Conditions: Locally Advanced Lung Non-Small Cell Carcinoma Stage III Lung Cancer AJCC v8 Stage IIIA Lung Cancer AJCC v8 Stage IIIB Lung Cancer AJCC v8 Stage IIIC Lung Cancer AJCC v8
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This phase II trial studies two questions in patients with stage III NSCLC: 1) does it improve cancer control to add the drug Durvalumab, a type of immunotherapy, earlier in the treatment course; and 2) by intensifying treatment with durvalumab, is it possible to avoid mediastinal radiation to decrease side effects, without decreasing cancer control?

Detailed description:
OUTLINE:

Patients will receive platinum doublet chemotherapy per standard of care with durvalumab for 8 weeks, concurrent with a short course of radiation to the primary lung tumor. Patients will then undergo repeat evaluation of the mediastinal lymph nodes. If there is no cancer in the lymph nodes, patients will receive 2 years of adjuvant durvalumab. If there is still cancer in the lymph nodes, patients will receive 6 weeks of radiation to the mediastinal lymph nodes, and 2 years of adjuvant durvalumab.

After the completion of study treatment, patients are followed up for 12 months.

Arms:
arm 1: Patients with squamous cell cancer receive standard of care chemotherapy consisting of cisplatin on days 1, 8, 29, and 36, and etoposide on days 1-5 and 29-33. Cycles repeat every 4 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with non-squamous cell cancer receive standard of care chemotherapy consisting of cisplatin and pemetrexed on days 1, 22, and 43. Cycles repeat every 3 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. All patients receive durvalumab IV over 1 hour Q4W. Radiation to the primary tumor will be given over 8-15 fractions during weeks 1-3 of chemotherapy. For patients who have residual disease in the mediastinal lymph nodes at week 9, radiation will be given to the lymph nodes starting week 11. Durvalumab is given for 2 years after completion of radiation in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cisplatin intervention 2: Durvalumab intervention 3: Etoposide intervention 4: Hypofractionated Radiation Therapy intervention 5: Pemetrexed
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Undergo hypofractionated radiation therapy intervention 5: Given IV

Protocol document:
ICF_000.pdf: 
 
 
Official Title: 
Adaptive-Dose to Mediastinum With Immunotherapy 
(Durvalumab MEDI4736) and Radiation in Locally-
Advanced Non-Small Cell Lung Cancer   
NCT number: 
NCT04372927 
Document Type:  
Informed Consent Form  
Date of the 
Document: 
11/18/2021 
 


ADMIRAL v. 2 10/11/2021  Page 1 of 14 
 
University of Washington 
Seattle Cancer Care Alliance 
Fred Hutchinson Cancer Research Center 
 
Consent to take part in a research study: 
Adaptive-Dose to Mediastinum with Immunotherapy 
(Durvalumab MEDI4736) and Radiation in Locally- advanced 
non-small cell lung cancer 
ADMIRAL Trial  
Principal Investigator: 
Jing Zeng, MD. 
University of Washington Department of Radiation Oncology; 
SCCA Proton Therapy Center. 206-598-4100 
 
Emergency number (24 hours): 206-589-3300 
Ask to speak to the Radiation Oncologist on-call. 
If you are serving as a legally authorized representative the terms “participant”, "you", and 
"your" refer to the person for whom you are providing consent. 
Important things to know about this study. 
You are invited to participate in a research study. The purpose of this research is to improve 
cancer control in stage III non-small cell lung cancer patients by using a combination of 
immunotherapy (durvalumab), chemotherapy, and radiation. 
People who agree to join the study will be asked to attend roughly 60 clinic visits over 2 years. 
The study involves imaging appointments, daily radiation for 6 weeks with weekly 
chemotherapy, and immunotherapy once every 4 weeks for 2 years.  
We do not know if durvalumab would help treat stage III non-small cell lung cancer, and it 
could even make your condition/disease worse. Durvalumab could cause side effects such as 
hepatitis, as described below in this form.  
You do not have to join this study. You can choose to receive standard methods to treat stage 
III non-small cell lung cancer instead of participating in this study. We will give you details 
about the purposes, procedures, risks and possible benefits related to this study. We will explain 
other choices that you have. We will also give you any other information that you need in order 
to make an informed decision about joining this study.  
Following is a more complete description of this study. Please read this description carefully. 
You can ask any questions you want to help you decide whether to join the study. If you join 
this study, we will give you a signed copy of this form to keep for future reference.  
 
IRO received 11/03/21
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 2 of 14 
We invite you to join this research study.  
Your doctor is inviting you to join this research study because you have stage III non- small 
cell lung cancer. Research is not the same as treatment or medical care. The purpose of this 
research is to answer scientific questions.  
You do not have to join this study. You are free to say yes or no, or to drop out after joining. 
If you say no, you will have no penalty or loss of benefits. Whatever you decide, your 
regular medical care would not change.  
Your study doctor will give you details about the purposes, procedures, risks and possible 
benefits related to this study. We will explain other choices that you have. We will also give 
you any other information that you need in order to make an informed decision about 
joining this study. Please take the time to read this form and ask questions. You may also 
discuss your decision with your family, friends, and healthcare team.  
If you join this study, we will give you a signed copy of this form to keep for future 
reference.  
Why are we doing this study?  
You are being asked to join this study because you are beginning treatment for stage III non-
small cell lung cancer. The purpose of the research is to examine two things:  
 
1) does it improve cancer control to add the drug durvalumab, a type of immunotherapy, 
earlier in the treatment course (starting at the same time as chemotherapy and radiation 
instead of waiting until after chemotherapy and radiation are over), and giving the drug for 
2 years instead of 1 year. 
2) could we skip part of the radiation treatment (radiation to lymph nodes in the middle of 
the chest) so we can decrease side effects, without decreasing cancer control.  
We want to know if the two changes above could improve cancer control and decrease side 
effects from treatment. If you join this study, we would give you immunotherapy 
(durvalumab), chemotherapy, and radiation and watch carefully for any side effects.  
How many people will take part in this study?  
Our goal is to enroll up to 40 people in this study.  
What research tests, procedures, and treatments are done in this study?  
Chemotherapy will be given per standard clinical care in this study. Durvalumab will be 
given during chemotherapy and radiation as part of the research study, and continue for 2 
years total, whereas the current standard of care is to give durvalumab for 1 year after 
chemotherapy and radiation. Typically, standard of care radiation is given to the tumor and 
lymph nodes for 30 treatments over 6 weeks. For this study, the radiation will be split into 
two parts. The initial part to the primary tumor will be a short course of 8-15 treatments. 
The second part, if needed (for patients who still have cancer in the lymph nodes), will be 
given for 30 treatments over 6 weeks.  
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 3 of 14 
Patients will undergo a second mediastinal lymph node evaluation procedure as part of the 
study, in order to see if the initial radiation/chemotherapy/durvalumab was able to eliminate 
all the cancer in the lymph nodes.  
There is also an optional PET/CT scan at baseline and after the initial 
radiation/chemotherapy/durvalumab treatment course. Standard of care blood draws will be 
drawn prior to every infusion during chemotherapy and durvalumab therapy. Study blood 
draws will take place a maximum of 9 times per patient during the 24-month study period 
and coupled to the standard of care blood draws if possible. Optional repeat lung tumor 
biopsy will be performed 1 month after radiation to the primary tumor (±2 weeks).  
Study blood draws  
Study blood draws will take place:  
-Prior to any treatment 
-1 week after completion of radiation to the primary tumor (±7 days) 
-Prior to mediastinal radiation for applicable patients 
-Every 4 months (±1 month) afterwards for 2 years or until disease progression 
 
Study blood draws will take place a maximum of 9 times per patient during the 24-month 
study period and coupled to the standard of care blood draws if possible.  
How long would you stay in this study?  
If you join this study, you would stay in this study for around 2 years. For the first 3 months, 
you will be receiving chemotherapy, radiation therapy, and durvalumab. After you are finished 
with radiation and chemotherapy, you will receive durvalumab for a total of 2 years.  
All patients will be followed per standard clinical care after completion of 2 years of 
durvalumab: at least every 6 months until 3 years from diagnosis, and yearly until 5 years from 
diagnosis. The follow-up period of this study is until disease progression.  
Doctors could take you out of this study at any time. This would happen if:  
• 
They think it is in your best interest not to continue in the study. 
• 
You are not able or willing to follow study procedures. 
• 
The whole study is stopped. 
If you withdraw from the study for any reason, previously collected information would remain 
in the study records and would be included in the analysis of results.  
This information could not be removed from the study records.  
What are the risks?  
In this part of the consent form, we describe the side effects we expect from the tests and 
treatments in this study. We carefully watch everyone in the study for side effects.  
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 4 of 14 
If you join this study, we would tell you if we discover new side effects that could affect you.  
While the goal of this clinical trial is to both improve survival and decrease toxicity, it is possible 
that the opposite results will be seen. Potential for increased toxicity could come from the 
following:  
 
  Receiving immunotherapy sooner could compromise administration and 
completion of standard-of-care regimens due to additional toxicities (e.g.,  
pneumonitis). Please see below for additional risks with immunotherapy. 
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 5 of 14 
Risks with durvalumab include, but are not limited to:  
• 
Diarrhea/colitis pneumonitis (respiratory and lung disease caused from 
inflammatory bowel disease)  
• 
Interstitial lung disease (scarring of the lungs) 
• 
Hypo- and hyper-thyroidism, type I diabetes mellitus, hypophysitis 
(inflammation of the pituitary gland) and adrenal insufficiency 
• 
Hepatitis (inflammation of the liver)/increases in transaminases 
• 
Nephritis (inflammation of the kidney)/increases in creatinine 
• 
Pancreatitis (inflammation of the pancreas) /increases in amylase and lipase 
• 
rash/pruritus/dermatitis 
• 
myocarditis (inflammation of the heart) 
• 
myositis/polymyositis (inflammation of muscles) 
• 
other rare or less frequent inflammatory events including neurotoxicities, 
infusion-related reactions, hypersensitivity reactions, and infections/serious 
infections. 
Risks with radiation used along with immunotherapy include:  
• 
fatigue 
• 
pneumonitis (inflammation of the lungs) 
• 
Patients could have higher toxicity rates from receiving a higher biological 
dose of radiation to the primary tumor. 
Side effects of research blood draw include:  
• 
Bruising or minor swelling at the site of needle injection 
• 
Light headedness or dizziness 
• 
Pressure from the rubber band around your upper arm to increase blood flow 
Side effects may be mild or very serious.  
Another potential risk is decreased survival due to worse cancer control, since 
mediastinal radiation is not given upfront in the induction phase, but given at week 
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 6 of 14 
12 if there is residual disease in the mediastinum. This could provide an opportunity 
for disease progression in the mediastinum, which otherwise might have been 
controlled by upfront radiation  
Radiation risks  
Some of the tests that you will have in this research study will expose you to radiation. 
Everyone receives a small amount of radiation every day called “background radiation”. 
This radiation is natural and comes from space, air, water, soil, and the food you eat. 
Each year you are exposed to about 3 milliSieverts (mSv) of this background radiation. 
A milliSievert is a unit of radiation dose. For comparison, the estimated radiation dose 
from each of these tests is listed below. The risk to your health from this level of 
radiation exposure is too low to be detectable and may be nonexistent.  
• 
Chest CT: 7mSv 
• 
Abdomen CT: 8 mSv 
• 
Pelvis CT: 6 mSv 
• 
Biopsy CT: 5 mSv 
• 
Head CT: 2 mSv PET/CT: 19 mSv 
Reproductive risks  
Female Patient of child-bearing potential:  
Durvalumab and radiation therapy may involve unknown risks to an embryo, fetus 
(unborn baby) or nursing infant. Therefore, you could not join this study if you are 
pregnant, if you are planning to become pregnant, or if you are breast-feeding.  
If you join this study, you would have to use an effective method of birth control 
from the time this form is signed until at 90 days after the last dose of durvalumab. If 
you are already using a method of birth control, you would have to check with the 
study doctor or a member of the study staff to make sure it is acceptable.  
If you became pregnant after joining this study, you would have to notify the study 
doctor immediately. Study drugs should be discontinued immediately.  
Male Patient reproductive risks:  
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.  
What are the benefits?  
We do not know if this study would help you. We are conducting this study to see its 
effects on people with non-small cell lung cancer. Overall, we believe the potential 
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 7 of 14 
benefits of the trial outweigh the risks. You might get better treatment results than 
standard of care treatments if you receive durvalumab and radiation treatment 
concurrent with chemotherapy, but your results could be the same or even worse. We 
hope the information from this study will help other people with stage III non-small 
cell lung cancer in the future.  
You have other choices besides this study.  
You do not have to join this study. You are free to say “yes” or “no”. Your regular 
medical care would not change if you decide to say “no”.  
You have other choices for treatment. Each of these choices has risks and benefits. 
You should talk to your doctor or healthcare provider about these choices.  
Other choices include:  
• 
Getting treatment or care for your cancer without being in a study (according 
to the discretion of your treating oncologist). This could include standard 
therapies that may include radiation, chemotherapy, other targeted therapies 
or even immunotherapies that may be FDA approved. 
• 
Receiving no treatment 
• 
Getting comfort care. This type of care addresses pain, tiredness, appetite 
problems, and other problems caused by the cancer. It does not treat the 
cancer directly. 
Enrollment in this study may exclude you from other research studies.  
Protecting Privacy as an Individual and the Confidentiality of Personal  
Information  
If you join this study, some people or organizations might need to look at your 
medical records and research records for quality assurance or data analysis. They 
include:  
• 
Researchers involved with this study. 
• 
AstraZeneca (the sponsor of the study) and their agents. 
• 
Institutional Review Boards (IRB), including the Fred Hutchinson Cancer 
Research Center IRB. An IRB is a group that reviews the study to protect the 
rights and welfare of research participants. 
• 
Fred Hutchinson Cancer Research Center, University of Washington, and 
Seattle Cancer Care Alliance. 
• 
Food and Drug Administration, and other regulatory agencies as required. 
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 8 of 14 
We will do our best to keep personal information confidential. But we cannot 
guarantee total confidentiality. Personal information may be given out if required by 
law. For example, workplace safety rules may require health workers to contact you 
about lab tests. Or a court may order study information to be disclosed. Such cases 
are rare.  
We will not use personal information in any reports about this study, such as journal 
articles or presentations at scientific meetings.  
If you join this study, information about your participation would be made part of 
your permanent medical record. This information would include a copy of this 
consent form. If an insurance company or employer or anyone else were authorized 
to see your medical record, they would see a copy of this consent form.  
How is my genetic information protected?  
A federal law called the Genetic Information Nondiscrimination Act (GINA) helps 
protect genetic information about people who join research studies.  
GINA restricts access to genetic information so that it cannot be used for health 
insurance coverage decisions. GINA prevents health insurance companies or group 
health plans from:  
• 
Asking for genetic information obtained in research studies, or 
• 
Using genetic information when making decisions regarding your eligibility 
or premiums 
GINA does not help or protect against genetic discrimination by companies that sell 
life, disability or long-term care insurance.  
Would we pay you if you join this study?  
The sponsor will provide study drug for this study. There is no payment for being in 
this study.  
Would you have extra costs if you join this study?  
The tests that are done exclusively for research will not be billed to you or your 
insurance company. These tests include:  
• 
Research blood collection 
• 
Optional research biopsy 
• 
Optional PET/CT scans 
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 9 of 14 
If you join this study, you or your insurance company would have to pay for the costs of 
standard treatment in this study.  
What if you get sick or hurt after you join this study?  
For a life threatening problem, call 911 right away or seek help immediately. Contact 
your study doctor when the medical emergency is over or as soon as you can.  
For all other medical problems or illness related to this research, immediately contact the 
study doctor, Dr. Jing Zeng. She will treat you or refer you for treatment. You or your 
health insurance will have to pay for the treatment. There are no funds to pay you for a 
research-related injury, added medical costs, loss of a job, or other costs to you or your 
family. State or national law may give you rights to seek payment for some of these 
expenses. You do not waive any right to seek payment by signing this consent form.  
You or your insurer will be billed for treatment of problems or complications that result 
from your condition or from standard clinical care.  
You would not lose any legal right to seek payment for treatment if you sign this form.  
What will my information and/or tissue samples be used for?  
Your information and tissue samples (such as blood and tumor cells) will be used for the 
purposes of this study.  
Your tissue samples might help researchers develop new products. This research could 
be done by for-profit companies. There is no plan to share with you any revenue 
generated from products developed using your tissue samples.  
During this study, if the researchers learn new information that may be important to your 
general health or to your disease or condition, they will share that information with you.  
In addition, be aware that by agreeing to participate in this study, your information or 
tissue samples could be used for future research studies or sent to other investigators for 
future research studies without additional consent from you. These future research 
studies will be reviewed by an oversight group known as an institutional review board if 
required by law. The information that identifies you will first be removed from your 
information or tissue samples. If you do not want your information or tissue samples to 
be used for future research studies without your consent, you should not participate in 
this study.  
Your tissue contains DNA. DNA makes up the genes that serve as the "instruction book" 
for the cells in our bodies. By studying genes, researchers can learn more about diseases 
such as cancer. There are many different types of genetic tests. The testing on your 
tissue samples might include genetic testing called whole genome sequencing. Whole 
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 10 of 14 
genome sequencing looks at all the genetic information in your cells. This type of testing 
can provide useful information to researchers. It can also present risks if the test results 
became known to others, for example you could have problems with family members or 
insurance companies. There is also a risk that these test results could be combined with 
other information to identify you.  
Your rights  
• 
You do not have to join this study. You are free to say “yes” or “no”. 
• 
If you get sick or hurt in this study, you do not lose any of your legal rights to 
seek payment by signing this form. 
• 
During the study, we might learn new information that you need to know. For 
example, some information may affect your health or well-being. Other 
information might make you change your mind about being in this study. If we 
learn these kinds of information, we would tell you. 
• 
If you join this study, you would not have to stay in it. You could stop at any 
time (even before you start). Your regular medical care would not change. You 
would have no penalty for stopping, but it would be better not to join the study if 
you think that you would change your mind later. 
• 
If you decide to drop out, we would want you to tell the study doctor. The doctor 
could tell you about the effects of stopping your treatment. You and the doctor 
could talk about the follow-up care and testing that would help the most. 
• 
Before you leave the study, the doctor might ask you to continue in the follow-up 
part of the study. 
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.  
Your responsibilities  
If you join this study, you would have some responsibilities.  
• 
Follow the schedule of study visits and procedures. 
• 
Take study medications as directed. 
• 
Prevent pregnancy. 
• 
Tell us about side effects
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 11 of 14 
  
