Conditions: Head and Neck Cancer Head and Neck Neoplasms
Keywords: Immuno-oncology Neoadjuvant Treatments Non-HPV Immunotherapy Head and Neck Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 21
Healthy volunteers: no

Brief summary:
Background:

Some people who get head and neck cancer will need surgery to treat their cancer. Research suggests that immunotherapy drugs may help fight head and neck cancer if given before surgery. In most cases, there is enough time between cancer diagnosis and surgery to test immunotherapy drugs. In this study, researchers are testing the safety and anti-cancer abilities of 3 drugs given before surgery for head and neck cancer.

Objective:

To learn if giving M7824 alone, or with the TriAd Vaccine (ETBX-011, ETBX-051 \& ETBX-061), or with TriAd vaccine plus Anktiva (N-803) can shrink previously untreated head and neck tumors before surgery or stop the tumors from coming back after all treatment.

Eligibility:

People age 18 and older who have a head and neck cancer that has not been treated before, and the tumor must be removed with surgery.

Design:

Participants will be screened in a separate protocol.

Participants will have the following tests:

* medical history and physical exams
* computed tomography or magnetic resonance imaging scans
* tumor, mucosa, and skin biopsies
* electrocardiograms to monitor heart activity
* endoscopies (a tube is inserted through the nose to see the upper airway)
* blood and urine tests.

All participants will get bintrafusp alfa (M7824) through an intravenous infusion. For this, a small plastic tube is put into an arm vein. Some may also get the TriAd vaccine. It is injected under the skin on the arms or legs. Some may also get N-803. It is injected under the skin on the stomach.

Participants will have clinic visits while they are getting treatment and after treatment ends.

After treatment ends, participants will have their scheduled surgery. There will be two follow up visits at the National Institutes of Health (NIH) after your surgery. They will be contacted by phone or email every 2 weeks for 3 months. Then they will be contacted every 3 months for 2 years.

...

Detailed description:
Background:

* Approximately 50% of patients with advanced, non-human papilloma virus (HPV) associated head and neck squamous cell carcinoma (HNSCC) will develop locoregional or distant relapse within two years of completing definitive standard-of-care treatment.
* Two ongoing clinical trials investigating neoadjuvant programmed cell death protein 1 (PD-1) blockade before surgical resection of HNSCC suggest that immunotherapy can both cytoreduce existing disease before surgery and reduce the risk of locoregional or distant disease relapse after surgery.
* Preliminary data from these studies suggest neoadjuvant treatments can be administered without delaying planned surgical intervention.
* Experiments conducted by the Laboratory of Tumor Immunology and Biology (LTIB) demonstrated synergistic activity with tumor-targeted adenoviral vaccine plus bintrafusp alfa (M7824) plus Anktiva (N-803) in humanized mice bearing human carcinomas and in vitro studies.
* M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1(PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF-beta) receptor type 2, a TGF-beta trap.
* Adenoviral vaccines targeting known shared tumor antigens can generate antigen-specific T cells.
* N-803 is an interleukin 15 (IL-15)/interleukin 15 receptor (IL-15R) alpha super agonist complex that can enhance both natural killer (NK) cell and T cell anti-tumor activity via expansion and activation.
* Activity observed with neoadjuvant anti-PD-1 agents alone provides rationale for testing of M7824 alone and in combination with other immune-oncologic agents that have been shown to work in concert with M7824 in preclinical studies.
* Analysis of pre- and post-treatment tissues from HNSCC patients presents a unique opportunity to interrogate the effects the above treatment(s) on tumor.
* A dose escalation of N-803 in combination with a flat dose of M7824 was conducted at the National Cancer Institute. Thirteen patients have been treated with the combination. No dose limiting toxicities (DLTs) were observed.

Objectives:

-Determine the rate of pathologic complete response (pCR) or clinical-to-pathological downstaging in patients with previously untreated intermediate/high risk, non-HPV associated, squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV) who receive any of the three proposed treatments: M7824 alone, M7824 plus TriAd vaccine, or M7824 plus TriAd vaccine plus N803 prior to definite surgery.

Eligibility:

* Patients must have histologically or cytologically confirmed, previously untreated intermediate/high risk, p16-negative (if oropharyngeal), squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV)
* Men or Women; Age greater than or equal to 18 years
* Eastern Cooperative Oncology Office (ECOG) performance status less than or equal to 1

Design:

* This protocol is a sequential window of opportunity trial of Anti-PD-L1/TGF-beta trap (M7824) alone and in combination with TriAd Vaccine (ETBX-011, ETBX-051 \& ETBX-061) and N-803 for non-HPV associated resectable Head and Neck Squamous Cell Carcinoma (HNSCC).
* Patients will be referred to the National Institutes of Health (NIH) for this immunotherapy treatment from surrounding academic medical centers and private physicians.
* Upon referral to the NIH, patients will be rapidly screened, and enrolled on the protocol, if appropriate.
* This trial will enroll patients in three arms sequentially to permit safety evaluation before adding the next agent.
* In the first arm of 12 patients, M7824 (1200 mg) will be administered intravenously on day 1 and 15.
* If no safety concerns, accrual will proceed to the 2nd arm, and 12 patients will enroll with M7824 (1200mg; intravenous) treatment on day 1 and 15 and TriAd vaccine (5 x 10 (11) viral particles (VP; subcutaneous) treatment on day 1 only.
* If no safety concerns, accrual will proceed to the 3rd arm, and 12 patients will enroll with M7824 ((1200mg; intravenous) treatment on day 1 and 15 plus TriAd vaccine (5 x 10(11) VP; subcutaneous injection) and N-803 (15mcg/kg, subcutaneously) treatment on day 1.
* After obtaining pre-treatment biopsies, imaging and blood collection, patients will receive the neoadjuvant immunotherapy at the NIH Clinical Center.
* Patients will then be sent back to their referring providers for their definitive standard of care surgery and adjuvant therapy as indicated based upon pathologic analysis of the surgical specimen. National Cancer Institute (NCI) investigators will have no role in directing the ensuing standard of care surgeries performed at outside institutions.
* For consistency in pathologic analysis of resection specimens, tissue blocks and/or slides will be obtained from outside institutions and be reviewed by the NCI Laboratory of Pathology.
* It is expected that up to 20 patients may enroll in one year. Thus, with 3 arms of 12 patients apiece, up to 36 evaluable patients may enroll. Accrual is expected to be completed within 2 years.

Arms:
arm 1: M7824 (Days 1, 15) arm 2: M7824 + TriAd vaccine (ETBX-011, ETBX-051 and ETBX-061) (Days 1) arm 3: M7824 + TriAd vaccine (Day 1) + N-803 (Day 1)

Interventions: intervention 1: M7824 intervention 2: N803 intervention 3: TriAd vaccine
Intervention descriptions: intervention 1: M7824 (1200 mg) will be administered intravenously on day 1 and 15 to patients enrolled in arm 1-3 (all three arms). intervention 2: N-803 (15 mcg/kg, subcutaneously) will be given on day 1 to patients enrolled in arm 3. intervention 3: TriAd vaccine (5 x 10e(11) viral particles (VP); subcutaneous injection) will be given on day 1 to patients enrolled in arm 2 and arm 3

Protocol document:
ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19/2021
Page 1 of 22
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Jason M. Redman, MD
STUDY TITLE: A Sequential Window of Opportunity Trial of Anti-PD-L1/TGF-β trap (M7824) 
Alone and in Combination with TriAd Vaccine and N-803 for Resectable Head and Neck 
Squamous Cell Carcinoma not Associated with Human Papillomavirus Infection
STUDY SITE: NIH Clinical Center
Cohort: Affected Patients 
Consent Version:  11/19/2021
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Study PI:                            Jason M. Redman, MD
                                Phone:  240-858-3305
                                Email:  jason.redman@nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you to in 
making your decision about participating in this study. Additional information that may help 
you make a decision can be found in other sections of the document. Taking part in research at 
the NIH is your choice.
You are being asked to join this study because you have a kind of head and neck cancer which 
has not been treated before, and your tumor requires surgical removal.
The purpose of this study is to learn if giving therapy aimed at your immune system 
(immunotherapy) could help shrink your tumor before surgery. The time-period between your 
cancer diagnosis and surgery gives us an opportunity to test immunotherapy drugs. We also 
want to find out whether it is safe to give the drugs together to determine if giving you 
immunotherapy before surgery helps prevent your tumor from coming back in the future. 
The immunotherapy drugs you may receive include:

M7824 -a drug that blocks pathways that cancer cells use to prevent your immune system 
from fighting your cancer.

Tri-Ad vaccine - combination of three cancer vaccines (ETBX-011, ETBX-061, and 
ETBX-051) that are designed to teach your immune system how to target and then kill 
cancer cells. 
IRB NUMBER: 20C0024
IRB APPROVAL DATE: 11/30/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19/2021
Page 2 of 22
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

N-803 - a drug that can supercharge and increase the number of different types of 
immune cells called T cells and NK cells that may be able to kill your tumor cells. 
M7824, N-803 and Tri-Ad vaccine are all investigational which means that they have not been 
approved by the U.S. Food and Drug Administration (FDA) to treat head and neck cancer. 
However, the FDA has given us permission to use M7824, N-803 and TriAd in this study.
For people with your type of cancer, treatments are not typically given before you receive your 
head and neck cancer treatment from your regular cancer doctors. If you choose to not take part 
in this study, your head and neck cancer treatment given by your regular cancer doctors will not 
change. This study adds these immunotherapy drugs before the treatment you would receive 
anyway. Side effects can occur with immunotherapy drugs as explained later in consent. By 
participating in this study, you will be at risk of experiencing these side effects.  
If you decide to join this study, here are some of the most important things you should know: 
Depending on when you enter the study, you will have treatment with M7824 alone (group A), 
M7824 + TriAd vaccine (group B) or M7824 + TriAd vaccine + N-803 (group C). The first few 
participants enrolled with be in group A.  If we find that it is safe, the next set of participants 
will be enrolled in group B.  If that combination is well tolerated, the final set of participants 
will be enrolled in group C. 
The treatment is given as follows:

M7824 is given as an IV (intravenous) infusion. A small plastic tube is put into a vein in 
your arm and the medication is given once on day 1 and day 15 of treatment.

