Conditions: Stage III Non-small-cell Lung Cancer
Keywords: Stage III NSCLC Durvalumab Elderly Poor-risk chemoradiation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
Elderly (age 70 years or older) or \>18 years old AND poor risk (ECOG 2) newly diagnosed stage IIIA-C (AJCC 8th edition) inoperable non-small cell lung cancer (NSCLC) patients are eligible to participate in this phase II open label study of concurrent, split course chemoradiation followed by Durvalumab (MEDI4736).

Detailed description:
The rationale for the study is to identify another cohort of stage III NSCLC for whom adjuvant Durvalumab can be safely given, expanding its utilization and benefits. With a unique, extremely well-tolerated 4-phase split course CRT regimen preceding the administration of Durvalumab, we expect to be able to offer adjuvant Durvalumab to a significant proportion of patients on study.

Patients who have completed four cycles of chemoradiation (Radiation is 60 Gy in 30 fractions administered over 12 weeks with 1-1.5 week breaks between cycles; Chemotherapy is once every 3 weeks for up to 4 cycles) will go on to receive durvalumab (MEDI4736) monotherapy as 1500mg durvalumab (MEDI4736) via IV infusion Q4W for up to a maximum of 12 months (up to 13 doses/cycles) with the last administration on week 48 until confirmed disease progression unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.

Primary objectives are:

1. To determine the percentage of poor risk and/or elderly unresectable stage III NSCLC patients who complete split course chemoradiation
2. To determine the safety and tolerability of durvalumab (MEDI4736) after completion of chemoradiation in this group of patients.

Secondary Objectives are:

1. To determine the 1-year overall survival rate
2. To determine the 1-year progression-free survival rate
3. To determine the 1-year loco-regional progression-free survival rate
4. To determine rate of grade 3 and 4 toxicities with this regimen in the selected patient population

Arms:
arm 1: Concurrent, Split Course Chemoradiation Followed by Durvalumab (MEDI4736) in Poor Risk and/or Elderly Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer

Interventions: intervention 1: Durvalumab
Intervention descriptions: intervention 1: Adjuvant Durvalumab in Poor Risk and/or Elderly Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer who have completed concurrent, split course chemoradiation without progression of disease

Protocol document:
ICF_002.pdf: 
Title of Study: Phase II trial of concurrent, split course chemoradiation followed by Durvalumab 
(MEDI4736) in poor risk and/or elderly patients with newly diagnosed stage III non-small cell 
lung cancer 
NCT04441138 
Date of consent: 23Nov2023 


 
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CONSENT/AUTHORIZATION FOR PARTICIPATION IN A RESEARCH 
STUDY 
 
Site Principal Investigator: 
Gaurav Marwaha, MD 
 
 
Department: 
Radiation Oncology 
 
Address and Contact Information: Dept. of Radiation Oncology 
Rush University Medical Center 
500 South Paulina 
Chicago IL 60612 
 
 
Protocol Title: 
Phase II trial of concurrent, split course chemoradiation 
followed by Durvalumab (MEDI4736) in poor risk and/or 
elderly patients with newly diagnosed stage III non-small 
cell lung cancer 
 
Sponsor(s): 
Dr. Gaurav Marwaha (with AstraZeneca as a 
collaborator/funder) 
 
Name of Participant:  __________________________________________________________ 
 
 
Key Information: 
 
You are being invited to participate in a research study. Research studies answer important 
questions that might help change or improve the way we do things in the future. 
 
This consent form will give you information about the study to help you decide whether you 
want to participate. Please read this form, and ask any questions you have, before agreeing to be 
in the study. 
 
Taking part in this research study is voluntary. You do not have to participate in this study and 
may choose to leave the study at any time. If you decide not to participate in this study or leave 
the study at a later time, your health care, benefits, or relationship with Rush University Medical 
Center will not change or be affected. 
 
The purpose of this study is to assess the safety and efficacy of a combined course of 
chemotherapy and radiation (chemoradiation) followed by immunotherapy (durvalumab) for 
poor risk or elderly patients with locally advanced non-small cell lung cancer (NSCLC). 
Combined chemoradiation followed by durvalumab is standard of care/FDA approved for 
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patients with locally advanced non-small cell lung cancer (NSCLC) with an excellent 
performance status (i.e. very “fit” patients). Several approaches are standard for poor risk/elderly 
patients with locally advanced non-small cell lung cancer (NSCLC): a combination of 
chemotherapy and radiation; chemotherapy  followed by immunotherapy; or radiation followed 
by immunotherapy. If you agree to participate in this study, combined chemotherapy and 
radiation therapy, followed by durvalumab, would last 1 year at the most, and we would continue 
to follow your health to see how you are doing as long as the study is open.  
 
During your follow-up visits, you will be asked to have a clinical assessment by your oncologists 
and research nurses, provide blood for standard laboratory tests, answer questions about your 
health, and have imaging scans (CT scans, MRI scans, and/or PET/CT scans). For a detailed list 
of study procedures, please see the “What are the activities you will be doing if you participate in 
this study?” section of this consent form. 
 
There are risks to you for participating in this study, some of which may be serious, life-
threatening or may not go away. In this study, risks depend on treatment modalities, and include 
but are not limited to: Radiation related: Fatigue, skin irritation, lung inflammation, swallowing 
discomfort; Chemotherapy related: fatigue, drop in blood counts (number of red blood cells, 
white blood cells, or platelets) infection, hair loss, neuropathy (pain or altered sensation in 
hands/toes); Durvalumab related: Inflammation in any part of the body (e.g. in bowel, causing 
diarrhea; in skin causing rash; in thyroid causing thyroid dysfunction, in lung causing 
cough/shortness of breath; in liver causing hepatitis) infusion-related reactions, allergic reactions 
and infections/serious infections. A serious infection is an infection that may cause 
hospitalization or death. 
 
 Based on experience with durvalumab, patients with the exact same diagnosis and stage of lung 
cancer have experienced an overall and progression free survival benefit, in addition to a 
reduction in risk for brain metastases. However, because individuals respond differently to 
therapy, no one can know in advance if it will be helpful for you. 
 
There are other options available to you if you decide not to participate in this study. You may 
choose another form of treatment or care for your locally advanced lung cancer without being in 
a study such as chemotherapy + radiation without immunotherapy, radiation therapy alone, 
and/or systemic therapies alone (chemotherapy and/or immunotherapy). You should discuss 
other options with your study doctor. 
 
 
Detailed Information: Please review the rest of this document for details about 
the above topics and additional information you should know before making a 
decision about whether or not you will participate in this study. 
 
Why are you being invited to participate in this study? 
You are being asked to participate in this study because patients with the same disease as you 
have experienced survival benefit from adding durvalumab after completion of 
chemotherapy/radiation. This regimen has not been used much in elderly patients and/or patients 
with other medical issues (“poor risk” patients), and we hope to see a similar benefit in elderly 
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subjects and/or subjects with other medical issues ( “poor risk” subjects) .  
 
How many participants will take part in this study? 
Approximately 30 participants are expected to take part in this study at Rush University Medical 
Center.  
 
What are the activities you will be doing if you participate in this study? 
 
If you agree to be in this study, you will be asked to participate in the following activities:  
 
Screening Activities 
• Physical exam 
• Vital signs (height, weight, temperature, blood pressure, etc.) 
• ECG (electrocardiogram) – a test that measures the electrical activity of your heart 
• Blood and urine tests to make sure you are healthy enough to participate 
• Thyroid tests 
• If you have known HIV disease or active hepatitis or tuberculosis you will not be allowed 
to participate. If we discover during the study that you have tested positive for a 
reportable infectious disease (tuberculosis, HIV and/or hepatitis), we will  be required to 
report such findings to the Illinois Department of Public Health, according to applicable 
Illinois laws. The study doctor will refer you to a doctor for counseling and treatment. 
The Sponsor, Dr. Marwaha with AstraZeneca, will not cover the cost of this treatment or 
further care. This means that along with the test result your personal information (name, 
birth date, phone number and address) will be released to the public health authorities. 
• Pregnancy test for women who are able to have children (if positive, patient will be 
excluded) 
• Performance status. Performance status is a score that estimates your ability to perform 
certain activities of daily living (ADLs) without the help of others and general well-
being. 
• PET/CT imaging  
• MRI brain or CT  chest/abdomen/pelvis, brain  
o Magnetic resonance imaging (MRI) scans (brain): 
MRI scans use powerful magnets. Some MRI scanners are very narrow. Talk to 
the study doctor if you have metal in your body or if you are uncomfortable in 
small spaces. With a certain type of dye used for MRI scans, some participants 
with kidney disease may have a severe reaction. This could include skin 
thickening, joint pain and/or swelling, and, in rare cases, lung and heart problems, 
and even death. 
o Computed tomography (CT) scans (chest/abdomen/pelvis, brain): 
Some people can have allergic reactions to the dye put in their veins for these 
tests. The allergic reactions can cause itching or rash. More serious allergic 
reactions can cause difficulty breathing, dangerously low blood pressure, or 
kidney damage. X-rays and CT scans use radiation. Please talk to the study doctor 
about the amount of radiation from these scans. 
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• Tumor biopsy for PD-L1 testing. A previously collected sample may be used if the 
existing sample is not older than 3 years old. Your doctor will discuss with you whether a 
new tumor biopsy is needed or whether an existing sample is enough.  
• Pulmonary function testing – tests to show how well the lungs are working  
• Complete a quality of life (QOL) that require you to answer questions about your health 
 
 
Study Visits 
A “cycle” of chemotherapy and radiation consists of 21 days. Radiation will occur daily on 
weekdays for either 7 or 8 consecutive weekdays per cycle, for a total of 30 radiation treatments 
over the entire 4 cycles. Once a week during radiation therapy, you will meet with the Radiation 
Oncologist for a clinical check in/physical exam. You will receive FDA approved chemotherapy 
regimen (“chemotherapy” refers to therapy involving drugs) in combination with radiation 
therapy (“radiation therapy” refers to therapy involving radiation) such as carboplatin  
pemetrexed (carbo pem), carboplatin paclitaxel (carbo tax) and carboplatin etoposide (carbo 
etoposide).During chemotherapy weeks, you will meet with the Oncologist for routine lab work 
(blood counts and chemistries (serum, plasma or hematology tests), and a clinical visit/physical 
exam. These visits are all consistent with standard of care, or what we would do for patients not 
on a clinical study.  
 
 
Once you have completed four cycles of chemoradiation, you will have “restaging scans,” 
consisting of CT chest/abdomen/pelvis as well as routine lab work. If your disease has not spread 
or progressed, and you are believed to remain a candidate for immunotherapy (as deemed by 
your Medical Oncologist), you will go on to receive durvalumab as an IV infusion (through a 
needle into your vein) every 4 weeks (i.e. 28 days, also known as a cycle) for up to a maximum 
of 12 months (up to 13 doses/cycles).  
 
Durvalumab Cycles 1-12, Day 1 
• Targeted physical exam based on symptoms  
• Vital signs 
• ECG, if your doctor thinks an ECG is needed 
• Blood tests to make sure you are healthy enough to participate 
• Pregnancy test for women who are able to have children 
• ECOG performance status. 
• Durvalumab will be infused over the course of one hour 
•  You will complete a quality of life (QOL) questionnaire 
 
 
Durvalumab Cycles 1-3, Day 14 
Clinical follow-up with Medical Oncologist  
Follow-up after completion of treatment  
Visits every 3 months with blood work and imaging (possibly more frequently if any concerns) 
for 1 year after completion of treatment, then per standard of care less frequent follow-up 
thereafter (every 4 months for years 3-5, then every year for years 5+). We would continue to 
follow your health to see how you are doing as long as the study is open. 
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Imaging Scans 
To see how your disease is responding to the study treatment, CT scans will be done every 3 
months for the first 48 weeks, and then every 3-6 months thereafter. Brain MRIs will be 
performed annually in follow-up or for new neurological symptoms. 
 
What are the radiation risks of participating in this study? 
CT scans deliver a low dose of radiation, considered to be safe and per standard of care for 
locally advanced NSCLC. MRIs are also considered to be safe and per standard of care for 
surveillance of NSCLC. MRI may affect the accuracy or optimal use of any metallic devices that 
are implanted in your body. The radiology department can provide additional details regarding 
risks associated with these imaging modalities should you desire to know more at (312) 942-
5751. 
 
Will you be contacted about participating in future research? 
If you agree, we may contact you after your participation in this study about participating in 
future research. Please initial and date one of the following options: 
 
_______ 
_____________ Yes, I agree to be contacted about future research. 
Initials  
Date 
 
_______ 
_____________ No, I do NOT agree to be contacted about future research. 
Initials  
Date 
 
What are the risks and discomforts of participating in this study? 
There are risks to you for participating in this study, some of which may be serious, life-
threatening or may not go away.  
 
Radiation risks are generally mild. Most participants experience some fatigue (exhaustion), dry 
cough, difficulty or pain with swallowing certain foods/drinks, and/or skin irritation over the 
chest/back. Some risks that are more rare are severe fatigue, symptomatic lung inflammation 
and/or lung fibrosis, damage to the heart/cardiac vessels, spinal cord injury, and bleeding events. 
 
Chemotherapy risks include fatigue, drops in blood counts (number of red blood cells, white 
blood cells, or platelets), infection, hair loss, neuropathy (pain or weakness in fingers, toes), 
fevers, nausea/vomiting, changes in taste, mouth ulcers, kidney injury, and hearing loss. 
 
Risks with durvalumab include, but are not limited to,  
 
• Lung problems (pneumonitis). Signs and symptoms may include new or worsening 
cough, shortness of breath, and chest pain. 
 
• Liver problems (hepatitis). Signs and symptoms may include yellowing of your skin or 
the whites of your eyes, severe nausea or vomiting, pain on the right side of your stomach 
area (abdomen), drowsiness, dark urine (tea colored), bleeding or bruising more easily 
than normal, and feeling less hungry than usual. 
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• Intestinal problems (colitis). Signs and symptoms may include diarrhea or more bowel 
movements than usual; stools that are black, tarry, sticky, or have blood or mucus; and 
severe stomach-area (abdomen) pain or tenderness. 
 
• Hormone gland problems (especially the thyroid, adrenals, pituitary, and pancreas). Signs 
and symptoms that your hormone glands are not working properly may include 
headaches that will not go away or unusual headaches; extreme tiredness; weight gain or 
weight loss; dizziness or fainting; feeling more hungry or thirsty than usual; hair loss; 
feeling cold; constipation; your voice gets deeper; urinating more often than usual; 
nausea or vomiting; stomach-area (abdomen) pain; and changes in mood or behavior, 
such as decreased sex drive, irritability, or forgetfulness. 
 
• Kidney problems, including nephritis and kidney failure. Signs of kidney problems may 
include decrease in the amount of urine, blood in your urine, swelling of your ankles, and 
loss of appetite. 
 
• Interstitial lung disease (ILD) is an umbrella term used for a large group of diseases that 
cause scarring (fibrosis) of the lungs. Uncommon side effects (affects between 1 and 2 in 
1,000 patients treated) 
o Scarring of lung tissue (interstitial lung disease): May cause breathlessness, a 
cough that does not go away, and feeling tired all the time 
 
• Skin problems. Signs may include rash, itching, and skin blistering. 
 
• Guillain-Barre (gee-YAH-buh-RAY) syndrome is a rare disorder in which your body's 
immune system attacks your nerves. Weakness and tingling in your hands and feet are 
usually the first symptoms. 
 
• Inflammation inside your eye known as Uveitis. This usually happens when your immune 
system is fighting an eye infection — but it can also happen when your immune system 
attacks healthy tissue in your eyes. This usually occur in 1 out of 1000 patients. 
 
• Inflammation or swelling of the joints also known as Immune-mediated arthritis. Which 
means that your immune system attacks healthy cells in your body by mistake, causing 
inflammation (painful swelling) in the affected parts of the body. (Uncommon side 
effects affects between 1 and 2 in 1,000 patients) 
 
• Problems in other organs. Signs and symptoms may include neck stiffness; headache; 
confusion; fever; chest pain, shortness of breath, or irregular heartbeat (myocarditis); 
changes in mood or behavior; low red blood cells (anemia); excessive bleeding or 
bruising; muscle weakness or muscle pain; blurry vision, double vision, or other vision 
problems; and eye pain or redness. 
 
• Severe infections. Signs and symptoms may include fever, cough, frequent urination, 
pain when urinating, and flu-like symptoms. 
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• Severe infusion reactions. Signs and symptoms may include chills or shaking, itching or 
rash, flushing, shortness of breath or wheezing, dizziness, fever, feeling like passing out, 
back or neck pain, and facial swelling. 
 
There may be other risks that may happen that we cannot predict. 
 
What are the reproductive risks of participating in this study? 
 
Women 
If you are pregnant or breastfeeding, you cannot take part in this study. A pregnancy test is 
required and will be given before you start treatment and throughout the study. You are 
responsible for using an effective birth control method such as birth control pills, barrier method 
(such as condoms or diaphragms), intrauterine device (IUD), hormone implants or surgical 
sterility while you are taking part in this study. Once you have completed treatment, you may 
discontinue birth control after 12 months after completion of your study treatment. If you 
become pregnant, you must notify the study doctor immediately. 
 
Interactions with some drugs, including antibiotics can affect birth control pills. You should 
discuss with the study doctor a second method of birth control during the study, if birth control 
pills are used. 
 
 
Men 
You are responsible for using an effective birth control method, such as the ones listed above. If 
you are a male and your female partner becomes pregnant, you must notify your study doctor 
immediately. Once you have completed treatment, you may discontinue birth control after 12 
months after completion of your study treatment. 
 
What if there is new information that may affect your decision to participate in this study? 
During this study, you will be told about important findings (either good or bad), such as changes 
in the risks or benefits of participation in the study or new choices to participation that might 
cause you to change your mind about being in the study. If new information is shared with you, 
you may be asked to sign a revised consent form in order to continue participating in this study. 
 
Will you receive your individual results from the study? 
Generally, activities performed for research purposes are not meant to provide clinical 
information. We may learn things about you from this study which could be important to your 
health or treatment. If this happens, this information will be shared with you. The therapies 
involved may impact your overall health, blood work, and or imaging scans. These are all part of 
routine follow-up regardless of whether or not you are enrolled on the study, and all of these 
results will be shared with you.  
 
Can you leave or be removed from this 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 leave this study. If you leave this study 
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before the final study visit, the study doctor may ask you to complete the final steps. Risks to 
withdrawal could compromise your overall outcomes from your disease. Withdrawal from the 
study can otherwise happen immediately.  
 
The researchers and sponsor also have the right to stop your participation in this study without 
your consent if: 
• They believe it is in your best interests; 
• You do not follow the instructions; 
• The study is cancelled for any reason. 
 
What about confidentiality of your medical information? 
This authorization is voluntary. Rush University Medical Center and its affiliates (“Rush”) will 
not withhold or refuse your treatment, payment, enrollment, or eligibility for benefits if you sign 
this authorization. You do not have to sign this authorization, but that means that you cannot be 
in the study or receive study-related treatment. 
 
By signing this document, you voluntarily authorize (give permission to) Dr. Marwaha, Dr. 
Fidler, their study team, and other Rush personnel involved with the conduct and review of this 
study (which may include off-site personnel) to use or disclose (release) health information that 
identifies you for the study described in this document. 
 
During the study, Dr. Marwaha and his study team will collect Protected Health Information 
(PHI) about you for the purposes of this research. PHI is your health information that includes 
your medical history and new information obtained as a result of this study. Some of this 
information will come from your medical record. The health information that Rush may use or 
disclose for this research includes: all information in the medical record.  
 
Dr. Marwaha and his study team may share your health information and the results of your 
study-related procedures and tests with people outside of Rush who assist with the conduct and 
review of this study. The persons who receive your health information may not be required by 
Federal privacy laws to protect it and may share your information with others without your 
permission, but only if permitted by the laws governing them. Your health information described 
above may be used or disclosed to: 
• To the Researchers  
• The study Sponsor, and to AstraZeneca and its representatives 
• Monitoring agencies such as the Food and Drug Administration (FDA). 
 
While you participate in the study you will have access to your medical record, but Dr. Marwaha 
and Dr. Fidler and study team are not required to release to your study information that is not 
part of your medical record. Rush is required by law to protect your health information, and 
study records that identify you will be kept confidential. The results of study tests/procedures 
performed as part of this study may become part of your medical record. Any study information 
in your medical record will be kept indefinitely. Your identity will not be revealed on any report, 
publication, or at scientific meetings.  
 
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You have a right to inspect and copy the information to be disclosed with this authorization and 
you may obtain a copy of the information by contacting the office listed above. 
 
If you no longer want to be in the study and do not want your future health information to be 
used, you may change your mind and revoke (take back) this authorization at any time by writing 
to Dr. Marwaha at 500 S. Paulina, Chicago, IL 60612. If the authorization is revoked, you will 
no longer be allowed to participate in the study and previously authorized individuals/entities 
may still use or disclose health information that they have already obtained about you as 
necessary to maintain the integrity or reliability of the current study. 
 
This authorization is valid for the entirety of this research study. It will expire upon completion 
of the study or if you revoke (take back) the authorization. 
 
If you withdraw from this study, the data already collected from you may not be removed from 
the study records. The study doctor and/or study team may ask you whether they can continue to 
collect follow-up data on you. If follow-up information will be requested, you will be asked to 
sign a separate consent form before this information can be collected. 
 
Records of participation in this study will be maintained and kept confidential as required by 
law. Names will be replaced by coded identification numbers.  
 
The Rush Institutional Review Board (IRB) will have access to your files as they pertain to this 
research study. The IRB is a special committee that reviews new and ongoing human research 
studies to check that the rules and regulations are followed regarding the protection of the rights 
and welfare of human participants. 
 
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. This 
research study can be found by searching for the following Clinical Trial Registry Number 
(NCT#): NCT04441138.  
 
What are the costs to participate in this study? 
There are no additional costs to you for participating in this research. 
 
You or your insurer will be responsible for paying for the cost of the following: chemotherapy, 
radiation therapy, and immunotherapy.  
 