For more information  
If you have questions or concerns about this study, you can talk to your doctor anytime. 
Other people you could talk to are listed below.  
If you have questions about: 
Call: 
This study (including complaints 
and requests for information) 
206-598-4100 (Dr. Jing Zeng) 
If you get sick or hurt in this 
study 
206-598-4100 (Dr. Jing Zeng) 
Your rights as a research 
participant 
206-667-5900 or email irodirector@fredhutch.org 
(Director of Institutional Review Office, Fred 
Hutchinson Cancer Research Center) 
206-543-0098 (Human Subjects Division, 
University of Washington) 
Your bills and health insurance 
coverage 
The financial services department at the medical 
center where you will be treated: 
Seattle Cancer Care Alliance: 
Patient Financial Services 206-606-6226 
(phone)1st Floor Seattle Cancer Care Alliance (in-
person) 
825 Eastlake Ave. E 
Seattle, WA 98019 
University of Washington Medical Center 
Patient Financial Services 206-598-1950 (phone) 
UW Tower (in-person) 
4333 Brooklyn Ave. NE 
Seattle, WA 98195 
Emergency number (24 hours): 206-589-3300 
Ask to speak to the Radiation Oncologist on-call. 
 
 
 
 
 
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 12 of 14 
  
  
Making Your Choice  
Please think about your choice on whether to participate in this optional portion of the 
study. When you decide, please circle YES or NO. Please initial and date in the spaces 
provided. 
 
Tumor Biopsy (Optional)  
The additional research biopsy part of this study is completely optional. You can still 
participate in this study without undergoing the research biopsy. It is important to 
understand that the results of this research biopsy are not designed specifically to help 
you. This is an opportunity for us to get more information regarding your type of cancer. 
Information from this research will not be included in your medical record. For those 
who give permission for the research tumor biopsy, the biopsy will be scheduled before 
you begin radiation treatment and 16- weeks after you end radiation treatment. There 
will be a separate procedure consent form that will outline the risks associated with the 
area planned for biopsy. You and your insurance company will not be charged for this 
research procedure.  
Do you agree to donate your tumor tissue to study cancer? 
 
YES  NO  
Initials:  
Date:    
PET/CT Scan (Optional) 
The optional PET/CT scan will replace the pre-treatment CT scan and the Week 9 
restaging CT scan. You can still participate in this study without undergoing the PET/CT 
imaging. You and your insurance company will not be charged for this research 
procedure. 
Do you agree to receive the PET/CT scan? 
 
YES 
   NO    Initials: _________________ 
Date:______________   
 
 
 
 
FHCRC IRB Approval  
11/18/2021 
Document Released Date


ADMIRAL v. 2 10/11/2021  Page 13 of 14 
  
Signatures  
Please sign below if you:  
• 
have read this form (or had it read to you); 
• 
had the opportunity to ask any questions you have; 
• 
had the opportunity to discuss the research with the person obtaining consent; 
and 
• 
agree to participate in this study. 
Participant:  
 
Printed Name  
Signature  
Date  
Legally Authorized Representative: Please sign below if you:  
• 
have read this form (or had it read to you); 
• 
had the opportunity to ask questions; 
• 
had the opportunity to discuss the research with the person obtaining consent; 
and 
• 
agree to consent on behalf of the participant for him or her to participate in 
this study. 
Legally authorized representative:  
 
Printed Name  
Signature  
Date  
 
Relation to the participant  
If you served as an interpreter or impartial witness during the consent process, sign 
below to indicate you attest to the accuracy of the presentation and the participant’s 
apparent understanding of and willingness to participate in the research.  
Impartial Witness or Interpreter:  
 
Printed Name  
Signature  
Date  
FHCRC IRB Approval  
11/18/2021 
Document Released Date


Admiral v. 2 10/11/2021 Page 14 of 14 
Researcher’s statement  
I have discussed the research study, including procedures and risks, with the 
person signing above. A copy of the signed consent form will be given to the 
participant.  
Person obtaining consent signature:  
 
Printed Name  
Signature  
Date  
Current consent version date: 2.0  
 
FHCRC IRB Approval  
11/18/2021 
Document Released Date

Prot_SAP_002.pdf: 
 
 
Official Title: 
ADMIRAL Trial: Adaptive-Dose to Mediastinum with 
Immunotherapy (Durvalumab MEDI4736) and Radiation in 
Locally-advanced non-small cell lung cancer  
NCT Number: 
NCT04372927 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
May 5, 2022 
 
 


Page 1 of 102 
 
 
Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
Study Number ESR-18-14261 
Edition Number V2.0 
Date 9/21/2021 
 
Investigational Drug 
Substance(s) 
Durvalumab (MEDI4736) 
Study Number 
ESR-18-14261 
Version Number 
V2.0 
Date 
September 21st, 2021 
ADMIRAL Trial: Adaptive-Dose to Mediastinum with Immunotherapy 
(Durvalumab MEDI4736) and Radiation in Locally-advanced non-small cell 
lung cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRO received 04/13/22
FHCRC IRB Approval  
05 05 2022 
Document Released Date


Page 2 of 102 
Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
Study Number ESR-18-14261 
Edition Number V2.0 
Date 9/21/2021 
 
 
 
 
PROTOCOL SYNOPSIS 
Clinical Protocol  
 
Study Title: ADMIRAL Trial: Adaptive-Dose to Mediastinum with Immunotherapy (Durvalumab 
MEDI4736) and Radiation in Locally-advanced non-small cell lung cancer 
Protocol Number: 10459 
Clinical Phase: Phase II 
Study Duration: 2 years 
Investigational Product(s) and Reference Therapy: 
The study will enroll patients with unresectable stage III NSCLC, who are typically treated with 
concurrent chemoradiation per standard of care, plus 1-year of adjuvant durvalumab (MEDI4736) 
based on results of the PACIFIC trial, showing a survival benefit to adding 1-year of adjuvant 
durvalumab after concurrent chemoradiation for unresectable NSCLC. 
The two investigation components of this study are: 1) giving durvalumab for 2 years starting with 
concurrent chemoradiation, which is being tested in a large randomized trial PACIFIC-2; and 2) 
instead of radiating all visible lung cancer to 60 Gy in 30 daily fractions over 6 weeks per standard of 
care, only the primary lung tumor will initially receive treatment with hypofractionated radiation 
therapy (60 Gy in 15 fractions given over 3 weeks). Mediastinal nodal disease will only receive 
radiation if there is persistent disease after initial induction therapy (chemo-immunotherapy plus 
radiation to the primary lung tumor). 
Durvalumab will be supplied in glass vials containing 500 mg of liquid solution at a concentration of 
50 mg/mL for infusion after dilution. 
Research Hypothesis 
Adaptive radiation therapy to the mediastinum with hypofractionated radiation to the primary tumor 
(concurrent with chemo-immunotherapy), will improve progression-free survival (PFS) due to better 
local control of the primary lung tumor, as well as decrease toxicity when compared to historical 
controls (PACIFIC-2, randomized trial comparing chemoradiation versus chemoradiation plus 
concurrent durvalumab, and adjuvant durvalumab), in patients with unresectable locally advanced 
NSCLC. 
Objectives: 
Primary Objectives: 
The study will enroll patients with stage III NSCLC. The primary objective is to compare the 1-year 
PFS rate in patients treated with concurrent chemotherapy, durvalumab and hypofractionated radiation 


Page 3 of 102 
Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
Study Number ESR-18-14261 
Edition Number V2.0 
Date 9/21/2021 
 
 
 
therapy to the primary lung tumor followed by response adaptive mediastinal radiation and durvalumab 
relative to expected data on durvalumab maintenance therapy (PACIFIC-2 trial). 
Secondary Objective(s): 
A key secondary objective will be an evaluation of the frequency and severity of pneumonitis. 
Additional secondary objectives include: 
 
To evaluate overall survival; 
 
To evaluate the pathologic response rate of the mediastinum to chemo-immunotherapy plus 
primary lung tumor radiation 
 
To evaluate the frequency and severity of toxicities graded with CTCAE, version 5 
Exploratory Objective(s): 
Immune profile on peripheral blood and tumor. 
Study Design: 
 
All patients will undergo standard of care staging with PET/CT, MRI/CT head, and mediastinal 
evaluation with EBUS or mediastinoscopy. 
 
Induction therapy will include: 
 
1a) Squamous cell carcinoma: cisplatin/etoposide every 4 weeks for 2 cycles (weeks 1 to 8, cisplatin 
50 mg/m2 on days 1, 8, 29, and 36; etoposide 50 mg/m2 on days 1-5, and 29-33); 
 
OR 
 
1b) Non-squamous cell carcinoma: cisplatin/pemetrexed every 3 weeks for 3 cycles (weeks 1 to 8, 
cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on days 1, 22, and 43); 
 
AND 
 
2) durvalumab 1,500 mg q4 weeks 
AND 
3) hypofractionated radiation to the primary lung tumor (60 Gy in 15 fractions from weeks 1 to 3, or 60 
Gy in 8 fractions from weeks 1-2, radiation fractionation depends on tumor anatomy). 
 
Compared to standard of care chemoradiation for stage III NSCLC, this regimen gives similar 
chemotherapy, adds durvalumab, removes mediastinal radiation, and gives a higher biological radiation 
dose to the primary tumor (60 Gy in 8-15 fractions instead of 30 fractions). 


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Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
Study Number ESR-18-14261 
Edition Number V2.0 
Date 9/21/2021 
 
 
 
At week 9, patients will be restaged with CT c/a/p, and those with pathologically enlarged mediastinal 
nodes will undergo repeat EBUS/mediastinoscopy. If pathologically positive lymph nodes are found, 
radiation will be given to the mediastinum (2 Gy/fraction to 60 Gy) starting week 12. 
Durvalumab will continue be given every 4 weeks for 2 years from the start of concurrent 
chemoradiotherapy (as tested in PACIFIC-2 trial). 
Number of Centers: 3 
Number of Patients: 40 
Study Population: Unresectable stage III NSCLC 
Inclusion Criteria: 
 
Histologically or cytologically documented NSCLC 
 
Stage III NSCLC according to AJCC staging v8 
 
At least one mediastinal site of disease that is discontiguous from all other visible sites of disease 
and can be excluded from primary tumor site radiation (i.e. at least 10 mm separation between 
tumors) 
 
A maximum of 20 patients with bulky mediastinal disease will be allowed on this trial, defined as 
at least one contiguous mediastinal mass with minimum diameter >2 cm, that is not contiguous 
with the primary tumor (and therefore would not be irradiated during radiation to the primary 
tumor) 
 
No surgery for lung cancer for at least 3 years (from consent) 
 
Age 18 years or older 
 
ECOG 0-1 
 
No other malignancies for at least 3 years, excluding low grade or non-invasive malignancies such 
as skin cancers, prostate cancers, and DCIS 
 
Women cannot be pregnant and must be willing to use contraception if premenopausal 
 
Adequate organ function as defined by: ANC>1500/mm3, platelets>100k/mm3, hemoglobin >9.0 
g/dL, creatinine CL>40 mL/min, serum bilirubin <1.5x ULN, AST and ALT <2.5x ULN 
 
Weight >30 kg 
 
See section 4.1 for more durvalumab-specific requirements 
Exclusion Criteria: 
 
Prior anti-PD-1 or PD-L1 antibodies, including durvalumab 
 
Prior chemotherapy in the past 3 years 
 
Prior thoracic radiation that would preclude curative-intent radiation dose as outlined in this study 
 
Active or previous autoimmune disease (within the past 2 years) or a history of primary 
immunodeficiency; 


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Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
Study Number ESR-18-14261 
Edition Number V2.0 
Date 9/21/2021 
 
 
 
 
Evidence of uncontrolled, concurrent illness or ongoing or active infections 
 
See Section 4.2 for more durvalumab-specific requirements 
Investigational Product(s), Dose and Mode of Administration: 
Patients will receive 1500 mg durvalumab via IV infusion Q4W, starting with chemoradiation, for up to 
a maximum of 2 months (up to 24 doses/cycles), until confirmed disease progression, or unacceptable 
toxicity, withdrawal of consent, or another discontinuation criterion is met. 
Radiation treatment planning in this study will try to eliminate mediastinal radiation in patients who 
achieve a complete response to induction therapy. For patients whose primary lung tumor is physically 
separate from the involved mediastinal nodes, it will not be difficult to safety deliver radiation to 
mediastinal nodes (in patients who did not have a complete response to induction therapy) after 
radiation to the primary tumor (given during induction therapy). For patients where the primary lung 
tumor is contiguous with hilar or mediastinal nodal disease, the contiguous volume will be treated with 
hypofractionated radiation during weeks 1-3, but all other involved (but non-contiguous) mediastinal 
nodes will not be treated, allowing response assessment at week 9. This will allow for additional 
radiation to the previously untreated mediastinal nodes without exceeding normal tissue constraints. At 
the time of initial treatment planning, all patients will be planned for two radiation courses: 1) initial 
radiation to the primary+contiguous nodes if present, and 2) radiation to previously untreated 
mediastinal nodes if residual disease found on week 9 EBUS/mediastinoscopy; this ensures that normal 
tissue dose constraints will be met even if the second course of radiation is required. All patients not 
able to meet normal tissue dose constraints, will not be enrolled on the trial. 
Study Assessments and Criteria for Evaluation: 
Safety Assessments: 
Toxicity per CTCAE v5 
Efficacy Assessments: 
 
The primary endpoint is 1-year progression-free survival (PFS): PFS is defined as the duration from 
study registration to progression, symptomatic deterioration, or death due to any cause, whichever 
comes first. PFS for patients last known to be alive and progression-free, will be censored at the 
date of last contact. 
 
