Coordinating Center.
6.2.2
Coordinating Center
All patients receiving study drugs will be evaluated for safety. The safety parameters 
include all laboratory and hematologic abnormalities, CNS observations, physical 
examination findings, and spontaneous reports of adverse events reported to the 
investigator by patients.  All toxicities encountered during the study will be evaluated 
according to the NCI Clinical Toxicity Criteria Scale (0-5) using the NCI’s CTCAE 
Criteria Version 4.0 and recorded prior to each course of therapy.  A copy of the 
CTCAE Criteria can be downloaded from the CTEP home page 
http://ctep.cancer.gov/reporting/ctc.html   
Life- threatening toxicities should be reported immediately to the Protocol PI, site PI, 
and the respective site IRB where the toxicity occurred.
6.3
Reporting Serious Adverse Events


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The Division of Surgical Oncology, Department of Surgery, at Emory University 
School of Medicine will report SAEs in accordance with Emory University IRB policies 
and procedures and this protocol.
Participating Multicenter Institution SAE reporting requirements will be as follows:

Any Serious Adverse Event (SAE) will be reported to the local institution’s
IRB and the Coordinating Center as specified below. The circulation of unexpected 
and related SAEs to the participating institutions will be performed by the 
coordinating center.

Any adverse event falling under the definition of serious will be reported immediately 
to the Protocol PI. 

Symptoms related to progressive disease will not be reported as toxicity or as Serious 
Adverse Events.  

Participating institutions will notify the Coordinating Center of all life-threatening 
serious adverse events or Deaths within 24 hours of knowledge of the event. 

SAEs that do not result in death but are serious and unexpected and related, are to be 
reported within 5 working days from the time the research team becomes aware of the 
event.

SAEs that do not result in death and unrelated, are to be reported within 5 working 
days from the time the research team becomes aware of the event.

The Coordinating Center will notify the Protocol PI or his designee of the SAE. 

The initial SAE report from the participating institution will be forwarded to the 
Protocol PI or his designee for review and signature. 

The Emory University Multicenter Serious Adverse Event Report form will be used for 
the study by all participating institutions, and the Coordinating Center will maintain 
documentation of all Adverse Event Reporting.

Serious adverse events will be captured from the time the patient signs consent until 30 
days after the last dose of drug.  Serious adverse events must be followed until clinical 
recovery is complete and laboratory tests have returned to baseline, progression of the 
event has stabilized or there has been acceptable resolution of the event.
                
Follow up Information:
Additional information may be added to a previously submitted report by any of the following 
methods:

Adding to the original  Multicenter SAE report and submitting it as follow-up

Adding supplemental summary information and submitting it as follow-up with the 
original  Multicenter SAE form 

Summarizing new information and faxing it with a cover letter including subject 
identifiers (i.e. D.O.B. initial, subject number), protocol description and number, if 
assigned, suspect drug, brief adverse event description, and notation that additional or 
follow-up information is being submitted  (The subject identifiers are important so that 
the new information is added to the correct initial report)
6.4
Additional Adverse Event Reporting by the Coordinating Center (CRSC)


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Emory University and the participating centers will ensure that investigators will comply with all 
safety reporting regulations as set forth in the Code of Federal Regulations and the protocol.  The 
Coordinating Center at Emory University and each participating center will notify Celgene of the 
occurrence of; 

Serious Adverse Events (SAE) within twenty four (24) hours of becoming 
aware of a confirmed adverse event.  

Any correspondence to the FDA regarding adverse events or other safety 
issues will be simultaneously submitted to Celgene.

The MedWatch 3500A form should be utilized to report serious adverse 
events to the FDA.

Non-serious adverse drug reactions are to be reported as required in the 
protocol and in accordance with the procedures outlined in the protocol 
(Adverse Event [AE] data capture via AE CRF) and this DQMP.   
            