If you have health insurance the insurance may or may not pay for the costs associated with your 
participation in this study. You will have to pay for any co-payments, deductibles or co-
insurance amounts that your insurance coverage requires. Our Social Work team will work with 
your insurance company to verify coverages.  
 
If you do not have insurance, you will be billed for the amount you have to pay. 
 
Will you be paid for your participation in this study? 
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You will not be paid for being in this study. 
 
What if you are injured as a result of your participation in this study?  
If you get ill or injured from being in the study, Rush University Medical Center will help you 
get medical treatment. You should let the study doctor know right away that you are ill or 
injured. If you believe you have become ill or injured from this study, you should contact a 
member of the study team as soon as possible. Dr. Marwaha’s office phone is (312) 942-5751. 
Dr. Fidler’s office phone is (312) 942-5904. 
 
You should let any health care provider who treats you know that you are in a research study. If 
you do seek medical treatment, please take a copy of this document with you because it may help 
the doctors where you seek treatment to treat you. It will also provide the doctors where you seek 
treatment with information they may need if they want to contact your study doctor. 
 
You or your health insurance plan will be billed. No money has been set aside to pay the costs of 
this treatment. Health insurance plans may or may not cover costs of research-related injury or 
illness. You should check with your insurance company before deciding to participate in this 
research study. Costs not covered by insurance could be substantial. 
 
Rush University Medical Center has no program for financial compensation or other forms of 
compensation for injuries which you may incur as a result of participation in this study. 
 
By signing this form, you are not giving up any legal rights to seek compensation of injury. 
 
What other information should you know about? 
 
Investigator Financial Disclosure 
 This research study is supported by money from AstraZeneca, LP. Drs. Fidler and Bonomi 
(investigators on this study) receive extra money from AstraZeneca, LP for activities that are not 
a part of this research. The activities are for consulting and speaking engagements for 
AstraZeneca, LP. It was determined that the relationships are considered unlikely to affect your 
safety and/or the scientific quality of the study. This decision was given to the IRB for its review 
and approval of the study. If you would like more information, please contact Drs. Fidler and/or 
Bonomi at (312) 942-5904. 
 
Who can you contact for more information about this study? 
Questions are encouraged. If you have further questions about this study, you may call any of the 
following: 
 
Research Nurses: 312-CANCER-1  
Thoracic Medical Oncology Nurses: 312-563-4880 
Radiation Oncology: 312-942-5751 
 
Who can you contact if you have concerns about your rights as a study participant? 
Questions about the rights of research participants may be addressed to the Rush University 
Medical Center Office of Research Affairs at 1-800-876-0772. 
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What are your rights as a study participant? 
Taking part in this study is voluntary. If you choose not to participate in this study or to leave the 
study at any time, your health care, benefits or relationship at Rush University Medical Center 
will not change or be affected. 
 
If you choose to leave this study and you do not want any of your information to be used, you 
must inform Dr. Marwaha in writing at the address on the first page. Dr. Marwaha may still use 
your information that was collected prior to your written notice. 
 
 
 
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Expiration Date: 3/29/2024   Amendment Date: 1/16/2024


 
Rush Template Version Date: 07/2023 
Consent/Authorization Version Date: 11/13/2023 
 
Page 12 of 12 
SIGNATURE BY THE PARTICIPANT  
By signing below, you are consenting to participate in this research study. You have read the 
information given or someone has read it to you. You have had the opportunity to ask questions, 
which have been answered satisfactorily to you by the study staff. You do not waive any of your 
legal rights by signing this consent form. You will be given a signed copy of this consent. 
 
_________________________________ 
_______________________ __________________ 
Name of Participant  
 
 
Signature of Participant 
Date of Signature  
 
 
SIGNATURE BY THE INVESTIGATOR/INDIVIDUAL OBTAINING CONSENT: 
I attest that all the elements of informed consent described in this consent document have been 
discussed fully in non-technical terms with the participant. I further attest that all questions asked 
by the participant were answered to the best of my knowledge. 
 
_______________________________________________________ 
__________________ 
Signature of Individual Obtaining Consent  
 
 
 
Date of Signature 
 
 
SIGNATURE BY WITNESS/INTERPRETER: 
I observed the signing of this consent document and attest that, to the best of my knowledge, the 
person signing the consent form is the and the person signing the form has done so voluntarily. 
 
_______________________________________________________ 
Name of Witness/Interpreter 
 
_______________________________________________________ 
__________________ 
Signature of Witness/Interpreter 
 
 
 
 
 
Date of Signature 
 
 
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Expiration Date: 3/29/2024   Amendment Date: 1/16/2024

Prot_000.pdf: 
Clinical Study Protocol 
Drug Substance: Durvalumab (MEDI4736)  
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 1 of 121 
 
 
Investigational Drug 
Substance(s) 
Durvalumab (MEDI4736)  
Study Number 
ESR 18-14205 
Version Number 
5 
Date 
05/09/2023 
Phase II Trial of concurrent, split course chemoradiation followed by 
Durvalumab (MEDI4736) in poor risk and/or elderly patients with newly 
diagnosed stage III non-small cell lung cancer 
Sponsor: Dr. Gaurav Marwaha 
Collaborator/Funder: AstraZeneca 
 
 
 
 
 
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Amendment Date: 6/12/2023


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 2 of 121 
 
PROTOCOL SYNOPSIS 
Clinical Protocol ESR-18-14205 
Study Title: Phase II Trial of concurrent, split course chemoradiation followed by Durvalumab 
(MEDI4736) in poor risk and/or elderly patients with newly diagnosed unresectable stage III non-small 
cell lung cancer 
 
Protocol Number: ESR-18-14205 
 
Clinical Phase: II 
 
Study Duration: 18 months enrollment 
 
Investigational Product(s) and Reference Therapy: 
Durvalumab (MEDI4736) will be supplied in glass vials containing 500 mg of liquid solution at a 
concentration of 50 mg/mL for intravenous (IV) administration/infusion after dilution. 
Radiation (60 Gy in 30 fractions administered over 12 weeks with 1-1.5 week breaks between cycles) 
and chemotherapy (once every 3 weeks for 4 cycles) will precede Durvalumab (MEDI4736) 
utilization.  
 
Research Hypotheses:  
1. We hypothesize that concurrent four phase, split course chemoradiation followed by Durvalumab is 
feasible (safe and tolerable) in elderly / poor risk unresectable stage III NSCLC patients. 
2. Specifically, we hypothesize that 80% of patients enrolled will safely complete 4 cycles of 
concurrent split-course CRT, and in those to go on to receive Durvalumab, we expect no more than 
20% of patients to have to therapy terminated for Durvalumab-related toxicities. 
3. Without Durvalumab, the median survival is known to be 20 months in this patient population; we 
expect that adding Durvalumab in the treatment regimen will improve the median survival to 30 
months. 
4. Without Durvalumab, the median progression free survival (PFS) is known to be 11 months in this 
patient population; we expect that adding Durvalumab in the treatment regimen will improve the 
median PFS to 17 months. 
Objectives: 
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Amendment Date: 6/12/2023


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 3 of 121 
 
Primary Objectives: 1. To determine the percentage of poor risk and/or elderly unresectable stage III 
NSCLC patients who complete split course chemoradiation; 2. To determine the safety and tolerability 
of durvalumab (MEDI4736) after completion of chemoradiation in this group of patients.    
Secondary Objective(s):  
1. To determine the 1-year overall survival rate 
2. To determine the 1-year progression-free survival rate 
3. To determine the 1-year loco-regional progression-free survival rate 
4. To determine rate of grade 3 and 4 toxicities with this regimen in the selected patient population 
 
Study Design: Non-Randomized, Prospective 
Number of Centers: 2 – RUMC & ROPH 
Number of Patients: 30 
Study Population: 
Elderly (age 70 years or older) or >18 years old AND poor risk (ECOG 2) stage IIIA-C (AJCC 8th 
edition) inoperable non-small cell lung cancer (NSCLC)  
Inclusion Criteria: 
• 
Participants must have histologically or cytologically confirmed stage IIIA-C (AJCC 8th edition) 
non-small cell lung cancer that will be treated with curative intent. 
• 
Participants must have been deemed medically inoperable by multidisciplinary team/tumor board 
• 
Participants must have been staged with a PET/CT or CT within 45 days of enrollment (if PET/CT 
out of window, CT Chest/Abdomen/Pelvis within 21 days of enrollment is acceptable) 
• 
Participants must be elderly (age 70 years or older) or >18 years old AND poor risk (ECOG 2) see 
section 4.1.1 
• 
Participants ideally have endobronchial ultrasound biopsy (EBUS) or mediastinoscopy to confirm 
nodal status, but can be deferred if PET/CT imaging characteristics are highly suggestive of nodal 
metastases 
• 
Participants must have normal organ and marrow function: Leukocytes >3000/mcL; ANC 
>1500/mcL; PLT >100000/mcL; total bilirubin within normal limits (≤1.5x); AST/ALT <2.5x 
institutional upper limit of normal; creatinine clearance ≥30  
• 
Body weight >30kg 
• 
Mean lung dose < 20 Gy and lung V20<35% 
• 
No disease progression after CRT  
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Amendment Date: 6/12/2023


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 4 of 121 
 
• 
See Section 4 for full detail 
Exclusion Criteria: 
Participants who exhibit any of the following conditions at screening will not be eligible for admission 
into the study: 
• 
History of allergic reactions attributed to compounds of similar chemical or biologic composition 
to carboplatin, pemetrexed (for patients with adenocarcinoma), etoposide (for patients with 
squamous cell carcinoma), or immunotherapy 
• 
Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, 
symptomatic CHF. 
• 
Angina pectoris, cardiac arrhythmia, or psychiatric/social situations that would limit compliance 
with study requirements. 
• 
Pregnant women 
• 
Known HIV+ patients 
• 
See section 4 for full detail  
Investigational Product(s), Dose and Mode of Administration: 
Patients who have completed four cycles of chemoradiation will go on to receive durvalumab 
(MEDI4736) monotherapy as 1500mg durvalumab (MEDI4736) via IV infusion Q4W for up to a 
maximum of 12 months (up to 13 doses/cycles) with the last administration on week 48 until confirmed 
disease progression unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met. (N.B If a patient’s weight falls to 30kg (≤30 kg), then the patient should 
receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W after consultation between 
Investigator and Study Physician, until the weight improves to above 30 kg >30 kg, at which point the 
patient should start receiving the fixed dosing of durvalumab 1500 mg Q4W).  
Weight-based dosing (20 mg/kg) should be utilized for patients whose body weight falls to ≤30 kg while 
on study. 
Study Assessments and Criteria for Evaluation: 
Safety Assessments: Safety will be monitored continually throughout the protocol. Assessments 
include adverse events, serious adverse events, vital signs, and physical and laboratory examinations, 
as well as immune-mediated adverse events. 
Chemotherapy safety measurements are described in detail in the protocol. Briefly, any grade 3-5 
toxicities will be reported.  Repeat chemotherapy doses will be administered only if hematologic 
treatment parameters and patient has recovered adequately from previous cycles of chemotherapy. 
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Amendment Date: 6/12/2023


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 5 of 121 
 
SAEs possibly, probably or definitely related to RT (including grade 3-4 congestive heart failure, 
pneumonitis, arrhythmias, and myocardial infarction, grade 4 esophagitis, and any AEs that lead to 
hospitalization) that causes either an interruption or early termination of RT will be reported. The 
proportion of patients who have tolerated the treatment will be provided. All adverse events will be 
graded according to CTCAE v 5.0 
Durvalumab safety measurements are described in detail in protocol. The tolerability of therapy is 
defined as having one or no safety events defined as: 1) grade 4-5 non-hematologic serious adverse 
events (SAEs) as defined in CTCAE v5.0, probably or definitely related to protocol treatment by 90 
days from the start of Durvalumab; 2) Any adverse events that lead to prolonged dose delays (defined 
as skipping at least 2 doses of Durvalumab; 3) Permanent discontinuation of Durvalumab due to 
toxicity within the first 30 days of starting Durvalumab. 
1.) Rate of completion of therapy (Defined as percentage of patients able to: A. Complete 4 
cycles of concurrent split course CRT and B. Receive adjuvant course of Durvalumab) 
 
Efficacy Assessments:  
2.) Survival analyses: Kaplan Meier 
3.) Response to trimodality therapy (chemoradiation plus Durvalumab), which will be 
evaluated in this study using the revised RECIST guideline 
(https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf) with the following 
definitions: 
• 
Complete Response (CR): Disappearance of all target lesions 
• 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum LD 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to quality for Progressive Disease (PD), taking as reference the smallest sum 
LD since the treatment started.  
Progression is defined as change in a known lesion(s) not related to post-treatment effects as defined 
below:  
• At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum 
LD recorded since the treatment started or the appearance of one or more new lesions. Additionally, 
the absolute increase must be greater than 5 mm.  
• Appearance of ≥1 new lesions not related to post-treatment effect.  
 
Progression is further divided into local, regional or distant progression:  
• Local: Progression within the PTV.  
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Amendment Date: 6/12/2023


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 6 of 121 
 
• Regional: Progression outside the PTV but within the same lobe of the lung as the primary tumor or 
in regional lymph nodes (AJCC 8th edition)  
• Distant: Progression at any other site (including pleural or pericardial effusion)  
 
Statistical Methods/Sample Size Determination/Data Analysis: 
For the primary endpoint of completion rate of chemotherapy/split course chest radiation, where we 
anticipate 80% completion, a sample size of n=30 provides power of about 0.8 in a non-inferiority test 
with non-inferiority margin of 0.18 and alpha =0.05. This will allow estimation of the completion rate 
within ±0.13 using a 90% confidence interval (normal approximation) or within a total width of 0.30 
(using exact Binomial interval).  
 
For the endpoint of completion of durvalumab post-chemoradiation, we estimate post-chemoradiation 
n of 24 (assuming 80% completion of chemoradiation). This will allow estimation of durvalumab 
completion rate within ±0.13 using a 90% confidence interval (normal approximation) or within a total 
width of 0.30 (using exact Binomial interval). 
 
For the secondary endpoints, with n=30 subjects, we estimate 70% power to detect improvement in 
PFS for adding Durvalumab and 55% power to detect improvement in OS, each at a liberal 0.10 level 
of significance and without adjusting for multiplicity. (Without Durvalumab, the median survival is 
known to be 20 months in this patient population; we expect that adding Durvalumab in the treatment 
regimen will improve the median survival to 30 months. Without Durvalumab, the median progression 
free survival (PFS) is known to be 11 months in this patient population; we expect that adding 
Durvalumab in the treatment regimen will improve the median PFS to 17 months.) 
 
 
 
 
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Amendment Date: 6/12/2023


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 7 of 121 
 
 
SCHEDULE OF STUDY ASSESSMENTS  
 
Screening 
(prior to 
CRT) 
During 4 
cycles of 
CRT 
(12 weeks) 
C1 
Du
rv
a 
C2 
Du
rv
a 
C3 
Dur
va 
C4 
Durv
a 
C5 to C12 Durva or PD 
C13 Durva 
or final visit 
Follow-up 
(q3mths for year 
1 from end of 
durvalumab, 
q4mths for year 2 
from end of 
durvalumab)u 
Week 
 
1-12 
 
Q4W ±3 days unless dosing needs to be held 
for toxicity reasons 
 
 
Day 
 
1-84 
 
Q28days ±3 days unless dosing needs to be 
held for toxicity reasons 
 
 
Informed consent: study proceduresb 
X 
 
 
 
 
 
 
 
 
Physical Exam  
X 
Xx 
 
 
 
 
 
 
X 
Quality of life (QOL) v 
 
Xv 
X 
 
 
X 
Xv 
 
 
Targeted physical exam (based on 
symptoms) 
 
 
X 
X 
X 
X 
X 
X 
 
Vital signsc 
X 
Xx 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
Xx 
X 
X 
X 
X 
X 
X 
 
ECGd 
X (optional) 
 
As clinically indicated 
 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 8 of 121 
 
 
Screening 
(prior to 
CRT) 
During 4 
cycles of 
CRT 
(12 weeks) 
C1 
Du
rv
a 
C2 
Du
rv
a 
C3 
Dur
va 
C4 
Durv
a 
C5 to C12 Durva or PD 
C13 Durva 
or final visit 
Follow-up 
(q3mths for year 
1 from end of 
durvalumab, 
q4mths for year 2 
from end of 
durvalumab)u 
Week 
 
1-12 
 
Q4W ±3 days unless dosing needs to be held 
for toxicity reasons 
 
 
Day 
 
1-84 
 
Q28days ±3 days unless dosing needs to be 
held for toxicity reasons 
 
 
Pulmonary Function Tests (FEV1 and 
DLCO)t 
X (optional) 
 
 
 
Demography and Medical History, 
including baseline characteristics and 
tobacco use 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Clinical chemistrye 
X 
 
Xf 
X 
X 
X 
X 
X 
 
Hematologye  (CMP and CBC with 
differential) 
X 
Xx 
Xf 
X 
X 
X 
X 
X 
 
TSHg, (reflex free T3 or free T4h) 
X 
Xn 
X 
 
 
X 
Every 3 cycles unless 
clinically indicated 
X 
Xp 
Hepatitis B and C and HIVr 
X 
 
 
 
 
 
 
 
 
TB tests 
X 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 9 of 121 
 
 
Screening 
(prior to 
CRT) 
During 4 
cycles of 
CRT 
(12 weeks) 
C1 
Du
rv
a 
C2 
Du
rv
a 
C3 
Dur
va 
C4 
Durv
a 
C5 to C12 Durva or PD 
C13 Durva 
or final visit 
Follow-up 
(q3mths for year 
1 from end of 
durvalumab, 
q4mths for year 2 
from end of 
durvalumab)u 
Week 
 
1-12 
 
Q4W ±3 days unless dosing needs to be held 
for toxicity reasons 
 
 
Day 
 
1-84 
 
Q28days ±3 days unless dosing needs to be 
held for toxicity reasons 
 
 
Pregnancy testi 
X 
 
X 
X 
X 
X 
X 
X 
 
WHO/ECOG performance status 
X 
 
X 
X 
X 
X 
X 
X 
X 
AE/SAE assessment j 
 
Xx 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Durvalumab (monotherapy) k 
 
 
X 
X 
X 
X 
X 
X 
 
Tumor biopsy (newly acquired or 
archival ≤3 months old)a 
X 
 
 
 
 
 
 
 
 
Tumor biopsy (archival, if available, for 
patients who submit a newly acquired 
biopsy at screening for PD-L1 status) 
X 
 
 
 
 
 
 
 
 
CT scan chest (through adrenals) 
 
 
Xo 
 
 
 
 
 
X 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 10 of 121 
 
 
Screening 
(prior to 
CRT) 
During 4 
cycles of 
CRT 
(12 weeks) 
C1 
Du
rv
a 
C2 
Du
rv
a 
C3 
Dur
va 
C4 
Durv
a 
C5 to C12 Durva or PD 
C13 Durva 
or final visit 
Follow-up 
(q3mths for year 
1 from end of 
durvalumab, 
q4mths for year 2 
from end of 
durvalumab)u 
Week 
 
1-12 
 
Q4W ±3 days unless dosing needs to be held 
for toxicity reasons 
 
 
Day 
 
1-84 
 
Q28days ±3 days unless dosing needs to be 
held for toxicity reasons 
 
 
Tumor evaluation (CT or PET/CT) 
(RECIST 1.1) l,m 
X 
 
CT or PET/CT within 4 weeks of starting C1 Durva. 
Q3m ± 1w for the first 48 weeks (relative to the date of starting Durva), 
and then q3-6m ± 1w thereafter until confirmed objective disease 
progression/death (whichever comes first).  The schedule of q3m ± 1 
week for first 48 weeks and then q3-6m ±1 w thereafter MUST be 
followed regardless of any delays in dosing 
 
Brain MRI with contrast or brain CT with 
contrast if there is a contraindication for 
MRI 
X 
 
 
XW 
a 
Every effort should be made to minimize the time between trial enrollment and starting treatment. (i.e. within 14 days of enrollment) 
b            Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor biopsy sample 
acquisition and analysis prior to randomization 
c 
Body weight is recorded at each visit along with vital signs as per institutional guidelines. Measured height recorded at screening only. 
d 
Any clinically significant abnormalities detected require triplicate ECG results. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated 
from 3 ECGs (within 15 minutes at 5 minutes apart) <<for durvalumab monotherapy. 
e 
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if clinically indicated. 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 11 of 121 
 
f         If screening clinical chemistry and hematology assessments are performed within 7 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1.  
g 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at day 1. 
h            Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system. 
i 
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy test within 7 days 
prior to the first dose of study drug and then every 4 weeks. Pregnancy test may occur on Day 1, but results must be available and reviewed by the treating physician or 
Investigator prior to commencing an infusion  
j 
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed  
k 
Results for LFTs, electrolytes and creatinine must be available before commencing an infusion (within 3 days) and reviewed by the treating physician or Investigator prior to 
dosing. 
l 
RECIST assessments will be performed on images from CT (preferred), each preferably with IV contrast of the chest, abdomen (including liver and adrenal glands) and pelvis. 
Pelvic imaging is recommended only when primary or metastatic disease in the pelvic region is likely.  Additional anatomy should be imaged based on signs and symptoms of 
individual patients at baseline and follow-up.  Baseline assessments should be performed no more than 28 days before the date of randomization and, ideally, should be 
performed as close as possible to and prior to the start of IP.  The confirmatory scans should be performed preferably at the next scheduled imaging visit and no less than 4 
weeks after the prior assessment of PD (in the absence of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, 
every attempt should be made to perform the subsequent assessments at their next scheduled visit.   
m 
Patients will have scans done q3m for the first 48 weeks, and then q3-6m thereafter (relative to the date of randomization) until confirmed objective disease progression. 
Patients with confirmed PD who continue to receive durvalumab at the discretion of the Investigator (following consultation with AstraZeneca) can receive treatment for a 
maximum of 12 months until no longer having clinical benefit. 
n 
As clinically indicated. 
o  
or to progression, whichever occurs first. 
p  
until return to normal limits and then as clinically indicated.   
r          Testing performed for known disease and perform testing at screening to determine eligibility. Please refer to exclusion criteria number 16.  
s              Testing performed for known disease or investigator suspicion of exposure, perform testing at screening. 
t              Only performed if deemed tolerable by the investigator 
u              Detail follow up schedule attached on appendix 3 and appendix 4  
v             All patients enrolled in the study who read English or Spanish will complete the EORTC QLQ-C30 quality of life (QOL) assessment at the start of CRT, C1D1 of Durvalumab, 
and then every 12 weeks during Durvalumab. QOL for patients who are at treatment completion, discontinued due to DLT’s, discontinued due to progressive disease see Appendix 
3 or Appendix 4.  
w         Brain MRIs will be performed annually on follow-ups or for new neurological symptoms.  