Overall survival (OS): OS is defined as the duration from study registration to death due to any 
cause. OS for patients last known to be alive will be censored at the date of last contact. 
 
Pathologic response (CR, PR) to mediastinum 
 
Objective response (CR or PR) rate  
Statistical Methods and Data Analysis: 


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Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
Study Number ESR-18-14261 
Edition Number V2.0 
Date 9/21/2021 
 
 
 
This study will compare the 1-year PFS rate in patients treated with concurrent chemotherapy, 
durvalumab and hypofractionated radiation therapy to the primary lung tumor followed by response 
adaptive mediastinal radiation and durvalumab relative to historical data on durvalumab maintenance 
therapy (PACIFIC data used for sample size calculations as data from PACIFIC-2 is not yet available). 
Sample Size Determination: 
 
The 1-year PFS rate in the PACIFIC trial was 56%, but the PACIFIC trial study population is different 
from this trial in that it enrolled only patients who completed chemoradiation, did not have progression 
of disease, and recovered from excess toxicity, before enrolling to receive adjuvant durvalumab. This 
study will enroll patients at initial diagnosis, prior to starting chemoradiation.  This study’s patient 
population is analogous to SWOG S0023, in which 75% of stage III patients were able to receive 
consolidation chemotherapy following induction chemoradiotherapy. We assume that all patients who 
were unable to receive consolidation therapy progressed prior to one year (or had significant long term 
toxicity which leads to worse outcomes). Therefore, our estimate of the historical 1-year PFS rate with 
maintenance durvalumab following induction chemotherapy is 42% (75% x 56%). This number may 
be updated as more information from the trials become available. A design with 40 patients has 90% 
power to rule out a 1-year PFS rate of 42% at the 1-sided 5% level, if the true 1-year is 65%. The 
observation of at least 22 patients (55%) alive and progression free at 1 year would be considered 
evidence to rule out a 1-year PFS rate of 42%. Sample size calculations were performed using 
https://stattools.crab.org/Calculators/oneArmBinomialColored.html. 
With 40 patients, binary proportions (response, toxicity) can be estimated within 16% with 95% 
confidence. Survival distributions will be estimated using the method of Kaplan-Meier. Confidence 
interval for median times will be estimated using the method of Brookmeyer-Crowley. 
The incidence of grade 3 or worse pneumonitis attributable to treatment will be evaluated and 
compared against the PACIFIC trial results. 


Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
Study Number ESR-18-14261 
Edition Number V2.0 
Date 9/21/2021 
Page 7 of 102 
 
 
 
 
 
SCHEDULE OF STUDY ASSESSMENTS 
 
Pre-treatment a 
Week1-4 
Week5-8 
Week 9-11 
Week 12-18 
C6 to C24 or PD 
Informed Consent 
Informed consent 
X 
Demography, including 
baseline characteristics and 
tobacco use 
X 
Eligibility criteria 
X 
Study procedures 
Treatment Visits (vitals, PE, 
ECOG, meds, AE assessment) b 
X 
X 
 
X 
X 
X 
X 
Cisplatin/etoposide c 
X 
 
X 
Durvalumab Q4 weeks d 
X 
 
X 
X 
X 
X 
Radiation e 
X 
X(if applicable) 
EBUS/Mediastinoscopy f 
X 
X 
Study blood draw g 
X 
 
X 
X 
X 
X (every 4 months) 
Repeat biopsy of primary lung 
tumor (optional) h 
X 
Laboratory Assessments 


Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
Study Number ESR-18-14261 
Edition Number V2.0 
Date 9/21/2021 
Page 8 of 102 
 
 
 
Pre-treatment a 
Week1-4 
Week5-8 
Week 9-11 
Week 12-18 
C6 to C24 or PD 
Labs i 
X 
X 
 
X 
X 
X 
X 
Hepatitis B and C and HIV 
X 
Pregnancy test j 
X 
Efficacy evaluations 
Tumor evaluation (CT) k 
Xm 
Xm 
Q12w ± 3w for the first 52 weeks (r 
the date of consent), and then standa 
elative to 
rd of care 
Please see section 7 for more detailed explanation of study procedures.  All patients will be followed per standard clinical care after 
completion of cycle 24 of durvalumab: at least every 6 months until 3 years from diagnosis, and yearly until 5 years from diagnosis. 
 
a 
All pre-treatment procedures must be performed up to 45 days before Day 1, except for histology which has no time restriction. 
b 
Treatment visits will be per standard of care, which is typically at least every 4 weeks during chemotherapy and durvalumab, and weekly during radiation treatment. 
c 
Chemotherapy dosing interval may be prolonged or dose withheld if deemed clinically appropriate by treating oncologist. Chemotherapy should start within 3 days of radiation 
therapy. 
d 
Dosing interval may prolonged or dose withheld if deemed clinically appropriate by treating oncologist. 
e 
Radiation to the primary tumor is delivered during week 1-3 of treatment.  First dose of radiation should be within 3 days of first dose of chemotherapy.  For patients who have 
residual disease in the mediastinum on repeat EBUS/mediastinoscopy, radiation to the mediastinum should ideally begin within 3 weeks of repeat EBUS/mediastinoscopy but 
may be up to 6 weeks.. 
f 
Either an EBUS or mediastiastinoscopy must be performed to provide pathologic evaluation of the mediastinal nodes prior to starting treatment. For patients who do not have 
systemic progression on repeat CT at week 9, a repeat EBUS or mediastinoscopy must be performed to evaluate the mediastinal lymph nodes. This should ideally take place 
within 3 weeks of the restaging CT at week 9 but may be up to 6 weeks.  
g 
 Study blood draws will take place prior to initiation of any therapy (within 45 days), 1 week after completion of radiation to the primary tumor (±7 calendar days), prior to 
mediastinal radiation (less than 4 weeks) for applicable patients, and every 4 months (±1 month) afterwards for 2 years or until disease progression. 
h 
Optional repeat lung tumor biopsy will be performed 1 month after radiation to the primary tumor (±2 weeks). 
i 
Standard of care lab assessments will be drawn prior to every cycle during chemotherapy and durvalumab therapy. 
j 
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable. 


Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
Study Number ESR-18-14261 
Edition Number V2.0 
Date 9/21/2021 
Page 9 of 102 
 
 
 
 
k 
 Patients will have a pre-treatment scan, a scan at week 9 (±10 calendar days), and then Q12w ± 4w for the first 52 weeks (relative to the date of consent), and then standard of 
care thereafter. 
m 
An optional research PET/CT will be offered to patients, which will be paid for by the study and not billed to insurance.  This PET/CT can replace the standard of care CT 
scan at baseline and the week 9 scan. 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 10 of 102 
 
 
 
 
 
TABLE OF CONTENTS 
PAGE 
PROTOCOL SYNOPSIS ........................................................................................................... 2 
SCHEDULE OF STUDY ASSESSMENTS ............................................................................. 7 
TABLE OF CONTENTS ......................................................................................................... 10 
1. 
INTRODUCTION ................................................................................................... 14 
1.1 
Disease background ................................................................................................. 14 
1.1.1 
Limitations in standard of care chemoradiation for unresectable NSCLC .............. 14 
1.1.2 
Durvalumab in NSCLC ............................................................................................. 15 
1.1.3 
Response rate to chemo-immunotherapy in NSCLC ............................................... 16 
1.1.4 
Rationale for hypofractionated radiation and immunotherapy combination .......... 16 
1.1.5 
Safety of combination chemoimmunotherapy plus radiation to the thorax ............ 17 
1.2 
Research hypothesis ............................................................................................... 18 
1.3 
Rationale for conducting this study ......................................................................... 18 
1.4 
Benefit/risk and ethical assessment ........................................................................... 21 
1.4.1 
Potential benefits ...................................................................................................... 21 
1.4.2 
Overall risks ............................................................................................................. 21 
1.4.3 
Overall benefit-risk .................................................................................................. 22 
2. 
STUDY OBJECTIVES ........................................................................................... 23 
2.1 
Primary objective(s) ................................................................................................ 23 
2.2 
Secondary objective(s) ............................................................................................. 23 
2.3 
Exploratory objective(s) .......................................................................................... 23 
3. 
STUDY DESIGN .................................................................................................... 25 
3.1 
Overview of study design ........................................................................................ 25 
3.2 
Study schema ........................................................................................................... 25 
3.3 
Study oversight for safety evaluation ...................................................................... 26 
4. 
PATIENT SELECTION .......................................................................................... 27 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 11 of 102 
 
 
4.1 
Inclusion criteria ..................................................................................................... 27 
4.2 
Exclusion criteria ................................................................................................... 29 
4.3 
Withdrawal of patients from study treatment and/or study .................................... 31 
5. 
TREATMENT PLAN ............................................................................................. 34 
5.1 
Study Registration ................................................................................................... 34 
5.2 
Durvalumab.............................................................................................................. 34 
5.2.1 
Formulation/packaging/storage ............................................................................... 34 
5.2.2 
Durvalumab doses and treatment regimens ............................................................ 34 
5.2.3 
Study drug preparation ............................................................................................ 34 
5.2.4 
Monitoring of dose administration .......................................................................... 35 
5.2.5 
Disposition of unused investigational study drug .................................................. 36 
5.3 
Chemotherapy .......................................................................................................... 36 
5.4 
Radiation Therapy .................................................................................................. 36 
5.4.1 
Simulation ................................................................................................................ 37 
5.4.2 
Definition of target volumes and margins .............................................................. 37 
5.4.3 
Definition of critical structures ................................................................................ 40 
5.4.4 
Treatment planning .................................................................................................. 41 
5.4.5 
Patient specific quality assurance ............................................................................ 43 
5.4.6 
Daily treatment localization/Image guided radiation therapy (IGRT) ................... 43 
5.4.7 
Case review .............................................................................................................. 43 
5.5 
Toxicity management guidelines............................................................................. 43 
6. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) .................................................................................................... 44 
6.1 
Restrictions during the study ................................................................................... 44 
6.2 
Concomitant treatment(s) ........................................................................................ 46 
6.2.1 
Permitted concomitant medications ........................................................................ 46 
6.2.2 
Excluded concomitant medications ......................................................................... 46 
7. 
STUDY PROCEDURES ......................................................................................... 48 
7.1 
Schedule of study procedures .................................................................................. 48 


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Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
7.1.1 
Screening phase ....................................................................................................... 48 
7.1.2 
Treatment phase ....................................................................................................... 48 
7.1.3 
Blood draws ............................................................................................................. 48 
8. 
ASSESSMENT OF SAFETY ................................................................................. 50 
8.1 
Early patient review for safety ................................................................................ 50 
8.2 
Safety parameters ..................................................................................................... 50 
8.2.2 
Definition of serious adverse events........................................................................ 51 
8.2.3 
Definition of adverse events of special interest (AESI) .......................................... 51 
8.3 
Assessment of safety parameters ............................................................................. 53 
8.3.1 
Assessment of severity ............................................................................................ 53 
8.4 
Recording of adverse events and serious adverse events ......................................... 54 
8.4.1 
Study recording period and follow-up for adverse events and serious 
adverse events .......................................................................................................... 56 
8.4.2 
Causality collection ................................................................................................. 56 
8.4.3 
Relationship to protocol procedures ........................................................................ 56 
8.4.4 
Adverse events based on signs and symptoms ........................................................ 57 
8.4.5 
Adverse events based on examinations and tests .................................................... 57 
8.4.6 
Disease progression ................................................................................................. 57 
8.4.7 
New cancers ............................................................................................................. 58 
8.4.8 
Deaths....................................................................................................................... 58 
8.4.9 
Follow-up of unresolved adverse events ................................................................. 58 
8.4.10 
Post-study events ..................................................................................................... 59 
8.5 
Reporting of serious adverse events ........................................................................ 59 
8.5.1 
Reporting of deaths to AstraZeneca ........................................................................ 59 
8.5.2 
Overdose .................................................................................................................. 59 
8.5.3 
Hepatic function abnormality .................................................................................. 60 
8.5.4 
Pregnancy ................................................................................................................. 60 
8.5.5 
Paternal exposure ..................................................................................................... 61 
8.6 
Medication error ..................................................................................................... 61 


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Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............. 64 
9.1 
Description of analysis sets ..................................................................................... 64 
9.1.1 
Efficacy and safety analysis set ................................................................................. 64 
9.2 
Methods of statistical analyses ................................................................................ 64 
9.2.1 
Safety analyses ......................................................................................................... 64 
9.2.2 
Efficacy analyses ..................................................................................................... 64 
9.2.3 
Exploratory analyses ................................................................................................ 65 
9.2.4 
Interim analyses ....................................................................................................... 65 
9.3 
Determination of sample size .................................................................................. 65 
10. 
ETHICAL AND REGULATORY REQUIREMENTS .......................................... 66 
11. 
STUDY MANAGEMENT ...................................................................................... 66 
12. 
DATA MANAGEMENT ........................................................................................ 66 
13. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ..................... 67 
13.1 
Identity of investigational product(s) ...................................................................... 67 
14. 
LIST OF REFERENCES ........................................................................................ 68 
Appendix 1. TOXICITY MANAGEMENT GUIDELINES………………………………..70 


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Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
1. 
INTRODUCTION 
 
We propose a trial of hypofractionated radiation to the primary lung tumor, with concurrent 
chemo-immunotherapy in patients with unresectable locally advanced NSCLC, followed by 
response-adaptive mediastinal radiation. We hope to decrease toxicity by eliminating 
mediastinal radiation in patients who have a complete response to the induction 
chemoimmunotherapy plus primary tumor radiation, and improve local control of the primary 
tumor by delivering a higher biologic dose of radiation. 
 