TriAd vaccine and N-803 are given as an injection under the skin. This is similar to 
receiving a vaccine shot. If you receive these treatments, N803 and TriAd vaccines are  
given on day 1 of treatment.
We will collect samples (biopsies) of your tumor, normal mucosa (lining of your food pipe) and 
skin before you begin any study therapy. We will try to collect these samples in clinic, but if it 
is not safe to do so, we will collect them in the operating room under anesthesia. Before 
treatment begins you will have new CT scans performed. 
You will be seen in the NIH Clinical Center by your study team 1-2 times weekly while you are 
receiving treatment. Each of these clinic visits will take 2-4 hours. The treatments will be given 
in the Oncology Outpatient Center. Three to four weeks after your study therapy started, you 
will have new CT scans and possibly more biopsies. These visits are important for your safety 
and they are required. You will then be sent back to your regular cancer doctors for surgery and 
any required treatment such as radiation after your surgery. The standard treatment is not part 
of the study. Starting about two weeks after and going through three months after your last dose 
of study therapy, we will check in with you by phone or email every two weeks.  During this 
period we will also need to see you once at the Clinical Center approximately 4- 5 weeks after 
your last dose. At three months after your last dose, you will visit the NIH Clinical Center for 
follow-up tests. You will have tests done (physical exams, blood work and scans) to see how 
you are doing and to see how you are healing from your treatments. We will also collect blood 
IRB NUMBER: 20C0024
IRB APPROVAL DATE: 11/30/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19/2021
Page 3 of 22
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
samples from you for research purposes. Starting after three -month visit, you will receive a 
phone/email check-in every 3 months till you are 2 years out from surgery.
You may experience side effects from taking part in this study. Some can be mild or very serious, 
temporary, long-lasting, or permanent, any may include death. For example: M7824 may cause 
skin problems (such as rash), inflammation to organs inside the body, low red blood cell count 
(anemia) and bleeding. It is possible that the anemia and/or bleeding may be so severe that you 
require a blood transfusion. You cannot join this study if you are not willing to have a blood 
transfusion. It is possible that one or more side effects from these drugs could cause a delay in 
your planned surgery. It is also possible that M7824 could increase your risk of bleeding during 
or after surgery. Some common side effects due to TriAd vaccine are pain, tenderness, swelling 
or redness at the injection site. Some common risks due to N803 include fatigue, nausea, 
vomiting, fever, chills, sweats, decreased appetite and joint pains. Risks have been explained in 
detail later in the consent. If you are in group C, you may also have to temporarily stop taking 
some of your current medications (like beta blockers) for two weeks because it interacts with 
N-803.
Just as we do not know what side effects you might have, we cannot know if you will benefit 
from taking part in this study. However, your taking part in this study can help us learn about 
cancer treatment and may help others in the future.
M7824 has been tried in other types cancers. Recently, the manufacturer of the drug closed 3 
large studies because the drug was not shown to help those patients more than standard 
therapies. In addition, in some cases it seemed like the drug might make the cancer grow 
faster. However, the type of cancer treated in those studies was not the same as your cancer.
You are free to stop participating in the trial at any time. If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe more about the research study.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information described in this document. Some people have personal, religious, or ethical 
beliefs that may limit the kinds of medical or research treatments they would want to receive (such 
as blood transfusions). Take the time needed to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
IRB NUMBER: 20C0024
IRB APPROVAL DATE: 11/30/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19/2021
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
This is a research study. The main purpose of this study is to learn if giving M7824 alone or in 
combination with TriAd vaccine and N-803 can shrink your previously untreated head and neck 
tumor prior to your planned surgery or help prevent your tumor from coming back after all of your 
treatment. Prior clinical studies with these investigational agents have helped researchers learn 
about the recommended doses that are safe when each study drug is given alone, but we do not 
have information about whether they are safe when given together.  As part of this study, we will 
also test the safety of the combination.
WHAT WILL HAPPEN DURING THE STUDY?
Before signing this consent, you will have been screened on another protocol to find out if you met 
the criteria to join the study.  Once you have met criteria and decide to enroll, you will undergo 
treatments on day 1 and 15. 
You will need to visit the NIH Clinical Center 1-2 times weekly for testing during the treatment 
period. It is important that you come to all of these scheduled visits. 
Depending on when you enter the study, you will receive M7824 alone (group A), M7824 + TriAd 
vaccine (group B) or M7824 + TriAd vaccine + N-803 (group C).

If you are enrolled in group A, you will receive M7824 alone on days 1 and 15 

If you are enrolled in group B, you will receive M7824 on days 1 and 15 plus TriAd vaccine 
on day 1. 

If you are enrolled in group C, you will receive M7824 on days 1 and 15 plus TriAd vaccine 
with N-803 on day 1. 
The day before receiving your first treatments on day 1, you will have biopsies performed in either 
the ENT clinic or in the operating room under anesthesia.
The following standard tests are done to assess your health and tumor status:
Within 14 days before starting the treatment

Your vital signs (e.g. pulse, blood pressure, breathing rate) will be measured as part of 
medical exam.

Medical history and physical exam

CT or MRI scan (if not done within 28 days before you start treatment)

Routine laboratory tests

EKG (electrocardiogram) to monitor your heart

Pregnancy test for women (if not done within 3 days before you start treatment).

As a part of clinical testing, we will use a flexible tube inserted through your nose to see 
your upper airway (endoscopy) and will do a test to check your immune markers
IRB NUMBER: 20C0024
IRB APPROVAL DATE: 11/30/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19/2021
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

During the study:
Day 1 (usually a Friday when treatment starts): 

Your vital signs (e.g. pulse, blood pressure, breathing rate) will be measured before and 
after M7824 infusion.

All participants (groups A, B and C) will receive M7824 through an IV 

For the prevention of possible allergic reactions, you may receive an antihistamine such as 
Benadryl and acetaminophen (Tylenol) before the M7824 infusion. 

If you are enrolled in group B, TriAd vaccine (injection under the skin on your arms or 
legs) will be given with M7824. 

If you are enrolled in group C, N-803 (injection under the skin on your stomach) and 
TriAd vaccine (as said above) will be given with M7824.
Day 15 (usually a Friday): 

Physical examination and check-up to see how you are doing

Medical history and vital signs

Routine blood and urine tests 

Endoscopy 

You will receive M7824 alone (group A, B or C)
Day 21-28:

Endoscopy 

CT scans/MRI

Routine blood tests
Additional research testing
In addition to the tests that we will conduct to determine whether you are having side effects or 
if you are responding to the study therapy, we will also use blood and tumor biopsy samples 
from you for purpose of research only. Tests on these samples will look at the effects of therapy 
on your immune system and tumor activity. Unless noted otherwise below, the blood samples 
will be collected at baseline (before you receive any study intervention), at every visit on day 8, 
15, 21-28, 105 (± 3 days) and at surgery. We will collect tissue samples at baseline (required) 
and during day 21-28 (optional) or at surgery. Providing tissue samples is optional and it will 
not impact your participation for this study. A separate consent form will be provided to you at 
the time of the biopsy for you to grant permission to that procedure if you agree to this biopsy. 
The samples included for these studies include:

blood (around 1 cup total volume over time)

tissue 
All of your blood and tissue samples collected for research purposes on this study may be used to 
look for specific changes in the DNA that could be used to develop new ways of diagnosing and 
treating cancer. DNA (also called deoxyribonucleic acid) in cells carries genetic information and 
passes it from one generation of cells to the next – like an instruction manual. Normal tissue 
IRB NUMBER: 20C0024
IRB APPROVAL DATE: 11/30/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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contains the DNA (instructions) that you were born with, DNA in tumor cells has changed – or 
mutated – and we think that these changes in the DNA is what causes tumors to form and to grow. 
To look at your DNA, we may use do what is called “whole genome sequencing.”  This where we 
will do special tests in the lab to look at the entire sequence, or order, of how your DNA is put 
together.  This is what makes you unique.  
To determine which parts of the DNA have mutated, we will compare the DNA in your tumor cells 
to DNA from your normal cells. We will then analyze the results from similar tumors to see if 
there are any changes in the DNA that are common to a particular type of tumor. To examine the 
tumor and normal tissue we may use several different techniques depending on the type of tissue 
we collect. These could include growing cell lines (cells which keep dividing and growing in the 
laboratory, sometimes for years allowing us to continually study those cells), xenograft studies 
(placing or growing cells in another animal, such as mice), and looking in detail at the parts of the 
genes that produce specific proteins.
However, you should know that the analyses that we perform in our laboratory are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 
is certified to perform genetic testing or testing for routine clinical care. For these reasons, we will 
not give you the results of the research tests done on your research samples in most cases.  There 
may be exceptions to what we share with you and this is described later in this consent form in the 
section for “Return of research results.” 
HOW LONG WILL THE STUDY TAKE?
After you have completed study therapy
You will return the care of your surgeon to have your scheduled surgery.
Starting about two weeks after your last dose of study therapy (~ day 28) and going through three 
months after your last dose of study therapy (~day 105), we will check in with you by phone or 
email every two weeks.
In addition, we will need to see you at the Clinical Center four to five weeks after you have 
completed study therapy (~ day 49) so we can do blood tests. Day 49 visit can be scheduled up to 
eight weeks after you have completed therapy as it depends upon how long you stay in the hospital 
for surgery and may be skipped if your study doctor decides it is safe to do so.  Three months after 
your last dose (~day 105) we will see you again at the Clinical Center for additional blood tests, 
medical history, physical examination and an endoscopy.
Long-term follow-up visit
We will contact you every 3 months by telephone/email to ask questions about your state of health 
until you are 2 years out from surgery.
If you agree to take part in this study, your involvement is expected to last for 2 years.
IRB NUMBER: 20C0024
IRB APPROVAL DATE: 11/30/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19/2021
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have approximately 40 people participate in this study at the NIH. 
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
There are risks, discomforts, and inconveniences associated with any research study. These 
deserve careful thought. You should talk with the study doctors if you have any questions.
It is probable that you will experience some of the side effects listed, but it is unlikely that you will 
experience all of them. You will be watched closely, and we will give you medicines to try and 
prevent or reverse the side effects. However, doctors don’t know all the side effects that may 
happen. Side effects may be mild or very serious.  In some cases, side effects can be serious, long 
lasting, or may never go away. We will tell you if we learn any new information that may affect 
your health, welfare, or decision to stay in this study. You should talk to your study doctor about 
any side effects that you have while taking part in the study.
It is possible that one or more side effects from these immunotherapy drugs could delay your 
surgery. Your regular cancer doctors need to be aware that you are participating in this study. 
Risks of M7824
Common (occurring in more than 5% of patients)

Tiredness 

Nausea 

Diarrhea

Constipation

Vomiting

Swelling of your lower legs or hands

Fever

Decreased appetite

Loss of body fluids (dehydration)

Wart-like growths on the skin called keratoacanthomas that can turn into skin cancer. These 
usually go away after treatment but we can remove them if they do not.