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 12 of 121 
 
x         Perform PE, vital signs, Con Med’s, AE’s, Hematology on Day 1 of each cycle of chemotherapy. 
 
 
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated. 
C  Cycle; ECG  Electrocardiogram; IM  Intramuscular; LFT  Liver function test;; qXw  Every X weeks; qXw  Every X weeks; SNP  Single nucleotide polymorphism; 
T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid-stimulating hormone. 
 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 13 of 121 
 
TABLE OF CONTENTS 
PAGE 
 
PROTOCOL SYNOPSIS ......................................................................................................... 2 
SCHEDULE OF STUDY ASSESSMENTS ............................................................................ 7 
TABLE OF CONTENTS ....................................................................................................... 13 
ABBREVIATIONS AND DEFINITION OF TERMS .......................................................... 18 
1. 
INTRODUCTION ................................................................................................. 22 
1.2 
Immunotherapies .................................................................................................... 23 
1.3 
Durvalumab background/non-clinical and clinical experience .............................. 25 
1.4 
Research hypotheses .............................................................................................. 25 
1.5 
Rationale for conducting this study ....................................................................... 26 
1.6 
Benefit/risk and ethical assessment ....................................................................... 28 
1.6.1 
Potential benefits .................................................................................................... 28 
1.6.2 
Overall risks ........................................................................................................... 28 
2. 
STUDY OBJECTIVES .......................................................................................... 30 
2.1 
Primary objective(s) ............................................................................................... 30 
2.2 
Secondary objective(s) ........................................................................................... 30 
3. 
STUDY DESIGN ................................................................................................... 31 
3.1 
Overview of study design ...................................................................................... 31 
3.2 
Study schema ......................................................................................................... 31 
3.3 
Study oversight for safety evaluation / discontinuation of therapies ..................... 32 
4. 
PATIENT SELECTION ........................................................................................ 33 
4.1.1 
Inclusion criteria .................................................................................................... 33 
4.2  
Patient withdrawal………………………………………………………… 
4.2.1 
Replacement of patients ......................................................................................... 41 
5. 
INVESTIGATIONAL PRODUCT(S) ................................................................... 41 
5.1 
Durvalumab ............................................................................................................ 41 
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Amendment Date: 6/12/2023


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 14 of 121 
 
5.1.1 
Formulation/packaging/storage .............................................................................. 41 
5.1.2 
Durvalumab doses and treatment regimens ........................................................... 41 
5.1.3 
Study drug preparation ........................................................................................... 41 
5.1.4 
Monitoring of dose administration ......................................................................... 43 
5.1.5 
Accountability and dispensation ............................................................................ 44 
5.1.6 
Disposition of unused investigational study drug .................................................. 44 
5.2 
Radiation Therapy Details: .................................................................................... 44 
6. 
TREATMENT PLAN ............................................................................................ 46 
6.1 
Patient enrollment .................................................................................................. 46 
 
Patient registration can occur only after evaluation for eligibility is 
complete, eligibility criteria have been met. Patients must have signed and 
dated all applicable consents and authorization forms. There will be no 
randomization in this study. ................................................................................... 46 
Dosage and administration ..................................................................................................... 46 
6.2 
Definition of DLT .................................................................................................. 46 
6.3 
Toxicity management guidelines ........................................................................... 48 
6.3.1 
Durvalumab ............................................................................................................ 48 
7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) .................................................................................................. 49 
7.1 
Restrictions during the study ................................................................................. 49 
7.2 
Concomitant treatment(s) ....................................................................................... 51 
7.2.1 
Permitted concomitant medications ....................................................................... 51 
7.2.2 
Excluded concomitant medications ....................................................................... 51 
8. 
STUDY PROCEDURES ....................................................................................... 54 
8.1 
Schedule of Events ................................................................................................. 54 
8.1.1 
Screening phase ..................................................................................................... 54 
8.1.2 
Treatment phase ..................................................................................................... 55 
8.1.3 
End of treatment ..................................................................................................... 55 
8.2 
Description of study procedures ............................................................................ 56 
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Amendment Date: 6/12/2023


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 15 of 121 
 
8.2.1 
Medical history and physical examination, weight, and vital signs....................... 56 
8.2.2 
Clinical laboratory tests ......................................................................................... 56 
8.3 
Biological sampling procedures ............................................................................. 58 
8.3.1 
Immunogenicity sampling and evaluation methods .............................................. 58 
8.3.2 
Archival tumor samples and fresh tumor biopsies use beyond PD-L1 (not 
mandated) ............................................................................................................... 59 
9. 
DISEASE EVALUATION AND METHODS ...................................................... 59 
9.1.1 
Efficacy variable .................................................................................................... 60 
10. 
ASSESSMENT OF SAFETY ................................................................................ 63 
10.1.1 
Safety parameters ................................................................................................... 63 
10.1.2 
Definition of serious adverse events ...................................................................... 63 
10.1.3 
Definition of adverse events of special interest (AESI) ......................................... 64 
10.2 
Assessment of safety parameters ........................................................................... 67 
10.2.1 
Assessment of severity ........................................................................................... 67 
10.3 
Recording of adverse events and serious adverse events ....................................... 68 
10.3.1 
Study recording period and follow-up for adverse events and serious 
adverse events ........................................................................................................ 69 
10.3.2 
Causality collection ................................................................................................ 70 
10.3.3 
Relationship to protocol procedures ...................................................................... 70 
10.3.4 
Adverse events based on signs and symptoms ...................................................... 71 
10.3.5 
Adverse events based on examinations and tests ................................................... 71 
10.3.6 
Hy’s Law ................................................................................................................ 71 
10.3.7 
Disease progression ............................................................................................... 71 
10.3.8 
New cancers ........................................................................................................... 72 
10.3.9 
Deaths .................................................................................................................... 72 
10.3.10 
Reporting of serious adverse events....................................................................... 73 
10.3.11 
Reporting of deaths to AstraZeneca ....................................................................... 74 
10.3.12 
Other events requiring reporting ............................................................................ 75 
10.3.13 
Overdose ................................................................................................................ 75 
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10.3.14 
Hepatic function abnormality................................................................................. 75 
10.3.15 
Pregnancy ............................................................................................................... 76 
10.3.16 
Maternal exposure .................................................................................................. 76 
10.3.17 
Paternal exposure ................................................................................................... 76 
10.4 
Medication error ..................................................................................................... 77 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 79 
11.1 
Description of analysis sets .................................................................................... 79 
11.1.1 
Safety analysis set .................................................................................................. 79 
11.1.2 
Efficacy analysis set ............................................................................................... 79 
11.2 
Methods of statistical analyses ............................................................................... 80 
11.2.1 
Safety analyses ....................................................................................................... 80 
11.2.2 
Efficacy analyses ................................................................................................... 80 
11.3 
Determination of sample size ................................................................................. 81 
12. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 82 
12.1 
Ethical conduct of the study ................................................................................... 82 
12.2 
Ethics and regulatory review ................................................................................. 82 
12.3 
Informed consent ................................................................................................... 82 
12.4 
Changes to the protocol and informed consent form ............................................. 82 
13. 
STUDY MANAGEMENT .................................................................................... 83 
13.1 
Training of study site personnel ............................................................................. 83 
13.2 
Monitoring of the study ......................................................................................... 83 
13.2.1 
Source data ............................................................................................................. 83 
13.3 
Study timetable and end of study ........................................................................... 83 
THE STUDY CHAIRS WILL MEET EVERY 6 MONTHS TO MONITOR THE 
TRIAL FOR SAFETY. INTERIM REPORTS WITH DESCRIPTIVE 
STATISTICS WILL BE PREPARED TWICE A YEAR UNTIL THE 
INITIAL PAPER REPORTING THE TREATMENT RESULTS HAS 
BEEN ACCEPTED FOR PUBLICATION. IN GENERAL, THE 
INTERIM REPORTS WILL CONTAIN INFORMATION ABOUT THE 
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PATIENT ACCRUAL RATE WITH A PROJECTED COMPLETION 
DATE FOR THE ACCRUAL PHASE; DATA QUALITY; 
COMPLIANCE RATE OF TREATMENT DELIVERY WITH THE 
DISTRIBUTIONS OF IMPORTANT PROGNOSTIC BASELINE 
VARIABLES; AND THE FREQUENCIES AND SEVERITY OF 
ADVERSE EVENTS. THE INTERIM REPORTS WILL NOT CONTAIN 
RESULTS. THESE REPORTS WILL BE SUBMITTED TO THE RUSH 
PROTOCOL REVIEW AND MONITORING COMMITTEE. ............................ 83 
14. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 84 
14.1 
Identity of investigational product(s) ..................................................................... 84 
15. 
LIST OF REFERENCES ....................................................................................... 85 
 
LIST OF TABLES 
Table 1. Highly Effective Methods of Contraception (<1% Failure Rate) .............................. 50 
Table 2. Supportive Medications .............................................................................................. 51 
Table 3. Prohibited Concomitant Medications ......................................................................... 51 
Table 4. Hematology Laboratory Tests .................................................................................... 57 
Table 5. Clinical Chemistry (Serum or Plasma) Laboratory Tests........................................... 57 
Table 6. Urinalysis Testsa ......................................................................................................... 58 
Table 7. List of Investigational Products for This Study .......................................................... 84 
 
LIST OF FIGURES 
Figure 1. Example of Study Flow Chart ................................................................................... 31 
Figure 2. Durvalumab (MEDI4736) Monotherapy Dosing Schedule ...................................... 43 
 
 
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LIST OF APPENDICES 
 
Appendix 1. Dosing Modification and Toxicity Management Guidelines for Immune-
 
Mediated, Infusion- Related, and Non-Immune–Mediated Reactions  ..... Error! 
Bookmark not defined. 
Appendix 2. Durvalumab Dose Calculations ...................................................................... 116 
Appendix 3. Schedule of Study Procedures: Follow-Up for Patients Who Have Completed 
Durvalumab  Treatment and Achieved Disease Control (Until Confirmed 
Progression of Disease) and  Patients Who Have Discontinued Durvalumab 
Due to Toxicity in the Absence of Confirmed  Progression of Disease ......... 117 
Appendix 4.  Schedule of Study Procedures: Follow-Up for Patients Who Have 
 
Discontinued Durvalumab Treatment Due to Confirmed Progression of 
 
Disease at the Discretion of the Investigator ................................................. 120 
 ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APC 
Antigen-presenting cells 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
CDC 
Complement-dependent cytotoxicity 
CI 
Confidence interval 
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CL 
Clearance 
Cmax 
Peak concentration 
Cmax,ss 
Peak concentration at steady state 
Cmin 
Trough concentration 
Cmin,ss 
Trough concentration at steady state 
CNS 
Central nervous system 
CR 
Complete response 
CRT 
Concurrent chemotherapy and radiation therapy 
CT 
Computed tomography 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen-4 
DC 
Disease control 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Disodium edetate dihydrate 
GCP 
Good Clinical Practice 
Gy 
Gray (J/kg) – measure of radiation therapy dose 
HCl 
Hydrochloride 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IGF 
Insulin-like growth factor 
IHC 
Immunohistochemistry  
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IL 
Interleukin 
imAE 
Immune-mediated adverse event 
IMRT 
Intensity Modulated Radiation Therapy 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
MAb 
Monoclonal antibody 
MDT 
Multi-disciplinary Team 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
Micro ribonucleic acid 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MTD 
Maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
NK 
Natural killer 
NSCLC 
Non-small cell lung cancer 
OR 
Objective response 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PRO 
Patient-reported outcome 
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Q2W 
Every 2 weeks 
Q3M 
Every 3 months 
Q3W 
Every 3 weeks 
Q4W 
Every 4 weeks 
Q12W 
Every 12 weeks 
QoL 
Quality of life 
QTcF 
QT interval on ECG corrected using the Frederica’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SD 
Stable disease 
sPD-L1 
Soluble programmed cell death ligand 1 
t½ 
Half life 
TIL 
Tumor infiltrating lymphocyte 
Tmax 
Time to peak concentration 
Tmax,ss 
Time to peak concentration at steady state 
TNF-α 
Tumor necrosis factor alpha 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
USA 
United States of America 
WHO 
World Health Organization 
 
 
 
 
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1. 
INTRODUCTION 
1.1 Background and Rationale 
Definitive chemoradiation followed by durvalumab is the standard of care treatment for 
inoperable stage III non-small cell lung cancer. For the first time in twenty years (since the 
adoption of concurrent chemoradiation), a breakthrough in terms of overall survival was made 
in this patient population, thanks to the addition of durvalumab (Antonia 2018). The landmark 
study published by Antonia, et al suggested a statistically significant improvement in overall 
survival: The 2 year overall survival rate was 66.3% (95% CI, 61.7 to 70.4) in the durvalumab 
group versus 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P = 0.005). 
Additionally, progression free survival (PFS) increased from 5.6 to 17.2 months with the 
addition of durvalumab. Notably only 15% of patients on the Durvalumab arm had to 
discontinue therapy due to adverse events (Antonia 2017). The landmark study included high 
functioning patients only, that is World Health Organization performance status of 0-1, and 
the median age of patients enrolled was 64 years. In the cohort of patients ≥65 years, the 
durvalumab arm remained superior (HR for disease progression or death of 0.74; CI0.54-
1.01).  
With many newly-diagnosed stage III NSCLC patients ineligible for this new standard of care 
regimen due to poor performance status (ECOG 2), competing risks, or advanced age with or 
without other comorbidities, treatment is often deescalated and/or “non-curative therapies” are 
offered instead. These alternate regimens often omit chemotherapy or immunotherapy, and/or 
use an abbreviated radiotherapy regimen. 
Expanding the eligibility criteria is one potential way to increase the access and utilization of 
curative therapies (Bonomi 2018). Certain comorbidities, prior cancer histories, and/or prior 
oncologic therapies, may not necessarily obviate curative strategies in this patient population. 
In addition, an emerging need exists to optimize the therapeutic window for poor risk/elderly 
patients, such that they may derive the greatest benefit.  
Continuous course chemoradiation is difficult to tolerate for poor risk patients, given the 
compounded side effects of multimodality treatment without a break. One large study from 
Hoosier and US Oncology suggested significantly higher rates of grade 3 and 4 toxicities and 
higher rates of hospitalization compared to younger patients <70yo treated with a definitive 
CRT regimen (Jalal 2011). In a larger scale, pooled analysis of individual patient data from 
cooperative group studies of concurrent CRT, significantly fewer elderly (≥70yo) compared 
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with younger patients: completed treatment, discontinued treatment because of AEs, died 
during treatment, and refused further treatment (Stinchcombe 2017). 
As such, alternative strategies for administering curative doses of chemotherapy and radiation 
therapy have been explored. Split-course radiation with chemotherapy, in particular, has been 
described with favorable outcomes, approximating those seen in continuous regimen 
approaches (Garg 2014; Gielda 2011). 
In the split course approach largely adopted by a single high-volume institution, patients 
receive a full four cycles of chemotherapy, with radiation concurrently for 7-8 fractions at the 
start of each cycle (such that 1-1.5 week breaks from radiation are built into each cycle). 
These patients do not, however, receive any adjuvant or maintenance therapies after 
completion of chemoradiation, as they would be ineligible for durvalumab off study. 
One of the radiation developments that has helped more patients complete their course of 
radiation is intensity modulated radiation therapy (IMRT); it has also been shown to have an 
association with improved survival and lesser toxicities when utilized in the treatment of 
locally advanced NSCLC (Koshy 2017; Chun 2017). More conformal techniques have 
enabled less heart and lung doses, specifically, reducing the short and long term impact of 
high dose radiotherapy in this patient population (Koshy 2017; Chun 2017). IMRT, coupled 
with improvements in image guidance have facilitated highly individualized, precise, and 
often adaptable (based on real-time cone beam CTs) radiotherapy plans. 
We thus propose this phase II trial using four-phase, split course chemoradiation using IMRT, 
followed by up to 12 months of Durvalumab in elderly (greater than or equal to 70 years old) 
and/or poor-risk (ECOG PS 2; Creatinine clearance <60) patients with newly diagnosed stage 
III NSCLC. 
1.2 
Immunotherapies 
It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors (Dunn et al 
2004).   
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-
cell activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells (Keir 
et al 2008). It has 2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) 
(Okazaki and Honjo 2007).  The PD-1 and PD-L1/PD-L2 belong to the family of immune 
checkpoint proteins that act as co-inhibitory factors, which can halt or limit the development of 
T cell response.  When PD-L1 binds to PD-1, an inhibitory signal is transmitted into the T cell, 
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which reduces cytokine production and suppresses T-cell proliferation. Tumor cells exploit this 
immune checkpoint pathway as a mechanism to evade detection and inhibit immune response. 
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 
2016).  Importantly, PD-L1 is commonly over-expressed on tumor cells or on non-transformed cells in 
the tumor microenvironment (Pardoll 2012). PD-L1 expressed on the tumor cells binds to PD-1 receptors 
on the activated T-cells leading to the inhibition of cytotoxic T cells. These deactivated T cells remain 
inhibited in the tumor microenvironment. The PD-1/PD-L1 pathway represents an adaptive immune 
resistance mechanism that is exerted by tumor cells in response to endogenous anti-tumor activity. 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of 
evading immune detection and elimination. The binding of an anti–PD-L1 agent to the PD-L1 receptor 
inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on immune cells. This 
activity overcomes PD-L1–mediated inhibition of antitumor immunity. While functional blockade of 
PD-L1 results in T-cell reactivation, this mechanism of action is different from direct agonism of a 
stimulatory receptor such as CD28. 
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti–PD-L1 antibody could 
be used therapeutically to enhance antitumor immune responses in patients with cancer. Results of non-
clinical and clinical studies of monoclonal antibodies (mAbs) targeting the PD-L1/PD-1 pathway have 
shown evidence of clinical activity and a manageable safety profile, supporting the hypothesis that an 
anti–PD-L1 antibody could be used to therapeutically enhance antitumor immune response in cancer 
patients (Error! Reference source not found.; Hirano et al. 2005; Iwai et al. 2002; Okudaira et al. 2009; 
Topalian et al. 2012; Zhang et al. 2008) with responses that tend to be more pronounced in patients with 
tumors that express PD-L1 (Powles et al. 2014; Rizvi et al. 2015; Segal et al. 2015). In addition, high 
mutational burden (e.g., in bladder carcinoma [Error! Reference source not found.]) may contribute 
to the responses seen with immune therapy. 
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively expressed by 
regulatory T cells and upregulated on activated T cells. CTLA-4 delivers a negative regulatory signal to 
T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on antigen-presenting cells (Fife and 
Bluestone 2008). Blockade of CTLA-4 binding to CD80/86 by anti–CTLA-4 antibodies results in 
markedly enhanced T-cell activation and antitumor activity in animal models, including killing of 
established murine solid tumors and induction of protective antitumor immunity. Therefore, it is 
expected that treatment with an anti–CTLA-4 antibody will lead to increased activation of the human 
immune system, increasing antitumor activity in patients with solid tumors. 
Pre-clinical data have now been added to with a wealth of clinical data showing that blockade of negative 
regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 
ligand 1 (PD-L1) has promising clinical activity. Ipilimumab was granted United States (US) Food and 
Drug Administration (FDA) approval for the treatment of metastatic melanoma and is currently under 
investigation for several other malignancies, whilst nivolumab and pembrolizumab, two anti–PD-1 
agents, and atezolizumab, an anti–PD-L1, agent have been granted approvals by agencies such 
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as the US FDA and the European Medicines Agency approval for the treatment of a number of 
malignancies including metastatic melanoma, squamous and non-squamous cell non-small-cell 
lung cancer and urothelial carcinoma. In addition, there are data from agents in the anti–PD-
1/PD-L1class showing clinical activity in a wide range of tumor types. 
1.3 
Durvalumab background/non-clinical and clinical 
experience 
The non-clinical and clinical experience is fully described in the most current version of the 
durvalumab Investigator’s Brochure.  
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune 
for use in the treatment of cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document). ). The 
proposed mechanism of action (MOA) for durvalumab is interference in the interaction of 
PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions 
releases the inhibition of immune responses, including those that may result in tumor 
elimination. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of 
PD-L1 on primary human T cells resulting in the restored proliferation of IFN-γ (Stewart et al 
2015). In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models 
via a T-cell-dependent mechanism (Stewart et al 2015). Based on these data, durvalumab is 
expected to stimulate the patient’s antitumor immune response by binding to PD-L1 and shifting 
the balance toward an antitumor response. Durvalumab has been engineered to reduce antibody-
dependent cellular cytotoxicity and complement-dependent cytotoxicity.  
To date durvalumab has been given to more than 6000 patients as part of ongoing studies 
either as monotherapy or in combination with other anti-cancer agents. Details on the safety 
profile of durvalumab monotherapy are summarized in Section 0 and Section 6.2. Refer to the 
current durvalumab Investigator’s Brochure for a complete summary of non-clinical and 
clinical information including safety, efficacy and pharmacokinetics.  
1.4 
Research hypotheses 
1. We hypothesize that concurrent four phase, split course chemoradiation followed by 
Durvalumab is feasible (safe and tolerable) in elderly / poor risk stage III NSCLC patients. 
2. We hypothesize that >80% of patients enrolled will complete split course chemoradiation, 
and be eligible to receive adjuvant Durvalumab 
3. Without Durvalumab, the median survival is known to be 20 months in this patient 
population; we expect that adding Durvalumab in the treatment regimen will improve the 
median survival to 30 months. 
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4. Without Durvalumab, the median progression free survival (PFS) is known to be 11 months 
in this patient population; we expect that adding Durvalumab in the treatment regimen will 
improve the median PFS to 17 months. 
1.5 
Rationale for conducting this study 
The rationale for the study is to identify another cohort of stage III NSCLC for whom 
adjuvant Durvalumab can be safely given, expanding its utilization and benefits. With a 
unique, extremely well-tolerated 4-phase split course CRT regimen preceding the 
administration of Durvalumab, we expect to be able to offer adjuvant Durvalumab to a 
significant proportion of patients on study.   
1. Primary Objectives: To determine the completion rate of 4-cycle split course CRT and 
to determine the feasibility (safety/tolerability) of durvalumab post chemoradiation in 
poor risk and/or elderly stage III NSCLC patients. 
2. Secondary Objectives 
a. To determine the 1-year overall survival rate 
b. To determine the 1-year progression-free survival rate 
c. To determine the 1-year loco-regional progression-free survival rate 
d. To determine rate of grade 3 and 4 toxicities with this regimen in the selected 
patient population 
1.5.1.1 Durvalumab monotherapy dose rationale 
A durvalumab dose of 20 mg/kg Q4W is supported by in-vitro data, non-clinical activity, 
clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with 
advanced solid tumors and from a Phase I trial performed in Japanese patients with advanced 
solid tumor (D4190C00002). 
PK/Pharmacodynamics data 
Based on available PK/pharmacodynamics data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition. The PK approached 
linearity at ≥3 mg/kg Q2W, suggesting near complete target saturation (membrane-bound and 
sPD-L1), and further shows that the durvalumab dosing frequency can be adapted to a particular 
regimen given the linearity seen at doses higher than 3 mg/kg. The expected half-life with doses 
≥3 mg/kg Q2W is approximately 21 days. A dose-dependent suppression in peripheral sPD-L1 
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was observed over the dose range studied, consistent with engagement of durvalumab with PD-
L1. A low level of immunogenicity has been observed. No patients have experienced immune-
complex disease following exposure to durvalumab (For further information on 
immunogenicity, please see the current IB).  
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
Q2W or 15 mg/kg Q3W (Fairman et al. 2014). Multiple simulations indicate that a similar 
overall exposure is expected following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as 
represented by AUCss (4 weeks). Median Cmax,ss is expected to be higher with 20 mg/kg Q4W 
(~1.5 fold) and median Ctrough,ss is expected to be higher with 10 mg/kg Q2W (~1.25 fold). 
Clinical activity with the 20 mg/kg Q4W dosing regimen is anticipated to be consistent with 
10 mg/kg Q2W with the proposed similar dose of 20 mg/kg Q4W expected to (a) achieve 
complete target saturation in majority of patients; (b) account for anticipated variability in PK, 
pharmacodynamics, and clinical activity in diverse cancer populations; (c) maintain sufficient 
PK exposure in case of ADA impact; and (d) achieve PK exposure that yielded maximal 
antitumor activity in animal models. 
Given the similar area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both regimens 
maintain complete sPD-L1 suppression at trough, and the available clinical data, the 20 mg/kg 
Q4W and 10 mg/kg Q2W regimens are expected to have similar efficacy and safety profiles, 
supporting further development with a dose of 20 mg/kg Q4W.  
Clinical data 
Refer to the current durvalumab Investigator’s Brochure for a complete summary of clinical 
information including safety, efficacy and pharmacokinetics at the 20mg/kg Q4W regimen. 
1.5.1.2 Rationale for fixed dosing 
A population PK model was developed for durvalumab using monotherapy data from a Phase I 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on the PK of 
durvalumab (coefficient of ≤0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed 
dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median and 95th percentiles) using the population PK model. A fixed dose 
of 750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A 
total of 1000 patients were simulated using body WT distribution of 40–120 kg. Simulation 
results demonstrate that body WT-based and fixed dosing regimens yield similar median steady 
state PK concentrations with slightly less overall between-patient variability with fixed dosing 
regimen.  
Similar findings have been reported by others (Ng et al. 2006, Wang et al. 2009, Zhang 
et al. 2012, Narwal et al. 2013). Wang and colleagues investigated 12 monoclonal antibodies 
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and found that fixed and body size-based dosing perform similarly, with fixed dosing being 
better for 7 of 12 antibodies (Wang et al. 2009)]. In addition, they investigated 18 therapeutic 
proteins and peptides and showed that fixed dosing performed better for 12 of 18 in terms of 
reducing the between-patient variability in pharmacokinetic/pharmacodynamics parameters 
(Zhang et al. 2012).  
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 
kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the 
current study. 
1.6 
Benefit/risk and ethical assessment 
1.6.1 
 Potential benefits 
1.6.1.1 
Durvalumab 
Durvalumab may improve survival and progression-free survival in this patient population as 
it did in the favorable-risk patients enrolled on the landmark NEJM study. Additionally, 
Durvalumab may reduce incidence of distant metastases and brain metastases.  
1.6.2 
Overall risks 
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells. By stimulating the immune system however, there is the potential 
for adverse effects on other tissues. 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune mediated mechanism and which 
may require more frequent monitoring and/or unique interventions such as 
immunosuppressant and/or endocrine therapy. These immune mediated effects can occur in 
nearly any organ system, and are most commonly seen as gastrointestinal AEs such as colitis 
and diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis and 
liver enzyme elevations, skin events such as rash and dermatitis and endocrinopathies 
including hypo- and hyper-thyroidism. 
1.6.2.1 Durvalumab 
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal perforation, 
pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus, 
hypophysitis and adrenal insufficiency) hepatitis/increases in transaminases, nephritis/increases 
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in creatinine, pancreatitis/increases in amylase and lipase, rash/pruritus/dermatitis, myocarditis, 
myositis/polymyositis, other rare or less frequent inflammatory events including neurotoxicity, 
infusion-related reactions, hypersensitivity reactions and infections/serious infections.  
For information on all identified and potential risks with durvalumab please always refer to the 
current version of the durvalumab IB. 
Further information on these risks can be found in the current version of the durvalumab IB. 
In monotherapy clinical studies AEs (all grades) reported very commonly (≥ 10% of patients) 
are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back 
pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 9% of patients experienced an AE that resulted in permanent discontinuation of 
durvalumab and approximately 6% of patients experienced an SAE that was considered to be 
related to durvalumab by the study investigator. 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated (Appendix  
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB. 
1.6.2.2 Overall benefit-risk 
Given the overall well-tolerated nature of Durvalumab (most often better tolerated than 
chemotherapy), and its potential to improve survival, the benefits for this trial far outweigh the 
risks.  
 