1.1 
Disease background 
1.1.1 
Limitations in standard of care chemoradiation for unresectable 
NSCLC 
Current standard of care in the management of locally advanced non-small cell lung cancer 
(NSCLC) is concurrent chemo-radiation followed by a year of adjuvant durvalumab1,2. Standard 
radiation treatment is conventionally fractionated radiation therapy (1.8-2.0 Gy per day to total 
60-70 Gy) to all visible sites of disease, which includes both the primary lung tumor and 
involved mediastinal lymph nodes3. This standard-of-care approach achieves local control in 
30-50% of patients, but has several limitations3. 
 
First, mediastinal radiation is associated with significant toxicity, including those that predict 
for mortality in locally advanced NSCLC, specifically: radiation pneumonitis, cardiac dose, and 
esophagitis3. Radiation  pneumonitis risk, counter-intuitively, is mostly due to mediastinal 
radiation and not due to radiation to the primary lung tumor. This is because the spinal cord can 
only tolerate 45-50 Gy of radiation, but enlarged mediastinal nodes are treated to 60-70 Gy; 
therefore, oblique beams that avoid the spinal cord are used to treat the mediastinum, which 
significantly increases dose spillage into normal lung4. When early stage lung tumors are 
radiated to high doses with hypofractionated radiation, such as stereotactic ablative radiotherapy 
(SABR), the rates of pneumonitis are low because the early stage tumors are node negative and 
do not typically involve mediastinal radiation, compared to radiation for stage III NSCLC, 
which typically treats a large region of the mediastinum4,5. 
 
A second significant disadvantage of mediastinal radiation in the era of immunotherapy, is the 
fact that the primary lymph node drainage basin for lung tumors is the mediastinum6. Radiation 
to the mediastinal nodes could suppress any mounting anti-tumor immune response in the 
region. Consequently, mediastinal radiation enhances toxicity and is likely immuno-suppressive 
when delivered in the setting of locally advanced NSCLC. This potentially detracts from a good 
clinical outcome, and the added toxicity likely impedes the ability to graft on combinatory 
immunotherapy. 
 
Additionally, we also know from surgical series that approximately 31% of patients will clear 
their mediastinal and regional nodes and that an additional 29% of patients will clear their N2 


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Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
nodal disease alone (ie downstaging to N1 disease) with chemotherapy alone and that this is 
associates with a median survival of 35 months or more.7 The mediastinal nodal clearance rate 
with chemo-immunotherapy is not known, but likely higher given the greater efficacy of this 
regimen in advanced NSCLC when compared with chemotherapy alone.8 It is unlikely that 
these downstaged patients derive a significant benefit from the addition of mediastinal radiation. 
 
Finally, a third consequence of mediastinal radiation is that more effective radiation dosing 
regiments, such as SABR or hypofractionated approaches, cannot be utilized due to toxicity of 
hypofractionated radiation therapy when given to mediastinal normal tissues such as esophagus, 
blood vessels, and airways9. Although SABR and hypofractionated radiation have shown 
substantially higher local control rates (80-90%) than conventional fractionation radiation in 
early stage NSCLC, these dose regimens have not become standard of care in locally advanced 
NSCLC because of toxicity observed in the mediastinum9-11. 
 
1.1.2 
Durvalumab in NSCLC 
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. 
 
In the landmark trial PACIFIC, patients with unresectable NSCLC who received adjuvant 
durvalumab after standard of care chemoradiation had improved survival compared to patients 
who received standard of care maintenance therapy.1,2 Durvalumab is currently FDA approved 
for adjuvant therapy in patients receiving concurrent chemoradiation for NSCLC, and given 
for a year of adjuvant therapy per standard of care.  Results from the randomized trial 
PACIFIC-2 are anticipated, which added the durvalumab to begin concurrent with 
chemoradiation, and for 2 years of therapy total. While results from this trial are still 
forthcoming, there have been no early toxicity signals from this trial.  Our current study is 
based on the PACIFIC-2 regimen, with durvalumab beginning concurrent with 
chemoradiation (although we only radiate the primary and not the mediastinum, and the 
radiation is hypofractionated to deliver a higher biologic dose). 


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Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
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. Even more patients are 
being treated per standard of care after results of the PACIFIC trial led to FDA approval of 1- 
year of adjuvant durvalumab after chemoradiation for unresectable NSCLC.  Refer to the 
current durvalumab Investigator’s Brochure for a complete summary of non-clinical and 
clinical information including safety, efficacy and pharmacokinetics. 
 
1.1.3 
Response rate to chemo-immunotherapy in NSCLC 
Chemotherapy is effective in sterilizing mediastinal (N2) nodal disease in surgical series in 
about 60% of patients7,12. One would expect the mediastinal clearance rate to be higher when 
checkpoint inhibitors (PD-1 or PD-L1 inhibitors specifically) are employed in addition to 
chemotherapy. Large studies are currently underwent but encouraging results from smaller 
phase II trials show pathologic complete response rates in the mediastinum of up to 70% after 
neoadjuvant chemotherapy plus PD-1/PD-L1 inhibitors prior to surgical resection13,14. For 
patients with metastatic NSCLC, where chemotherapy plus checkpoint inhibitors have become 
standard of care first-line treatment, the objective response rates seen in large randomized trials 
are 48-57%15,16. Therefore, it is reasonable to question the added value of mediastinal radiation, 
specifically in those individuals who will achieve sterilization with chemo-immunotherapy 
alone, where the toxicity of mediastinal radiation will outweigh the benefit. 
 
1.1.4 
Rationale for hypofractionated radiation and immunotherapy 
combination 
Radiation causes release of tumor antigens and cytokines into the tumor microenvironment, 
which leads to an inflammatory response and infiltration of immune cells including T-cells 
(both cytotoxic and regulatory), dendritic cells, macrophages, and myeloid-derived suppressor 
cells (MDSCs)17.  Peripheral blood from patients with metastatic melanoma receiving  
standard photon radiation to a single site of disease while on ipilimumab show that radiation 
induces an increase in percentage of CD4+ T-cells, ratio of CD8+ T-cells to Tregs, decrease in 
MDSCs, and increase in HLA-DR expression on monocytes18,19. Clinical reports have been 
published with radiation to one tumor causing an abscopal effect that leads to systemic 
regression of disease outside the radiation field, even in patients who have previously 
progressed on immunotherapy18,20,21. Although the exact mechanism of the radiation induced 
abscopal effect is unclear, published data supports it is partially due to T-cell effector function 
in the irradiated tumor, especially CD8+ T-cells19,22.  There is also growing evidence that 
cytokine release is a major mechanism, which can lead to a decrease in MDSCs18,23,24. 
 
In the landmark trial PACIFIC, that established adjuvant durvalumab after chemoradiation for 
unresectable NSCLC as standard of care, patients that initiated durvalumab after 2 weeks of 
radiation completion had improved survival compared with patients who waited longer to 
initiate durvalumab1,2.  The exact cause of this phenomenon is unclear, but has been 
hypothesized to be related to immune changes after radiation that enhanced the efficacy of 
durvalumab.  While the optimal radiation regimens for harnessing the proimmunogenic effects 


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of radiation remain to be defined, pre-clinical data suggests that the ability of radiation to 
promote anti-tumor immunity may be dependent on the dose and fractionation employed. 
Compared to conventionally fractionated radiation therapy (such as 60 Gy in 30 daily 
fractions typically employed to treat stage III NSCLC), hypofractionated radiotherapy at a 
higher dose per day over fewer days have been shown to result in a greater degree of 
stromal/vascular damage and increased apoptosis of tumor cells25, which may ultimately lead 
to an environment of enhanced antigen presentation. Animal models support this theory and 
suggest that a threshold likely exists in regard to the radiation fraction size necessary to induce 
an optimal immune response with ablative doses generating greater immunostimulatory 
effects as compared to conventional radiation doses26. Clinically, the ability to deliver ablative 
doses to tumors with acceptable toxicity has become possible over the past decade with 
technologic advancements in image guidance and radiation dose delivery. In the setting of 
early-stage lung cancer, phase I/II trials demonstrate that the use of hypofractionated radiation 
yields improved survival as compared to conventional fractionated treatment with local 
control rates comparable to surgical resection27.  Toxicity rates, including pneumonitis, 
esophagitis, and cardiac toxicity, are generally lower with hypofractionated ablative radiation 
to non-central tumors27. 
 
Therefore, we propose hypofractionated radiation to the primary tumor, which avoids the 
toxicity of mediastinal radiation, but potentially allows for a synergistic interaction between 
the radiation and immunotherapy, as part of the induction/initial phase of our trial schema. 
 
1.1.5 
Safety of combination chemoimmunotherapy plus radiation to the 
thorax 
We propose a trial of hypofractionated radiation to the primary lung tumor, with concurrent 
chemo-immunotherapy in patients with unresectable locally advanced NSCLC, followed by 
response-adaptive mediastinal radiation. 
 
The combination of chemotherapy and PD-1/PD-L1 checkpoint inhibition is currently standard 
of care in metastatic NSCLC, with a well characterized safety profile15,16. The safety profile of 
chemoradiation for NSCLC and adjuvant durvalumab is also well characterized and standard of 
care for unresectable stage III NSCLC2. PACIFIC-2 is a large randomized trial looking at 
concurrent chemoradiation, versus concurrent chemoradiation plus durvalumab, starting 
concurrent with radiation with a total of 2 years of durvalumab therapy. Results from this trial 
are pending, but there has been no early safety signals prompting early trial termination. 
Hypofractionated radiation for lung cancer is also well characterized and carries relatively low 
toxicity risk when not treating large regions of the mediastinum27. 
 
Numerous prospective and retrospective clinical series have been published assessing the safety 
of radiation plus immunotherapy, with the general conclusion that the combination is generally 
safe, and may lead to an improved response rate to immunotherapy. For example, the ETOP 
NICOLAS trial added nivolumab (a PD-1 inhibitor) concurrently to chemoradiotherapy in 


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standard first line treatment of stage III NSCLC, and saw no significant increase in toxicity after 
the first 82 patients.28 A multicentric retrospective study of 104 patients looked at safety of 
combined PD-1 pathway inhibition and radiation therapy for non-small-cell lung cancer, where 
radiation was given within 6 months preceding, concomitantly, or 3 months after nivolumab 
administration29. There was no increased risk of severe or unexpected toxicities. A retrospective 
comparison of 50 patients who received checkpoint inhibitor and brain radiation, versus 113 
patients who only received brain radiation, saw no difference in toxicity rates between patients 
who did and did not receive checkpoint inhibitors in addition to brain radiation30. Another 
retrospective study of 59 patients treated with hypofractionated body radiotherapy within 8 
weeks of checkpoint inhibitor therapy concluded the combination is safe and promising31. A 
randomized phase 1 trial of pembrolizumab (a PD-1 inhibitor) with sequential versus 
concomitant stereotactic body radiotherapy in metastatic urothelial carcinoma also concluded 
that the combination treatment was well tolerated32. 
 
1.2 
Research hypothesis 
Adaptive radiation therapy to the mediastinum with hypofractionated radiation to the primary 
tumor (concurrent with chemo-immunotherapy), will improve progression-free survival (PFS) 
due to better local control of the primary lung tumor, as well as decrease toxicity when 
compared to historical controls (PACIFIC-2, randomized trial comparing chemoradiation 
versus chemoradiation plus concurrent durvalumab, and adjuvant durvalumab), in patients 
with unresectable locally advanced NSCLC. 
 
1.3 
Rationale for conducting this study 
Rational for this study is to improve clinical outcomes, both by decreasing toxicity, and by 
improving disease control. Radiation to the mediastinum is the cause of most of the radiation 
toxicity in the treatment of unresectable NSCLC, including pneumonitis, esophagitis, and heart 
dose3. By eliminating this in a significant cohort of patients, who will experience a complete 
response from induction chemoradiation (plus radiation to the primary tumor), we propose to 
decrease toxicity, and potentially increase survival by allowing better tolerance of adjuvant 
immunotherapy. In the PACIFIC trial that showed a survival benefit to the addition of 1-year 
of durvalumab after chemoradiation for unresectable NSCLC, the number one toxicity requiring 
stopping durvalumab therapy was pneumonitis. If eliminating mediastinal radiation can 
decrease pneumonitis rates, that can lead to better tolerance of immunotherapy. We also 
propose to increase radiation dose to the primary tumor (accelerating the radiation from 60 Gy 
in 30 daily treatments to 15 daily treatments), which could improve local control of the primary 
tumor, improving disease outcome. 


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1.3.1.1 
Radiation dose rationale 
Hypofractionated radiation therapy to 60 Gy in 8-15 fractions has been shown in prospective 
trials to be safe and efficacious for lung cancer, especially tumors that do not involve large areas 
of the mediastinum.27,33 This regimen results in a higher biological dose to the tumor than a 
slower, conventional fractionation course (60 Gy in 30 daily fractions), which can improve local 
control.34,35 
 
Mediastinal radiation can be safely delivered to 60 Gy in 30 daily fractions with concurrent 
chemo per standard of care. There is also early data that this radiation regimen is also safe to 
deliver concurrent with chemoimmunotherapy.28 Radiation alone in the mediastinum can be 
delivered safely in 25-30 fractions to around 60 Gy, as assessed by prospective dose escalation 
trials.36 
 
1.3.1.2 
Durvalumab 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/Pharmacodynamic data 
Based on available PK/pharmacodynamic 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 17 days. A dose-dependent suppression in peripheral sPD-L1 
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 


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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. 
 
1.3.1.3 
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 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. 


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1.4 
Benefit/risk and ethical assessment 
1.4.1 
Potential benefits 
The goal of this clinical trial is to both improve survival and decrease toxicity.  One potential 
benefit of this trial is improved survival, due to the following factors: 
 
 Patients receive immunotherapy sooner than standard of care (at initial treatment, 
instead of after completion of chemoradiation and allowing time for recovering). 
 
 Patients receive a higher biological dose of radiation to the primary tumor than 
standard of care, potentially improving local control (60 Gy in 8-15 daily fractions 
over 1.5-3 weeks, instead of in 30 fractions over 6 weeks). 
 
Another potential benefit is decreased toxicity, since mediastinal radiation will not be given to 
patients with complete response in the mediastinum to induction therapy, therefore decreasing 
rates of esophagitis, pneumonitis, heart toxicity, etc. 
 