Rash, blisters, skin discoloration and other skin abnormalities

Bleeding has been frequently observed in people receiving M7824. Participants may 
experience bleeding in different organs such as gums, nose, ears, eyes, vagina, breast, blood in 
the urine, stool, or bleeding in the internal organs or skull, coughing up or vomiting blood. 
Occasionally, this bleeding can be serious and potentially life threatening and require you to 
have a blood transfusion. If you experience any bleeding on this trial, please tell the study team 
IRB NUMBER: 20C0024
IRB APPROVAL DATE: 11/30/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19/2021
Page 8 of 22
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
immediately. Tell your doctor if you've had a life-long problem of frequent or excessive 
bleeding or bruising. 
o
It is possible that M7824 could increase the risk of bleeding during or after your 
surgery.
o
Unfortunately, we cannot tell you for sure how likely it is that you may experience 
bleeding as this is a new event that we have seen in patients in other studies at NCI.  
However, if we learn more information that may be helpful, we will update you.

Shortness of breath

Cough

Anemia - low number of red blood cells that can cause tiredness and shortness of breath.  May 
require a transfusion.

Abdominal pain

Headache

Itching
Occasional (occurring in less than 5% of patients)

Chills (feeling cold)

Blood clots that form throughout the body, blocking small blood vessels. Symptoms may 
include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts 
of the body

Easy bruising

Reaction to other drugs such as rash, anaphylaxis, and changes in blood

Infusion-related reaction, including dizziness or fainting (low blood pressure), flushing, rash, 
fever, shortness of breath or sick to your stomach, or pain at the site of infusion. Although 
usually reversible with treatment, it can be severe or life threatening.

Back pain

Cancerous growth on the skin that can be removed r

Stroke

Slow wound healing. If you are having surgery, please discuss with your doctor.

Thickening of the skin, nails

Allergic reactions or reactions related to the infusions might occur during treatment. Usually, 
these reactions are mild to moderate and can be treated with drugs but could also be severe to 
life-threatening which could require advanced cardiac life support and even fatal reactions 
might occur. 
IRB NUMBER: 20C0024
IRB APPROVAL DATE: 11/30/2021


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For the prevention of infusion-related side effects and possible allergic reactions you may receive 
a premedication of an antihistamine drug and acetaminophen 60 to 120 minutes before the 1st and 
2nd infusion.
In addition, immune-related side effects are possible. These adverse events are caused by over 
activity of your body’s immune-system caused by M7824. The immune system normally protects 
you from infections and foreign substances, such as cancer. If the immune system is overactive, it 
may think that parts of the body, including vital organs, are foreign substances and attack them.
Examples of these side effects are listed below. In rare cases, immune-related side effects can be 
life threatening or fatal.
Types of immune-related side effects:

pneumonitis (inflammatory disease of the lung): symptoms may include but are not limited 
to a new or worsening cough, shortness of breath possibly with fever. Preliminary data 
suggested that there may be the tendency of higher frequency and severity in Japanese 
patients compared with non-Japanese patients: tell your study doctor right away if you have 
any of these symptoms as it may need to be treated urgently

hypothyroidism (decreased function of the thyroid gland seen on labs that your doctors will 
check)

hyperthyroidism (increased function of thyroid gland seen on labs that your doctors will 
check)

thyroiditis (inflammatory disease of the thyroid gland seen on labs that your doctors will 
check)

autoimmune hepatitis (inflammatory disease of the liver caused by the body’s immune 
system seen on labs that your doctors will check): Signs and symptoms of this include 
yellowing of the skin or whites of the eyes, dark urine, severe nausea and vomiting, pain 
in the upper right side of your abdomen, skin itchiness, not feeling hungry and bleeding or 
bruising more easily than normal

thrombocytopenia (decrease of the blood platelets that can cause bleeding in extreme cases. 
Your doctor will use blood work to check your platelets

inflammatory eye disease 

diabetes mellitus (high blood sugar levels)

decreased function of the adrenal glands or other glands that produce important hormones. 
This may cause stomach pains, vomiting, muscle weakness and fatigue, depression, low 
blood pressure, weight loss, kidney problems, and changes in mood and personality. These 
complications may be permanent and may require hormone replacement 
o
On a different clinical trial, people who received M7824 in combination N-803 and 
a vaccine similar to the Tri-Ad vaccine used in this study had an increased risk of 
developing decreased adrenal function, requiring daily medication for life. People 
who developed this condition received treatment for at least 2 months or more, 
before developing this condition. This is more treatment than you will receive on 
this trial. Whether or not receiving Tri-Ad vaccine in combination with M7824 and 
N-803 on this study will increase your risk of this condition is unknown. Since this  
condition could occur months after receiving immunotherapy, it is important that 
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you tell your outside doctor that  you were on an  immunotherapy if you experience 
decreased energy, headaches, persistent nausea/vomiting, or dizziness after you are 
done with your NIH follow up  period.

inflammatory disease of muscles characterized by pain and tenderness

colitis (inflammatory disease of the large intestine): It may cause abdominal pain and 
diarrhea with or without blood. Fever may be present. It may require you to receive 
additional fluids. If left untreated, in rare occasions this may lead to a tear in the wall of 
the intestine which can be serious and life threatening

impairment of the brain function

myocarditis (heart inflammation)

inflammation of the pancreas

Skin rash with blisters

Kidney problems: you may have an increase of creatinine levels in a blood test (creatinine 
is a protein marker that measures kidney function) but not have any symptoms or feel 
unwell. Uncommonly a patient may experience nephritis which is an inflammation of the 
kidneys that stops the kidneys from working properly

Problems with the pituitary gland (hypopituitarism): Hypopituitarism refers to decreased 
output of hormones from the pituitary gland in the brain and may be caused by 
inflammation of the pituitary gland (hypophysitis). Symptoms may include headaches, 
thirstiness, and trouble seeing or double vision, leakage of breast milk or irregular periods 
in women. These complications may be permanent and may require hormone replacement

Liver problems: Increases in the blood level of substances called enzymes found within 
your liver cells. The enzyme changes are unlikely to make you feel unwell, however, if 
these blood enzyme levels become very high, your study doctor may need to stop the study 
medication

Nervous system problems: symptoms can include unusual weakness of legs, arms, or face, 
numbness, or tingling in hands or feet. In rare situations, there is the potential for the 
inflammation of the nervous system to be severe.
In addition to the above, we have seen a few cases of nodular regenerative hyperplasia.  This is 
when small growths, or nodules, occur in the liver.  These usually do not cause symptoms, but can 
occasionally be associated with high blood pressure in the vein to the liver which could over time 
lead to liver damage.
Risks of Tri-Ad Vaccine
The combination of the ETBX-011, ETBX-061, and ETBX-051 vaccines with other agents on 
this study has not been previously given to humans before, so risks and discomforts may occur 
that we cannot predict. While in the study, you may have side effects. They may be mild or very 
serious. Please tell your nurse or doctor about any side effects you experience. Your study doctor 
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may give you medications to try to help lessen some of the side effects. All subjects in the study 
will be monitored for side effects.
The side effects listed below have occurred in people receiving ETBX-011. ETBX-061 and 
ETBX-051. 
Likely (Occurring in more than 50% of patients) 

Pain, tenderness, swelling or redness at the injection site

Fever 

Flu-like symptoms 

Myalgia (muscle pain)

Chills
Less Likely (Occurring in less than 5% of patients) 

Anorexia

Nausea 

Headache
Risks of N-803
Common (Occurring in more than 50% of patients) side effects of N-803 are listed below. One 
or more of these side effects may begin 1-2 days after receiving N-803 and go away a few days 
later.

Fatigue

Large red rash and/or swelling at the site of injection that fades over 1-2 weeks

Fever

Chills

Sweats
Other potential side effects of N-803 (Occurring in less than 15% of patients) 

Fast heart rate

Dry eyes

Abnormal liver enzymes

Flushing

Itching rash

Stomach pain

Decreased appetite

Nausea

Vomiting

Diarrhea

Joint pain

Headache

Blood in the urine
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
Muscle pains

Altered taste

Redness, soreness, or swelling at the injection site 2 to 3 days after injection 

Shortness of breath

Constipation

Leg swelling

Low blood pressure

Cough

Muscle twitching

Dehydration

Anemia (low red blood cell counts)

Low white blood cell counts

Atrial fibrillation, a quivering or irregular heartbeat (arrhythmia), that can lead to blood 
clots, stroke, heart failure and other heart-related complication and may require the addition 
of a blood thinner.
More than one of these side effects may happen at the same time. If you experience any of these 
symptoms, follow the instructions provided by your study doctor.
Risks of study procedures
Blood draws
Risks include temporary discomfort, pain, redness, bleeding, bruising, and swelling at the site
where the needle is inserted, and/or very rarely inflammation/infection of the vein, which could
require antibiotics. You may also experience dizziness, nausea, or rarely, fainting during blood
taking. Please tell the study doctor if you do not feel well after having your blood drawn.
Tumor, normal mucosa and skin biopsies
There may be some temporary pain or discomfort during the procedure and afterwards in the area 
where the tissue was removed. You may also experience some bruising around the biopsy site over 
the following days. In rare cases an infection or bleeding may occur. If your tumors are not 
accessible in the clinic or a biopsy in the clinic is deemed unsafe by the study doctor, biopsies may 
be performed in the operating room under general anesthesia. Side effects of general anesthesia 
may include temporary confusion, difficulty passing urine, bruising or soreness from the IV drip, 
nausea and vomiting, shivering and feeling cold, and sore throat.
Nasopharyngo-laryngoscopy (Endoscopy) 
In this procedure, a physician gently places a small, thin, flexible endoscope with a camera down 
through your nose to view your upper airway anatomy above the vocal cords. This procedure 
takes only a few minutes, is painless and does not require any sedation. It is a normal part of an 
ENT exam. 
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CT scans due to contrast dye
If contrast dye is used, there is a risk for allergic reaction to the dye. If you are allergic to or 
sensitive to medications, contrast dye, iodine, or shellfish, please notify your study doctor. If you 
have had kidney failure or other kidney problems in the past, please notify your study doctor. 
What are the risks related to pregnancy? 
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study. You will need to practice an effective form of birth control before starting study treatment, 
during study treatment, and for 2 months after you finish study treatment (the restricted period).  
For a portion of the study, you will need to use effective birth control methods and try not to 
become pregnant. Your study team will provide additional details on how long this will be required 
and what methods may be used. If you become pregnant, there may be unknown risks to the fetus 
or unborn child, or risks that we did not anticipate. There may be long-term effects of the treatment 
being studied that could increase the risk of harm to a fetus. You must tell the study doctor if your 
birth control method fails during the restricted period. If you think or know you have become 
pregnant during the restricted period please contact the study team as soon as possible. 
If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant the restricted period. There may be unknown risks to a fetus or risks 
we did not anticipate. You and your partner must agree to use birth control if you want to take part 
in this study. If you think your partner has become pregnant during the restricted time, please 
contact the study team as soon as possible.  If you and your partner plan for your partner to become 
pregnant after the restricted time, please discuss this with the study team.
What are the risks of radiation from being in the study? 
During your participation in this research study, you will be exposed to radiation from up to 3 CT 
scans of the neck and chest area in a year.  The amount of radiation exposure you will receive from 
these procedures is equal to approximately 0.99 rem. A rem is a unit of absorbed radiation.  
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT and bone scans that you get in this study will expose you to the roughly the same amount 
of radiation as 3.3 years of background radiation.  Most of the time, this amount of extra radiation 
is not harmful to you. However, scientists believe that being exposed to too much radiation can 
cause harmful side effects. This could include getting a new cancer.  We estimate that this could 
happen in about 1 out of every 1000 people who get a very large amount of extra radiation.
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
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become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time. 
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Privacy Risks Associated with Return of Incidental or Secondary Findings
Although your genetic information is unique to you, you do share some genetic information with 
your children, parents, brothers, sisters, and other blood relatives. Consequently, it may be possible 
that genetic information from them could be used to help identify you.  Similarly, it may be 
possible that genetic information from you could be used to help identify them.  Patterns of genetic 
variation also can be used by law enforcement agencies to identify a person or his/her blood 
relatives.  
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. However, the potential benefit to you might be 
shrinking of your tumor or decrease in yoursymptoms, such as pain, that are caused by the cancer.  
Because there is not much information about the drug’s effect on your cancer, we do not know if 
you will benefit from taking part in this study.
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because what we learn in this study may 
eventually be used to treat others with your disease. 
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WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could: 