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2. 
STUDY OBJECTIVES 
2.1 
Primary objective(s) 
To determine the percentage of poor risk/elderly stage III NSCLC patients who complete 
chemotherapy/split course chest radiation and are able to proceed to treatment with 
durvalumab and to determine safety/tolerability of durvalumab post chemoradiation in this 
group of patients.  
2.2 
Secondary objective(s) 
a. 
To determine the 1-year overall survival rate 
b. 
To determine the 1-year progression-free survival rate 
c. 
To determine the 1-year loco-regional progression-free survival rate 
d.       To determine rate of grade 3 and 4 toxicities with this regimen in the selected 
patient population 
 
 
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3. 
STUDY DESIGN 
3.1 
Overview of study design 
This is a non-randomized, prospective phase II clinical trial.  
Radiation and chemotherapy will begin on the same day (Day 1) and be administered on an 
outpatient basis. On days on which both modalities are being delivered, the sequence of 
treatments does not matter. Radiation will commence and continue for 7-8 fractions over the 
first 2 weeks on weekdays only (e.g. M-F, M-W), and then be held for the remainder of the 
second week and the third week. Radiation will resume at the start of cycle 2 (Day 22 +/- 2 
days) of therapy at the same time of initiation of cycle 2 of chemotherapy. During this second 
phase of radiation, 7-8 (to total 15+/- 2 days) fractions will be delivered before the next break 
(second half of week 5 and week 6). At the start of cycle 3 (Day 43 +/- 2 days), radiation will 
resume with 7-8 consecutive weekday treatments alongside cycle 3 of chemotherapy. The last 
phase of therapy will begin cycle 4 (Day 64 +/- 2 days) with 7-8 (to total 30) consecutive 
weekdays of radiotherapy alongside cycle 4 of chemotherapy. The radiation treatments should 
thus alternate 8/7/8/7 or 7/8/7/8 to complete 30 total fractions over the four phases of 
chemoradiation. Chemotherapy will consist of four, 21 day cycles of an FDA approved 
carboplatin doublet (pemetrexed for pemetrexed eligible patients and paclitaxel or etoposide 
for those pemetrexed ineligible as outlined in section 5.3 of the protocol). Within 4 weeks of 
completion of chemoradiation, provided no progression on restaging CT chest scans, patients 
will start their course of Durvalumab (1500mg IV every 28 days (+/- 2 days for up to 12 
months). 
Radiation, chemotherapy, and durvalumab will be held/adjusted according to the protocol (see 
section 3.3) 
3.2 
Study schema 
Figure 1.  
 
 
 
 
Screening/ 
enrolment 
Chemotherapy + 
Radiation: 
60 Gy / 30 fx in 4 
split cycles 
CT Chest and labs 
within 4 weeks of 
CRT completion, 
with no evidence of 
disease progression 
Durvalumab 
1500mg IV q28d 
for up to 12m 
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3.3 
Study oversight for safety evaluation / 
discontinuation of therapies 
 
Safety will be monitored by Rush University Medical Center’s internal Data Safety Monitoring 
Board on a 6 month basis or if any grade 5 toxicities occur. If three or more grade 5 toxicities 
occur, the study will be halted.  
Radiation-Related Toxicities:  
Any grade 3-4 cardiopulmonary SAEs (congestive heart failure, pneumonitis, arrhythmias, and 
myocardial infarction), grade 4 esophagitis, or any AEs that lead to radiation therapy related 
hospitalizations that make continued RT infeasible should require RT to be held. RT could be 
resumed if AEs return to grade 2 or less, but if the AEs do not return to grade 2 or less within 14 
days, RT will be permanently discontinued.  
 
Chemotherapy-Related Toxicities: 
Dose modifications of 20%: for weight loss greater than 10% of initial body weight, for grade 4 
toxicity, or for delay in treatment due to parameters not being met (see 5.3). 
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade 
adverse events. Patients will be evaluated clinically and with standard laboratory tests before each 
cycle of chemotherapy as specified in Study Calendar & Evaluations. Subjects will be evaluated 
for serious adverse events, and adverse events requiring chemotherapy drug interruption or 
discontinuation as specified in Study Calendar & Evaluations. Specifically, any grade 3 non-
hematologic toxicities and any grade 4 hematologic toxicities will be reported. 
 
Chemotherapy will be held/modified for the following:  
A. With any cardiopulmonary SAEs (congestive heart failure, pneumonitis, arrhythmias, 
myocardial infarction), grade 4 esophagitis, or any AEs that lead to radiation therapy 
related hospitalization that make continued RT infeasible.  Chemotherapy will be resumed 
with the following cycle of radiation, thus potentially extending chemotherapy cycle length 
beyond 21 days.  
B. As outlined in section 5.3 
 
MEDI4736 (Durvalumab) Related-Toxicities:  
For MEDI4736 (durvalumab), there will not be any dose escalation or de-escalation. If the 
MEDI4736 (durvalumab) dose is held or interrupted, it will not be made up. If the patient meets 
retreatment criteria, the full dose of 1500 mg will be administered. If the patient does not meet 
retreatment criteria before the next scheduled dose, if/when the toxicity resolves to the point where 
treatment is possible, the doses of MEDI4736 (durvalumab) are applied off schedule every 4 
weeks. MEDI4736 (durvalumab) must be withheld for drug-related toxicities and severe or life-
threatening AEs as per the CTCAE v5.0. The drug will be permanently discontinued for the 
following conditions:  Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day 
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(or equivalent) within 12 weeks after last dose of study drug; recurrence of a previously 
experienced Grade 3 treatment-related AE following resumption of dosing. Please see Toxicity 
Management Guidelines.  
 
4. 
PATIENT SELECTION 
4.1.1 
Inclusion criteria 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
1. Participants must have histologically or cytologically confirmed stage IIIA-C (AJCC 8th 
edition) non-small cell lung cancer that will be treated with curative intent. 
2. Participants must have been deemed medically inoperable by multidisciplinary team/tumor 
board. 
3. Participants must have been staged with a PET/CT within 45 days of enrollment (if PET/CT 
out of window, CT Chest/Abdomen/Pelvis within 21 days of enrollment is acceptable). 
4. Patients must have undergone an MRI Brain w/IV contrast, or CT brain if MRI not feasible, 
confirming no evidence of brain metastases, within 30 days of enrollment.  
5. Participants must be elderly (age 70 years or older and PS 0-1) or >18 years old AND poor 
risk (ECOG 2) 
6. Participants ideally have endobronchial ultrasound biopsy (EBUS) or mediastinoscopy to 
confirm nodal status, but can be deferred if PET/CT imaging characteristics are highly 
suggestive of nodal metastases 
7. Participants should have a life expectancy of >6 months 
8. Participants must have normal organ and marrow function: Leukocytes >3000/mcL; ANC 
>1500/mcL; PLT>100000/mcL; Hemoglobin ≥9.0 g/dL 
9. Serum bilirubin ≤1.5x institutional upper limit of normal (ULN) 
10. AST/ALT <2.5x institutional upper limit of normal 
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11. Measured creatinine clearance (CL) >30 mL/min or Calculated creatinine CL>30 mL/min by 
the Cockcroft-Gault formula 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)    
72 x serum creatinine (mg/dL) 
 
 
 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)    x 0.85 
72 x serum creatinine (mg/dL) 
 
12. Patients must be capable of giving signed informed consent which includes compliance with 
the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 
Written informed consent and any locally required authorization (e.g., Health Insurance 
Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in 
the EU) obtained from the patient/legal representative prior to performing any protocol-related 
procedures, including screening evaluations.   
13. Body weight >30kg  
14. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female 
pre-menopausal patients. Women will be considered post-menopausal if they have been 
amenorrheic for 12 months without an alternative medical cause. The following age-specific 
requirements apply:  
− 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
− 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 year 
ago, had chemotherapy-induced menopause with last menses >1 year ago, or 
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underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
15. Patient is willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up. 
16. Concurrent enrollment on RUSH IIT Protocol EERENs: A Phase II Single Arm Study is 
allowed for those patients enrolled in this trial. 
 
  
4.1.2 Exclusion criteria 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study: 
1. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to carboplatin, pemetrexed (for patients with adenocarcinoma), etoposide (for 
patients with squamous cell carcinoma), or immunotherapy 
2.  If deemed by treating oncologic physicians, Patients that have uncontrolled intercurrent 
illness, including but not limited to: ongoing or active infection, symptomatic congestive heart 
failure, symptomatic hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung 
disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric 
illness/social situations that would limit compliance with study requirement, substantially 
increase risk of incurring AEs or compromise the ability of the patient to give written informed 
consent 
3. Pregnant women 
4. Patients known to be HIV+  
5. Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study or during the follow-up period of an interventional study 
6. Receipt of the last dose of anticancer therapy (CRT) ≤7 days prior to the first dose of study 
drug. If sufficient wash-out time has not occurred due to the schedule or PK properties of an 
agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the 
investigator 
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7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the 
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria  
a. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician. 
b. Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab may be included only after consultation with the 
Study Physician.  
17. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. 
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone 
replacement therapy) is acceptable.  
18. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 
19. History of allogenic organ transplantation. 
20. Active or prior documented autoimmune or inflammatory disorders (including inflammatory 
bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of 
diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome 
[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, 
uveitis, etc]). The following are exceptions to this criterion: 
a. Patients with vitiligo or alopecia 
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement  
c. Any chronic skin condition that does not require systemic therapy 
d. Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician 
e. Patients with celiac disease controlled by diet alone 
21. History of another primary malignancy except for 
a. Malignancy treated with curative intent and with no known active disease ≥5 
years before the first dose of IP and of low potential risk for recurrence 
b. Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
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c. Adequately treated carcinoma in situ without evidence of disease 
22. History of leptomeningeal carcinomatosis 
23. History of active primary immunodeficiency  
24. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local practice), 
hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human 
immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved 
HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence 
of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
25. Current or prior use of immunosuppressive medication within 14 days before the first dose of 
durvalumab. The following are exceptions to this criterion: 
a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection) 
b. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of 
prednisone or its equivalent 
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
26. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, 
if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last 
dose of IP. 
27. Female patients who are pregnant or breastfeeding or male or female patients of reproductive 
potential who are not willing to employ effective birth control from screening to 90 days 
after the last dose of durvalumab monotherapy. 
28. Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients. 
29. Prior randomisation or treatment in a previous durvalumab clinical study regardless of 
treatment arm assignment.  
30. Patients who have received prior anti–PD-1, anti PD-L1, including durvalumab or anti 
CTLA-4: 
a. Must not have experienced a toxicity that led to permanent discontinuation of 
prior immunotherapy.  
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b. All AEs while receiving prior immunotherapy must have completely resolved or 
resolved to baseline prior to screening for this study. 
c. Must not have experienced a ≥Grade 3 immune related AE or an immune related 
neurologic or ocular AE of any grade while receiving prior immunotherapy. 
NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to be enrolled if 
they are stably maintained on appropriate replacement therapy and are 
asymptomatic. 
d. Must not have required the use of additional immunosuppression other than 
corticosteroids for the management of an AE, not have experienced recurrence of 
an AE if re-challenged, and not currently require maintenance doses of > 10 mg 
prednisone or equivalent per day. 
31. Judgment by the investigator that the patient is unsuitable to participate in the study and the 
patient is unlikely to comply with study procedures, restrictions and requirements. 
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.2 
Withdrawal of patients from study treatment and/or study 
Permanent discontinuation of Durvalumab  
An individual patient will not receive any further investigational product if any of the following 
occur in the patient in question: 
1. An individual patient will not receive any further durvalumab if their weight falls to 30kg or 
less. 
2. Withdrawal of consent or lost to follow-up. 
3. Adverse event that, in the opinion of the investigator or the sponsor, contraindicates        
 
further dosing. 
4. Patient is determined to have met one or more of the exclusion criteria for study
 
participation at study entry and continuing investigational therapy might constitute a
 
safety risk. 
5. Pregnancy or intent to become pregnant. 
6. Any AE that meets criteria for discontinuation as defined in Section 6.3 
7. Grade ≥3 infusion reaction 
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8. Patient noncompliance that, in the opinion of the investigator or sponsor, warrants
 
withdrawal; e.g., refusal to adhere to scheduled visits 
9. Initiation of alternative anticancer therapy including another investigational agent 
10. Confirmation of PD and investigator determination that the patient is no longer benefiting
 
from treatment with durvalumab. 
11. Patients who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 10.3.1, including the collection of any protocol-specified 
blood specimens, unless consent is withdrawn or the patient is lost to follow-up or enrolled in 
another clinical study. All patients will be followed for survival. Patients who decline to 
return to the site for evaluations will be offered follow-up by phone every 3 months as an 
alternative 
 
 
 
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4.2 
Withdrawal of consent 
Patients are free to withdraw from the study at any time (IP and assessments) without prejudice to 
further treatment. 
Patients who withdraw consent for further participation in the study will not receive any further IP 
or further study observation, with the exception of follow-up for survival, which will continue until 
the end of the study unless the patient has expressly withdrawn their consent to survival follow-
up. Note that the patient may be offered additional tests or tapering of treatment to withdraw safely. 
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and the 
presence of any AE. The Investigator will follow up AEs outside of the clinical study.  
An individual patient will not receive any further IP (durvalumab monotherapy) if any of the 
following occur in the patient in question: 
• 
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing. 
• 
Pregnancy or intent to become pregnant. 
• 
Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (e.g., refusal to adhere to 
scheduled visits) 
• 
Initiation of alternative anticancer therapy including another investigational agent 
• 
Clinical progression, i.e., Investigator determination that the patient is no longer 
benefiting from treatment with IP, with or without radiological progression by 
RECIST 1.1. 
Any AE that meets criteria for discontinuation as defined in the Dosing Modification and Toxicity 
Management Guidelines (Appendix 1) 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to: 
• all further participation in the study including any further follow up (e.g., survival contact 
telephone calls) 
• withdrawal of consent to the use of their study generated data 
• withdrawal to the use of any samples  
 
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4.2.1 
Replacement of patients 
5. 
PATIENTS WHO DO NOT REMAIN ON THE STUDY UP TO 
THIS TIME FOR REASONS OTHER THAN DLT WILL BE 
REPLACED WITH ANOTHER PATIENT AT THE SAME DOSE 
LEVEL. INVESTIGATIONAL PRODUCT(S) 
5.1 
Durvalumab 
5.1.1 
Formulation/packaging/storage 
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for infusion 
after dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL. The nominal fill volume is 
10.0 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be 
frozen. Drug product should be kept in original packaging until use to prevent prolonged light 
exposure.  
5.1.2 
Durvalumab doses and treatment regimens 
Patients will receive 1500 mg durvalumab via IV infusion q4w for up to 12 months unless 
criteria for discontinuation are met. Patients will receive 20mg/kg if weight drops and 
participants are allowed to stay in the study.  
5.1.3 
Study drug preparation 
Patients will receive 1500mg durvalumab (MEDI4736) via IV infusion Q4W for up to a maximum 
of 12 months (up to 13 doses/cycles) with the last administration on week 48, or until confirmed 
disease progression unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met. (If a patient’s weight falls to 30kg or below the patient should 
receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W until the weight 
improves to >30 kg, at which point the patient should start receiving the fixed dosing of 
durvalumab 1500mg Q4W.  
See Figure 2. 
Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab (MEDI4736) for administration must be prepared by the Investigator’s or 
site’s designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab (MEDI4736) vial to the start of administration should not exceed:  
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• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
A dose of 1500mg (for patients >30kg in weight) will be administered using an IV bag containing 
0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) concentration 
ranging from 1 to 15 mg/mL and delivered through an IV administration set with a 0.2- or 0.22-
μm filter.  Add 30.0 mL of durvalumab (MEDI4736) (ie, 1500mg of durvalumab [MEDI4736]) to 
the IV bag. The IV bag size should be selected such that the final concentration is within 1 to 15 
mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.   
If patient weight falls to ≤ 30 kg weight-based dosing at 20 mg/kg will be administered using an 
IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL and delivered through an IV administration set with a 
0.2- or 0.22-μm filter.     
Standard infusion time 1 hour, however.  In the event that if there are interruptions during infusion, 
the total allowed infusion time should not exceed 8 hours at room temperature.  
Do not co-administer other drugs through the same infusion line. 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the infusion 
set used after the contents of the IV bag are fully administered or complete the infusion according 
to institutional policy to ensure the full dose is administered. 
If either preparation time or infusion time exceeds the time limits a new dose must be prepared 
from new vials.  Durvalumab (MEDI4736) does not contain preservatives, and any unused portion 
must be discarded.  
 