1.4.2 
Overall risks 
While the goal of this clinical trial is to both improve survival and decrease toxicity, it is possible 
that the opposite results will be seen. Potential for increased toxicity could come from the 
following: 
 
 Patients could have higher toxicity rates from receiving immunotherapy sooner than 
standard of care (at initial treatment, instead of after completion of chemoradiation and 
allowing time for recovering). Risks with durvalumab include, but are not limited to, 
diarrhea/colitis pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I 
diabetes mellitus, hypophysitis and adrenal insufficiency) hepatitis/increases in 
transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and 
lipase, rash/pruritus/dermatitis, myocarditis, myositis/polymyositis, other rare or less 
frequent inflammatory events including neurotoxicities, 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. 
 
 Patients could have higher toxicity rates from receiving radiation concurrent with 
immunotherapy in this study. Based on published clinical data, there does not seem to 
be new, unusual toxicities from the combination of radiation and immunotherapy, but 
the toxicity profiles do overlap, such as fatigue and pneumonitis. 
 
 Patients could have higher toxicity rates from receiving a higher biological dose of 
radiation to the primary tumor (60 Gy in 8-15 daily fractions over 1.5-3 weeks, instead 
of in 30 fractions over 6 weeks). 


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Another potential risk is decreased survival due to worse cancer control, since mediastinal 
radiation is not given upfront in the induction phase, but given at week 12 if there is residual 
disease in the mediastinum. This could provide an opportunity for disease progression in the 
mediastinum, which otherwise might have been controlled by upfront radiation. 
 
1.4.3 
Overall benefit-risk 
Overall, we believe the potential benefits of the trial outweigh the risks.  This trial allows 
patients to receive the maximal systemic therapy upfront (platinum-doublet chemotherapy and 
checkpoint inhibitor immunotherapy), and metastatic disease is the number one mode of 
treatment failure after concurrent chemoradiation for unresectable NSCLC.  Patients still 
receive radiation to all visible sites of disease on the trial, but those who have a favourable 
response to induction therapy can forgo mediastinal radiation, which is the source of most of 
the toxicity in radiation for unresectable NSCLC.  This toxicity reduction on the radiation 
front, also potentially improves the patient’s ability to tolerate more systemic therapy. 


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2. 
STUDY OBJECTIVES 
2.1 
Primary objective(s) 
The primary objective is to compare the 1-year PFS rate in patients treated with concurrent 
chemotherapy, durvalumab and hypofractionated radiation therapy to the primary lung tumor 
followed by response adaptive mediastinal radiation and durvalumab relative to historical data 
on durvalumab maintenance therapy (PACIFIC-2 trial). The primary endpoint is progression- 
free survival (PFS): PFS is defined as the duration from study registration to progression, 
symptomatic deterioration, or death due to any cause, whichever comes first. 
PFS for patients last known to be alive and progression free, will be censored at the date of 
last contact. Progression will be determined by the radiologist and treating physician. 
2.2 
Secondary objective(s) 
A key secondary objective will be an evaluation of the frequency and severity of pneumonitis. 
 
Additional secondary objectives include: 
 To evaluate Overall survival (OS): OS is defined as the duration from study 
registration to death due to any cause. OS for patients last known to be alive will be 
censored at the date of last contact 
 To evaluate the pathologic response rate of the mediastinum to chemo-immunotherapy 
plus primary lung tumor radiation 
 To evaluate the objective response rate (CR or PR, confirmed and unconfirmed). 
Response rate will calculated as the percentage of patients achieving a PR or CR, 
and will be presented along with the 95% CI. 
 To evaluate the frequency and severity of toxicities  graded with CTCAE, version 5. 
Toxicities will be summarized as the proportion of patients with such toxicities, in 
addition to total number of toxicities (allowing for multiple toxicities within a patient) 
among all patients. 
2.3 
Exploratory objective(s) 
Immune profile on peripheral blood and tumor, which can include but are not limited to the 
following: 
 Changes in peripheral blood immune cell subpopulations measured via multi-parameter 
flow cytometry: 
o Important 
T-cell 
subsets 
using 
markers 
such 
as: 
CD3/CD8/CD4/Foxp3/CD45RA/CD45RO/CCR7/CD28/CD27/CD57/CD25/H 
LA-DR/CTLA4/PD-1 


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o NK cells will be assessed using CD16/CD56/CD69. 
o B-cells and dendritic cells will be analyzed using: CD19, CD123, CD11c, 
CD86, MHC class I and II, CD70, and CD54. 
o MDSC will be assessed using: CD11b, CD 14, CD33. 
 Next generation sequencing of the T-cell receptor-β locus in genomic DNA from sorted 
CD4+ and CD8+ T cell subsets from blood samples using the TRB ImmunoSeq kit 
(Adaptive Biotechnologies). 
 Tumor biopsies (pre- and post-treatment of a non-radiated site) in select patients who 
consent will be assessed for: cell death, tumor infiltrating lymphocytes, expression of 
cell surface markers including HLA, PDL1, etc., and undergo multiparameter flow 
cytometry as well as TCR sequencing. 


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3. 
STUDY DESIGN 
 
3.1 
Overview of study design 
This is a single-arm, phase II, multi-institutional trial for patients with unresectable NSCLC. 
Target accrual is 40 patients, distributed relatively evenly across 2-3 sites.  Patients with 
unresectable NSCLC are typically treated with concurrent chemoradiation per standard of 
care, plus 1-year of adjuvant durvalumab. 
 
The two investigation components of this study are: 1) giving durvalumab for 2 years starting 
with concurrent chemoradiation, which is being tested in a large randomized trial PACIFIC-2; 
and 2) instead of radiating all visible lung cancer to 60 Gy in 30 daily fractions over 6 weeks 
per standard of care, only the primary lung tumor will initially receive treatment with 
hypofractionated radiation therapy (60 Gy in 8-15 fractions given over 3 weeks).  Mediastinal 
nodal disease will only receive radiation if there is persistent disease after initial induction 
therapy (chemo-immunotherapy plus radiation to the primary lung tumor). 
 
3.2 
Study schema 
All patients will undergo standard of care staging with PET/CT, MRI/CT head, and 
mediastinal evaluation with EBUS or mediastinoscopy. 
 
Induction therapy will include: 
 
1a) Squamous cell carcinoma: cisplatin/etoposide every 4 weeks for 2 cycles (weeks 1 to 8, 
cisplatin 50 mg/m2 on days 1, 8, 29, and 36; etoposide 50 mg/m2 on days 1-5, and 29-33); 
 
OR 
 
1b) Non-squamous cell carcinoma: cisplatin/pemetrexed every 3 weeks for 3 cycles (weeks 1 
to 8, cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on days 1, 22, and 43); 
 
AND 
 
2) durvalumab 1,500 mg q4 weeks 
AND 
3) hypofractionated radiation to the primary lung tumor (60 Gy in 15 fractions from weeks 1 
to 3, or 60 Gy in 8 fractions from weeks 1-2, radiation fractionation depends on tumor 
anatomy). 


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At week 9, patients will be restaged with CT c/a/p, and those with pathologically enlarged 
mediastinal nodes will undergo repeat EBUS/mediastinoscopy. If pathologically positive 
lymph nodes are found, radiation will be given to the mediastinum (2 Gy/fraction to 60 Gy) 
starting week 12. 
 
Durvalumab will continue be given every 4 weeks for 2 years from the start of concurrent 
chemoradiotherapy (as tested in PACIFIC-2 trial). 
 
 
Figure 1. Study Schema. 
3.3 
Study oversight for safety evaluation 
Oversight for this study will be provided by the Principal Investigator with delegation of 
appropriate responsibilities to sub-investigators and designated study personnel.  They will 
ensure all entry criteria are met prior to the initiation of the protocol and all study procedures 
and reporting of adverse events are performed according to the IRB-approved protocol. 
 
Early stopping of this trial will be 2 or more grade 5 adverse events (AEs) occurring within ≤ 
30 days after the end of radiation treatment to the primary tumor, defined as possibly, 
probably, or definitely related to radiation treatment (per CTCAE, v.5.0).  All AE’s grade 4 or 
higher must be reported to the PI within 48 hours, except hematologic AEs (i.e. abnormal lab 
values). 


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4. 
PATIENT SELECTION 
 
Eligible patients for this trial have unresectable non-small cell lung cancer, fit for treatment 
with concurrent chemoradiation and immunotherapy. 
 
4.1 
Inclusion criteria 
For inclusion in the study patients must fulfill all of the following criteria: 
 
1. 
Histologically or cytologically documented NSCLC 
 
2. 
Stage III NSCLC according to AJCC staging v8 
 
3. 
At least one mediastinal site of disease that is discontiguous from all other visible 
sites of disease and can be excluded from primary tumor site radiation (i.e. at least 
10 mm separation between tumors) 
 
4. 
A maximum of 20 patients with bulky mediastinal disease will be allowed on this 
trial, defined as at least one contiguous mediastinal mass with minimum diameter 
>2 cm, that is not contiguous with the primary tumor (and therefore would not be 
irradiated during radiation to the primary tumor) 
 
5. 
No surgery for lung cancer for at least 3 years 
 
6. 
No other malignancies for at least 3 years, excluding low grade or non-invasive 
malignancies such as skin cancers, prostate cancers, and DCIS 
 
7. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
 
8. 
Age > 18 years at time of study entry. 
 
9. 
Life expectancy of > at least 3 months 
 
10. 
Body weight >30 kg 
 
11. 
Adequate normal organ and marrow function as defined below: 
 
 
Hemoglobin ≥9.0 g/dL 
 
 
Absolute neutrophil count (ANC) 1.5 (or 1.0) x (> 1500 per mm3) 
 
 
Platelet count ≥100,000 per mm3 


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 
Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not 
apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of 
hemolysis or hepatic pathology), who will be allowed only in consultation with 
their physician. 
 
 
AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless 
liver metastases are present, in which case it must be ≤5x ULN 
 
 
Measured creatinine clearance (CL) >60 mL/min or Calculated creatinine 
CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or 
by 24-hour urine collection for determination of creatinine clearance: 
 
 
 
 
L) 
 
 
 
 
x 0.85 
L) 
12. 
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 (eg, 
Health Insurance Portability and Accountability Act in) obtained from the 
patient/legal representative prior to performing any protocol-related procedures, 
including screening evaluations. 
 
13. 
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). 
Males: 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
72 x serum creatinine (mg/d 
Females: 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)   
72 x serum creatinine (mg/d 


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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, 
or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy). 
 
14. 
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. 
 
4.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
 
1. Prior anti-CTLA-4, PD-1 or PD-L1 antibodies including durvalumab 
 
2. Prior chemotherapy in the past 3 years from consent 
 
3. 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. 
 
4. Prior thoracic radiation that would preclude curative-intent radiation dose as outlined 
in this study 
 
5. Concurrent enrolment in another clinical study, unless it is an observational (non- 
interventional) clinical study or during the follow-up period of an interventional 
study 
 
6. History of allogenic organ transplantation. 
 
7. 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 


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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 
 
8. Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled 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 
 
9. History of leptomeningeal carcinomatosis 
 
10. History of active primary immunodeficiency 
 
11. 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. 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. 
 
12. 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 


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c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
 
13. 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. 
 
14. 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. 
 
15. Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients. 
 
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3. 
 
4.3 
Withdrawal of patients from study treatment and/or study 
Permanent discontinuation of study treatment 
 
Discontinuation of study treatment, for any reason, does not impact the patient’s participation 
in the study. A patient who decides to discontinue treatment will always be asked about the 
reason(s) for discontinuation and the presence of any AE. The patient should continue 
attending subsequent study visits, and data collection should continue according to the study 
protocol. If the patient does not agree to continue in-person study visits, a modified follow-up 
must be arranged to ensure the collection of endpoints and safety information. This follow-up 
could be a telephone contact with the patient, a contact with a relative or treating physician, or 
information from medical records. The approach taken should be recorded in the medical 
records. A patient that agrees to modified follow-up is not considered to have withdrawn 
consent or to have withdrawn from the study. 
 
Patients who are permanently discontinued from further receipt of treatment, regardless of the 
reason, will be identified as having permanently discontinued treatment. Patients who are 
permanently discontinued will enter follow-up. 
 
Patients who permanently discontinue durvalumab for reasons other than objective disease 
progression should continue to have scans performed q12w ±2w for the first 52 weeks, or 
death (whichever comes first). 
 
If a patient is discontinued for  progression documented by the radiologist and confirmed by 
the treating physician, then the patient should have 1 additional follow-up scan performed 
preferably at the next (and no later than the next) scheduled imaging visit, and no less than 4 
weeks after the prior assessment of PD. 
 
All patients will be followed for survival until the end of the study. 


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Drug Substance Durvalumab 
(MEDI4736) Study Number 
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Edition Number V2.0 
Page 32 of 102 
 
 
 
Patients who decline to return to the site for evaluations should be contacted by telephone as 
an alternative. 
 
 
Lost to follow-up 
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed, such that there is insufficient information to determine the 
patient’s status at that time. Patients who refuse to continue participation in the study, 
including telephone contact, should be documented as “withdrawal of consent” rather than 
“lost to follow-up.” Investigators should document attempts to re-establish contact with 
missing patients throughout the study period. If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and evaluations should 
resume according to the protocol. 
 
 
Lost to Follow up – site personnel should check hospital records, the patients’ 
current physician, and a publicly available death registry (if available) to obtain a 
current survival status. (The applicable CRF modules will be updated.) 
 
 
In the event that the patient has actively withdrawn consent to the processing of 
their personal data, the survival status of the patient can be obtained by site 
personnel from publicly available death registries (if available) where it is possible 
to do so under applicable local laws to obtain a current survival status. (The 
applicable CRF modules will be updated.) 
 
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. 
 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent 
to: 


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(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
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 
All further participation in the study including any further follow up (eg, survival 
contact telephone calls) 
 
 
Withdrawal to the use of any samples 


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(MEDI4736) Study Number 
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Edition Number V2.0 
Page 34 of 102 
 
 
 
5. 
TREATMENT PLAN 
 
5.1 
Study Registration 
Potentially eligible patients will be identified by study investigators and screened for 
eligibility by the study team.  Subjects will be registered by the FHCRC/UW Study 
Coordinator and entered into the OnCore System. Information regarding OnCore and the 
Clinical Trial Management System (CTMS) system is available at https://www.iths.org/ctms/. 
A complete, signed, study consent and HIPAA consent are required for registration. 
5.2 
Durvalumab 
Durvalumab is FDA approved as standard of care adjuvant therapy for 1-year after 
chemoradiation for unresectable NSCLC.  In this study, durvalumab is considered an 
investigational agent since it is being given concurrent with chemoradiation, and for 2-year 
duration.  Drug administration details given in this study are generally consistent with current 
standard of care for FDA approved indications for durvalumab. 
 
5.2.1 
Formulation/packaging/storage 
Durvalumab will be supplied by AstraZeneca as a 500- mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab, 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. 
 
5.2.2 
Durvalumab doses and treatment regimens 
All patients will receive 1500 mg durvalumab via IV infusion Q4W for up to a maximum of 24 
months (up to 24 doses/cycles) until confirmed disease progression, or unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met. If a patient’s weight falls to 
30 kg or below (≤30 kg) the patient should be withdrawn from study. 
 