choose to be treated with surgery alone and not have additional study therapy treatment, 
radiation or with drugs already approved by the FDA for your disease

choose to take part in a different study, if one is available

choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms.
You should discuss with your doctor your other choices and their risks and benefits.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research. These are known as “incidental medical 
findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations. 
Since the analyses that we perform in our laboratory are not nearly as sensitive as the tests that are 
performed in a laboratory that is certified to perform genetic testing, the genetic changes that we 
find may or may not be valid.  Therefore, we do not plan to inform you of all of the genetic results 
of testing on your tissue and blood that is performed in our research lab. However, in the unlikely 
event that we discover a finding believed to be clinically important based on medical standards at 
the time we first analyze your results, we will contact you. This could be many years in the future. 
We will ask you to have an additional tube of blood drawn to verify the findings we have seen in 
our lab. If the results are verified, you will be re-contacted and offered a referral to a genetic 
healthcare provider to discuss the results.
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:
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
if he/she believes that it is in your best interest

if your disease worsens or comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if you become pregnant

if the M7824 and/or TriAd vaccine and/or N-803 may become unavailable

if new information shows that another treatment would be better for you

if you do not follow the study rules

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.  
After therapy is stopped, we would like to see you for a safety visit after around one month of your 
last dose.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to EMD Serono and Immunity 
bio (previously NantCell) or designated representatives.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will Your Specimens or Data Be Saved for Use in Other Research Studies?
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding head and neck cancer, or other 
diseases or conditions. This could include studies to develop other research tests, treatments, 
drugs, or devices, that may lead to the development of a commercial product by the NIH and/or 
its research or commercial partners. There are no plans to provide financial compensation to you 
if this happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you. 
I give permission for my coded specimens and data to be stored and used for future research as 
described above.
_____ Yes
_____ No
Initials
Initials
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Will Your Specimens or Data Be Shared for Use in Other Research Studies?
We may share your coded specimens and data with other researchers.  If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you.  They may be doing research in areas similar to this research or in other unrelated areas. 
These researchers may be at NIH, other research centers and institutions, or commercial entities. 
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above.
_____ Yes 
_____ No
Initials
Initials
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them. 
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places.  When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you.  We will not contact you to 
ask your permission or otherwise inform you before we do this.  We might do this even if you 
answered "no" to the above questions.  If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data.
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. These researchers will not have 
access to any of your identifiers, such as your name, date of birth, address, or medical record 
number; and your data will be labeled with only a code. We cannot offer you a choice of whether 
your data to be placed in this database or not.  If you do not wish to have your data placed in this 
database, you should not enroll in this study.  
Will Your Genomic Data Be Shared Outside of This Study?
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
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receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 
non-researchers will be able to access summary information about all the participants included 
in the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
As part of this study, we will put your genomic data in a large database which will be freely 
available to the public. These databases are commonly called data repositories. These data are 
intended for other researchers to use and learn from but anyone can gain access to them, including 
law enforcement. The information in this database will include but is not limited to genetic 
information, race, ethnicity and sex.  If your individual data are placed in one of these repositories, 
they will be labeled with a code and not with your name or other information that could be used to 
easily identify you.  This information when combined with information from other public sources 
could be used to identify you, though we believe it is unlikely that this will happen.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we 
cannot offer you a choice of whether your data will be shared.  If you do not wish to have your 
data placed in a repository, you should not enroll in this study.  
How Long Will Your Specimens and Data be Stored by the NIH?
Your specimens and data may be stored by the NIH indefinitely.
Risks of Storage and Sharing of Specimens and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
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On this study, the NCI will cover the cost for some of your expenses. Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. Someone will work 
with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CONFLICT OF INTEREST(COI) 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide.  You may ask your research team for a copy 
of the COI Guide or for more information.  Members of the research team who do not work for 
NIH are expected to follow these guidelines or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH.
The NIH and the research team for this study are using drugs and vaccine developed by EMD 
Serono and Immunity Bio (previously NantCell) through a joint study with your study team and 
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CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
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.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Some of your health information, and/or information about your specimen, from this study will 
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IRB NUMBER: 20C0024
IRB APPROVAL DATE: 11/30/2021


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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
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your medical records for research, quality assurance, and data analysis include:

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
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
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M7824 and Immunity Bio (previously NantCell), the pharmaceutical company who 
produces N-803 and TriAd vaccine.
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IRB NUMBER: 20C0024
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Prot_SAP_002.pdf: 
1 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
Abbreviated Title: Neoadjuvant IO for HNSCC 
NIH Protocol #: 20C0024  
Version Date: March 26, 2025 
NCT Number: NCT04247282   
Title: A Sequential Window of Opportunity Trial of Anti-PD-L1/TGF-β trap (M7824) Alone 
and in Combination with TriAd Vaccine, and N-803 for Resectable Head and Neck Squamous 
Cell Carcinoma not Associated with Human Papillomavirus Infection. 
NCI Principal Investigator: Hoyoung Maeng, MD 
  
Center for Immuno-Oncology (CIO) 
 
Center for Cancer Research (CCR) 
 
National Cancer Institute (NCI) 
 
10 Center Drive Room 3B37 
 
Bethesda, MD 20892 
 
Phone: 240-781-3235 
 
 
 
 
E-mail: hoyoung.maeng@nih.gov  
 
Drug Name  M7824 
(Bintrafusp alfa, 
MSB0011359C) 
N-803  
(ALT-803) 
ETBX-011 
ETBX-061 
ETBX-051 
     Collectively called TriAd vaccine 
 Sponsor 
CCR, NCI 
 
IND Number 019285 
 
Manufacturer EMD Serono 
ImmunityBio, 
Inc. (previously 
NantCell) 
ImmunityBio, 
Inc.  
(previously 
NantCell) 
ImmunityBio, 
Inc. (previously 
NantCell) 
ImmunityBio, 
Inc. (previously 
NantCell) 
Supplier 
EMD Serono 
ImmunityBio, 
Inc. (previously 
NantCell) 
ImmunityBio, 
Inc. (previously 
NantCell) 
ImmunityBio, 
Inc. (previously 
NantCell) 
ImmunityBio, 
Inc. (previously 
NantCell) 
Commercial Agents: None  


2 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
 
PRÉCIS  
Background: 
• Approximately 50% of patients with advanced, non-HPV associated head and neck 
squamous cell carcinoma (HNSCC) will develop locoregional or distant relapse within 
two years of completing definitive standard-of-care treatment.  
• Two ongoing clinical trials investigating neoadjuvant PD-1 blockade before surgical 
resection of HNSCC suggest that immunotherapy can both cytoreduce existing disease 
before surgery and reduce the risk of locoregional or distant disease relapse after surgery.  
• Preliminary data from these studies suggest neoadjuvant treatments can be administered 
without delaying planned surgical intervention. 
• Experiments conducted by the Laboratory of Tumor Immunology and Biology (LTIB) 
demonstrated synergistic activity with tumor-targeted adenoviral vaccine plus M7824 
plus N-803 in humanized mice bearing human carcinomas and in vitro studies.  
• M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 
(PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF-
β) receptor type 2, a TGF-β trap.  
• Adenoviral vaccines targeting known shared tumor antigens can generate antigen-specific 
T cells. 
• N-803 is an IL-15/IL-15Rα super agonist complex that can enhance both NK cell and T 
cell anti-tumor activity via expansion and activation. 
• Activity observed with neoadjuvant anti-PD-1 agents alone provides rationale for testing 
of M7824 alone and in combination with other immune-oncologic agents that have been 
shown to work in concert with M7824 in preclinical studies. 
• Analysis of pre- and post-treatment tissues from HNSCC patients presents a unique 
opportunity to interrogate the effects the above treatment(s) on tumor. 
• A dose escalation of N-803 in combination with a flat dose of M7824 was conducted at 
the National Cancer Institute. Thirteen patients have been treated with the combination. 
No DLTs were observed. 
Objectives: 
• Determine the rate of pathologic complete response (pCR) or clinical-to-pathological 
downstaging in patients with previously untreated intermediate/high risk, non-HPV 
associated , squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, 
III or IV) who receive any of the three proposed treatments: M7824 alone, M7824 plus 
TriAd vaccine, or M7824 plus TriAd vaccine plus N803 prior to definite surgery. 
Eligibility: 
• Patients must have histologically or cytologically confirmed, previously untreated 
intermediate/high risk, p16-negative (if oropharyngeal), squamous cell carcinoma of the 
head and neck (T1-T4, N0-N3, M0 stage II, III or IV) 
• Men or Women; Age >18 years  
• ECOG performance status ≤ 1  