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Figure 2. Durvalumab (MEDI4736) Monotherapy Dosing Schedule 
 
5.1.4 
Monitoring of dose administration 
Patients will be monitored before, during and after the infusion with assessment of vital signs at 
the times specified in the Schedule of Assessment. Patients are monitored (pulse rate, blood 
pressure) every 30 minutes during the infusion period (including times where infusion rate is 
slowed or temporarily stopped). 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion. For patients with a ≤Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate. 
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator. If the 
infusion-related reaction is Grade 3 or higher in severity, study drug will be discontinued. Standard 
infusion time 1 hour, however.  In the event that if there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours at room temperature. If time exceeded, then new 
preparation will be required.  
For management of patients who experience an infusion reaction, please refer to the toxicity and 
management guidelines in Appendix 1. 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs and 
medical equipment to treat acute anaphylactic reactions must be immediately available, and study 
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personnel must be trained to recognize and treat anaphylaxis. The study site must have immediate 
access to emergency resuscitation teams and equipment in addition to the ability to admit patients 
to an intensive care unit if necessary. 
5.1.5 
Accountability and dispensation 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab (MEDI4736) to the investigator as a 500-mg vial solution for infusion after dilution. 
After last patient is placed in follow up, pharmacy will follow internal SOP for destroying drug.   
5.1.6 
Disposition of unused investigational study drug 
The site will account for all investigational study drug dispensed and also for appropriate 
destruction. Certificates of delivery and destruction will be signed. 
5.2 RADIATION THERAPY DETAILS: 
CT simulation for radiation will be acquired alongside 4DCT, i.e. 4 dimensional CAT scan 
(which incorporates tumor motion into planning). The free breathing scan will be performed 
using 1-3mm cuts with or without IV contrast (based on discretion of Radiation Oncologist for 
target delineation). Radiation therapy will be administered with photons, 6-18 MVs. Effort 
should be made to maximize the utilization of 6MV photons as the primary treatment energy. 
Prescription will be 60 Gy / 30 fractions to the 
PTV, such that at least 93% of the PTV is receiving the prescription dose of 60 Gy. No elective 
coverage will be part of the planning process, unless there are intervening areas of concern 
deemed clinically necessary to cover by treating Radiation Oncologist (e.g. coverage of level 4R 
LN if 2R and 7 are both positive). Hot spots outside the PTV will be limited to no more than 
10% hot and no more than 15% hot within the PTV.  
Intensity modulated radiation therapy (IMRT), step-and-shoot or VMAT (volumetric modulated 
arc therapy) will be a requirement with daily CBCTs (cone beam cat scans) for image guidance. 
Adaptive re-planning will be allowed after a minimum of 2 phases (i.e. 30 Gy) of concurrent 
chemoradiation if deemed appropriate by the treating Radiation Oncologist. The following 
organs at risk will be routinely contoured: heart, lungs, brachial plexus, esophagus, spinal cord. 
The GTV will be contoured and include gross disease (biopsy proven, PET-avid, or CT criteria 
for nodal disease - >1cm in short axis). The CTV will include a 5mm expansion on the primary 
lung tumor respecting anatomic boundaries and an expansion of nodal volume to include 
involved LN station. The ITV will reflect MIP and 4DCT/gated imaging acquired at the time of 
CT simulation, and an ICTV will be created reflecting the physiological motion of the CTV. The 
PTV will be at least 3, but no more than 5mm margin expansion on the ICTV. 
 
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The following OAR parameters will be required: 
Spinal Cord dmax <50 Gy 
Heart mean dose < 30 Gy and/or V50<25% 
Total Lungs mean dose <20 Gy and V20<32% and V5<75% 
Brachial Plexus dmax <66 Gy 
Esophagus mean dose <30 Gy and dmax <66 Gy 
5.3 Chemotherapy Details: 
5.3.1 Non-squamous histology 
Chemotherapy will be Carboplatin/Pemetrexed (delivered on one day, every three weeks for four 
cycles) for adenocarcinoma histology and creatinine clearance > 45.  For patients with creatinine 
clearance <45 patients will receive carboplatin/paclitaxel (carboplatin AUC =4 day 1, paclitaxel 
80mg/m2 day 1 and day 8 or 21 day cycle or Carboplatin/Etoposide (carboplatin AUC =4 day 1, 
etoposide 80mg/m2 days 1-3, every three weeks for four cycles), per decision of investigator.  
Dose adjustments can be made at the discretion of the treating Medical Oncologists. 
 5.3.2 Squamous cell carcinoma histology 
Patients will receive carboplatin/paclitaxel (carboplatin AUC =4 day 1, paclitaxel 80mg/m2 day 
1 and day 8 or 21 day cycle or Carboplatin/Etoposide (carboplatin AUC =4 day 1, etoposide 
80mg/m2 days 1-3, every three weeks for four cycles), per decision of investigator. 
Dose adjustments can be made at the discretion of the treating Medical Oncologists. 
5.3.3 Treatment parameters: 
Treatment will be based on most recent weight prior to each cycle of chemotherapy. 
Treatment parameters for each cycle: 
1. Absolute neutrophil count above 1000/microliter 
2. Platelets above 100,000 per microliter 
3. Dose modifications of 20%: for weight loss greater than 10% of initial body weight, for grade 
4 toxicity, or for delay in treatment due to parameters not being met 
 
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6. 
TREATMENT PLAN 
6.1 
Patient enrollment  
Patient registration can occur only after evaluation for eligibility is complete and 
eligibility criteria have been met. Patients must have signed and dated all applicable 
consents and authorization forms. There will be no randomization in this study.  
Dosage and administration 
See section 5 for chemotherapy, radiation therapy, and Durvalumab treatment 
parameters. 
6.2 
Definition of DLT 
Dose-limiting toxicities (DLTs) will be evaluated during the trial. The period for evaluating DLTs 
will be from the time of first administration of durvalumab until 3 months after last administration. 
Patients who do not remain on the study up to this time for reasons other than DLT will be replaced 
with another patient at the same dose level. Grading of DLTs will follow the guidelines provided 
in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
 
Prior to the DLT definition section in a protocol, the rules for identifying the maximum tolerated 
dose should be clearly defined (e.g., if ≥2/6 DLTs occur in a dose escalation cohort). 
A DLT is defined as the occurrence of an adverse event (AE) that is at least possibly related to 
the investigational product (IP) or investigational regimen (IR), with two exceptions: any 
grade of vitiligo or alopecia will not qualify as a DLT. AEs that are at least possibly related to 
durvalumab- and/or tremelimumab-containing regimens shall be assessed as DLTs if they 
meet any of the following criteria: 
 
Hematologic toxicity: 
• Grade ≥3 neutropenia complicated by fever >38.3°C 
• Grade 4 neutropenia (lasting more than 7 days) 
• Grade ≥3 thrombocytopenia with significant bleeding 
• Grade 4 thrombocytopenia (regardless of duration) 
• Grade 4 anemia (regardless of duration) 
 
Non-hematologic toxicity: 
• Any Grade 4 non-immune-mediated AE 
• Any Grade 4 immune-mediated AE, excluding endocrinopathies 
• Any Grade 3 non-immune mediated AE that does not resolve to ≤Grade 1 or baseline within 
30 days with optimal medical management 
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• Any Grade 3 immune-mediated AE – excluding diarrhea/colitis, pneumonitis, hepatitis, rash, 
neurotoxicity, myocarditis, myositis/polymyositis, endocrinopathies and nephritis – that does 
not resolve to ≤Grade 1 or baseline within 30 days after onset of the event despite optimal 
medical management including systemic corticosteroids 
• Grade 3 diarrhea or colitis that does not resolve to ≤Grade 1 within 14 days 
[both immune- and non-immune-mediated indicated here; the same is the case if not 
specified in remaining bullet points below] 
• Grade 3 noninfectious pneumonitis 
• Grade 2 noninfectious pneumonitis that does not resolve to ≤Grade 1 within 3 days of the 
initiation of maximal supportive care 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3×ULN with 
concurrent increase in total bilirubin (TBL) ≥2×ULN without evidence of cholestasis or 
alternative explanations (e.g., viral hepatitis, disease progression in the liver; i.e., “Hy’s 
Law”) 
• ALT or AST >8×ULN or TBL>5×ULN 
• Grade 3 immune-mediated rash that does not resolve to ≤Grade 1 or baseline within 30 days 
• Grade 2 rash covering > 30% BSA that does not resolve to ≤Grade 1 or baseline within 30 
days  
• Any grade of immune-mediated rash with bullous formation 
• Grade 3 immune-mediated neurotoxicity (excluding Guillain-Barre and myasthenia gravis) 
that does not resolve to ≤Grade 1 within 30 days 
• Grade 2 or 3 immune-mediated peripheral neuromotor syndrome (such as Guillain-Barre and 
myasthenia gravis) that does not resolve to ≤Grade 1 within 30 days or that exhibits signs of 
respiratory insufficiency or autonomic instability 
• Grade 3 immune-mediated myocarditis 
• Any symptomatic immune-mediated myocarditis that does not become asymptomatic within 
3 days of initiating optimal medical management including systemic corticosteroids 
• Grade 2 or 3 immune-mediated myositis/polymyositis that does not resolve to Grade ≤1 
within 30 days of initiating optimal medical management including systemic corticosteroids 
or that exhibits signs of respiratory insufficiency regardless of optimal medical management 
• Immune-mediated increase in creatinine >3×ULN, or >3×baseline for patients with a 
baseline creatinine elevated above ULN 
 
 
The DLT assessment period is from the time of first dose of IP/IR and ends upon administration 
of the first dose of IP/IR on Cycle 2, Day 1 (28 day cycle).  
 
Any treatment-related toxicities that first occurred during the DLT period must be followed for 
resolution to determine if the event qualifies as a DLT as specified in the DLT criteria above. 
 
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Immune-related AEs are defined as AEs of an immune nature (i.e., inflammatory) in the absence 
of a clear alternative etiology. In the absence of a clinically significant abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to designation 
as a DLT.  
6.3 
Toxicity management guidelines  
6.3.1 
Durvalumab  
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab are provided in the durvalumab Toxicity 
Management Guidelines (TMGs).  
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related. 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see section 4.1.2 and the Dosing Modification and Toxicity Management Guidelines 
in Appendix 1). 
Following the first dose of IP, subsequent administration of durvalumab can be modified based on 
toxicities observed as described in the Dosing Modification and Toxicity Management Guidelines 
in Appendix 1. These guidelines have been prepared to assist the Investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs 
considered causally related to durvalumab monotherapy by the reporting investigator 
NOTE: Dose reductions are not permitted. In case of doubt, the Investigator should consult with 
the Company. 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related. 
All toxicities will be graded according to NCI CTCAE, Version5.0.  
 
 
 
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7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
7.1 
Restrictions during the study 
The following restrictions apply while the patient is receiving study treatment and for the specified 
times before and after: 
Female patient of child-bearing potential 
− 
Female patients of childbearing potential who are not abstinent and intend to be 
sexually active with a non-sterilized male partner must use at least 1 highly 
effective method of contraception (Table 1) from the time of screening throughout 
the total duration of the drug treatment and the drug washout period (90 days after 
the last dose of durvalumab monotherapy). Non-sterilized male partners of a female 
patient of childbearing potential must use male condom plus spermicide throughout 
this period. Cessation of birth control after this point should be discussed with a 
responsible physician.  Periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of birth control.  Female patients should also 
refrain from breastfeeding throughout this period.  
Male patients with a female partner of childbearing potential 
− 
Non-sterilized male patients who are not abstinent and intend to be sexually active 
with a female partner of childbearing potential must use a male condom plus 
spermicide from the time of screening throughout the total duration of the drug 
treatment and the drug washout period (90 days after the last dose of durvalumab 
monotherapy). However, periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception.  Male patients 
should refrain from sperm donation throughout this period. 
− 
Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Table 1).   
N.B Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.   
Women will be considered post-menopausal if they have been amenorrheic for 12 months without 
an alternative medical cause.  The following age-specific requirements apply:  
• 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels 
in the post-menopausal range for the institution. 
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• 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago. 
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly are described in Table 1.  Note that 
some contraception methods are not considered highly effective (e.g. male or female condom with 
or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper 
containing intrauterine device; progestogen-only oral hormonal contraceptive pills where 
inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which 
is considered highly effective]; and triphasic combined oral contraceptive pills). 
Table 1. Highly Effective Methods of Contraception (<1% Failure Rate) 
• Barrier/Intrauterine methods 
• Hormonal Methods 
• Copper T intrauterine device 
• Levonorgestrel-releasing intrauterine 
system (e.g., Mirena®)a 
 
• Implants: Etonogestrel-releasing 
implants: e.g. Implanon® or 
Norplant®  
• Intravaginal: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: e.g. NuvaRing®  
• Injection: Medroxyprogesterone 
injection: e.g. Depo-Provera®  
• Combined Pill: Normal and low dose 
combined oral contraceptive pill 
• Patch: 
Norelgestromin/ethinylestradiol-
releasing transdermal system: e.g. 
Ortho Evra®  
• Minipillc: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only 
highly effective progesterone-based  
a 
This is also considered a hormonal method 
 
Blood donation 
Patients should not donate blood while participating in this study, or for at least 90 days following 
the last infusion of durvalumab 90 days after receipt of the final dose of durvalumab. 
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7.2 
Concomitant treatment(s) 
7.2.1 
Permitted concomitant medications 
Table 2. Supportive Medications 
Supportive medication/class of drug: 
Usage: 
Concomitant 
medications 
or 
treatments 
(e.g., acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above  
To be administered as prescribed by the 
Investigator 
Best 
supportive 
care 
(including 
antibiotics, 
nutritional 
support, 
correction 
of 
metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy to 
non-target lesions, etc.]) 
Should be used, when necessary, for all 
patients 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
 
7.2.2 
Excluded concomitant medications 
Table 3. Prohibited Concomitant Medications 
Prohibited medication/class of drug: 
Usage: 
Any investigational anticancer therapy 
other than those under investigation in this 
study 
Should not be given concomitantly whilst the 
patient is on study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 
other than those under investigation in this 
study 
Should not be given concomitantly whilst the 
patient is on study treatment 
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Prohibited medication/class of drug: 
Usage: 
Any 
concurrent 
chemotherapy, 
radiotherapy, immunotherapy, or biologic 
or hormonal therapy for cancer treatment 
other than those under investigation in this 
study 
Should not be given concomitantly whilst the 
patient is on study treatment. (Concurrent use of 
hormones for non-cancer-related conditions 
[e.g., insulin 
for 
diabetes 
and 
hormone 
replacement 
therapy] 
is 
acceptable. 
Local 
treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable [e.g., by 
local surgery or radiotherapy]) 
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Prohibited medication/class of drug: 
Usage: 
Immunosuppressive medications including, 
but not limited to, systemic corticosteroids 
at doses exceeding 10 mg/day of prednisone 
or equivalent, methotrexate, azathioprine, 
and tumor necrosis factor-α blockers 
Should not be given concomitantly or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions: 
• Usage during CRT 
• Use of immunosuppressive medications 
for the management of IP-related AEs,  
• Use in patients with contrast allergies.  
• In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted. 
  
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential 
for the management of non-immunotherapy 
related events experienced by the patient (e.g., 
chronic obstructive pulmonary disease, radiation, 
nausea, etc.). 
EGFR TKIs  
Should not be given concomitantly. 
Should be used with caution in the 90 days post 
last dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence 
of transaminase increases (with 1st generation 
EGFR TKIs) has been reported when durvalumab 
has been given concomitantly. 
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP (including SoC) 
Herbal and natural remedies which may 
have immune-modulating effects 
Should not be given concomitantly unless agreed 
by the sponsor 
 
 
 
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8. 
STUDY PROCEDURES 
8.1 
Schedule of Events 
See page 7 for the Schedule of Events. 
For all treatment arms 
• 
PRO, QoL (in Spanish for Spanish speakers), and tumor efficacy (RECIST) 
assessment dates are not affected by dose delays and remain as originally scheduled, 
as they are based on the date of randomization (not the date of therapy).  All other 
scheduled assessments must be performed relative to the start of the dosing cycle such 
that all laboratory procedures, etc. required for dosing should be performed within 
3 days prior to dosing. 
For durvalumab monotherapy  
• 
Patients may delay dosing under certain circumstances.  
− 
Dosing may be delayed per Toxicity Management Guidelines, due to either 
an immune or a non-immune-related AE. 
− 
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible 
− 
Dosing intervals of subsequent cycles may be shortened as clinically 
feasible in order to gradually align treatment cycles with the schedule of 
tumor efficacy (RECIST) and PRO assessments. Subsequent time between 2 
consecutive doses cannot be less than 22 days, based on the half-lives of 
durvalumab (see current Investigator Brochure for durvalumab).  
8.1.1 Screening phase 
 
 
Screening procedures will be performed up to 5 days before Day 1 of CRT, unless otherwise 
specified. All patients must first read, understand, and sign the IRB/REB/IEC-approved ICF 
before any study-specific screening procedures are performed. After signing the ICF, completing 
all screening procedures, and being deemed eligible for entry, patients will be enrolled in the 
study. Procedures that are performed prior to the signing of the ICF and are considered standard 
of care may be used as screening assessments if they fall within the 28-day screening window.  
The following procedures will be performed during the Screening Visit: 
• Informed Consent 
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• Review of eligibility criteria 
• Medical history and demographics, tobacco use 
• Complete physical exam  
• ECOG Performance Status 
• Vitals signs, weight and height  
• 12-lead ECG 
• Pulmonary function testing performed if deemed tolerable by the investigator 
• Hep B/ Hep C testing 
• HIV testing for known HIV positive patients 
• Tumor biopsy 
• Review of prior/concomitant medications  
• Brain Imaging by CT/MRI 
• Tumor evaluation PET/CT 
• Clinical laboratory tests for: 
o Hematology (see Table 4) 
o Clinical chemistry (see Table 5) 
o TSH 
o Creatinine Clearance 
o Serum or Urine pregnancy test (for women of childbearing potential only) 
o Urinalysis (see Table 6) discretion of the investigator 
8.1.2 
Treatment phase  
Procedures to be conducted during the treatment phase of the study are presented in the Schedule 
of Assessments. Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) do 
not need to be repeated on C1D1. 
8.1.3 
End of treatment 
End of treatment is defined as the last planned dosing visit within the 12-month dosing period. 
For patients who discontinue durvalumab prior to 12 months, end of treatment is considered the 
last visit where the decision is made to discontinue treatment. All required procedures may be 
completed within ±7 days of the end of treatment visit. Repeat disease assessment is not required 
if performed within 28 days prior to the end of treatment visit. 
Assessments for patients who have completed durvalumab treatment and achieved disease 
control or have discontinued durvalumab due to toxicity in the absence of confirmed progressive 
disease are provided in Appendix 3. 
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Assessments for patients who have discontinued durvalumab treatment due to confirmed PD are 
presented in Appendix . 
All patients will be followed for survival until the end of the study regardless of further 
treatments, or until the sponsor ends the study.  
8.2 
Description of study procedures 
8.2.1 
Medical history and physical examination, weight, and vital signs 
Findings from medical history (obtained at screening) and physical examination shall be given a 
baseline grade according to the procedure for AEs. Increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the pre-study grade or below. 
Physical examinations will be performed on study days noted in the Schedule of Assessments. 
A complete physical examination will be performed and will include an assessment of the 
following (as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 
skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, 
musculoskeletal (including spine and extremities), genital/rectal, and neurological systems and at 
screening only, measured height.  
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules. Bodyweight is also recorded at each visit along with vital 
signs. 
First infusion of Durvalumab  
On the first infusion day, patients will be monitored, and vital signs collected/recorded in eCRF 
prior to infusion of IP.  
Patients should be carefully monitored and BP and other vital signs should be measured during 
and post infusion as per institution standard and as clinically indicated. If the infusion takes 
longer than 60 minutes, then BP and pulse measurements should follow the principles as 
described above or be taken more frequently if clinically indicated. A 1-hour observation period 
is recommended after the first infusion of durvalumab.  
Subsequent infusions of Durvalumab 
BP, pulse and other vital signs should be measured, collected/recorded in eCRF prior to the start 
of the infusion. Patients should be carefully monitored, and BP and other vital signs should be 
measured during and post infusion as per institution standard and as clinically indicated. Clinical 
laboratory tests 
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The following clinical laboratory tests will be performed (see the Schedule of Assessments, 
Appendix 3 and Appendix 4 for the timepoints of each test): 
 
Table 4. Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular hemoglobin 
Total white cell count 
Mean corpuscular hemoglobin concentration 
 
 
 
Note: a 
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by DM if entered 
as percentage. Total white cell count therefore has to be provided. 
 