5.2.3 
Study drug preparation 
 
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: 
 
 
24 hours at 2°C to 8°C (36°F to 46°F) 


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Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
 
4 hours at room temperature 
 
A dose of 1500 mg (for patients >30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 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 (i.e., 1500 mg of durvalumab) 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. 
 
Standard infusion time is one hour. However, 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 does not contain preservatives, and any unused portion must be 
discarded. 
 
5.2.4 
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 is one hour, however if there are interruptions during infusion, the total allowed 
infusion time should not exceed 8 hours at room temperature. The standard infusion time is 
one hour, however if there are interruptions during infusion, the total allowed time from infusion 
start to completion of infusion should not exceed 8 hours at room temperature, with maximum  
total time at room temperature not exceeding 4 hours (otherwise requires new 


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Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
infusion preparation). 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 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. 
 
5.2.5 
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 must be signed. 
 
5.3 
Chemotherapy 
Chemotherapy for this study will be given per standard of care.  The drugs and dosing 
regimen for this study will be: 
 
Squamous cell carcinoma: cisplatin/etoposide every 4 weeks for 2 cycles (weeks 1 to 8, 
cisplatin 50 mg/m2 on days 1, 8, 29, and 36; etoposide 50 mg/m2 on days 1-5, and 29-33); 
 
OR 
 
Non-squamous cell carcinoma: cisplatin/pemetrexed every 3 weeks for 3 cycles (weeks 1 to 8, 
cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on days 1, 22, and 43); 
 
Dose reductions and changes in dosing schedules are allowed at the discretion of the treating 
medical oncologist if clinically indicated. 
 
5.4 
Radiation Therapy 
Radiation therapy delivered on this study will meet all requirements considered standard 
clinical care.  All patients will be treated with conformal radiation treatment or intensity- 
modulated radiation techniques.  Both photon therapy and proton therapy are allowed.  All 
patients will be planned for both the initial phase of radiation to the primary lung tumor, and 
the subsequent mediastinal radiation (only given to patients who do not have a complete 
response in the mediastinum), at the time of initial simulation, to ensure that the mediastinal 
nodes will be able to be safely radiated without exceeding normal tissue constraints. 


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Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
5.4.1 
Simulation 
All patients should undergo 4-D CT-based simulation with motion evaluation with slice 
thickness ≤3mm, scanning from at least C3 to below both kidneys (top of iliac crest).  IV 
contrast use is encouraged but not required.  Patients are treated supine with arms up with 
immobilization devices. 
 
5.4.2 
Definition of target volumes and margins 
Contouring of gross tumor volume (GTV), internal gross tumor volume (IGTV), clinical 
target volume (CTV), and planning target volume (PTV) are per routine standard of care, and 
detailed in Table 1.  Please see Figure 2 for example contours of GTV_primary, outlined in 
red, and GTV_mediastinum, outlined in green. 
 
Table 1. Guidelines for target volumes. 
 
Contour Name 
Description 
Margin 
GTV_primary 
Primary lung tumor, other lung parenchymal tumors if 
applicable (i.e. satellite nodules), and any contiguous 
involved lymph nodes. 
None. 
GTV_mediastinum Any involved mediastinal nodes (defined per routine 
standard of care, either by CT enlargement, PET avidity, or 
positivity on pathologic evaluation with EBUS or 
mediastinoscopy) that are not included in the GTV_primary 
None. 
IGTV_primary 
Encompass respiratory motion for GTV_primary based on 4- 
D CT 
None. 
IGTV_mediastinum Encompass respiratory motion for GTV_mediastinum based 
on 4-D CT 
None. 
CTV_primary 
IGTV_primary plus microscopic disease extension. When the 
CTV margin extends into critical normal organs, the volume 
can be reduced as clinically appropriate. 
5-8 mm 
CTV_mediastinum 
IGTV_mediastinum plus microscopic disease extension. 
When the CTV margin extends into critical normal organs, 
the volume can be reduced as clinically appropriate. 
5-8 mm 
PTV_primary 
CTV_primary plus margin for setup error.  Value depends on 
institutional guidelines. 
5-10 
mm 


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Drug Substance Durvalumab 
(MEDI4736) Study Number 
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Edition Number V2.0 
 
 
 
PTV_mediastinum 
CTV_mediastnum plus margin for setup error.  Value 
depends on institutional guidelines. 
5-10 
mm 
 
 
PTV_primary and PTV_mediastinum must not be contiguous for patients to be eligible for 
this trial (at least 1 mm separation between the two volumes).  The trial inclusion criteria of a 
site of mediastinal disease that is >10 mm away from all other sites of disease selects for 
patients who will be able to have two separate PTV volumes. 
 
For patients who need mediastinal radiation due to lack of complete response in the 
mediastinum to induction therapy, they will undergo repeat simulation and a new 
GTV_mediastinum, IGTV_mediastinum, CTV_mediastinum, and PTV_mediastinum must be 
contoured on the new scan. 


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Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
 
 
Patient A 
Patient B 
Figure 2. Example Contours. Top panel: Two axial 
PET/CT images from example Patient A, with a 
primary lung tumor (GTV_primary in green) that is 
geographically located apart from the involved 
mediastinal lymph nodes (GTV_mediastinum in red). 
Middle and bottom panel: two axial and one coronal 
PET/CT images from example Patient B, with a 
primary lung tumor that is contiguous with hilar and 
mediastinal nodal involvement (GTV+primary in red), 
and a second site of visible disease in the mediastinum 
that is >10 mm away from the GTV_primary, 
contoured as GTV_mediastinum in green. 


Clinical Study Protocol 
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(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
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5.4.3 
Definition of critical structures 
Normal organs will be contoured per RTOG contouring guidelines as published in the lung 
atlas: https://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx.  Organs that must be 
contoured are listed and described in Table 2 below. 
 
Table 2. Normal tissue contouring guidelines. 
 
Contour Name 
Description 
Required/Required 
when applicable 
BrachialPlex_L 
Left brachial plexus, required if within 5 
cm of PTV 
Required when applicable 
BrachialPlex_R 
Right brachial plexus, required if within 
5 cm of PTV 
Required when applicable 
Bronchus 
Carina down to lobar bronchus, 
terminating at segmental bifurcation, 
including proximal 2 cm of trachea 
Required when applicable 
Esophagus 
Entire extent of esophagus from below 
cricopharyngeus to gastroesophageal 
function 
Required 
GreatVessels 
Required if within 5 cm of PTV 
Required when applicable 
Heart 
Entire pericardial sac 
Required 
Liver 
Required if within 5 cm of PTV 
Required when applicable 
Lung_L 
All inflated and collapsed lung should 
be contoured. Does not include GTV. 
Required 
Lung_R 
All inflated and collapsed lung should 
be contoured. Does not include GTV. 
Required 
Lungs 
All inflated and collapsed lung should 
be contoured.  Does not include GTV. 
Required 
Kidneys 
Required if within 5 cm of PTV 
Required when applicable 
Skin 
5 mm skin rhind 
Required 


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(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 41 of 102 
 
 
 
SpinalCord 
Bony limits of spinal canal 
Required 
Stomach 
Required if within 5 cm of PTV 
Required when applicable 
Trachea 
Trachea down to exclude proximal 2 cm 
Required when applicable 
 
 
5.4.4 
Treatment planning 
Prescription to PTV_primary is 60 Gy in 8-15 fractions.  Choice of 8 or 15 fraction regimen 
will depend on ability to meet dose constraints (detailed in Table 3), and overall assessment of 
radiation treatment plan safety. The 8 fraction regimen is preferred, but the 15 fraction is 
allowed if there are safety concerns about the 8 fraction plan or inability to meet dose 
constraints as outlined in Table 3 below.  The 8 fraction plan may not be safely delivered to 
ultra-central tumor volumes (defined as tumors touching the main bronchus), and the 15 
fraction regimen is preferred in this setting. 
 
Prescription to PTV_mediastinum is 60 Gy in 30 fractions. Treatment planning should meet 
all requirements considered standard clinical care.  Planning technique is not specified on this 
trial, although highly conformal techniques that minimize normal tissue dose are encouraged 
(i.e. IMRT/VMAT, proton therapy).  Treatment planning should account for respiratory 
motion (i.e. plan on 4D average CT, and/or 4D robustness optimization). 
 
All patients will undergo treatment planning to two PTV volumes at the initial simulation: 
PTV_primary and PTV_mediastinum. Each individual plan and the composite plan must meet 
all dose constraints as specified in Table 3 below. Constraints are given for each organ for an 
8 fraction treatment regimen, a 15 fraction treatment regimen (since PTV_primary is treated in 
8-15 fractions), a 30 fraction treatment regimen (since PTV_mediastinum is treated in 30 
fractions), and an equivalent dose in 2 Gy fractions (EQD2Gy) constraint for the composite 
plan.  Alpha/beta ratio of 3 is used for EQD2Gy calculations for normal tissues.  For patients 
who need mediastinal radiation due to lack of complete response in the mediastinum to 
induction therapy, they will undergo repeat simulation and a new GTV_mediastinum, 
IGTV_mediastinum, CTV_mediastinum, and PTV_mediastinum must be contoured on the 
new simulation scan.  A composite plan must be generated with the initial PTV_primary 
radiation treatment, and the composite plan must meet all dose constraints as specified in 
Table 3 below. 


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(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 42 of 102 
 
 
 
Table 3. Treatment planning guidelines. 
 
Structure 
Goal for 8 
fractions 
Goal for 15 
fractions 
Goal for 30 
fractions 
Composite Goal 
in EQD2Gy 
PTV_ 
primary 
V57Gy>95% 
goal; 
V57Gy>90% 
accepted 
V57Gy>95% 
goal; 
V57Gy>90% 
accepted 
PTV_ 
mediastinum 
V57Gy>95% 
goal; 
V57Gy>90% 
accepted 
BrachialPlex 
_L, 
BrachialPlex 
_R 
D0.035cc<32 Gy 
goal; 
D0.035cc<36 Gy 
accepted 
D0.035cc<45 Gy 
goal; 
D0.035cc<50 Gy 
accepted 
D0.035cc<66 Gy D0.035cc<66 Gy 
Bronchus 
D0.035cc<32 Gy 
goal; 
D0.035cc<36 Gy 
accepted 
D0.035cc<40 Gy 
goal; 
D0.035cc<45 Gy 
accepted 
D0.035cc<66 Gy D0.035cc<74 Gy 
Esophagus 
D0.035cc<32 Gy 
goal; 
D0.035cc<36 Gy 
accepted 
D0.035cc<50 Gy 
goal; 
D0.035cc<55 Gy 
accepted 
D0.035cc<66 Gy D0.035cc<74 Gy 
GreatVessels 
D0.035cc<32 Gy 
goal; 
D0.035cc<36 Gy 
accepted 
D0.035cc<48 Gy 
goal; 
D0.035cc<54 Gy 
accepted 
D0.035cc<66 Gy D0.035cc<74 Gy 
Heart 
D0.035cc<36 Gy 
goal; 
D0.035cc<40 Gy 
accepted 
D0.035cc<40 Gy 
goal; 
D0.035cc<45 Gy 
accepted 
D0.035cc<66 Gy D0.035cc<74 Gy 
Liver 
Mean dose <10 
Gy 
Mean dose <18 
Gy 
Mean dose <20 
Gy 
Mean dose <20 
Gy 
Lungs 
Mean dose <10 
Gy; 
V20Gy < 10%; 
V5Gy<30% 
Mean dose <18 
Gy; 
V18Gy < 37%; 
V5Gy<60% 
Mean dose <20 
Gy; 
V20Gy < 37%; 
V5Gy<60% 
Mean dose <20 
Gy; 
V20Gy < 37%; 
V5Gy<60% 
Kidneys 
Mean dose <8 
Gy goal 
Mean dose <10 
Gy goal 
Mean dose <12 
Gy 
Mean dose <12 
Gy 
SpinalCord 
D0.035cc<28 Gy D0.035cc<36 Gy 
goal; 
D0.035cc<50 Gy D0.035cc<50 Gy 


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(MEDI4736) Study Number 
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Edition Number V2.0 
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D0.035cc<39 Gy 
accepted 
Stomach 
D0.035cc<32 Gy 
goal; 
D0.035cc<36 Gy 
accepted 
D0.035cc<45 Gy 
goal; 
D0.035cc<50 Gy 
accepted 
D0.035cc<60 Gy D0.035cc<60 Gy 
Trachea 
D0.035cc<32 Gy 
goal; 
D0.035cc<36 Gy 
accepted 
D0.035cc<40 Gy 
goal; 
D0.035cc<45 Gy 
accepted 
D0.035cc<66 Gy D0.035cc<74 Gy 
 
 
5.4.5 
Patient specific quality assurance 
Any patient-specific QA that needs to be acquired should follow institutional guidelines. For 
intensity-modulated techniques, patient specific QA is highly recommended. 
 
5.4.6 
Daily treatment localization/Image guided radiation therapy (IGRT) 
Daily image guidance is required. This can be in the form of daily cone-beam CT (CBCT), or 
daily orthogonal x-rays. If daily orthogonal x-rays are used, weekly CT (CBCT or simulation 
CT) is required to verify anatomy. IGRT matching will be per routine clinical care. 
 
5.4.7 
Case review 
Principal investigator will review first 3 cases per site prior to treatment initiation. All future 
cases will be reviewed without one week of treatment start. 
 
5.5 
Toxicity management guidelines 
Durvalumab is FDA approved as adjuvant treatment after chemoradiation for unresectable 
NSCLC. Although this trial gives durvalumab for 2 years as opposed to the current FDA 
approval of 1 year, toxicities will be managed per standard of care. Guidelines for the 
management of immune-mediated reactions, infusion-related reactions, and non-immune- 
mediated reactions for durvalumab are provided in the durvalumab/tremelimumab Toxicity 
Management Guidelines (TMGs, current version dated November 2017, CTCAE version 5.0), 
included as Appendix 1. 
 
Management of chemotherapy and radiation related toxicities will also be per standard clinical 
care.  All toxicities will be graded according to NCI CTCAE, Version5.0. 


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(MEDI4736) Study Number 
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Edition Number V2.0 
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6. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
6.1 
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 2) 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-sterilised 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 2). 
 
N.B Females of childbearing potential are defined as those who are not surgically sterile (ie, 
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: 


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(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 45 of 102 
 
 
 
 
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. 
 
 
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 (ie, 
less than 1% per year) when used consistently and correctly are described in Table 2. 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 


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(MEDI4736) Study Number 
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Edition Number V2.0 
Page 46 of 102 
 
 
 
Blood donation 
Patients should not donate blood while receiving active therapy in this study, for at least 90 days 
following the last infusion of durvalumab. 
 