Celgene’s contact information for submitting SAEs:
Facsimile: 908-673-9115
  
7.
PROTOCOL DEVIATIONS AND UNANTICIPATED PROBLEMS
Neither the FDA nor the ICH GCP guidelines define the terms “protocol violation” or 
“protocol deviation.” The definition is often left to the lead institution IRB.  Accordingly, 
since Emory University is the lead institution and the Protocol PI must adhere to those 
policies set by the Emory University IRB, the definitions for protocol deviation as 
described by the Emory University IRB will be applied for reporting purposes for all 
institutions participating in the Emory University Multicenter Project. 
7.1
Definitions
Minor Protocol Deviation / Protocol Non-Compliance: Noncompliance with the required 
elements of the protocol that does not have a significant effect on the subject’s rights, safety, 
welfare, and/or the integrity of the data.  Deviations may be caused by the action of, or the 
omission of, the subject, the investigator, the research team, or natural events.  Continuing 
non-compliance of the protocol may meet reporting requirements.
Protocol Deviation / Non-Compliance: 
The PI shall review any instance of a deviation from a research protocol that has not been 
approved in advance by the IRB or non-compliance with a research protocol to determine if 
the protocol deviation/protocol non-compliance meets any of the following criteria: 
(a) Adversely affects the rights, welfare or safety of subjects. 
(b) Adversely affects the integrity of the research data. 
(c) Adversely affects the subject’s willingness to continue participation in the research. 
(d) Concerns study documentation associated with an FDA-regulated study. 
(e) Was a protocol deviation undertaken to prevent immediate hazard to a human subject.  
Examples include but are not limited to: 
Informed Consent Document


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
ICD not signed and dated by the participant

Protocol specific procedures conducted prior to obtaining informed consent

ICD used was not current IRB-approved version at the time of participant 
registration

Participant not re-consented within timelines
Eligibility

Enrollment of ineligible participant
Treatment and Procedures

Incorrect agent/treatment/procedure used

Additional agent/treatment/procedure used which is excluded by protocol

Errors in dosing (error greater than +/- 10%)

Dose modifications not followed per protocol or unjustified

Unjustified continuation of treatment
Disease Outcome and Response

Tumor measurements/evaluation of status or disease not performed or documented 
adequately to assess baseline or interpret response

Documented response status cannot be verified
Adverse Events

Serious or Unexpected Adverse Events not reported as required by protocol and IRB policy
Evaluations

Protocol- specified laboratory, diagnostic tests, or evaluations to assess participant eligibility, 
safety, or response not completed
Unanticipated Problems (UAPs): 
Unanticipated Problem Involving Risks to Participants or Others (referred to herein as 
UAP): Any unexpected problem related to the Research, including any Unexpected Adverse 
Experience, whether Serious or not, that affects the rights, safety or welfare of subject or 
others or that significantly impacts the integrity of the Research data. The problem may be 
physical, or it could involve social harm or risk (i.e., breach of confidentiality or harm to a 
subject’s reputation) or psychological or legal harm or risk thereof in the future. The 
problem may or may not involve drugs or devices. Examples: (a) breach of confidentiality 
stemming from theft of lap top computer containing identifiable data; (b) protocol 
violations; (c) complaints about research procedures or treatment by research study 
personnel. 
(Please note: it is important to bear in mind that a UP as defined here is not the opposite of 
an Anticipated Problem (defined above). The key distinction lies in the qualifying phrase 
“involving risk to participants or others.” By contrast, the true opposite of an Anticipated 


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Problem would be an Adverse Experience or event (including an experience or event 
associated with a drug or device) that negatively affects the rights, safety or welfare of 
subjects and that is not described as such in the materials describing risks associated with the 
study.)
Examples include but are not limited to: 

Participant complaints 

Breach of confidentiality of research data 

Lost, stolen or destruction of confidential information

Disqualification or suspension of investigators

Change in FDA labeling or withdrawal from marketing of a drug, device or biologic agent

Injury to research staff or others while conducting study-related procedures

Expected events not reported in a timely manner as required by the protocol or IRB policy

New information becomes available that may affect the participant's willingness to participate

Issues with preparation, storage or handling of a study drug or device

Unaccounted for study drug

Drug stability issues

Changes made to the research without prior IRB approval in order to eliminate apparent 
immediate harm
7.2
Reporting Procedures
The Protocol Principal Investigator: The Protocol PI will be responsible for ensuring that 
all protocol deviations/UAPs involving subjects at an Emory site are promptly reported to 
the IRB per Emory University institutional guidelines. 
Participating Institutions: Protocol deviations/UAPs occurring at a participating institution 
will be promptly reported to the coordinating center at Emory University even if they do not 
meet local IRB reporting requirements. Participating institutions should also report to their 
IRB according to their local policies and procedures. A copy of the participating institution’s 
deviation report and the local IRB response will be included in the site’s protocol regulatory 
file. The local IRB response to the report will be forwarded to the Coordinating Center upon 
receipt.
Coordinating Center:  Upon receipt of the deviation report from the participating 
institution, the Coordinating Center will submit the report to the Protocol PI for review 
before the submission to the Winship DSMC. 
8.
QUALITY ASSURANCE
The quality assurance process for a clinical trial research study requires verification of protocol 
compliance and data accuracy. Emory University provides quality assurance oversight for the 
protocol with three basic mechanisms: 
1)Ongoing monitoring of protocol compliance
2)Verification of study data 
3)On-Site Audit 