Table 5. Clinical Chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 
Alanine aminotransferase 
Lipase 
Amylase 
Magnesium 
Aspartate aminotransferase 
Potassium 
Bicarbonate 
Sodium 
Calcium  
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local practice 
 
Uric acid 
a        Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If 
total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome) then fractionate into direct 
and indirect bilirubin. 
b 
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these parameters 
is routinely measured then either lipase or amylase is acceptable. 
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c 
Bicarbonate (where available), chloride, creatinine clearance, and magnesium testing are to be performed at 
baseline, on Day 0 (unless all screening laboratory clinical chemistry assessments are performed within 3 days 
prior to Day 0), and if clinically indicated. 
d    Creatinine Clearance will be calculated by data management using Cockcroft-Gault (using actual body                             
weight).  
e 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated. Free T3 or 
free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related to the 
endocrine system 
 
 
Table 6. Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 
a Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for red 
blood cells for clinical signs of infection. Obtain per primary investigator’s discretion. 
If a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN, refer to 
Appendix 1 for further instructions on cases of increases in liver biochemistry and evaluation of 
Hy’s Law. These cases should be reported as SAEs if, after evaluation, they meet the criteria for a 
Hy’s law case or if any of the individual liver test parameters fulfill any of the SAE criteria.  
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. Situations in which laboratory safety results should be reported as AEs 
are described in Section 10.3.5. 
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation from 
IP must have further tests performed until the laboratory values have returned to Grade 1 or 2, 
unless these values are not likely to improve because of the underlying disease. 
8.3 Biological sampling procedures 
8.3.1 
Immunogenicity sampling and evaluation methods 
PD-L1 testing 
Perform PD-L1 testing per local assay 
• Tissue will be processed per institutional policies.  
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8.3.2 Archival tumor samples and fresh tumor biopsies use beyond PD-L1 (not mandated) 
8.3.2.1 
Fresh tumor biopsies 
Tumor biopsies will be performed prior to the start of therapy. Methods for obtaining biopsy can 
include: image-guided core needle biopsy. Tissue will be processed per institutional policies. 
Analyses to be conducted with biopsy and archival tumor samples include: 
immunohistochemistry, tumor mutation analysis, RNA analysis. 
9. 
DISEASE EVALUATION AND METHODS 
Rate of completion of therapy (defined as percentage of patients able to receive adjuvant 
course of Durvalumab) 
Response to trimodality therapy (chemoradiation plus Durvalumab), which will be 
evaluated in this study using the revised RECIST guideline 
(https://www.eortc.be/Recist/documents/RECISTGuidelines.pdf) with the following 
definitions: 
• 
Complete Response (CR): Disappearance of all target lesions 
• 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum LD 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to quality for Progressive Disease (PD), taking as reference the smallest 
sum LD since the treatment started.  
Progression is defined as change in a known lesion(s) not related to post-treatment effects as 
defined below:  
• At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest 
sum LD recorded since the treatment started or the appearance of one or more new lesions. 
Additionally, the absolute increase must be greater than 5 mm.  
• Appearance of ≥1 new lesions not related to post-treatment effect.  
 
Progression is further divided into local, regional or distant progression:  
• Local: Progression within the PTV.  
• Regional: Progression outside the PTV but within the same lobe of the lung as the primary 
tumor or in regional lymph nodes (AJCC 8th edition)  
• Distant: Progression at any other site (including pleural or pericardial effusion)  
 
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The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013): 
• Response to immunotherapy may be delayed 
• Response to immunotherapy may occur after PD by conventional criteria 
• The appearance of new lesions may not represent PD with immunotherapy 
• SD while on immunotherapy may be durable and represent clinical benefit. 
 
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of 
anticancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating 
anticancer compounds, the study may wish to implement the following in addition to standard 
RECIST 1.1 criteria: 
• RECIST will be modified so that PD must be confirmed at the next scheduled visit, 
preferably, and no earlier than 4 weeks after the initial assessment of PD in the absence of 
clinically significant deterioration. Treatment with durvalumab would continue between 
the initial assessment of progression and confirmation for progression.  
• In addition, patients may continue to receive durvalumab beyond confirmed PD in the 
absence of clinically significant deterioration and if investigators consider that patients 
continue to receive benefit from treatment.  
Modification of RECIST as described may discourage the early discontinuation of durvalumab 
and provide a more complete evaluation of its antitumor activity than would be seen with 
conventional response criteria. Nonetheless, the efficacy analysis will be conducted by 
programmatically deriving each efficacy endpoint based on RECIST 1.1 criteria. 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anticancer therapy other than durvalumab or with symptomatic 
progression that requires urgent medical intervention (e.g., central nervous system metastasis, 
respiratory failure due to tumor compression, spinal cord compression). 
Patients who have disease control following completion of 12 months of treatment or patients who 
are withdrawn from durvalumab treatment for reasons other than confirmed PD will continue to 
have objective tumor assessments (see Appendix ). 
9.1.1 
Efficacy variable 
Confirmation of progression guidelines are set for the following reasons:  
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• 
For patient management and treatment decisions 
• 
In the absence of significant clinical deterioration, to promote the collection of 
additional scans after the first radiologic RECIST 1.1 assessment of progressive disease 
(PD) in order to distinguish pseudo progression from true radiologic progression, also 
known as RECIST 1.1 modified for confirmation of progression 
• 
When scans are evaluated by Investigator and by BICR, to reduce informative censoring 
by Investigator assessments (Investigator assesses PD at a time-point earlier than does 
BICR). 
Confirmed objective disease progression refers to either of the following scenarios: 1. clinical 
progression/deterioration followed by a radiologic verification scan (PD by RECIST 1.1); or 2. In 
the absence of significant clinical deterioration, radiologic PD by RECIST 1.1 followed by a 
second radiologic confirmation scan with PD assessed according to the specific confirmation of 
progression criteria listed below. RECIST 1.1 modified for confirmation of progression refers to 
the second scenario above. The confirmatory scan should occur preferably at the next scheduled 
imaging visit and no earlier than 4 weeks following the date of the immediate prior assessment of 
RECIST 1.1 PD. 
Immediate prior radiologic progression would be considered confirmed if any the following 
criteria are met in the confirmatory scan: 
• 
≥20% increase in the sum diameters of target lesions (TLs) compared with the nadir at 
2 consecutive visits, with an absolute increase of at least 5 mm in sum of diameters 
compared to nadir, 
• 
And/or significant progression (worsening) of non-target lesions (NTLs) and/or of pre-
existing new lesions at the confirmatory scan time-point compared with the immediate 
prior time-point (Note: Pre-existing new lesions are evaluated as NTLs at the 
confirmatory scan time-point), 
• 
And/or additional new unequivocal lesions at the confirmatory scan time-point. 
NOTE: In order to have confirmed objective disease progression, there should be two consecutive 
assessments meeting the PD definition: the first PD by RECIST 1.1 and the second PD using the 
confirmation of progression criteria (above). If the first assessment fulfilling the PD definition by 
RECIST 1.1 is not confirmed continue with assessments until the next PD by RECIST 1.1, which 
in turn will need its own immediate subsequent confirmation scan. In the absence of significant 
clinical deterioration, treatment with study drug may continue between the initial assessment of 
progression and the scan to confirm progression. 
If the confirmation scan confirms progression, then the date of the prior scan with PD should be 
declared as the date of progression. 
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If progression is not confirmed, in the absence of significant clinical deterioration, then the patient 
should continue study drug and on-treatment assessments until the next PD which will also require 
a follow-up confirmation scan. If the first PD is not confirmed by the immediate next scan, 
then the Investigator should not change the PD assessment of the first scan. 
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiologic progression, then the patient should still continue to be followed until confirmed 
objective disease progression. 
Following confirmed progression, patients should continue to be followed up for survival status 
every 3 months as outlined in the follow-up schedules of assessments in Appendix 4  
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10. 
ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
10.1.1 
Safety parameters 
10.1.1.1 
Definition of adverse events 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a patient’s pre-existing 
condition. An abnormal laboratory finding (including ECG finding) that requires an action or 
intervention by the investigator, or a finding judged by the investigator to represent a change 
beyond the range of normal physiologic fluctuation, should be reported as an AE. 
Adverse events may be treatment emergent (i.e., occurring after initial receipt of investigational 
product) or non-treatment emergent. A non-treatment emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the patient has received investigational product.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the 
patient being enrolled into the study) for a documented pre-existing condition, that did not worsen 
from baseline, is not considered an AE (serious or nonserious). An untoward medical event 
occurring during the prescheduled elective procedure or routinely scheduled treatment should be 
recorded as an AE or SAE. 
The term AE is used to include both serious and non-serious AEs. 
10.1.2 
Definition of serious adverse events 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the 
following criteria: 
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• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital abnormality or birth defect in offspring of the patient 
• 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
• 
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or development of 
drug dependency or drug abuse 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to AstraZeneca. 
10.1.3 
Definition of adverse events of special interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring. An AESI may be 
serious or non-serious.  
If the Investigator has any questions in regards to an event being an imAE, the Investigator should 
promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
• 
Diarrhea / Colitis and intestinal perforation 
• 
Pneumonitis / ILD 
• 
hepatitis / transaminase increases 
• 
Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus) 
• 
Rash / Dermatitis 
• 
Nephritis / Blood creatinine increases 
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• 
Pancreatitis/ serum lipase and amylase increases   
• 
Myocarditis 
• 
Myositis / Polymyositis 
• 
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
• 
Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and 
other events involving the eye, skin, haematological and rheumatological events 
vasculitis, non-infectious meningitis and non-infectious encephalitis. 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab Investigator’s Brochure. More specific guidelines for their evaluation and 
treatment are described in detail in the Dosing Modification and Toxicity Management Guidelines 
(please see Appendix 1). These guidelines have been prepared by the Sponsor to assist the 
Investigator in the exercise of his/her clinical judgment in treating these types of toxicities. These 
guidelines apply to AEs considered causally related to the study drug/study regimen by the 
reporting investigator. 
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality suggestive 
of pneumonitis/interstitial lung disease is observed, toxicity management as described in detail in 
the Dosing Modification and Toxicity Management Guidelines (see Appendix 1.) will be applied. 
The results of the full diagnostic workup (including high-resolution computed tomography 
(HRCT), blood and sputum culture, hematological parameters etc.) will be captured in the eCRF. 
It is strongly recommended to perform a full diagnostic workup, to exclude alternative causes such 
as lymphangitis carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have 
been excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing 
Modification and Toxicity Management Guidelines should be followed.  
Pneumonitis (ILD) investigation 
The following assessments, and additional assessments if required, will be performed to enhance 
the investigation and diagnosis of potential cases of pneumonitis. The results of the assessment 
will be collected. 
• 
Physical examination 
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− 
Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including 
auscultation for lung field will be assessed. 
• 
SpO2 
− 
Saturation of peripheral oxygen (SpO2) 
• 
Other items 
− 
When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible: 
(i) 
ILD Markers (KL-6, SP-D) and β-D-glucan 
(ii) 
Tumor markers: Particular tumor markers which are related to disease 
progression.  
Additional Clinical chemistry: CRP, LDH 
 
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10.2 
Assessment of safety parameters 
10.2.1 
Assessment of severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v5.0. 
The determination of severity for all other events not listed in the CTCAE should be made by 
the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below. 
Grade 1 (mild)  
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
 
Grade 2 (moderate)  
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities 
of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the patient. 
 
Grade 3 (severe)  
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the patient. 
 
Grade 4 (life-threatening)  
An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or with physical or mental disabilities that 
affect or limit the ability of the patient to perform activities of daily 
living (eating, ambulation, toileting, etc). 
 
Grade 5 (fatal)  
 
Death (loss of life) as a result of an event. 
 
 
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 10.1.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE. 
 
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10.2.2 
Per internal Rush Cancer Center Standard Operating procedures, Rush Cancer Center Data 
Safety Monitoring committee with be overseeing patient safety for this trial. 
10.3 
Recording of adverse events and serious adverse events 
Grade 3-4 non hematologic and grade 4 hematologic SAEs will be collected from the time of the 
patient starting concurrent chemotherapy and radiation until the follow-up period is completed (90 
days after the last dose of durvalumab).  If an event that starts post the defined safety, follow up 
period noted above is considered to be due to a late onset toxicity to study drug then it should be 
reported as an AE or SAE as applicable. 
During the course of the study, all SAEs should be proactively followed up for each patient for as 
long as the event is ongoing.  Every effort should be made to obtain a resolution for all events, 
even if the events continue after the patient has discontinued study drug or the study has completed. 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF.  
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
The following variables will be collected for each AE: 
In addition, the following variables will be collected for SAEs as applicable: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
The maximum CTCAE grade reported 
• 
Changes in CTCAE grade 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IPs (yes or no) 
• 
Action taken with regard to IPs 
• 
Administration of treatment for the AE 
• 
Outcome 
In addition, the following variables will be collected for SAEs: 
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• 
Date the AE met criteria for SAE 
• 
Date the Investigator became aware of the SAE 
• 
Seriousness criteria fulfilled 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Whether an autopsy was performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment in relation to other medication, as explained in 
Section 10.3.2 
• 
Description of the SAE 
The grading scales found in the NCI CTCAE version 5.0 will be utilized for all events with an 
assigned CTCAE grading. For those events without assigned CTCAE grades, the recommendation 
in the CTCAE criteria that converts mild, moderate, and severe events into CTCAE grades should 
be used. A copy of the CTCAE version 5.0can be downloaded from the Cancer Therapy Evaluation 
Program website (http://ctep.cancer.gov). 
• 
Events, which are unequivocally due to disease progression, should not 
be reported as an AE during the study. 
10.3.1 
Study recording period and follow-up for adverse events and 
serious adverse events 
Adverse events and serious adverse events will be recorded from initiation of treatment period 
and including the follow-up period (90 days after the last dose of durvalumab).  
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During the course of the study all AEs and SAEs should be proactively followed up for each 
patient. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
If a patient discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related SAEs must be captured until the 
patient is considered to have confirmed PD and will have no further tumor assessments. 
The investigator is responsible for following all SAEs until resolution, until the patient returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
10.3.2 
Causality collection 
The Investigator will assess causal relationship between the IPs and each AE and answer “yes” or 
“no” to the question “Do you consider that there is a reasonable possibility that the event may have 
been caused by the investigational product?” 
For SAEs causal relationship will also be assessed for other medication and study procedures. Note 
that for SAEs that could be associated with any study procedure, the causal relationship is implied 
as “yes.” 
A guide to the interpretation of the causality question is found in Appendix 1. 
10.3.3 
Relationship to protocol procedures 
The Investigator is also required to provide an assessment of the relationship of SAEs to protocol 
procedures on the SAE report form. This includes both non-treatment–emergent (i.e., SAEs that 
occur prior to the administration of IP) and treatment-emergent SAEs. A protocol-related SAE 
may occur as a result of a procedure or intervention required during the study (e.g., blood 
collection). The following guidelines should be used by Investigators to assess the relationship of 
SAEs to the protocol: 
• 
Protocol related: The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the 
patient’s medical record. 
• 
Not protocol related: The event is related to an etiology other than the procedure or 
intervention that was described in the protocol. The alternative etiology must be 
documented in the study patient’s medical record. 
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10.3.4 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question from 
the study personnel: “Have you had any health problems since the previous visit/you were last 
asked?” or revealed by observation will be collected and recorded in the eCRF. When collecting 
AEs, the recording of diagnoses is preferred, when possible, to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not 
generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
10.3.5 
Adverse events based on examinations and tests 
The results from protocol-mandated laboratory tests and vital signs measurements will be 
summarized in the CSR. Deterioration as compared to baseline in protocol-mandated laboratory 
values and vital signs should therefore only be reported as AEs if they fulfill any of the SAE criteria 
or are the reason for discontinuation of treatment with the IPs. 
If deterioration in a laboratory value or vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result or vital sign 
will be considered as additional information. Whenever possible, the reporting Investigator should 
use the clinical rather than the laboratory term (e.g., anemia versus low hemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AEs. 
Deterioration of a laboratory value that is unequivocally due to disease progression should not be 
reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE. 
10.3.6 
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to be 
reported as SAEs. Please refer to Appendix 1 for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s law. 
10.3.7 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the IP is being studied. It may be an increase in the severity of the disease under 
study and/or increases in the symptoms of the disease. The development of new or progression of 
existing metastasis to the primary cancer under study should be considered as disease progression 
and not an AE. Events that are unequivocally due to disease progression should not be reported as 
an AE during the study. 
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10.3.8 
New cancers 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the IP and have been identified after the 
patient’s inclusion in this study. 
10.3.9 
Deaths 
All deaths that occur during the study treatment period, or within the protocol-defined follow-up 
period after the administration of the last dose of study drug, must be reported as follows: 
• 
Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the eCRF 
in the Statement of Death page. It should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the Study Monitor/Physician as an SAE 
within 24 hours. It should also be documented in the Statement of Death page in the 
eCRF. The report should contain a comment regarding the co involvement of PD, if 
appropriate, and should assign main and contributory causes of death. 
• 
Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the Statement of Death page in the eCRF. A postmortem may be 
helpful in the assessment of the cause of death, and if performed, a copy of the post-
mortem results should be forwarded to AstraZeneca Patient Safety or its representative 
within the usual timeframes. 
Deaths occurring after the protocol defined safety follow up period after the administration of the 
last dose of study drug should be documented in the Statement of Death page. If the death occurred 
as a result of an event that started after the defined safety follow up period and the event is 
considered to be due to a late onset toxicity to study drug, then it should also be reported as an 
SAE. 
AstraZeneca/MedImmune retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. After 
90 days, only patients with ongoing investigational product related SAEs will continue to be 
followed for safety. 
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AstraZeneca/MedImmune retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Post-study events 
 
After the patient has been permanently withdrawn from the study, there is no obligation for the 
investigator to actively report information on new AE or SAEs occurring in former study patients 
after the 90-day safety follow-up period for patients treated with durvalumab. However, if an 
investigator learns of any SAEs, including death, at any time after the patient has been 
permanently withdrawn from study, and he/she considers there is a reasonable possibility that the 
event is related to study treatment, the investigator should notify the study sponsor and 
AstraZeneca/MedImmune Drug Safety. 
 
10.3.10 
Reporting of serious adverse events 
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period immediately 
following the time that written informed consent is obtained through 90 days after the last dose 
of durvalumab or until the initiation of alternative anticancer therapy. The investigator and/or 
Sponsor are responsible for informing the Ethics Committee and/or the Regulatory Authority of 
the SAE as per local requirements. 
Note that all serious or unexpected adverse events must be reported to AstraZeneca regardless 
of the country where the study is conducted: 
The investigator and/or sponsor must inform the FDA, via a MedWatch/AdEERs form, of any 
serious or unexpected adverse events that occur in accordance with the reporting obligations of 
21 CFR 312.32, and will concurrently forward all such reports to AstraZeneca. A copy of the 
MedWatch/AdEERs report must be emailed to AstraZeneca at the time the event is reported to 
the FDA. It is the responsibility of the sponsor to compile all necessary information and ensure 
that the FDA receives a report according to the FDA reporting requirement timelines and to 
ensure that these reports are also submitted to AstraZeneca at the same time. 
* A cover page should accompany the MedWatch/AdEERs form indicating the following: 
• 
“Notification from an Investigator Sponsored Study” 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
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• 
The trial name/title and AstraZeneca ISS reference number (ESR-18-14205) 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events 
in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca preferably using the MedDRA coding language for serious adverse 
events. This information should be reported on a monthly basis and under no circumstance less 
frequently than quarterly.  
In the case of blinded trials, AstraZeneca will request that the Sponsor either provide a copy of 
the randomization code/ code break information or unblind those SAEs which require expedited 
reporting. 
 
10.3.11 
Reporting of deaths to AstraZeneca 
All deaths that occur during the study, or within the protocol (defined 90day post last dose of 
durvalumab safety follow-up period) must be reported to AstraZeneca as follows: 
• 
Death that is clearly the result of disease progression should be 
documented but should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease 
under study, the AE causing the death must be reported to AstraZeneca 
as a SAE within 24 hours (see Section 10.3.2 10 for further details). 
The report should contain a comment regarding the coinvolvement of 
progression of disease, if appropriate, and should assign main and 
contributory causes of death.  
• 
Deaths with an unknown cause should always be reported as a SAE.  
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab safety 
follow-up period will be documented <<as events for survival analysis>> but will not be 
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reported as an SAE. However, if an investigator learns of any SAEs, including death, at any time 
after the patient has been permanently withdrawn from study, and he/she considers there is a 
reasonable possibility that the event is related to study treatment, the investigator should notify 
the study sponsor and AstraZeneca/MedImmune Drug Safety. 
10.3.12 
Other events requiring reporting 
10.3.13 
Overdose 
An overdose is defined as a patient receiving a dose of durvalumab in excess of that specified in 
the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study patient with durvalumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox (see 
Section 10.3.2 10 for contact information). If the overdose results in an AE, the AE must also be 
recorded as an AE (see Section 10.3). Overdose does not automatically make an AE serious, but 
if the consequences of the overdose are serious, for example death or hospitalization, the event is 
serious and must be recorded and reported as an SAE (see Section 10.1.2 and Section 10.3.2 10). 
There is currently no specific treatment in the event of an overdose of durvalumab.  
The investigator will use clinical judgment to treat any overdose. 
10.3.14 
Hepatic function abnormality 
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law case in 
a study patient, with or without associated clinical manifestations, is required to be reported as 
“hepatic function abnormal” within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca Patient Safety using the designated Safety e-mailbox (see Section 10.3.2 10 for 
contact information), unless a definitive underlying diagnosis for the abnormality (e.g., 
cholelithiasis or bile duct obstruction) that is unrelated to investigational product has been 
confirmed. The criteria for a potential Hy’s Law case is Aspartate Aminotransferase (AST) or 
Alanine Aminotransferase (ALT) ≥3x Upper Limit of Normal (ULN) together with Total Bilirubin 
(TBL) ≥2xULN at any point during the study following the start of study medication irrespective 
of an increase in Alkaline Phosphatase (ALP). 
• If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study patient 
will be based on the clinical judgment of the investigator. 
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• If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study patient must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  
10.3.15 
Pregnancy 
10.3.16 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately.  
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may 
have interfered with the effectiveness of a contraceptive medication. Congenital abnormalities or 
birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective 
abortions without complications should not be handled as AEs. The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) should be followed up and documented even if the patient was discontinued from the 
study.  
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, i.e., immediately, but no 
later than 24 hours of when he or she becomes aware of it.  
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs and within 30 days for all other pregnancies.  
The same timelines apply when outcome information is available.  
10.3.17 
Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of durvalumab + any drug combination therapy or 90 days after the 
last dose of durvalumab monotherapy, whichever is the longer time period.  
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 180 days after the last dose 
of durvalumab + any drug combination therapy or 90 days after the last dose of durvalumab 
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monotherapy, whichever is the longer time period should, if possible, be followed up and 
documented.  
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient’s partner. Therefore, the local study team should 
adopt the generic ICF template in line with local procedures and submit it to the relevant Ethics 
Committees (ECs)/Institutional Review Boards (IRBs) prior to use.  
10.4 
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in the 
treatment process for an AstraZeneca study drug that either causes harm to the patient or has the 
potential to cause harm to the patient.  
A medication error is not lack of efficacy of the drug, but rather a human or process related failure 
while the drug is in control of the study site staff or patient. 
Medication error includes situations where an error:  
• Occurred 
• Was identified and intercepted before the patient received the drug 
• Did not occur, but circumstances were recognized that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 
• Drug name confusion 
• Dispensing error e.g. medication prepared incorrectly, even if it was not actually given to 
the patient 
• Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a solid 
tablet  
• Drug not stored as instructed e.g. kept in the fridge when it should be at room temperature  
• Wrong patient received the medication  
• Wrong drug administered to patient  
Examples of events that do not require reporting as medication errors in clinical studies: 
• Errors related to or resulting from IVRS/IWRS - including those that lead to one of the 
above listed events that would otherwise have been a medication error  
• Patient accidentally missed drug dose(s) e.g. forgot to take medication 
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• Accidental overdose (will be captured as an overdose) 
• Patient failed to return unused medication or empty packaging 
• Errors related to background and rescue medication, or standard of care medication in open 
label studies, even if an AZ product  
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the medication 
error.  
If a medication error occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within 1 or 5 calendar days if there is an SAE associated with the 
medication error (see Section 10.3.10) and within 30 days for all other medication errors. 
 