3 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
Design: 
• This protocol is a sequential window of opportunity trial of Anti-PD-L1/TGF-β trap 
(M7824) alone and in combination with TriAd Vaccine and N-803 for non-HPV 
associated resectable Head and Neck Squamous Cell Carcinoma (HNSCC).  
• Patients will be referred to the NIH for this immunotherapy treatment from surrounding 
academic medical centers and private physicians.  
• Upon referral to the NIH, patients will be rapidly screened, and enrolled on the protocol, 
if appropriate. 
• This trial will enroll patients in three arms sequentially to permit safety evaluation before 
adding the next agent. 
• In the first arm of 12 patients, M7824 (1200 mg) will be administered intravenously on 
day 1 and 15. 
• If no safety concerns, accrual will proceed to the 2nd arm, and 12 patients will enroll with 
M7824 (1200mg; intravenous) treatment on day 1 and 15 and TriAd vaccine (5 x 1011 
VP; subcutaneous) treatment on day 1 only. 
• If no safety concerns, accrual will proceed to the 3rd arm, and 12 patients will enroll with 
M7824 ((1200mg; intravenous) treatment on day 1 and 15 plus TriAd vaccine (5 x 1011 
VP; subcutaneous injection) and N-803 (15mcg/kg, subcutaneously) treatment on day 1. 
• After obtaining pre-treatment biopsies, imaging and blood collection, patients will 
receive the neoadjuvant immunotherapy at the NIH Clinical Center.  
• Patients will then be sent back to their referring providers for their definitive standard of 
care surgery and adjuvant therapy as indicated based upon pathologic analysis of the 
surgical specimen. NCI investigators will have no role in directing the ensuing standard 
of care surgeries performed at outside institutions.  
• For consistency in pathologic analysis of resection specimens, tissue blocks and/or slides 
will be obtained from outside institutions and be reviewed by the NCI Laboratory of 
Pathology.  
• It is expected that up to 20 patients may enroll in one year. Thus, with 3 arms of 12 
patients apiece, up to 36 evaluable patients may enroll. Accrual is expected to be 
completed within 2 years.  


4 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
 
TABLE OF CONTENTS  
PRÉCIS .......................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
STATEMENT OF COMPLIANCE ................................................................................................ 7 
1. 
INTRODUCTION ............................................................................................................... 8 
1.1 
Study Objectives .............................................................................................................. 8 
1.2 
Background and Rationale ............................................................................................... 8 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................................... 19 
2.1 
Eligibility Criteria .......................................................................................................... 19 
2.2 
Screening Evaluation ...................................................................................................... 22 
2.3 
Participant Registration and Status Update Procedures ................................................. 23 
2.4 
Baseline Evaluation ........................................................................................................ 24 
3 
STUDY IMPLEMENTATION ......................................................................................... 25 
3.1 
Study Design .................................................................................................................. 25 
3.2 
Drug Administration ...................................................................................................... 28 
3.3 
Dose Modifications ........................................................................................................ 29 
3.4 
Study Calendar ............................................................................................................... 32 
3.5 
Cost and Compensation .................................................................................................. 37 
3.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 37 
4 
CONCOMITANT MEDICATIONS/MEASURES ........................................................... 38 
4.1 
General guidance ............................................................................................................ 38 
4.2 
N-803 .............................................................................................................................. 38 
5 
BIOSPECIMEN COLLECTION ....................................................................................... 40 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies ........................................... 40 
5.2 
Sample Storage, Tracking and Disposition .................................................................... 44 
5.3 
Samples for Genetic/Genomic Analysis ........................................................................ 48 
6 
DATA COLLECTION AND EVALUATION .................................................................. 48 
6.1 
Data Collection ............................................................................................................... 48 
6.2 
Data Sharing Plans ......................................................................................................... 49 
6.3 
Response Criteria ........................................................................................................... 50 
6.4 
Toxicity Criteria ............................................................................................................. 56 


5 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
7 
NIH REPORTING REQUIREMENTS/DATA SAFETY MONITORING PLAN .......... 56 
7.1 
Definitions ...................................................................................................................... 56 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 56 
7.3 
NCI Clinical Director Reporting .................................................................................... 56 
7.4 
Institutional Biosafety Committee (IBC) Reporting Criteria ......................................... 57 
7.5 
NIH Required Data and Safety Monitoring Plan ........................................................... 58 
8 
Sponsor protocol/Safety Reporting .................................................................................... 59 
8.1 
Definitions ...................................................................................................................... 59 
8.2 
Assessment of Safety Events .......................................................................................... 60 
8.3 
Reporting of Serious Adverse Events ............................................................................ 61 
8.4 
Waiver of expedited reporting to CCR .......................................................................... 61 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 61 
8.6 
Reporting Pregnancy ...................................................................................................... 61 
8.7 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 62 
8.8 
Sponsor Protocol Deviation Reporting .......................................................................... 62 
9 
CLINICAL MONITORING .............................................................................................. 63 
10 
STATISTICAL CONSIDERATIONS............................................................................... 63 
10.1 
Statistical Hypothesis ................................................................................................. 63 
10.2 
Sample Size Determination ........................................................................................ 64 
10.3 
Populations for analysis .............................................................................................. 64 
10.4 
Statistical analysis ...................................................................................................... 65 
11 
COLLABORATIVE AGREEMENTS .............................................................................. 66 
11.1 
Cooperative Research and Development Agreement (CRADA) ............................... 66 
12 
HUMAN SUBJECTS PROTECTIONS ............................................................................ 66 
12.1 
Rationale For Subject Selection ................................................................................. 66 
12.2 
Participation of Children ............................................................................................ 67 
12.3 
Participation of Subjects Unable to Give Consent ..................................................... 67 
12.4 
RISK/Benefits Assessment ......................................................................................... 67 
12.5 
Consent Process and Documentation ......................................................................... 69 
13 
REGULATORY AND OPERATIONAL CONSIDERATIONS ...................................... 70 
13.1 
Study Discontinuation and Closure ............................................................................ 70 
13.2 
Quality Assurance and Quality Control...................................................................... 71 


6 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
13.3 
Conflict of Interest Policy........................................................................................... 71 
13.4 
Confidentiality and Privacy ........................................................................................ 71 
14 
PHARMACEUTICAL INFORMATION .......................................................................... 72 
14.1 
ETBX 011, 051, 061 ................................................................................................... 72 
14.2 
M7824 (Bintrafusp alfa, MSB0011359C) .................................................................. 76 
14.3 
N-803 (ALT-803) ....................................................................................................... 79 
15 
REFERENCES .................................................................................................................. 82 
Appendix A: -Performance Status Criteria ................................................................................... 85 


7 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 


8 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
 
1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
Determine the rate of pathologic complete response (pCR) or clinical-to-pathological 
downstaging in patients with previously untreated intermediate/high risk, non HPV-associated 
squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV) who 
receive any of the three proposed treatments: M7824 alone, M7824 plus TriAd vaccine, or 
M7824 plus TriAd vaccine plus N803. 
1.1.2 Secondary Objectives 
• Estimate the rate of grade 3 or 4 immune related adverse events (irAEs) 
• Determine the rate of treatment-related adverse events (AE) causing a delay of 4 weeks 
or more beyond planned surgery 
• Estimate the response rate of the primary disease by CT imaging (RECIST) 
• Estimate the one- and two-year recurrence free survival 
• One- and two-year overall survival 
1.1.3 Exploratory Objectives 
• Define immune infiltrate and localization using multiplex immunofluorescence 
• Define T cell clonality using Deep TCR-seq 
• Determine tumor infiltrating lymphocyte (TIL) responses to shared antigens and antigens 
predicted from exome and RNA sequencing  
• Assess antigen specific responses using peripheral T cell isolation 
• Multiparameter characterization of PBMC by flow cytometry 
• Assessment of changes in serum cytokines 
• Assessment of changes in TGFβ signaling in tumor, normal mucosa and skin 
 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Poor outcomes in patients with advanced stage, head and neck cancer not associated with 
HPV infection 
Definitive standard-of-care treatment for patients with locally-advanced or locoregionally 
advanced (stage II, III or IV) non-HPV associated head and neck squamous cell carcinoma 
(HNSCC) of the oral cavity, oropharynx, hypopharynx and larynx includes multi-modality 
therapy consisting of concurrent chemoradiation (CRT) or surgery followed by adjuvant 
radiotherapy with or without chemotherapy. In contrast to patients with human papillomavirus 
(HPV)-positive oropharyngeal cancer, patients with newly diagnosed advanced stage HPV-
negative HNSCC have poor outcomes after definitive standard-of-care treatment [1]. Negative 
p16 status is a surrogate marker for an HPV-negative tumor (p16-positive tumors are HPV-
positive) in tumors originating in the oropharynx. Involvement of HPV and therefore p16 status, 
have not been demonstrated to be biologically relevant in head and neck cancers originating in 


9 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
locations other than the oropharynx (e.g. oral cavity, larynx, hypopharynx or nasopharynx) [2]. 
Therefore, these tumors are considered to be ‘non-HPV associated.’ Despite maximum 
treatment, locoregional recurrence (LR) or distant metastasis (DM) will develop in 35% of 
patients with non-HPV-associated HNSCC in the first one year (Figure 1). Five-year overall 
survival (OS) is less than 50% [3]. Additionally, standard-of-care treatments for advanced stage 
HNSCC leave cured patients with devastating functional impairments [4]. More efficacious and 
less toxic treatments are needed for advanced stage, non-HPV associated, HNSCC. 
Figure 1: Disease-free survival in patients with advanced p16-negative HNSCC treated with radiotherapy (RT) or 
RT plus chemotherapy. 
 
1.2.2 Immunotherapy has clinical activity in patients with HNSCC 
HNSCC has features that make it ideal for immunotherapy. The majority of HNSCC specimens 
demonstrate evidence of T cell infiltration and PD-L1 expression indicative of an underlying 
immune response [5]. Additionally, HNSCCs harbor many genomic alterations that may give 
rise to an array of T cell neoantigens [6, 7]. Based on safety and improved overall survival 
reported in two clinical trials, both pembrolizumab and nivolumab, two programmed death 
receptor-1 (PD-1) monoclonal antibodies (mAbs), are FDA-approved for patients with 
recurrent/metastatic HNSCC that have failed systemic platinum-based chemotherapy [5, 8]. 
These studies demonstrate a manageable safety profile but objective responses in only 15-20% of 
patients following PD-1 blockade. Optimal timing of immune checkpoint blockade, or 
combination immunotherapy targeting resistance mechanisms, may enhance response rates and 
lead to improved patient survival.  