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8.1
Ongoing Monitoring of Protocol Compliance
The Coordinating Center will perform the ongoing protocol compliance monitoring based on 
the data provided in the CRF and source documents submitted via OnCore as agreed with the 
support of the Protocol PI, Participating PI and research staff. Monitoring will begin at the time 
of participant registration and will continue during protocol performance and completion. 
Monitoring plan of Subsite(s): 
 At the time of study initiation at a non-Emory site, the Protocol PI, Winship regulatory 
specialist, and Winship research coordinators will perform a site initiation teleconference. 
During this teleconference, the Emory team will review the study, enrollment, reporting, 
and regulatory compliance. The participating site will have internal monitoring meetings. 
These meetings which will include the participating site investigator, the clinical research 
coordinator and the regulatory affairs coordinator, will meet at least on a monthly basis to 
review and discuss study data to ensure subject safety. The research coordinators will 
maintain a spread sheet which will be de-identified and will summarize all the patient data 
for subjects actively being treated on the trial as well as a roadmap detailing pending 
tests/treatments for each individual subject. The spread sheet will be shared with the Emory 
PI via e-mail. Teleconferences will be conducted at least once monthly between the PI at 
Emory and the research team at the participating site(s). The purpose of the meetings is to 
discuss the enrollment, regulatory updates, monitor toxicities, and evaluate the progress of 
the trial.  Scheduled teleconferences may stop after all patients have completed assigned 
protocol therapy. The PI at Emory will communicate with participating sites via email as 
needed. The minutes from the teleconference will be maintained in the regulatory binder 
for the study. In addition electronic copies will be sent via email to the principal 
investigators at each site. Chart reviews will be performed on selected cases by the 
participating site staff to confirm that the data collection is accurate.
Winship’s MSC will perform an on-site or remote monitoring visit within the first three 
months of enrollment of the first subject. Quarterly monitoring visits will occur (annually 
once onsite and three times remotely) until subject follow-up is terminated. Monthly 
reviews of data in OnCore will be conducted to ensure compliance or identify 
discrepancies.  
8.2
Verification of Study Data
All data submitted to the Coordinating Center will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements. If study documents/data are submitted 
with missing pages, inaccurate or illegible data, the site will be notified and is required to 
resubmit the corrected document/data within 14 calendar days.
If study documents/data are not submitted on schedule, the Coordinating Center will notify the 
participating institution regarding the delinquency and describe a corrective action that includes 
deadline for bringing the data current.
Failure to comply with the delinquency notification will be communicated to the Protocol PI 
for further decision regarding the participating institution’s study participation.
8.2
On-Site Audit 


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As part of the quality assurance process, the Clinical Research Support Center (CRSC) will 
conduct on-site audits/inspections on multicenter human subject research projects for which 
Emory University is the lead institution.
The CRSC auditing staff will notify the site PI immediately of any findings that may suggest 
intentional misrepresentation of data or disregard for regulatory safeguards for any component 
of the audit. Documentation of all findings will be included in the final audit report submitted 
to the PI. 
9. EVALUATION OF PARTICIPATING INSTITUTION PERFORMANCE
The Emory University Coordinating Center and Clinical Research Support Center are bound 
by institutional and federal regulations in the conduct of cancer research trials. Protocol 
performance concerns are reported to the Protocol PI. 
9.1
Sub-Standard Performance  
The Protocol Principal Investigator is charged with considering the totality of an institution’s 
performance when evaluating each institution.
9.2
Corrective Actions:  
Institutions that fail to meet the performance goals of accrual, submission of timely accurate 
data, and adherence to protocol requirements may be recommended for a probationary period.  
Such institutions must respond with a corrective action plan and must demonstrate during the 
probationary period that deficiencies have been corrected, as evidenced by improved 
performance.  Institutions that fail to demonstrate significant improvement may be subject to 
reduced funding (if applicable) or revocation of participation as determined by the Protocol 
Principal Investigator.