6.2 
Concomitant treatment(s) 
6.2.1 
Permitted concomitant medications 
Table 2. Supportive Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Excluded concomitant medications 
Table 3. Prohibited Concomitant 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 
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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Edition Number V2.0 
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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]) 
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: 
• 
Use of immunosuppressive medications for the 
management of IP-related AEs, 
• 
Short-term premedication for patients receiving 
other drugs (chemotherapy) where the prescribing 
information for the agent requires the use of 
steroids for documented hypersensitivity reactions 
• 
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 


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(MEDI4736) Study Number 
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Edition Number V2.0 
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7. 
STUDY PROCEDURES 
7.1 
Schedule of study procedures 
7.1.1 
Screening phase 
Screening procedures will be performed up to 45 days before Day 1 of treatment, except for 
histology which has no time restriction. All screening procedures for this study are standard 
of care, there are no required study specific tests for screening.  After signing the IRB 
approved informed consent, completing all screening procedures, and being deemed eligible 
for entry, patients will be enrolled in the study. 
 
7.1.2 
Treatment phase 
 
Procedures to be conducted during the treatment phase of the study are presented in the 
Schedule of Assessments. Treatment visits will be per standard of care, which is typically at 
least every 4 weeks during chemotherapy and durvalumab, and weekly during radiation 
treatment.  Standard of care lab assessments will be drawn prior to every infusion during 
chemotherapy and durvalumab therapy.  Study blood draws will take place prior to 
initiation of any therapy (within 45 days), 1 week after completion of radiation to the 
primary tumor (±7 calendar days), prior to mediastinal radiation (less than 4 weeks) for 
applicable patients, and every 4 months (±1 month) afterwards for 2 years or until disease 
progression.  Either an EBUS or mediastiastinoscopy must be performed to provide 
pathologic evaluation of the mediastinal nodes prior to starting treatment, per standard of 
care. For patients who do not have systemic progression on repeat CT at week 9, a repeat 
EBUS or mediastinoscopy must be performed to evaluate the mediastinal lymph nodes. 
This should ideally take place within 3 weeks of the restaging CT at week 9 but may be up 
to 6 weeks. Optional repeat lung tumor biopsy will be performed 1 month after radiation to 
the primary tumor (±2 weeks). 
 
End of treatment is defined as the last planned dosing visit within the 24-month dosing period. 
For patients who discontinue durvalumab prior to 24 months, end of treatment is considered 
the last visit where the decision is made to discontinue treatment. 
 
7.1.3 
Blood draws 
 
Standard of care labs drawn during the study period includes hematology labs (Table 5), and 
clinical chemistry (Table 6).  Study blood draws will take place a maximum of 9 times per 
patient during the 24 months study period, as detailed on the study calendar.  Study blood 
draw will consist of 5 tubes. 


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Table 5. 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 
 
 
 
 
 
Table 6. Clinical Chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lipase b 
Alanine aminotransferase 
Magnesium 
Amylase 
Potassium 
Aspartate aminotransferase 
Sodium 
Bicarbonate 
Total bilirubina 
Calcium 
Total protein 
Chloride 
Blood urea nitrogen 
Creatinine c 
 
 
 
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, but one is acceptable. 
c Creatinine Clearance will be calculated by data management using Cockcroft-Gault (using actual body 
weight). 


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(MEDI4736) Study Number 
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8. 
ASSESSMENT OF SAFETY 
 
8.1 
Early patient review for safety 
Patients are seen and evaluated by the medical oncology team prior to each durvalumab infusion 
(every 4 weeks) for the entirely of the study duration per standard of care. During the 
chemotherapy portion of the study (weeks 1-8), patients are evaluated by the medical oncology 
team every one to two weeks as well. When patients are receiving radiation therapy (weeks 1- 
3 of the study, and weeks 12-18 for patients receiving mediastinal radiation), patients are 
evaluated weekly by the radiation oncology team per standard of care. Therefore, within the 
first 3 months of treatment for each patient, they will be assessed by the oncology teams at least 
8 times. 
 
8.2 
Safety parameters 
8.2.1.1 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 and 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 nontreatment emergent. A nontreatment-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. 


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The term AE is used to include both serious and non-serious AEs. 
 
8.2.2 
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: 
 
 
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. 
 
8.2.3 
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 


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Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
 
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 
 
 
Pancreatitis  / serum lipase and amylase increases 
 
 
Myocarditis 
 
 
Myositis / Polymyositis 
 
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
Intestinal Perforation 
 
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 eyeskin, haematological and rheumatological events, 
vasculitis, non-infectious meningitis and non-infectious encephalitis. It is possible 
that events with an inflammatory or immune mediated mechanism could occur in 
nearly all organs. 
 
In addition,  infusion-related  reactions  and  hypersensitivity/anaphylactic  reactions  with  a 
different underlying pharmacological aetiology 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 


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Edition Number V2.0 
 
 
 
parameters etc) will be captured in <<specify where this information will be recorded e.g. 
eCRF, CRF, etc)>> 
 
It is strongly recommended to perform a full diagnostic workup, to exclude alternative causes 
such as lymphangitic 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 
 
 
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 
 
8.3 
Assessment of safety parameters 
8.3.1 
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 


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Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
 
 
 
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. 
8.4 
Recording of adverse events and serious adverse events 
AEs and SAEs will be collected from the time of the patient signing the informed consent form 
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 AEs and 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. 


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(MEDI4736) Study Number 
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Edition Number V2.0 
 
 
 
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. 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 of whether treatment related 
 
 
Action taken with regard to cancer-directed treatment 
 
 
Administration of treatment for the AE 
 
 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
 
 
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 


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Edition Number V2.0 
 
 
 
 
Causality assessment in relation to study procedure(s) 
 
 
Causality assessment in relation to other medication 
 
 
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). 
 
8.4.1 
Study recording period and follow-up for adverse events and serious 
adverse events 
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. 
 
8.4.2 
Causality collection 
The Investigator will assess causal relationship between the study treatments 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 study treatment?” 
 
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.” 
 
8.4.3 
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: 


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(MEDI4736) Study Number 
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Edition Number V2.0 
 
 
 
 
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. 
 
8.4.4 
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 CRF. 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. 
 
8.4.5 
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 study treatments. 
 
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. 
 
8.4.6 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the study treatments are 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 


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Edition Number V2.0 
 
 
 
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. 
 
8.4.7 
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 study treatments and have 
been identified after the patient’s inclusion in this study. 
 
8.4.8 
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. 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. 
 
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. 
 
A post mortem 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. 
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. 
 
8.4.9 
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. 


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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. 
 
8.4.10 
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 Patient Safety. 
 
8.5 
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 is 
responsible for informing the Ethics Committee and/or the Regulatory Authority of the SAE 
as per local requirements. 
 
8.5.1 
Reporting of deaths to AstraZeneca 
All deaths must be recorded and reported as outlined in this protocol.  In addition, all SAEs 
resulting in death or death of unknown cause must be reported to AstraZeneca via 
AEMailboxClinicalTrialTCS@astrazeneca.com within 7 calendar days of awareness or sooner 
when required 
8.5.2 
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. The sponsor 
must report these to AstraZeneca/MedImmune Patient Safety or designee using the designated 
Safety e-mailbox (see Section 10.5 for contact information) within 7 calendar days or sooner 
when required (see Section 10.5). If the overdose results in an AE, the AE must also be 
recorded as an AE (see Section 10.5). Overdose does not automatically make an AE serious, 
but if the consequences of the overdose are serious, for example death or hospitalization, the 


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event is serious and must be recorded and reported as an SAE (see Section 10.5). There is 
currently no specific treatment in the event of an overdose of durvalumab. 
 
The investigator will use clinical judgment to treat any overdose. 
 
8.5.3 
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. The 
Sponsor must report these events to AstraZeneca Patient Safety using the designated Safety e- 
mailbox within 7 calendar days or sooner when required, 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. 
 
 
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. 
 
8.5.4 
Pregnancy 
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 


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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 sponsor within 1 day, i.e., immediately, but no later than 24 hours of when 
he or she becomes aware of it. 
 
The sponsor will work with the Investigator to ensure that all relevant information is provided 
within 1 to 5 calendar days. The Sponsor must report to AstraZeneca Patient Safety using the 
designated Safety e-mailbox (see Section 10.5 for contact information) within 7 calendar days 
or sooner when required (see Section 10.5), for pregnancies with SAEs and within 30 days for 
all other pregnancies. 
 
The same timelines apply when outcome information is available. 
 
8.5.5 
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 
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. 
 
8.6 
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. 


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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: 
 
 Patient accidentally missed drug dose(s) e.g. forgot to take medication 
 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 Sponsor within 1 day i.e., immediately but no later than 24 hours of when 
he or she becomes aware of it. 
 
The Sponsor works with the Investigator to ensure that all relevant information is completed 
within 1 or 5 calendar days. The Sponsor must report to AstraZeneca Patient Safety using the 


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designated Safety e-mailbox within 7 calendar days or sooner when required if there is an SAE 
associated with the medication error and within 30 days for all other medication errors. 


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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
The primary objective of this study is to evaluate the one-year progression-free survival rate in 
patients with stage III non-small cell lung cancer treated with chemotherapy and 
hypofractionated radiation to the primary tumor and adaptive radiation to the mediastinum, 
along with up to 2 years of durvalumab. The design of the study is a single arm phase II and 
the design is based on a comparison with expected data with PACIFIC 2. 
 
9.1 
Description of analysis sets 
9.1.1 
Efficacy and safety analysis set 
 
Given that this is a single arm phase II study, the primary analysis population (PAP) and the 
safety analysis population (SAP) are the same; the PAP and SAP will include eligible patients 
who started at least one therapy on trial (chemotherapy, or durvalumab, or radiation). 
 
9.2 
Methods of statistical analyses 
9.2.1 
Safety analyses 
 
The primary toxicity of interest is grade 3 or higher pneumonitis. The incidence of grade 3 or 
worse pneumonitis attributable to treatment will be evaluated and compared against the 
PACIFIC trial results. All toxicities of all grades will be monitored on study and reported. 
Binary proportions will be calculated with associated confidence intervals for binary 
outcomes, such as toxicity. 
 
9.2.2 
Efficacy analyses 
 
Efficacy analyses include an evaluation of PFS, OS, and response rate. The distribution of 
time to event outcomes will be evaluated using the method of Kaplan-Meier. Confidence 
intervals for median times will be determined using the Brookmeyer-Crowley method. 
Confidence intervals around landmark times will be determined using Greenwood’s formula 
for the variance and based on a log-log transformation applied on the survival function. Binary 
proportions will be calculated with associated confidence intervals for binary outcomes, such 
as response.  Means and/or medians will be calculated for continuous outcomes.  Confidence 
bounds will be provided for means and quartiles and ranges for median values.  All  
confidence bounds will be presented as 95% bounds. 


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9.2.3 
Exploratory analyses 
 
Exploratory outcomes will be summarized as described above for efficacy analyses.  Change 
in patient reported outcomes will be summarized by means.  The association between Immune 
profile measurements and efficacy outcomes (PFS, OS, response) will be evaluated using a 
Cox regression model for time-to-event outcomes and a logistic regression model for binary 
outcomes. 
 
9.2.4 
Interim analyses 
This study will include interim monitoring for safety; the trial will not include interim 
monitoring to assess early stopping for futility.  The study will not include interim monitoring 
for futility given that the primary endpoint is PFS at 1 years and insufficient information will 
be available to make interim decisions on this endpoint. 
 
9.3 
Determination of sample size 
As stated above, the primary objective of this study is to compare the 1-year PFS rate (PFS1) 
from the start of induction chemoradiotherapy in this study to historical data. The estimated 
null historical rate with standard of care is 42%.  This rate is based on the PFS1 in the 
PACIFIC trial and the estimated proportion of patients that will be able to proceed from 
induction chemoradiotherapy to maintenance durvalumab.  In PACIFIC, PFS1, measured  
from the start of maintenance durvalumab, was 56%.  To estimate the percentage of patients 
able to receive maintenacce therapy, we use the SWOG S0023 study in which 75% of stage III 
patients were able to receive consolidation chemotherapy following induction 
chemoradiotherapy. Further, we assume that all patients who were unable to receive 
consolidation therapy progressed prior to one year. Therefore, our estimate of the historical 1- 
year PFS rate with maintenance durvalumab following induction chemotherapy is 42% (75% 
x 56%). This number may be updated as more information from the trials become available. 
 
The target sample size for this study is 40 eligible patients who receive at least one dose of 
radiation therapy. A design with 40 patients has 90% power to rule out a 1-year PFS rate of 
42% at the 1-sided 5% level, if the true 1-year is 65%. The observation of at least 22 patients 
(55%) alive and progression free at 1 year would be considered evidence to rule out a 1-year 
PFS rate of 42%. Sample size calculations were performed using 
https://stattools.crab.org/Calculators/oneArmBinomialColored.html . 
 
With 40 patients, binary proportions (response, toxicity) can be estimated within 16% with 
95% confidence. Survival distributions will be estimated using the method of Kaplan-Meier. 
Confidence interval for median times will be estimated using the method of Brookmeyer- 
Crowley. 


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The estimated monthly accrual rate to the study is 2-3 patients per month, resulting in a total 
estimated duration of accrual of 18 months. The follow-up duration is 12 months. The total 
estimated time to analysis of the primary endpoint is 30 months. 
 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
 
 
11. 
STUDY MANAGEMENT 
 
Institutional support of trial monitoring will be in accordance with the FHCRC/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. Under  the 
provisions of this plan, FHCRC Clinical Research Support (CRS) coordinates data and 
compliance monitoring conducted by consultants, contract research organizations, or FHCRC 
employees unaffiliated with the conduct of the study. Independent monitoring visits occur at 
specified intervals determined by the assessed risk level of the study and the findings of 
previous visits per the institutional DSMP. 
 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data 
and Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and 
the FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB). 
The review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating subjects. 
The IRB reviews the study progress and safety information to assess continued acceptability 
of the risk-benefit ratio for human subjects. Approval of committees as applicable is necessary 
to continue the study. The trial will comply with the standard guidelines set forth by these 
regulatory committees and other institutional, state and federal guidelines. 
 
 
 
12. 
DATA MANAGEMENT 
 
The investigator will ensure that data collected conform to all established guidelines. Each 
subject is assigned a unique patient number to assure subject confidentiality. Subjects will not 


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be referred to by this number, by name, or by any other individual identifier in any publication 
or external presentation. The licensed medical records department, affiliated with the 
institution where the subject receives medical care, maintains all original inpatient and 
outpatient chart documents. 
 
Subject research files are stored in a secure place (or database). Access is restricted to 
authorized personnel. 
 