 
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11. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
11.1 
Description of analysis sets 
11.1.1 
Safety analysis set 
Safety Assessments: Safety will be monitored continually throughout the protocol. Assessments 
include serious adverse events, vital signs, and physical and laboratory examinations, as well as 
immune-mediated adverse events. 
Chemotherapy safety measurements are limited to grade 3-4 non hematologic toxicities and 
grade 4 hematologic toxicities. 
SAEs possibly, probably or definitely related to RT (including grade 3-4 congestive heart failure, 
pneumonitis, arrhythmias, and myocardial infarction, grade 4 esophagitis, and any AEs that lead 
to hospitalization) that causes either an interruption or early termination of RT will be reported. 
Proportion of patients who have tolerated the treatment will be provided. All adverse events will 
be graded according to CTCAE v 5.0. 
Durvalumab safety measurements are described in detail in protocol (section 10. The tolerability 
of therapy is defined as having one or no safety events defined as: 1) grade 4-5 non-hematologic 
serious adverse events (SAEs) as defined in CTCAE v5.0, probably or definitely related to 
protocol treatment by 90 days from the start of Durvalumab; 2) Any adverse events that lead to 
prolonged dose delays (defined as skipping at least 2 doses of Durvalumab; 3) Permanent 
discontinuation of Durvalumab due to toxicity within the first 30 days of starting Durvalumab. 
We expect 80% of patients enrolled to complete 4 cycles of concurrent split-course CRT, and in 
those to go on to receive Durvalumab, we expect no more than 20% of patients to have therapy 
terminated for Durvalumab-related toxicities. 
11.1.2 
Efficacy analysis set 
Efficacy analysis is part of the secondary objectives of the study. Efficacy endpoints include (i) 
overall survival (OS) and 1-year overall survival rate; (ii) progression-free survival and 1-year 
progression-free survival rate and (iii) loco-regional progression-free survival (PFS) and its 1-
year rate. The efficacy endpoint of OS will be measured as time from diagnosis to death from 
any cause.  PFS is defined as the time from diagnosis to the first occurrence of disease 
progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or 
death from any cause, whichever occurs first. Loco-regional progression-free survival will be 
defined in a similar way. Data for patients without disease progression or death will be censored 
at the last follow-up date. 
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11.2 
Methods of statistical analyses 
11.2.1 
Safety analyses 
The safety analyses will include all treated patients.  Safety will be assessed through summaries of 
AEs, changes in test results, changes in vital signs, and exposures. The results will be reported by 
tabulation and by descriptive summaries. 
The two primary objectives of the study are (i) completion of chemotherapy/split course chest 
radiation; and (ii) safety/tolerability of the durvalumab post-chemoradiation. The first objective 
will be assessed as a binary endpoint of yes/no completion for each patient. The completion rate, 
overall as well as stratified by demographic and clinical characteristics will be reported in tabular 
forms.  
The second primary objective of safety/tolerability of durvalumab will be measured by (a) the 
number of cycles of durvalumab received for each treated patient and (b) the binary endpoint of 
discontinuation of durvalumab. Each of these endpoints will be reported by descriptive summaries 
and tabulation. 
A secondary objective of the study is determination of grade 3 and 4 toxicities in the selected 
population. The binary endpoint of (yes/no) grade 3 and 4 toxicities will be tabulated. 
For each of the binary endpoints, the overall rate will be reported with 90% confidence interval. 
Due to the limited sample size, both asymptotic (such as Agresti-Coull) and exact Binomial 
confidence intervals will be reported. Similarly, the endpoint of number of cycles of durvalumab 
received will also be reported with 95% confidence interval. 
11.2.2 
Efficacy analyses 
The efficacy analyses will include all treated patients, grouped according to treatment actually 
received (those patients that completed all study treatments vs those that had study treatments 
discontinued). Efficacy endpoints include (i) overall survival (OS) and 1-year overall survival rate; 
(ii) progression-free survival and 1-year progression-free survival rate and (iii) loco-regional 
progression-free survival and its 1-year rate. OS, PFS and loco-regional-PFS will be analyzed and 
described by the Kaplan-Meier method. Median survival and, 25th and 75th percentiles will be 
reported along with confidence intervals, as appropriate. 1-year OS, 1-year PFS and 1 year loco-
regional-PFS will be estimated based on the Kaplan-Meier approach. 
 
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11.3 
Determination of sample size 
  
For the primary endpoint of completion rate of chemotherapy/split course chest radiation, where 
we anticipate 80% completion, a sample size of n=30 provides power of about 0.8 in a non-
inferiority test with non-inferiority margin of 0.18 and alpha =0.05. This will allow estimation of 
the completion rate within ±0.13 using a 90% confidence interval (normal approximation) or 
within a total width of 0.30 (using exact Binomial interval).  
For the endpoint of completion of durvalumab post-chemoradiation, we estimate post-
chemoradiation n of 24 (assuming 80% completion of chemoradiation). This will allow 
estimation of durvalumab completion rate within ±0.13 using a 90% confidence interval (normal 
approximation) or within a total width of 0.30 (using exact Binomial interval). 
 
12. 
FOR THE SECONDARY ENDPOINTS, WITH N= 30 SUBJECTS, 
WE ESTIMATE 70% POWER TO DETECT IMPROVEMENT IN 
PFS FOR ADDING DURVALUMAB AND 55% POWER TO 
DETECT IMPROVEMENT IN OS, EACH AT A LIBERAL 0.10 
LEVEL OF SIGNIFICANCE AND WITHOUT ADJUSTING FOR 
MULTIPLICITY. (WITHOUT DURVALUMAB, THE MEDIAN 
SURVIVAL IS KNOWN TO BE 20 MONTHS IN THIS PATIENT 
POPULATION; WE EXPECT THAT ADDING DURVALUMAB IN 
THE TREATMENT REGIMEN WILL IMPROVE THE MEDIAN 
SURVIVAL TO 30 MONTHS. WITHOUT DURVALUMAB, THE 
MEDIAN PROGRESSION FREE SURVIVAL (PFS) IS KNOWN 
TO BE 11 MONTHS IN THIS PATIENT POPULATION; WE 
EXPECT THAT ADDING DURVALUMAB IN THE TREATMENT 
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REGIMEN WILL IMPROVE THE MEDIAN PFS TO 17 
MONTHS.)ETHICAL AND REGULATORY REQUIREMENTS 
12.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Patient data protection. 
12.2 
Ethics and regulatory review 
Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board (IRB) or 
Research Ethics Board (REB) responsible for oversight of the patient according to institutional 
policy. 
The PI / Radiation Oncologist, Dr. Marwaha, will perform a pre-treatment RT Quality Assurance 
Review for each case enrolled. 
The Co-PI / Medical Oncologist, Dr. Fidler, will perform a pre-treatment chemotherapy / 
immunotherapy Quality Assurance Review for each case enrolled. 
The scoring mechanisms is: 1) Per Protocol, 2) Acceptable Variation, 3) Unacceptable 
Deviation, and 4) Not Evaluable. 
12.3 
Informed consent 
Patients must have signed and dated all applicable consents and authorization forms prior to 
enrollment and before performing screening procedures. The form will be signed and personally 
dated by the subject, parent, legal guardian or caretaker and by the Investigator, Sub investigator 
or study coordinator designated by the Investigator to conduct the informed consent discussion. 
Informed consent form used during the process must be the latest version IRB approved. A copy 
of the form is require to be given to the subject and the original version will be kept in the 
subject research chart.  
12.4 
Changes to the protocol and informed consent form 
Changes to the protocol and informed consent forms are permitted but must be approved by PI 
and Co-PIs and be in compliance with study site / AstraZeneca regulations. IRB approval of 
changes is required.  
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13. 
STUDY MANAGEMENT 
13.1 
Training of study site personnel 
Study site personnel will all have access to the protocol, and receive any specific training as 
deemed fit by the PI and Co-PIs.  
13.2 
Data collection 
Data collected during this study will be entered into a secure database (REDCap) using 
electronic case report forms, eCRF. Principal investigator is responsible for ensuring eCRFs are 
completed accurately and in a timely manner. Original records of observations, clinical findings 
and evaluations that are subsequently recorded as data will be made available to support the 
subject’s research record. The investigator will maintain adequate and accurate records to enable 
the conduct of the study to be fully documented and the study data to be subsequently verified. 
After study closure, the investigator will maintain all source documents and study-related 
documents. Records are to be retained and securely stored until the later of: (a) two (2) years 
following the date a New Drug Application is approved for the Study Drug that is the subject of 
the Clinical Trial; or (b) two (2) years after the Investigational New Drug Application for such 
Study Drug is terminated or withdrawn, or such longer period of time as may be required by site 
policies, applicable laws, rules or regulations.  
13.3 
Monitoring of the study 
13.3.1 
Source data 
Source data for every subject will be kept in the subject’s research chart at the coordinator’s 
office under double lock doors with accordance to FDA regulations. These files can be made 
available during monitoring visits to provide source verification for EDC correlation. Incorrect 
or missing entries on to the CRFs will be required and must be corrected immediately upon 
finding. 
13.4 
Study timetable and end of study 
The study chairs will meet every 6 months to monitor the trial for safety. Interim reports with 
descriptive statistics will be prepared twice a year until the initial paper reporting the treatment 
results has been accepted for publication. In general, the interim reports will contain information 
about the patient accrual rate with a projected completion date for the accrual phase; data quality; 
compliance rate of treatment delivery with the distributions of important prognostic baseline 
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variables; and the frequencies and severity of adverse events. The interim reports will not contain 
results. These reports will be submitted to the Rush Protocol Review and Monitoring Committee.  
14. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
14.1 
Identity of investigational product(s) 
 
Table 1. List of Investigational Products for This Study 
Investigational product 
Dosage form and strength 
Manufacturer 
Durvalumab 
50 mg/mL solution for infusion 
after dilution  
AstraZeneca 
 
 
 
 
 
 
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15. 
LIST OF REFERENCES 
 
Alexandrov et al. 2013 
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Blankin AV, et al. 
Signatures of mutational processes in human cancer. Nature. 2013 Aug 22;500:415-21. 
Antonia et al. 2018 
Antonia S, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after 
Chemoradiotherapy in Stage III NSCLC. N Engl J Med 2018; 379:2342-2350. 
 
Antonia et al. 2017 
Antonia, S. J., A. Villegas, D. Daniel, D. Vicente, S. Murakami, R. Hui, T. Yokoi, et al. 
Durvalumab after Chemoradiotherapy in Stage Iii Non-Small-Cell Lung Cancer. [In eng]. N Engl 
J Med 377, no. 20 (Nov 16 2017): 1919-29. 
 
Bonomi et al. 2018 
Bonomi, P., G. Blumenthal, A. S. Ferris, D. J. Stewart, W. K. D. Selig, L. M. Krug, J. Allen, et al. 
"Making Lung Cancer Clinical Trials More Inclusive: Recommendations for Expanding Eligibility 
Criteria." [In eng]. J Thorac Oncol 13, no. 6 (Jun 2018): 748-51. 
Brahmer et al. 2012 
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of 
anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun;366 (26):2455-65. 
Brahmer et al. 2014 
Brahmer JR, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Nivolumab (anti-PD-1, 
BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): 
Survival and clinical activity by subgroup analysis [ASCO abstract 8112]. J Clin Oncol 
2014;32(Suppl). 
Butte et al. 2007 
Butte MJ, Keir ME, Phamduy TB, Freeman GJ, Sharpe AH. PD-L1 interacts specifically with B7-
1 to inhibit T cell proliferation. Immunity. 2007;27:111-22. 
Chun et al. 2017 
Chun, S. G., C. Hu, H. Choy, R. U. Komaki, R. D. Timmerman, S. E. Schild, J. A. Bogart, et al. 
"Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-
Cell Lung Cancer: A Secondary Analysis of the Nrg Oncology Rtog 0617 Randomized Clinical 
Trial." [In eng]. J Clin Oncol 35, no. 1 (Jan 2017): 56-62. 
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Drake et al. 2013 
Drake CG, McDermott DF, Sznol M, Choueiri TK, Kluger HM, Powderly JD et al. Survival, 
safety, and response duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a 
phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): Long-
term patient follow-up [abstract 4514]. J Clin Oncol 2013;31(Suppl). 
Dunn et al. 2004 
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 
2004;22:329-60. 
Ellis et al. 2008 
Ellis S, Carroll KJ, Pemberton K. Analysis of duration of response in oncology trials. Contemp 
Clin Trials 2008;29(4):456-65. 
Fairman et al. 2014 
Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C, et al. Pharmacokinetics of 
durvalumab, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid 
tumours. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts;32(5s): (suppl; 
abstr 2602).  
Fife and Bluestone 2008 
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 
and PD-1 pathways. Immunol Rev. 2008;224:166-82. 
Garg et al. 2014 
Garg, S., B. T. Gielda, K. Kiel, J. V. Turian, M. J. Fidler, M. Batus, P. Bonomi, and D. J. Sher. 
"Patterns of Locoregional Failure in Stage Iii Non-Small Cell Lung Cancer Treated with Definitive 
Chemoradiation Therapy." [In eng]. Pract Radiat Oncol 4, no. 5 (Sep-Oct 2014): 342-48. 
Gielda et al. 2011 
Gielda, B. T., J. C. Marsh, T. W. Zusag, L. P. Faber, M. Liptay, S. Basu, W. H. Warren, et al. 
"Split-Course Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Single-
Institution Experience of 144 Patients." [In eng]. J Thorac Oncol 6, no. 6 (Jun 2011): 1079-86. 
Herbst et al. 2013 
Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria JC, Hamid O, et al. A study of MPDL3280A, 
an engineered PD-L1 antibody in patients with locally advanced or metastatic tumours [abstract 
3000]. J Clin Oncol 2013;31(Suppl 15). 
Hirano et al. 2005 
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and PD-
1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 
2005;65(3):1089-96. 
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Hodi et al. 2014 
Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP et al. Long-term 
survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with 
nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a Phase I trial [ASCO abstract 9002]. J Clin 
Oncol 2014; 32(Suppl). 
Iwai et al. 2002 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc 
Natl Acad Sci USA. 2002 Sep 17;99:12293-7. 
Jalal et al. 2011 
Jalal S.I., Riggs H.D., Melnyk A., et al. Updated survival and outcomes for older adults with 
inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent 
chest radiation with or without consolidation docetaxel: analysis of a phase III trial from the 
Hoosier Oncology Group (HOG) and US Oncology. Annals of Oncology 23: 1730–1738, 2012 
Keir et al. 2008 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol. 2008;26:677-704. 
Koshy et al. 2017 
Koshy, M., R. Malik, M. Spiotto, U. Mahmood, C. G. Rusthoven, and D. J. Sher. "Association 
between Intensity Modulated Radiotherapy and Survival in Patients with Stage Iii Non-Small Cell 
Lung Cancer Treated with Chemoradiotherapy." [In eng]. Lung Cancer 108 (Jun 2017): 222-27. 
 
Lan and DeMets 1983 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63 
Narwal et al. 2013 
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an investigational 
anti-interferon-alpha monoclonal antibody, in systemic lupus erythematosus. Clin Pharmacokinet 
2013;52:1017–27. 
Ng et al. 2006 
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab in 
cancer patients based on population pharmacokinetic analysis. Pharm Res 2006;23(6):1275–84. 
Okudaira et al. 2009 
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of B7-H1 or 
B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol. 2009 
Sep;35(4):741-9. 
ORA: 19010808-IRB02   Date IRB Approved: 3/29/2023   Amendment Date: 6/12/2023


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
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Pardoll 2012 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
2012;12:252-64. 
Paterson et al. 2011 
Paterson AM, Brown KE, Keir ME, Vanguri VK, Riella LV, Chandraker A, et al. The PD-L1:B7-
1 pathway restrains diabetogenic effector T cells in vivo. J Immunol. 2011;187:1097-105. 
Powles et al. 2014 
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) 
treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 
27;515(7528):558-62. 
Qin et al. 2016 
Qin A, Coffey, DG, Warent EH, Ramnath N. Mechanisms of immune evasion and current status 
of checkpoint inhibitors in non-small cell lung cancer. Cancer Med. 2016 Sep: 5(9): 2567-2578. 
 
Rizvi et al. 2015 
Rizvi N, Brahmer J, Ou S-H, Segal NH, Khleif SN, Hwu WJ. Safety and clinical activity of 
MEDI4736, an anti-programmed cell death-ligand-1 (PD-L1) antibody, in patients with nonsmall 
cell lung cancer (NSCLC). J Clin Oncol 2015;33:Abstract 8032. 
 
Schadendorf et al. 2013 
Schadendorf D, Hodi FS, Robert C et al. Pooled analysis of long-term survival data from phase II 
and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma 
[abstract 24]. Presented at European Cancer Congress 2013 (ECCO-ESMO-ESTRO); 27 
September to 01 October 2013; Amsterdam, The Netherlands.  
Segal et al. 2015 
Segal NH, Ou S-HI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer JR, et al. Safety and 
efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of 
the head and neck (SCCHN) expansion cohort. J Clin Oncol 2015;33:Abstract 3011. 
Stewart et al. 2015 
Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E, et al. Identification and 
characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer 
Immunol Res 2015;3(9):1052-62. 
Stinchcombe et al. 2017 
Stinchcombe T.E., Zhang Y., Vokes E.E., et al. Pooled Analysis of Individual Patient Data on 
Concurrent Chemoradiotherapy for Stage III Non–Small-Cell Lung Cancer in Elderly Patients 
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Compared With Younger Patients Who Participated in US National Cancer Institute Cooperative 
Group Studies. J Clin Oncol. 2017 Sep 1;35(25):2885-2892 
 
Topalian et al. 2012 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-
54. 
Topalian et al. 2014 
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH et al. Survival, 
durable tumor remission, and long-term safety in patients with advanced melanoma receiving 
nivolumab. J Clin Oncol, 2014;32:1020-30. 
Wang et al. 2009 
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009;49(9):1012–24. 
Wolchok et al. 2013 
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab 
plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-33. 
Yuan et al. 2011 
Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, et al. Integrated NY-ESO-
1 antibody and CD8+ T-cell responses correlated with clinical benefit in advanced melanoma 
patients treated with ipilimumab. Proc Natl Acad Sci U S A 2011;108:16723-8. 
Zhang et al. 2008 
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Anti-tumor immunotherapy by blockade of the 
PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy. 2008;10(7):711-9. 
Zhang et al. 2012 
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol 2012;52(1):18–28. 
Zou and Chen 2008 
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev 
Immunol. 2008;8(6):467-77. 
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APPENDIX 1. 
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions  Version (CTCAE v5.0) 
General Considerations 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v5.0. 
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/study 
regimen 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing 
 Grade 1 
No dose modification 
 Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper. 
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is controlled. 
It is recommended that management of immune-mediated adverse events (imAEs) 
follows the guidelines presented in this table: 
− 
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines. 
− 
Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) to a possible immune-
mediated event. In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related. General 
recommendations follow. 
− 
Symptomatic and topical therapy should be considered for low-grade (Grade 
1 or 2, unless otherwise specified) events.  
− 
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) 
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Some events with high likelihood for morbidity and/or mortality – e.g., 
myocarditis, or other similar events even if they are not currently noted in 
the guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if 
clinical suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation. 
− 
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2 to 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 


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AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI 
National Cancer Institute; PO By mouth. 
 
 
 
 
 
− 
 
2. 
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are at ≤10 mg/day or equivalent. 
   Grade 3 
Depending on the individual toxicity, study drug/study regimen may 
be permanently discontinued. Please refer to guidelines below. 
   Grade 4 
Permanently discontinue study drug/study regimen. 
 Note: For asymptomatic amylase or lipase levels of >2X ULN, hold study 
drug/study regimen, and if complete work up shows no evidence of pancreatitis, 
study drug/study regimen may be continued or resumed. 
Note: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper 
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).  
 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of 
taper). 
− 
More potent immunosuppressives such as TNF inhibitors (e.g., infliximab) 
(also refer to the individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if they are 
not currently noted in the guidelines – when these events are not responding 
to systemic steroids. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis 
carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
− 
Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit-risk analysis for that patient. 