10 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
1.2.3 Neoadjuvant immunotherapy may have increased clinical activity in HNSCC 
Treatment with immunotherapy before definitive extirpative surgery (neoadjuvant treatment) 
may optimally activate anti-tumor immunity. The use of up-front neoadjuvant or induction 
immunotherapy before standard-of-care treatment for HNSCC is being actively studied in at least 
nine clinical trials worldwide. Pre-clinical work from our laboratory demonstrates that PD-1 
mAb treatment before surgical removal of tumor in mice leads to greater induction of 
neoantigen-specific memory T cells and anti-tumor immunity compared to PD-1 mAb treatment 
after surgical removal of tumor in multiple models of head and neck cancer (Figure 2). This data 
suggests that immunotherapy administered when tumor antigen is present followed by removal 
of tumor may lead to enhanced immune responses. Immunotherapy in the up-front treatment 
setting before surgical resection may increase the magnitude of response or increase the 
percentage of patients that respond. Additionally, surgical specimens offer an opportunity to 
assess for alterations in clinical-to-pathologic staging and evidence of major pathologic response 
as trial outcome measures [9].  
Ongoing clinical trials at the Dana Farber Cancer Institute and University of Pittsburgh are 
exploring neoadjuvant pembrolizumab or nivolumab before surgery for advanced oral cavity 
cancer have set the precedent for this treatment schema. Preliminary results from these studies 
have demonstrated 1) no grade 3/4 adverse events, 2) no delays in pre-determined time to 
surgery with surgical treatment occurring two to three weeks following the final dose of 
immunotherapy, 3) improved disease-specific survival at the one-year mark, and 4) evidence of 
clinical activity with major pathologic responses in surgery specimens and clinical-to-pathologic 
downstaging [10] (NCT02296684), [11] (NCT02488759). Thus, neoadjuvant single agent 
immune checkpoint inhibitor immunotherapy before definitive surgical resection in patients with 
advanced HNSCC appears be safe and have clinical activity. 


11 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
Figure 2: Neoantigen-induced IFN production by tumor draining lymph nodes harvested 40 days after resection of 
oral carcinomas (left) in a syngeneic model of carcinogen-induced oral cavity squamous cell carcinoma called 
MOC1 (mouse oral cancer 1). Peripheral T cells were assessed for neoantigen: MHC class I tetramer positivity 40 
days after resection of oral carcinomas (right).   
 
1.2.4 Rationale for combination of I/O agents 
Preclinical studies are now revealing that an effective immuno-oncology strategy is the use of 
multiple immune-mediating agents, each targeting different components of the immune system. 
These include: (a) induction of an immune response via vaccination directed against tumor-
associated antigens, (b) potentiation of the systemic immune response by the use of 
immunocytokines (such as the N-803 [also known as ALT-803], an IL-15 super agonist fusion 
protein) to enhance both NK and CD8+ T-cell responses, and (c) reduction of 
immunosuppressive entities in the tumor microenvironment (TME) by the use of anti-PD1/PDL1 
mAb checkpoint inhibitors, and/or reduction of immunosuppressive cytokines such as TGF-β 
with the use of a bifunctional anti-PDL1/TGF-β2 “Trap” designated M7824. The LTIB, in 
collaboration with the Genitourinary Malignancies Branch (GMB), has developed and/or co-
developed these agents via a series of cooperative research and development agreements 
(CRADAs). Each has been interrogated in a series of preclinical studies and in Phase I/II clinical 
studies in the CCR as well as by other investigators. The preclinical studies and early clinical 
studies detailed below are demonstrating the relative lack of additional toxicities with enhanced 
clinical benefit employing combinations of these agents. Furthermore, preclinical studies are 
now demonstrating that the combined use of agents from each of the immune-mediating 
categories described above elicits the most immune-mediated anti-tumor activities. 


12 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
 Figure 3:  Combined effect of Ad-Twist vaccine and M7824 in EMT6 carcinoma model 
As previous shown in studies published by investigators within the LTIB [12], M7824 combined 
with tumor-targeted vaccine enhances antitumor activity in metastatic murine cancer models ( 
Figure 3). Additionally, M7824 can mediate ADCC and the addition of N-803 to M7824further 
enhances this ADCC activity.  [13] (Figure 4). 
Figure 4: ALT-803 enhances the NK-mediated lysis of avelumab and M7824 model 
Employing NSG-β2m‒/‒ mice bearing human breast MDA-MB-231 tumors and reconstituted 
with human PBMC, the combination of vaccine, N-803, and M7824 resulted in the greatest level 
of anti-tumor activity compared to the use of individual agents (Figure 5). 


13 
Abbreviated Title: Neoadjuvant IO for HNSCC 
Version Date: March 26, 2025 
 
Figure 5: Multimodal therapy in mice reconstituted with PBMCs from patients 
1.2.5 M7824  
TGFβ is an immunosuppressive cytokine highly expressed in HNSCC by tumor, stromal and 
infiltrating immune cells and is a mechanism of resistance to immune checkpoint inhibitor 
immunotherapy[14, 15]. M7824 is a bifunctional fusion protein combining anti-PD-L1 mAb and 
TGFβ receptor type 2, serving as a TGFβ trap ( Figure 6). By dually blocking PD-L1 and 
neutralizing TGFβ, M7824 treatment demonstrates robust anti-tumor immune activation in 
multiple pre-clinical models of cancer [16]. In a dose-escalation phase 1 study performed at the 
NIH Clinical Center, M7824 demonstrated a manageable safety profile and induced durable anti-
tumor responses, as well as reduction in circulating TGFβ (Figure 7) [17]. Four of nineteen 
patients (21%) experienced a grade 3 or 4 adverse event; these included one case of grade 2 
bullous pemphigoid, one case of grade 3 asymptomatic lipase increase, one case of grade 2 
colitis, and once case of grade 3 hypokalemia. Only grade 2 colitis occurred within 30 days of 
initiating M7824 treatment. 


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 Figure 6: M7824.   
Approximately one-third of patients with advanced non-HPV associated HNSCC harbor tumors 
without evidence of T cell infiltration [5], suggesting these tumors may lack T cell antigens or 
have antigen processing or presentation defects. NK cells recognize tumors cells through 
antigen-independent mechanisms and may play a role in anti-tumor immunity in these cancers. 
In addition to activating T cells, M7824 can induce NK cell anti-tumor activity through 
antibody-dependent cell-mediated cytotoxicity (ADCC) and the in vivo anti-tumor activity of 
M7824 is dependent upon both T cells and NK cells [12, 16]. Thus, M7824 dually activates T 
and NK cell activity along with local neutralization of immunosuppressive TGFβ to maximally 
activate anti-tumor immunity. 
Figure 7: Spider plot of clinical responses and mean serum TGFβ concentration in patients with recurrent/metastatic 
cancer receiving M7824.   
1.2.6 N-803 


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N-803 is an IL-15 superagonist complex that expands the numbers and enhances the activity of 
effector T and NK cells, leading to significant in vivo anti-tumor activity when combined with 
immune checkpoint blockade in multiple pre-clinical solid tumor models [18]. As discussed 
above, M7824 enhances ADCC-mediated NK cell cytotoxicity [12]. Specifically, experiments 
conducted in the LTIB show that N-803 and M7824 work synergistically to enhance NK cell-
mediated ADCC ( Figure 8A ) [19].  The combination of N-803 and immune checkpoint 
blockade (nivolumab) has been used clinically with a manageable safety profile and evidence of 
clinical activity [20]. No patient receiving this combination treatment experienced a grade 4 
adverse event. Grade 3 adverse events occurred in ≤10% of patients and included fever, fatigue, 
dizziness and alterations in clinical laboratory assessments. 
1.2.7 Clinical Safety and Experience with N-803 and anti-PD-1/L1 blockade at the NCI 
The combination of N-803 and immune checkpoint blockade (nivolumab) has been used 
clinically with a manageable safety profile and evidence of clinical activity [20]. No patient 
receiving this combination treatment experienced a grade 4 adverse event. Grade 3 adverse 
events occurred in ≤10% of patients and included fever, fatigue, dizziness and alterations in 
clinical laboratory assessments. Furthermore, investigators at the NIH Clinical center have 
experience with administration of combination M7824 and N-803. As of January 2019, 13 solid 
tumor cancer patients have been treated with the M7824 1,200 mg IV every 2 weeks + N-803 
(10-15 mcg/kg) SC every 2 weeks combination at the NCI. Four patients received a N-803 
dosing of 10 mcg/kg every 2 weeks and 9 patients received N-803 dosing of 15 m cg/kg. No 
dose limiting, or unexpected toxicities attributed to the combination were observed. One patient 
with microsatellite stable, metastatic rectal cancer achieved a dramatic drop in CEA and 
improvement of cough attributed to lung metastasis after 3 treatments of M7824 and N-803. 


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Imaging showed a partial response by RECIST version 1.1 criteria. (Figure 8B). Of note, this 
patient had received CEA, MUC1, and brachyury targeted adenoviral-based vaccine before 
enrolling on the M7824 + N-803 study.  
Figure 8: A) Carcinoembryonic antigen decrease in a microsatellite stable colorectal cancer patient, who had 
previously received TriAd vaccine, while on M7824 and N-803.B) Corresponding decrease in lung metastasis in the 
same patient. 
 
 
Pharmacodynamic data from Nant suggest optimal T cell and NK cell is achieved with 15 
mcg/kg dosing every 3 weeks. Therefore, a one-time dose of 15 mcg/kg N-803 on day 1 of 
treatment will be used in this study. 
1.2.8 Therapeutic brachyury, MUC1 and CEA adenovirus vaccines (TriAd vaccine) 
The ability of adenoviral vaccination platforms to induce antigen-specific immune responses in 
human cancers is well studied. While vaccination of individual HNSCC cancer patients against 
A 
B 


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predicted neoantigens has the potential to lead to tumor-specific immunity, the processes 
involved in developing personalized vaccines is cumbersome and costly.  
Vaccination against shared antigens commonly expressed in HNSCCs allows for the use of a 
standardized vaccine platform, and pre-clinical data suggests that “spreading” of T cell responses 
against neoantigens can be induced following vaccination against tumor-associated antigens 
(unpublished data, Hamilton laboratory). Query of expression data from the HNSCC cohort of 
The Cancer Genome Atlas demonstrates that brachyury, MUC1 and CEA are commonly 
expressed in HNSCCs and represent rational shared antigen targets. (Figure 9).   
Figure 9: Gene expression of brachyury, MUC1 and CEA from the HNSCC cohort of TCGA.   
1.2.9 Clinical Experience with brachyury, MUC1 and CEA adenovirus vaccines at the NCI 
Administration of adenoviral vaccines encoding for these tumor-associated antigens has shown a 
manageable toxicity profile and ability to induce antigen specific T cell response in phase I trial 
conducted by the GMB/LTIB at the NCI. The combination of ETBX-011 (CEA-targeted), ETBX 
-051 (brachyury-targeted) and ETBX-061 (MUC1-targeted) has been tested in ten subjects. No 
DLTs were observed. Common TRAEs were fever and injection site reactions, all grade 1 or 2. 
Preliminary immune response data from this trial is shown in Table 1. 
Table 1: Immunogenicity of TriAd vaccine (ETBX-011 and ETBX-061): Development of MUC-1, CEA and 
Brachyury specific T cell responses by intracellular cytokine staining.    
 