 
 
13. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
 
13.1 
Identity of investigational product(s) 
 
 
 
Table 4. List of Investigational Products for This Study 
Investigational product 
Dosage form and strength 
Manufacturer 
Durvalumab 
50 mg/mL solution for infusion 
after dilution 
MedImmune/AstraZeneca 


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Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage 
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Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal 
radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or 
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Palma DA, Senan S, Tsujino K, et al. Predicting radiation pneumonitis after 
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Morias S, Marcu LG, Short M, et al. Treatment-Related Adverse Effects in Lung 
Cancer Patients after Stereotactic Ablative Radiation Therapy. Journal of oncology.  
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Marciscano AE, Ghasemzadeh A, Nirschl TR, et al. Elective Nodal Irradiation 
Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and 
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Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or 
without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a 
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Bang A, Bezjak A. Stereotactic body radiotherapy for centrally located stage I non- 
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Timmerman R, Hu C, Michalski J, et al. Long-term Results of RTOG 0236: A Phase II 
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Nagata Y, Hiraoka M, Shibata T, et al. Prospective Trial of Stereotactic Body 
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Marulli G, Verderi E, Zuin A, et al. Outcomes and prognostic factors of non-small-cell 
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Neoadjuvant chemo/immunotherapy for the treatment of stages IIIA resectable non- 
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study-SLCG. Journal of Clinical Oncology. 2018;36(15):S8521. 
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Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemo-immunotherapy for the 
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Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for 
Squamous Non-Small-Cell Lung Cancer. The New England journal of medicine. Nov 
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Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy 
in Metastatic Non-Small-Cell Lung Cancer. The New England journal of medicine. 
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Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose 
radiotherapy induces an immune-mediated abscopal effect when combined with anti- 
CTLA-4 antibody. Clinical cancer research : an official journal of the American 
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Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases 
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Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment 
synergistically promote antitumor immunity in mice. The Journal of clinical 
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Kaminski JM, Shinohara E, Summers JB, Niermann KJ, Morimoto A, Brousal J. The 
controversial abscopal effect. Cancer treatment reviews. May 2005;31(3):159-172. 


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25. 
Park B, Yee C, Lee KM. The effect of radiation on the immune response to cancers. 
International journal of molecular sciences. Jan 10 2014;15(1):927-943. 
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Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with 
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Peters S, Felip E, Dafni U, et al. Safety evaluation of nivolumab added concurrently to 
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and radiation therapy for non-small-cell lung cancer: A multicentric retrospective 
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Hubbeling HG, Schapira EF, Horick NK, et al. Safety of Combined PD-1 Pathway 
Inhibition and Intracranial Radiation Therapy in Non-Small Cell Lung Cancer. Journal 
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immune checkpoint inhibitors and hypofractionated body radiotherapy. 
Oncoimmunology. 2018;7(7):e1440168. 
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Pembrolizumab with Sequential Versus Concomitant Stereotactic Body Radiotherapy 
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Westover KD, Loo BW, Jr., Gerber DE, et al. Precision Hypofractionated Radiation 
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Escalation Trial. International journal of radiation oncology, biology, physics. Sep 1 
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Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic radiotherapy 
(HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in 
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Wulf J, Baier K, Mueller G, Flentje MP. Dose-response in stereotactic irradiation of 
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36. 
Urbanic JJ, Wang X, Bogart JA, et al. Phase 1 Study of Accelerated Hypofractionated 
Radiation Therapy With Concurrent Chemotherapy for Stage III Non-Small Cell Lung 
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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and 
Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy with Tremelimumab or 
Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v5.0) 
General Considerations regarding Immune-Mediated Reactions 
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 of the start of the immune-mediated 
adverse event (imAE) 
 
Grade 3 recurrence of a previously experienced treatment-related imAE 
following resumption of dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution 
toGrade ≤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. 
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. 
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 
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 


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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and 
Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy with Tremelimumab or 
Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v5.0) 
General Considerations regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
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). 
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. 
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. 


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Pediatric Considerations regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks of the start of the immune-mediated event 
− 
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended. 
− 
The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG 
and plasmapheresis that are provided for adult patients should also be used 
for pediatric patients. 
− 
 The infliximab 5 mg/kg IV dose recommended for adults is the same as 
recommended for pediatric patients ≥ 6 years old.  For dosing in children 
younger than 6 years old, consult with a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, consult with a pediatric 
specialist. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring. 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 74 of 102 
 
 
 
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 consults. 
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  
 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 75 of 102 
 
 
 
(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)a 
− 
Consider Pulmonary and Infectious Disease consults. 
− 
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 consults; 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).a 
Diarrhea/Colitis 
Large intestine 
perforation/Intestine 
perforation 
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 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 76 of 102 
 
 
 
- 
When symptoms or evaluation indicate a perforation is 
suspected, consult a surgeon experienced in abdominal 
surgery immediately without any delay. 
− 
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, including 
perforation. 
− 
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 
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  


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 77 of 102 
 
 
 
pain; mucus or blood in 
stool) 
(Perforation: invasive 
intervention not 
indicated) 
workup, such as imaging and/or colonoscopy, to confirm 
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).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. If perforation is suspected, 
consult a surgeon experienced in abdominal surgery 
immediately without any delay . 
− 
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).a 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 78 of 102 
 
 
 
 
(Grade 3 Perforation: 
invasive intervention 
indicated; 
Grade 4 Perforation: 
life-threatening 
consequences; urgent 
intervention indicated) 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 79 of 102 
 
 
 
Hepatitis 
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis.
Any  Grade 
General Guidance 
For Any Grade 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, 
and TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications). 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients 
Grade 1  
(AST or ALT >ULN 
and ≤3.0×ULN if 
baseline normal, 1.5- 
3.0×baseline if baseline 
abnormal; and/or TB 
>ULN and ≤1.5×ULN 
if baseline normal, 
>1.0-1.5×baseline if 
baseline abnormal) 
  
 
No dose modifications. 
 
If it worsens, then treat as  Grade 2. 
− 
Continue LFT monitoring per protocol. 
Grade 2 
(AST or 
ALT >3.0×ULN and 
≤5.0×ULN if baseline 
normal, >3-5×baseline 
if baseline abnormal; 
and/or 
TB >1.5×ULN and 
≤3.0×ULN if baseline 
normal, >1.5- 
3.0×baseline if baseline 
abnormal) 
 
Hold study drug/study regimen dose 
until resolution to  Grade≤1. 
 If toxicity worsens, then treat as 
Grade 3. 
 
If toxicity improves to Grade≤1, 
resume study drug/study regimen 
after completion of steroid taper. 
For Grade 2: 
− 
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 ≤Grade 1 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. 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 80 of 102 
 
 
 
− 
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).a 
Grade 3 
(AST or 
ALT >5.0×ULN and 
≤20×ULN if baseline 
normal, >5-20× 
baseline if baseline 
abnormal; and/or 
TB >3.0×ULN  and 
≤10.0×ULN if baseline 
normal, >3.0-10.0× 
baseline if baseline 
abnormal) 
Grade 4 
(AST or ALT 
>20×ULN if baseline 
normal, >20×baseline 
if baseline abnormal; 
and/or 
TB >10×ULN if 
baseline normal, 
>10.0×baseline if 
baseline abnormal) 
For elevations in transaminases 
≤8×ULN, or elevations in TB ≤5×ULN: 
 Hold study drug/study regimen dose 
until resolution to Grade≤1 
 Resume study drug/study regimen if 
elevations downgrade to  Grade≤1 
within 14 days and after completion 
of steroid taper. 
 Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade≤1 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 
For Grade 3 or 4: 
− 
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. 
− 
Request Hepatology consult, and perform 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).a 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 81 of 102 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 82 of 102 
 
 
 
 
Hepatitis 
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
 
 
 
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
 
Any Elevations of 
AST, ALT, or TB as 
Described Below 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Isolated AST or ALT 
>ULN and 
≤5.0×ULN, whether 
normal or elevated at 
baseline 
 
General Guidance 
For Any Elevations Described: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, 
and TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications, worsening of liver 
cirrhosis [e.g., portal vein thrombosis]). 
− 
For HBV+ patients: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg 
− 
For HCV+ patients: evaluate quantitative HCV viral load 
− Consider consulting hepatologist/Infectious Disease specialist 
regarding change/implementation in/of antiviral medications 
for any patient with an elevated HBV viral load >2000 IU/ml 
− 
Consider consulting hepatologist/Infectious Disease specialist 
regarding change/implementation in/of antiviral HCV 
medications if HCV viral load increased by ≥2-fold 
− 
For HCV+ with HBcAB+: Evaluate for both HBV and HCV 
as above 
 
 
No dose modifications. 
 
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat as 
described for elevations in the row 
below. 
For all transaminase elevations, see 
instructions at bottom of shaded area if 
transaminase rise is not isolated but (at 
any time) occurs in setting of either 
increasing bilirubin or signs of 
DILI/liver decompensation 
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 83 of 102 
 
 
 
Isolated AST or ALT 
>5.0×ULN and 
≤8.0×ULN, if normal 
at baseline 
Isolated AST or ALT 
>2.0×baseline and 
≤12.5×ULN, if 
elevated >ULN at 
baseline 
 
Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤5.0×ULN. 
 If toxicity worsens, then treat as 
described for elevations in the rows 
below. 
If toxicity improves to AST or ALT 
≤5.0×ULN, resume study drug/study 
regimen after completion of steroid taper. 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 3 
days) until elevations of these are improving or resolved. 
−  
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver perfusion. 
− 
Consider, as necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, and 
investigator suspects toxicity to be immune-mediated AE, 
recommend to 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 workup and 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, consider additional 
abdominal workup (including liver biopsy) and imaging (i.e., 
liver ultrasound), and consider starting immunosuppressives 
(i.e., mycophenolate mofetil).a Discuss with study physician if 
mycophenolate mofetil is not available. Infliximab should 
NOT be used. 
Isolated AST or ALT 
>8.0×ULN and 
≤20.0×ULN, if normal 
at baseline 
Isolated AST or ALT 
>12.5×ULN and 
≤20.0×ULN, if 
elevated >ULN at 
baseline 
 
Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤5.0×ULN. 
 Resume study drug/study regimen if 
elevations downgrade to AST or 
ALT ≤5.0×ULN 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 
≤5.0×ULN within 14 days 
Permanently discontinue study 
drug/study regimen for any case meeting 
− 
Regular and frequent checking of LFTs (e.g., every 1-2 days) 
until elevations of these are improving or resolved. 
−  Consult hepatologist (unless investigator is hepatologist); 
obtain abdominal ultrasound, including Doppler assessment 
of liver perfusion; and consider liver biopsy. 
− 
Consider, as necessary, discussing with study physician. 
− 
If investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, obtain 
liver biopsy (if it has not been done already) and promptly 
start treatment with immunosuppressive therapy 
(mycophenolate mofetil). Discuss with study physician if 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 84 of 102 
 
 
 
Hy’s law criteria, in the absence of any 
alternative cause.b 
mycophenolate 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-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
Isolated AST or ALT 
>20×ULN, whether 
normal or elevated at 
baseline 
Permanently discontinue study 
drug/study regimen. 
Same as above 
(except would recommend obtaining liver biopsy early) 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if 
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase rise 
- 
For example, manage dosing for second level of transaminase rise (i.e., AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT 
>2.0×baseline and ≤12.5×ULN, if elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and 
≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and ≤20.0×ULN, if  elevated >ULN at baseline) 
- 
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen 
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). 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 85 of 102 
 
 
 
 
− 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. 
 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 86 of 102 
 
 
 
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 
drug/study regimen after completion 
of steroid taper. 
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. 
− 
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).a 
−  When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 87 of 102 
 
 
 
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).a 
Rash or Dermatitis 
(including Pemphigoid) 
Any Grade 
(refer to NCI CTCAE 
v 5.0 for definition of 
severity/grade 
depending on type of 
skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
−  IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED AND 
STUDY DRUG DISCONTINUED IF SUSPECT 
STEVENS-JOHNSON SYNDROME OR TOXIC 
EPIDERMAL NECROLYSIS. 
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. 
For Grade 2: 
− 
Obtain Dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 88 of 102 
 
 
 
 
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. 
− 
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 promptly. 
− 
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, 
then permanently discontinue study 
drug/study regimen. 
For Grade 4 (or life-threatening): 
Permanently discontinue study 
drug/study regimen. 
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. 
− 
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).a 
− 
Consider, as necessary, discussing with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, Type 1 
diabetes mellitus, 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
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, 


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(MEDI4736) Study Number 
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Edition Number V2.0 
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hypophysitis, 
v5.0 for defining the 
hypopituitarism, and 
CTC grade/severity) 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
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 asymptomatic elevations in serum amylase and lipase 
>ULN and <3×ULN, 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. 
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. 
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. 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 90 of 102 
 
 
 
 
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. 
3. 
Doses of prednisone are 
≤10 mg/day or equivalent. 
− 
 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).a 
− 
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) 
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. 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 91 of 102 
 
 
 
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. 
−  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).a 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain- 
Barre) 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v5.0 
for defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
 Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes, or medications). 
− 
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 Neurology consult as 
appropriate. 
− 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 92 of 102 
 
 
 
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. 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days. 
For Grade 4: 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing with study physician. 
− 
Obtain Neurology consult. 
− 
Consider hospitalization. 
− 
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. 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 93 of 102 
 
 
 
Permanently discontinue study 
drug/study regimen. 
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 Neurology 
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 
considered effective. Patients requiring treatment should be 
started with IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
Grade 1 
(Guillain-Barre [GB]: 
mild symptoms)  
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing with the study physician. 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 94 of 102 
 
 
 
(Myasthenia gravis 
[MG]: asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated) 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above. 
− 
Obtain a Neurology consult. 
Grade 2 
(GB: moderate 
symptoms; limiting 
instrumental ADL) 
(MG: moderate; 
minimal, local or 
noninvasive 
intervention indicated; 
limiting age- 
appropriate 
instrumental ADL) 
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. 
GUILLAIN-BARRE: 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 95 of 102 
 
 
 
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 
(Grade 3 GB: severe 
symptoms; limiting self 
care ADL; 
Grade 4 GB: life- 
threatening 
consequences; urgent 
intervention indicated; 
intubation) 
(Grade 3 MG: severe 
or medically significant 
but not immediately 
life-threatening; 
hospitalization or 
prolongation of 
existing hospitalization 
indicated; limiting self 
care ADL; 
Grade 4 MG: life- 
threatening 
consequences; urgent 
intervention indicated) 
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 Neurology 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 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 96 of 102 
 
 
 
 
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) 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 97 of 102 
 
 
 
Grade 1 
(asymptomatic or mild 
symptoms*; clinical or 
diagnostic observations 
only; intervention not 
indicated) 
*Treat myocarditis 
with mild symptoms as 
Grade 2. 
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. 
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; inter- 
vention indicated; new 
onset of symptoms*) 
(Grade 4: Life- 
threatening conse- 
quences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic 
support)) 
-  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).a 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 98 of 102 
 
 
 
* Consider “new onset 
of symptoms” as 
referring to patients 
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  
 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 99 of 102 
 
 
 
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). 
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).a 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 100 of 102 
 
 
 
 
Grade 3 or 4 
(Grade 3: pain 
associated with severe 
weakness; limiting 
self-care ADLs 
 
Grade 4:  life- 
threatening 
consequences; urgent 
intervention indicated) 
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. 
 
 
For Grade 4: 
-  Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 
− 
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).a 
 
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. 


Clinical Study Protocol 
Drug Substance Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 101 of 102 
 
 
 
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 Durvalumab 
(MEDI4736) Study Number 
ESR-18-14261 
Edition Number V2.0 
Page 102 of 102 
 
 
 
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.