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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan. 
Grade 1 
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications required. 
However, consider holding study 
drug/study regimen dose as clinically 
appropriate and during diagnostic work-
up for other etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated. 
− 
Consider Pulmonary and Infectious disease consult. 
Grade 2 
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL) 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. 
For Grade 2 (mild to moderate new symptoms): 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started 
− 
If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 


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(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])a 
− 
Consider pulmonary and infectious disease consult. 
− 
Consider, as necessary, discussing with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[e.g., tracheostomy or 
intubation]) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life-threatening): 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain Pulmonary and Infectious disease consult; consider, as 
necessary, discussing with study physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks’ dose) started. 
Caution: rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a 
Diarrhea/Colitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes 
in bowel habits such as increased frequency over baseline or 


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blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event. 
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
(Diarrhea: stool 
frequency of <4 over 
baseline per day) 
(Colitis: asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment. 
Grade 2 
(Diarrhea: stool 
frequency of 4 to 6 
over baseline per day; 
limiting instrumental 
ADL) (Colitis: 
abdominal pain; mucus 
or blood in stool) 
Hold study drug/study regimen until 
resolution to Grade ≤1 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then study drug/study regimen can 
be resumed after completion of 
steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
GI consult should be obtained for consideration of further 
workup, such as imaging and/or colonoscopy, to confirm 


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colitis and rule out perforation, and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 
mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as infliximab at 5 mg/kg once 
every 2 weeksa. Caution: it is important to rule out bowel 
perforation and refer to infliximab label for general guidance 
before using infliximab. 
− 
Consider, as necessary, discussing with study physician if no 
resolution to Grade ≤1 in 3 to 4 days. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3 diarrhea: 
stool frequency of ≥7 
over baseline per day; 
limiting self care ADL; 
Grade 4 diarrhea: life 
threatening 
consequences) 
(Grade 3 colitis: severe 
abdominal pain, fever; 
ileus; peritoneal signs; 
Grade 4 colitis: life-
threatening 
consequences, urgent 
intervention indicated) 
 
Grade 3 
Permanently discontinue study 
drug/study regimen for Grade 3 if 
toxicity does not improve to Grade ≤1 
within 14 days; study drug/study regimen 
can be resumed after completion of 
steroid taper. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen.  
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (e.g., infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 


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Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any elevation in AST, 
ALT or TB > ULN 
 
General Guidance 
 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, 
and TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications). 
 AST or ALT >ULN 
and ≤3.0×ULN and/or 
TB > ULN and 
≤1.5×ULN 
• 
No dose modifications. 
• 
If it worsens, then treat as described 
for elevations in the row below.  
− 
Continue LFT monitoring per protocol. 
 AST or  
ALT >3.0×ULN and 
≤5.0×ULN and/or  
TB >1.5×ULN and 
≤3.0×ULN 
• 
Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤3.0×ULN and/or TB   ≤1.5×ULN. 
• 
If toxicity worsens, then treat as 
described for elevations in the row 
below. 
• 
If toxicity improves to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN, or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper. 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 2 
days) until elevations of these are improving or resolved. 
− 
If no resolution to AST or ALT ≤3.0×ULN and/or TB   
≤1.5×ULN in 1 to 2 days, consider, as necessary, discussing 
with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil).a Discuss 
with study physician if mycophenolate mofetil is not 
available. Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 


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 AST or  
ALT >5.0×ULN 
and/or  
TB >3.0×ULN 
 
  
For elevations in transaminases 
≤8 × ULN, or elevations in TB 
≤5 × ULN: 
• Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤3.0×ULN and/or TB   ≤1.5×ULN, 
or baseline 
• Resume study drug/study regimen if 
elevations downgrade to AST or 
ALT ≤3.0×ULN and/or TB 
≤1.5×ULN, or baseline within 
14 days and after completion of 
steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN or 
baseline within 14 days. 
For elevations in transaminases 
>8 × ULN or elevations in bilirubin >5 × 
ULN, permanently discontinue study 
drug/study regimen. 
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria (AST and/or ALT 
>3×ULN + bilirubin >2×ULN without 
initial findings of cholestasis (i.e., 
elevated alkaline P04) and in the absence 
of any alternative cause.b 
− 
 Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used. 
− 
Perform hepatology consult, abdominal workup, and imaging 
as appropriate. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that may be related to 
changes in renal function (e.g., routine urinalysis, elevated 
serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, or 
proteinuria). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression or infections). 
− 
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event. 
 
 
Grade 1 
(serum creatinine > 
ULN to 1.5 × ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any accompanying 
symptoms. 
• 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
• 
If creatinine worsens, depending on the severity, 
treat as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
If baseline serum creatinine is elevated above normal, and 
there is a rise to > 1 to 1.5 × baseline, consider following 
recommendations in this row.  
Grade 2 
(serum creatinine >1.5 
to 3.0 × baseline; >1.5 
to 3.0 × ULN) 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.  
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 


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Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
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drug/study regimen after completion 
of steroid taper. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt treatment 
with IV methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
>3.0 × baseline; >3.0 
to 6.0 × ULN; 
 
Grade 4: serum 
creatinine >6.0 × ULN) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on daily basis. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt treatment 
with IV methylprednisolone 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI CTCAE 
v 5.0 for definition of 
severity/grade 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 


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depending on type of 
skin rash) 
− 
IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED AND 
STUDY DRUG DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 
Grade 2 
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, then treat as 
Grade 3. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, consider, as 
necessary, discussing with study physician and promptly start 
systemic steroids such as prednisone 1 to 2 mg/kg/day PO or 
IV equivalent. If > 30% body surface area is involved, 
consider initiation of systemic steroids sooner. 
− 
Consider skin biopsy if the event is persistent for >1 to 
2 weeks or recurs. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, 
For Grade 3 or 4 (or life-threatening): 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 


Clinical Study Protocol 
Drug Substance:   
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Edition Number 5 
Date 05/09/2023 
 
 
Page 102 of 121 
 
then permanently discontinue study 
drug/study regimen. 
 
For Grade 4 (or life-threatening): 
Permanently discontinue study 
drug/study regimen. 
 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
Consider, as necessary, discussing with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v5.0 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an endocrinologist for endocrine events. 
− 
Consider, as necessary, discussing with study physician. 
− 
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections). 
− 
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood glucose 
and ketone levels, HgA1c). 
− 
For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as 
there are no other signs or symptoms of pancreatic 
inflammation. 
− 
If a patient experiences an AE that is thought to be possibly 
of autoimmune nature (e.g., thyroiditis, pancreatitis, 
hypophysitis, or diabetes insipidus), the investigator should 
send a blood sample for appropriate autoimmune antibody 
testing. 
 


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Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 103 of 121 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSH elevation): 
− 
Monitor patient with appropriate endocrine function tests. 
− 
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of 
early-morning ACTH, cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin levels, 
as well as cosyntropin stimulation test (though it may not be 
useful in diagnosing early secondary adrenal insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out 
of range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated and consider 
consultation of an endocrinologist. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until patient is clinically stable. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement. 
For Grade 2 (including those with symptomatic endocrinopathy): 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. 
− 
For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or Type 1 DM, and as 
guided by an endocrinologist, consider short 
term- corticosteroids (e.g., 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and prompt initiation of 
treatment with relevant hormone replacement (e.g., 
hydrocortisone, sex hormones). 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a 


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Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
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3. 
Doses of prednisone are 
≤10 mg/day or equivalent. 
− 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory 
assessments/MRI as clinically indicated. 
Grade 3 or 4 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until endocrinopathy symptom(s) 
are controlled.  
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are 
≤10 mg/day or equivalent. 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. Hospitalization 
recommended. 
− 
For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or Type 1 DM, and as 
guided by an endocrinologist, promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones). 
− 
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity. 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v5.0 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes, or medications). 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
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autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
for defining the CTC 
grade/severity) 
− 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing (e.g., electromyogram 
and nerve conduction investigations). 
− 
Perform symptomatic treatment with neurological consult as 
appropriate. 
− 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
− 
Treat mild signs/symptoms as Grade 1 (e.g.  loss of deep 
tendon reflexes or paresthesia) 
Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade 
≤1. 
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade 
≤1. 
If toxicity worsens, then treat as 
Grade 3 or 4. 
Study drug/study regimen can be 
resumed once event improves to Grade 
≤1 and after completion of steroid taper. 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day prednisone PO or IV equivalent, consider 
additional workup and promptly treat with additional 
immunosuppressive therapy (e.g., IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing with study physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
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Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (e.g., IV IG). 
− 
Once stable, gradually taper steroids over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients 
may unpredictably experience acute decompensations that 
can result in substantial morbidity or in the worst case, death. 
Special care should be taken for certain sentinel symptoms 
that may predict a more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and signs of 
respiratory insufficiency or autonomic instability. 
− 
Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes or medications). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis. 
Given the importance of prompt and accurate diagnosis, it is 
essential to have a low threshold to obtain a neurological 
consult. 
− 
Neurophysiologic diagnostic testing (e.g., electromyogram 
and nerve conduction investigations, and “repetitive 
stimulation” if myasthenia is suspected) are routinely 
indicated upon suspicion of such conditions and may be best 
facilitated by means of a neurology consultation. 
− 
It is important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 


Clinical Study Protocol 
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Date 05/09/2023 
 
 
Page 107 of 121 
 
considered effective. Patients requiring treatment should be 
started with IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above. 
− 
Obtain a neurology consult. 
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if it does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability. 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. It is important to consider that 
steroid therapy (especially with high doses) may 
result in transient worsening of myasthenia and 
should typically be administered in a monitored 
setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or IV 
IG. Such decisions are best made in consultation 
with a neurologist, taking into account the unique 
needs of each patient. 
o 
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 


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Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 108 of 121 
 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre 
is not typically considered effective. 
o 
Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory 
insufficiency or autonomic instability. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Consider, as necessary, discussing with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or IV 
IG. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre 
is not typically considered effective. 
o 
Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
 


Clinical Study Protocol 
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Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 109 of 121 
 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function.  
− 
Consider, as necessary, discussing with the study physician. 
− 
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of 
breath, peripheral edema). As some symptoms can overlap 
with lung toxicities, simultaneously evaluate for and rule out 
pulmonary toxicity as well as other causes (e.g., pulmonary 
embolism, congestive heart failure, malignant pericardial 
effusion). A Cardiology consultation should be obtained 
early, with prompt assessment of whether and when to 
complete a cardiac biopsy, including any other diagnostic 
procedures. 
− 
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), monitoring 
of oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion 
abnormalities when needed. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections) 
 
Grade 1 
(asymptomatic or mild 
symptoms*; clinical or 
diagnostic observations 
only; intervention not 
indicated) 
 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0. 
 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, BNP, cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and laboratory work-up as 
clinically indicated. 
- 
Consider using steroids if clinical suspicion is high. 


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Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
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*Treat myocarditis 
with mild symptoms as 
Grade 2. 
 
Grade 2, 3 or 4 
(Grade 2: Symptoms 
with moderate activity 
or exertion) 
 
 (Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; 
intervention indicated; 
new onset of 
symptoms*) 
 
(Grade 4: Life-
threatening 
consequences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic 
support)) 
 
* Consider “new onset 
of symptoms” as 
referring to patients 
- If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves 
to Grade 0, then the decision to 
reinitiate study drug/study regimen 
will be based upon treating 
physician’s clinical judgment and 
after completion of steroid taper. If 
toxicity does not rapidly improve, 
permanently. discontinue study 
drug/study regimen. 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures 
including a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 


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Study Number ESR-18-14205    
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Date 05/09/2023 
 
 
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with prior episode of 
myocarditis. 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, hips, neck and back, 
but rarely affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing can occur 
and progress rapidly. Increased general feelings of tiredness 
and fatigue may occur, and there can be new-onset falling, 
difficulty getting up from a fall, and trouble climbing stairs, 
standing up from a seated position, and/or reaching up. 
− 
If poly/myositis is suspected, a Neurology consultation 
should be obtained early, with prompt guidance on diagnostic 
procedures. Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine 
myoglobin, and additional laboratory work-up as indicated, 
including a number of possible rheumatological/antibody 
tests (i.e., consider whether a rheumatologist consultation is 
indicated and could guide need for rheumatoid factor, 
antinuclear antibody, anti-smooth muscle, antisynthetase 
[such as anti-Jo-1], and/or signal-recognition particle 
antibodies). Confirmatory testing may include 
electromyography, nerve conduction studies, MRI of the 
muscles, and/or a muscle biopsy. Consider Barium swallow 
for evaluation of dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections). 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
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Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study physician. 
 
Grade 2 
(moderate pain 
associated with 
weakness; pain limiting 
instrumental activities 
of daily living [ADLs]) 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
- Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly 
start IV methylprednisolone 2 to 4 mg/kg/day systemic 
steroids along with receiving input from Neurology 
consultant  
− 
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
Grade 3 or 4 
(Grade 3: pain 
associated with severe 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 113 of 121 
 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate 
aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; 
imAE immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic 
resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as 
Pneumocystis carinii pneumonia); PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating 
hormone; ULN Upper limit of normal. 
 
 
weakness; limiting 
self-care ADLs 
 
Grade 4:  life-
threatening 
consequences; urgent 
intervention indicated) 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory 
insufficiency. 
 
For Grade 4: 
- Permanently discontinue study 
drug/study regimen. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from Neurology 
consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 114 of 121 
 
Infusion-Related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event. 
 
For Grade 2: 
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 
 
 
 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 115 of 121 
 
Non–Immune-Mediated Reactions 
Severity Grade of the Event 
(NCI CTCAE version 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 116 of 121 
 
Appendix 2. 
Durvalumab Weight-based Dose Calculations 
Durvalumab Dosing 
For patients weighing ≤ 30 kg, durvalumab should be dosed at 20 mg/kg  
Example:  
1. Cohort dose: 20 mg/kg 
2. Patient weight: 30 kg 
3. Dose for patient: 600 mg = 20 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag: [rounded to the nearest tenth mL (0.1 mL)]: 
Dose (mL) = 600 mg / 50 (mg/mL) = 12.0 mL 
5. The number of vials required for dose preparation:  
Number of vials = 12.0 (mL) / 10.0 (mL/vial) = 2 vials 
 
 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 117 of 121 
 
Appendix 3. 
Schedule of Study Procedures: Follow-Up for Patients Who Have Completed Durvalumab 
 
Treatment and Achieved Disease Control (Until Confirmed Progression of Disease) and 
 
Patients Who Have Discontinued Durvalumab Due to Toxicity in the Absence of Confirmed 
 
Progression of Disease 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
Every 4 Months  
(±2 weeks) for 2 years  
30 
3 
6 
9 
12 
 
Physical examinationa 
X 
X 
x 
x 
x 
x 
Vital signs (temperature, respiratory rate, blood pressure, 
pulse) 
X 
X 
 
 
 
 
Weight 
X 
X 
 
 
 
 
Urine hCG or serum βhCG d 
X 
X 
 
 
 
 
AE/SAE assessment 
X 
X 
 
 
 
 
Concomitant medications 
X 
X 
 
 
 
 
<<World Health Organisation>> <<ECOG>> performance 
status 
X 
X 
X  
x 
x 
X 
Subsequent anticancer therapy 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with patients who refuse to 
return for evaluations and agree to be contacted 
 
X 
X 
X 
X 
X (every 2 months) 
Hematology 
X 
X 
 
 
 
X 
Serum chemistry  
X 
X 
 
 
 
 
Thyroid function tests (TSH, and fT3 and fT4)b  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 118 of 121 
 
Appendix 3. 
Schedule of Study Procedures: Follow-Up for Patients Who Have Completed Durvalumab 
 
Treatment and Achieved Disease Control (Until Confirmed Progression of Disease) and 
 
Patients Who Have Discontinued Durvalumab Due to Toxicity in the Absence of Confirmed 
 
Progression of Disease 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
Every 4 Months  
(±2 weeks) for 2 years  
30 
3 
6 
9 
12 
 
 
 
 
 
 
 
 
 
 
Quality of life (QOL)c and health resource use, if applicable 
X 
 
X 
For patients who achieve disease control following 12 months/48 weeks of 
treatment, quality of life and information relating to health resource use should be 
completed every 12 weeks relative to the date of randomisation until confirmed 
PD by RECIST 1.1 by investigational site review. 
For patients who discontinue study drug due to toxicity or a reason other than 
confirmed PD, quality of life and information relating to health resource use 
should be completed relative to the date of randomisation as follows: every 8 
weeks for the first 48 weeks, then every 12 weeks until confirmed PD by 
RECIST 1.1 by investigational site review. 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 119 of 121 
 
Appendix 3. 
Schedule of Study Procedures: Follow-Up for Patients Who Have Completed Durvalumab 
 
Treatment and Achieved Disease Control (Until Confirmed Progression of Disease) and 
 
Patients Who Have Discontinued Durvalumab Due to Toxicity in the Absence of Confirmed 
 
Progression of Disease 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
Every 4 Months  
(±2 weeks) for 2 years  
30 
3 
6 
9 
12 
 
Tumor assessment (CT or PET/CT) 
For patients who achieve disease control following 12 months of treatment, tumor assessments should be 
performed every 12 weeks (±1 week) relative to the date of first infusion thereafter until confirmed PD by 
RECIST 1.1 by investigational site review. Please refer to Schedule of Study Assessments for timings of 
confirmatory scans.  
For patients who discontinue MEDI4736 due to toxicity (or symptomatic deterioration), tumor assessments 
should be performed relative to the relative to the date of first infusion as follows: every 8 weeks (±1 week) 
for the first 48 weeks (per Schedule of Assessments), then every 12 weeks(±1 week) until confirmed PD by 
RECIST 1.1 by investigational site review. Please refer to Schedule of Assessments for timings of 
confirmatory scans.  
Upon confirmed PD, scans should be conducted according to local standard clinical practice and submitted for 
central review until a new treatment is started (these scans are optional). 
MRI Brain  
Annually in follow-up or for new neurological symptoms.  
a  
Full physical exam 
b 
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to the 
endocrine system. 
c 
All patients enrolled in the study who read English or Spanish will complete the EORTC QLQ-C30 quality of life (QOL) assessment 
d                     For women of childbearing potential only. 
 
 
 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 120 of 121 
 
Appendix 4.  
Schedule of Study Procedures: Follow-Up for Patients Who Have Discontinued Durvalumab 
 
Treatment Due to Confirmed Progression of Disease at the Discretion of the Investigator 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
 Every 4 Months for 2 
years 
(±2 weeks) 
30 
3 
6 
9 
12 
 
Physical examinationa 
X 
x 
 
 
 
 
Vital signs (temperature, respiratory rate, blood pressure, pulse) 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
AE/SAE assessment 
X 
X 
 
 
 
 
Concomitant medications 
X 
X 
 
 
 
 
<<World Health Organisation>> <<ECOG>> performance statusb 
X 
X 
 
 
 
 
Subsequent anticancer therapy 
X 
X 
 
 
 
 
Survival status: phone contact with patients who refuse to return for 
evaluations and agree to be contacted 
 
X 
X 
X 
X 
X  
Urine hCG or serum βhCG e 
X 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
 
Serum chemistry  
X 
X 
 
 
 
 
Thyroid function tests (TSH, and fT3 and fT4)c 
X 
 
 
 
 
 
Quality of life  (patient reported outcomes)d and health resource use, if 
applicable 
X 
 
X 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance:   
Study Number ESR-18-14205    
Edition Number 5 
Date 05/09/2023 
 
 
Page 121 of 121 
 
Appendix 4.  
Schedule of Study Procedures: Follow-Up for Patients Who Have Discontinued Durvalumab 
 
Treatment Due to Confirmed Progression of Disease at the Discretion of the Investigator 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
 Every 4 Months for 2 
years 
(±2 weeks) 
30 
3 
6 
9 
12 
 
Tumor assessment (CT or PET/CT) 
For patients who continue on durvalumab post-confirmed progression at the investigator’s 
discretion (following consultation with the sponsor), tumor assessments should be performed 
relative to the date of first infusion per until durvalumab is stopped. 
For patients who discontinue durvalumab following confirmed progression, scans should be 
conducted according to local clinical practice and submitted for central review until a new 
treatment is started (these scans are optional). 
a  
Full physical exam 
b 
PS to be collected if available at the 2 monthly calls to obtain subsequent anticancer therapy and survival status 
c 
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to the 
endocrine system. 
d 
All patients enrolled in the study who read English or Spanish will complete the EORTC QLQ-C30 quality of life (QOL) assessment 
e               For women of childbearing potential only. 

SAP_001.pdf: 
Chemoradiation Followed by Durvalumab in Poor Risk and/or 
Elderly Patients with Stage III NSCLC 
NCT04441138 
November 19, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Methods/Sample Size Determination/Data Analysis: 
For the primary endpoint of completion rate of chemotherapy/split course chest radiation, 
where we anticipate 80% completion, a sample size of n=30 provides power of about 0.8 in a 
non-inferiority test with non-inferiority margin of 0.18 and alpha =0.05. This will allow 
estimation of the completion rate within ±0.13 using a 90% confidence interval (normal 
approximation) or within a total width of 0.30 (using exact Binomial interval).  
 
For the endpoint of completion of durvalumab post-chemoradiation, we estimate post-
chemoradiation n of 24 (assuming 80% completion of chemoradiation). This will allow 
estimation of durvalumab completion rate within ±0.13 using a 90% confidence interval 
(normal approximation) or within a total width of 0.30 (using exact Binomial interval). 
 
For the secondary endpoints, with n=30 subjects, we estimate 70% power to detect 
improvement in PFS for adding Durvalumab and 55% power to detect improvement in OS, each 
at a liberal 0.10 level of significance and without adjusting for multiplicity. (Without 
Durvalumab, the median survival is known to be 20 months in this patient population; we 
expect that adding Durvalumab in the treatment regimen will improve the median survival to 
30 months. Without Durvalumab, the median progression free survival (PFS) is known to be 11 
months in this patient population; we expect that adding Durvalumab in the treatment regimen 
will improve the median PFS to 17 months.)