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The immunogenicity of the TriAd vaccine (ETBX-011, ETBX-051 and ETBX-061) has been 
assessed in five patients enrolled in the Phase I study following 1 (n=1), 2 (n=5), and 3 (n=3) 
cycles of vaccination. Antigen-specific immune responses were assessed with a cytometry-based 
assay. T cells expressing the type I cytokines IFN-γ, IL-2, TNF-α, and/or the degranulation 
marker CD107a following stimulation with peptide pools encoding CEA, MUC-1, and 
Brachyury were measured before and after vaccination, as previously described [21, 22]. 
Including all time points examined, unpublished studies by the LTIB have found that 5/5 patients 
(100%) developed T cell responses to at least one of the antigens (MUC-1, CEA, Brachyury) 
encoded by the vaccine, with both CD4+ and CD8+ T cell responses noted. The demonstrated 
immunogenicity of the TriAd vaccine in advanced and diverse cancer patients enrolled in the 
Phase I study supports the use of this vaccine in combination immunotherapy studies in more 
homogeneous populations.   
1.2.10 Sequential arm administration of neoadjuvant M7824, N-803 and TriAd vaccine before 
surgery for advanced-stage, non-HPV associated HNSCC 
Cumulatively, these data provide the clinical and scientific rationale for the combination of 
M7824, N-803 and vaccine treatment in the window of opportunity setting before definitive 
surgical resection in patients with advanced non-HPV associated HNSCC. Studying 
immunotherapy in newly diagnosed, treatment naïve patients in the neoadjuvant setting allows 
pathologic, clinical and immune correlative hypotheses to be explored without reducing chance 
of cure with definitive standard-of-care treatment. Patients with newly diagnosed, advanced 
HNSCC generally require four to five weeks of treatment planning before definitive treatment 
begins, providing a treatment window associated with standard of care [23]. Patients will have 
the opportunity to benefit from neoadjuvant immunotherapy as they await surgical treatment. 
Since treatment will occur over 2 weeks during this 4-5week window, the treatment schedule 
will not delay the planned date of definitive surgery. In the window setting, clinical and scientific 
hypotheses can also be studied quickly given the short duration of neoadjuvant treatment. The 
multi-arm design of this study with sequential addition of immune-oncology agents allows for 
assessment of safety and clinical activity in each arm before enrolling subsequent arms.  
Our primary outcome measures are both based upon pathologic analysis of surgical resected 
tissues. The significance of a pathologic CR or clinical-to-pathologic downstaging in HNSCC is 
unknown. This may be determined from neoadjuvant immunotherapy clinical trials, such as the 
trial proposed here, that can correlate pCR and clinical-to-pathologic downstaging with 1- and 2-
year recurrence free survival. Since all forms of adjuvant treatment for HNSCC cause post-
treatment morbidity, identifying a neoadjuvant treatment that may eliminate the need for 
adjuvant chemotherapy or radiotherapy, in some patients, could limit post-treatment morbidity in 
patients that have surgical resection. Adjuvant therapy is based upon result from the surgical 
pathology report, with clear criteria that dictate whether adjuvant chemotherapy or radiotherapy 
are indicated. Clinical-to pathologic downstaging may eliminate the need for one or more 
adjuvant treatments. 
Pharmacodynamic data from Nant suggest optimal T cell and NK cell is achieved with 15 
mcg/kg dosing every 3 weeks. Therefore, a one-time dose of 15 mcg/kg N-803 on day 1 of 
treatment will be used in this study. M7824 is given at a flat dose of 1,200 mg intravenously. 


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This is the standard phase II dosing of this agent. TriAd vaccine will be given based on dosing 
from the phase I study of this vaccine platform. 
1.2.11 Rationale Summary 
• Clinical outcomes for non-HPV-associated HNSCC are poor. 
• Generating tumor associated antigen-specific T cells (e.g. CEA, MUC1, and brachyury) 
and then enabling their activity with combination immuno-oncologic (I/O) agents (e.g. 
M7824 and N-803) has been validated preclinically as a strategy for increasing immune-
mediated anti-tumor activity 
• M7824 and N-803 also work in concert to enhance anti-tumor activity in a non-antigen 
specific fashion (i.e. enhanced NK cell-mediated antibody dependent cellular 
cytotoxicity). 
• The window between diagnosis and resection of non-HPV associated HNSCC tumors 
presents a “window” opportunity to test minimally toxic combination immuno-oncologic 
agents’ ability to improve clinical outcomes. 
• Patients have the opportunity to benefit from immunotherapy during this period of time 
when they are normally scheduling and awaiting definitive surgery treatment for their 
HNSCC. 
• Pre-treatment biopsies and post-treatment biopsies or resected tumor samples can provide 
ample tissue for studies aimed at interrogating the effects of combination immuno-
oncologic treatments on tumor microenvironment and correlating those effects with 
clinical activity. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
• 
Patients must have histologically or cytologically confirmed, previously untreated 
intermediate/high risk, p16-negative (if oropharyngeal primary tumor), squamous cell 
carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV).  
• 
Male or female; Age >18 years.  
• 
ECOG performance status ≤ 1 (see Appendix A).  
• 
Prothombin time (PT) and partial thromboplastin time (PTT) within normal institutional 
limits. Patients with prolonged PTT determined to be due to lupus anticoagulant will not 
be excluded. 
• 
Patients must have adequate organ and marrow function as defined below:  
• Absolute neutrophil count ≥ 1000/mcL 
• Platelets ≥ 100,000/mcL  
• Hemoglobin ≥ 10.0 g/dL 
• Total bilirubin within normal institutional limits; in patients with Gilbert’s, ≤ 3.0 
mg/dL 
• AST (AGOT)/ALT (AGPT) ≤ 3X upper limit of normal.  


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• Creatinine within 1.5X upper limit of normal institutional limits 
• 
The effects of M7824, TriAd vaccines, and N-803 on the developing human fetus are 
unknown. For this reason, men and women of childbearing capacity must agree to use 
highly effective contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry, during the study and maintain such contraception until 2 months 
following the last dose of any study agent. Should a woman become pregnant or suspect 
she is pregnant while she or her partner is participating in this study, she should inform 
her treating physician immediately.  
• 
Ability of subject to understand and the willingness to sign a written informed consent 
document 
• 
Patients with successfully treated hepatitis C virus (HCV) are eligible if HCV viral load 
is undetectable.  
2.1.2 Exclusion Criteria 
• 
Patients who are immunocompromised as follows:  
• Human immunodeficiency virus (HIV) positive patients not on or not compliant 
with appropriate anti-retroviral therapy, patients with newly diagnosed (i.e. < 6 
months) HIV, patients with an HIV viral load exceeding 400 copies/mL, HIV+ 
patients with a CD4 count < 150 cells/µL, and HIV+ patients on antiretroviral 
therapy < 1 month are excluded. HIV-positive patients will also be excluded if the 
PI determines that there is a clinically significant drug-drug interaction. 
• Chronic administration (defined as daily or every other day for continued use >14 
days) of systemic corticosteroids or other immune suppressive drugs, within 14 
days before treatment on study. Physiologic daily dosing of steroids is allowed. 
Nasal, or inhaled steroid, topical steroid creams and eye drops for small body areas 
are allowed.  
• Patients who have undergone allogeneic peripheral stem cell transplantation, or 
solid organ transplantation requiring immunosuppression  


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• 
Pregnant women are excluded from this study because M7824 is an agent with the 
potential for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with M7824 breastfeeding should be discontinued if the mother is treated with M7824. 
These potential risks may also apply to other agents used in this study. 
• 
Patients with active systemic autoimmune disease, except patients with type 1 diabetes 
mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring current 
immunosuppression, or with other endocrine disorders on replacement hormones, are 
not excluded if the condition is well controlled.  
• 
Patients with a history of inflammatory bowel disease  
• 
Patients with a history inflammatory lung disease/interstitial lung disease/pulmonary 
fibrosis will be excluded. Patients with clinical findings (e.g. imaging) that are 
suggestive of inflammatory lung disease even if not experiencing symptoms of the 
disorder 
• 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to study agents to be used in the cohort the subject will be enrolled into. 
• 
Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, 
gentamicin or tobramycin). Patients enrolling on the M7824 only arm will be exempt 
from this exclusion. 
• 
Patients with a history of bleeding diathesis or recent clinically significant bleeding 
events considered by the Investigator as high risk for investigational drug treatment are 
excluded. 
• 
Any condition which, in the opinion of the investigator, would prevent full participation 
in this trial (including the long-term follow-up), or would interfere with the evaluation 
of the trial endpoints.  
• 
Patients with prior live vaccine, investigational drug, chemotherapy, immunotherapy or 
any prior radiotherapy (except for palliative bone directed therapy) within the past 28 
days prior to enrollment. Locally approved COVID vaccines are permitted.  
• 
Uncontrolled intercurrent acute or chronic illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure (>New York Heart Association 
Class I), hepatic disease, unstable angina pectoris, serious cardiac arrhythmia, requiring 
medication, 
uncontrolled 
hypertension 
(SBP>170/ 
DBP>105) 
or 
psychiatric 
illness/social situations within 12 months that would limit compliance with study 
requirements.  
• 
Patients who have undergone major surgery within 4 weeks prior to enrollment. A biopsy 
will not preclude a patient from starting study. 
• 
Patients with a history of hepatitis B (HBV) are excluded due to potential risk for viral 
reactivation and resulting liver injury in persons with latent HBV. 


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• 
Patients with treated or active brain metastases are not eligible because we are enrolling 
non-metastatic head and neck cancer patients in this trial. Standard of care treatment is 
different for head and neck cancer patients with and without metastatic disease. 
• 
Subjects unwilling to accept blood products as medically indicated.  
2.1.3 Recruitment Strategies  
Both men and women and members of all races and ethnic groups are eligible for this trial. This 
study will be listed on available websites (www.clinicaltrials.gov, https://ccr.cancer.gov/clinical-
trials) and participants will be recruited from the current patient population at NIH and referring 
academic medical centers and private physicians. This study will be posted on NIH websites and 
on NIH social media forums. There is no plan to advertise this study at this time. 
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Prior to the subject signing the research consent, subjects may be contacted by several means 
(e.g., email, mail, in person or telephone) for consideration as a potential protocol candidate, as 
follows:  
• Review of existing medical records, including medical history, physical evaluations, 
laboratory studies, etc.   
• Review of existing MRI, x-ray, or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes. 
2.2.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the consent for study 
01-C-0129 on which screening activities will be performed. 
Note:  Screening evaluation testing/procedures are conducted under the separate screening 
protocol, 01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural 
Research Program Clinical Protocols).  
Screening tests and procedures must be performed within 28 days prior to initiation of study 
therapy, unless otherwise specified: 
•  Complete medical history and physical examination (including height, weight, vital signs, 
and ECOG performance status). 
• Clinic-based flexible nasopharyngo-laryngoscopy and/or tracheoscopy to document disease 
to the extent that it can be evaluated without sedation or general anesthesia. This will include 
standard bright-light endoscopy and may include video-stroboscopy.  
•  CT of the neck and chest.  
•  Clinical laboratory tests* 


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• Serum Chemistries: 
o Acute care panel (Na+, K+, Cl-, total CO2, creatinine, glucose, blood urea nitrogen) 
o Hepatic panel (AST/GOT, ALT/GPT, total bilirubin, direct bilirubin 
o Mineral panel (albumin, calcium total, magnesium total, phosphorus) 
o Hematology: complete blood count (CBC) with differential and platelets 
o Urinalysis 
o Serum pregnancy test (β-HCG) for females of childbearing-potential and women 
< 12 months since the onset of menopause (within 3 days prior to enrollment).  
o HBV, HCV, HIV testing including viral load for HCV and HIV (within 3 months prior to 
enrollment).  CD4 testing may also be required for HIV+ patients  
• Histologic confirmation for p16 negativity* if the primary tumor is oropharyngeal (at any time 
point prior to enrollment). If there is no available tumor sample or pathology report, a biopsy 
will be performed to confirm the diagnosis using immunohistochemistry for p16. The E6H4 
anti-human P16 antibody clone will be used to stain FFPE tissues using standard 
deparaffinization, staining and mounting techniques.  
* Outside test results are acceptable if performed in designated time frame(s) listed above. 
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration 
& 
Status 
Updates 
found 
 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
2.3.1 Treatment Assignment Procedures 
• 
Cohorts 
Number Description 
1 
Previously untreated intermediate/high risk squamous cell 
carcinoma of the head and neck; T1-T4, N0-N3, M0 stage II, III 
or IV non-HPV associated squamous cell cancer that is surgically 
resectable 
• 
Arms 
Letter 
Description 
A 
M7824 (Days 1, 15) 
B 
M7824 + TriAd vaccine (ETBX-011, ETBX-051 and ETBX-061) 
(Days 1) 
C 
M7824 + TriAd vaccine (Days 1) + N-803 (Day 1) 


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• 
Arm Assignment 
Cohort 1 will be sequentially assigned to arm A, B or C. Enrollment will begin with arm A. After 
12 evaluable patients have accrued to arm A, enrollment to arm B will begin. After 12 evaluable 
patients have accrued to arm B, enrollment to arm C will begin. 
2.4 
BASELINE EVALUATION 
All subjects are required to complete baseline evaluations within 14 days prior to the first 
planned dosing of the study drug (any screening evaluation done within this 14-day time period 
can also serve for the baseline evaluation unless otherwise indicated): 
• Medical history and physical exam including weight, ECOG performance status and vital 
signs  
• CT scan of the neck and chest (within 28 days prior to first dosing of study drug).  
• Concomitant medications and baseline signs and symptoms evaluation 
• EKG 
• Serum pregnancy test (β-HCG) for females of childbearing-potential and women 
< 12 months since the onset of menopause (within 3 days prior to study therapy) 
• Serum Chemistries: 
o Acute care panel (Na+, K+, Cl-, total CO2, creatinine, glucose, blood urea nitrogen) 
o Hepatic panel (AST/GOT, ALT/GPT, total bilirubin, direct bilirubin 
o Mineral panel (albumin, calcium total, magnesium total, phosphorus)  
• Thyroid tests: TSH, free T3 and T4, 
• Lipase, amylase, LDH, GGT 
• Hematology: CBC with differential and platelets, PT, PTT 
• TBNK phenotyping  
• Urinalysis  
• CK, Uric Acid, Total Protein, CRP 
• HLA class I profile (any time prior to study treatment initiation) and may be deferred if it has 
previously been performed at the NIH. 
• For correlative studies: Blood and tissue sample will be collected. Please refer to section 5.1 
for details.  
• Biopsies of tumor, normal mucosa and skin: This pre-treatment biopsy is mandatory. 
Whenever possible, this will be done with local anesthesia in the clinic. When tumor is not 
safely accessible in the clinic, procedure will be done under general anesthesia in the 
operating room. If general anesthesia is required to biopsy the tumor, the normal mucosa and 
skin biopsies will be done under general anesthesia as well. Regional metastasis in the 
cervical lymph nodes may be sampled via core biopsies guided by bimanual palpation or 
ultrasound. 
• Clinic-based flexible nasopharyngo-laryngoscopy and/or tracheoscopy 


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3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This protocol is a window of opportunity neoadjuvant immunotherapy study. After obtaining 
pre-treatment biopsies, imaging and blood collection, patients will receive the neoadjuvant 
immunotherapy at the NIH Clinical Center. Patients will receive investigational immunotherapy 
on days 1 and 15, during the four to five-week period of time when patients have scheduled and 
are awaiting definitive surgery. Patients will then be taken off treatment on day 21-28 and post-
treatment imaging and blood collection will be performed at the NIH Clinical Center. Patients 
will then be sent back to their referring providers for their definitive standard of care surgery and 
adjuvant therapy as indicated based upon pathologic analysis of the surgical specimen. At 
outside institutions, surgery and adjuvant treatment will be performed and chosen solely by 
outside providers. NCI investigators will have no role in surgery or adjuvant treatments received 
at outside institutions. In some cases, standard of care surgery may be offered at the NIH Clinical 
Center under a separate NIDCD protocol (01-DC-0099). This protocol treats patients with 
neoadjuvant immunotherapy only; standard of care surgery and any indicated adjuvant therapy is 
not part of this protocol. Tissue blocks or slides from surgically resected tissues will be obtained 
from these outside institutions and reviewed by the Laboratory of Pathology to determine 
primary outcome measures. Secondary clinical outcome measures will be determined by CT 
imaging and by following patients that are off treatment but receiving standard of care surgery 
and adjuvant therapy. 
Immune correlative analyses may be performed on pre- and post-treatment tissues (tumor, 
normal mucosa and skin) and bloods. Pre-treatment biopsies will be obtained in the clinic setting 
(OP5 Otolaryngology clinic) under local anesthesia only whenever possible. When not possible 
or safe to obtain biopsies in the clinic, biopsies will be obtained under general anesthesia in the 
operating room at the NIH Clinical Center. Post-treatment biopsies will be obtained at the time 
of standard of care surgery if the surgery is being performed at the NIH Clinical Center or at 
Suburban Hospital. If the surgery will be performed at an outside academic institution other than 
Suburban Hospital, then biopsies will be performed in the clinic setting under local anesthesia. 
When not possible or safe to obtain biopsies in the clinic, post-treatment biopsies will not be 
obtained.  
If a patient’s condition precludes safe performance of any protocol-indicated procedure, the 
procedure may be canceled at the discretion of the investigator.  


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3.1.1 Design Schema 
 
 
• 
Staggered enrollment for Arm B and Arm C 
In order to minimize exposure to unanticipated adverse events for the first in human 
combinations administered to patients in Arm B and Arm C, staggered enrollment will be 
utilized for the first 3 patients enrolled to Arm B and Arm C.  
For Arms B and C: 
• An interval of 1 weeks without a DLT must pass between treatment of patient #1 and 
patient #2.  
• An interval of 1 weeks without a DLT must pass between treatment of patient #2 and 
patient #3.  


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• An interval of 1 weeks without a DLT must pass between treatment of patient #3 and 
patient #4. 
3.1.2 Dose Limiting Toxicity 
Dose-limiting toxicity (DLT) will be defined as any event at least possibly attributable to 
investigational agents that delays planned tumor resection surgery by >4 weeks or any one of the 
following adverse events, possibly attributable to study agents (M7824 and/or N-803 and/or 
TriAd vaccine), that occurs within 28 days after study agent administration. 
Any grade ≥ 4 hematologic toxicity or grade ≥ 3 anemia or grade 3 thrombocytopenia (platelets 
25-50,000) with associated bleeding, except CD4 lymphocyte count or other T lymphocyte 
subset count.  
• Any grade ≥ 3 non-hematologic toxicity, except for any of the following:  
o transient (≤ 48 hour) grade 3 fatigue, local reactions, flu like symptoms, fever, headache, 
or nausea, emesis, and diarrhea not controlled with adequate medical management, or 
o Any CTCAE Grade 3 skin toxicity lasting less than five days.  
o Electrolyte abnormalities that can be easily managed with replacement therapy. Grade 3 
hyperkalemia/hypokalemia that does not resolve to ≤ Grade 2 within 48 hours-72 hours 
with medical management will be considered a DLT. 
o Asymptomatic Grade 3 lipase or amylase elevation. 
o Grade 3 immune-related colitis or pneumonitis that resolves to grade 1 within 48 hours of 
initiating appropriate medical treatment 
o Any endocrinopathy that can be medically managed with hormone replacement  
• Since patients in this population undergo potentially curative resection, a treatment-related 
delay in planned surgery >4 weeks past the scheduled date will be considered a DLT. This is 
consistent with other neoadjuvant studies of checkpoint inhibitors in HNSCC patients. 
3.1.3 Study Stopping Rule  
Accrual will be halted if there is an occurrence of one grade 5 toxicity or two grade 4 toxicities 
in a given arm that are at least possibly attributable to the treatment regimen. This does not apply 
to asymptomatic grade 4 lab abnormalities (e.g. lipase elevation). Prior to resumption of the 
study, an expedited safety report will be sent to and reviewed by FDA. Serious adverse events 
(SAEs) also must be evaluated by the clinical investigators. 
After completed enrollment of arm A, enrollment to arm B will proceed if ≤1 patient in arm A 
experience a DLT. 
After completed enrollment of arm B, enrollment to arm C will proceed if ≤1 patient in arm B 
experience a DLT. 
If 2 patients in a given study arm experience a DLT, accrual to that arm will be halted. 


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3.2 
DRUG ADMINISTRATION 
3.2.1 General rule 
A window of +/-3 days for every two weeks study drug(s) dosing is allowed in the event of 
scheduling issues (i.e. holiday, bad weather or other scheduling issues). A minimum of 10 days 
must pass between the first M7824 administration and the second.  Any dose that cannot be 
accommodated within this window will be skipped and the dose not made up. 
3.2.2 M7824 
Subjects in Arms A, B and C will be scheduled to receive M7824 at a flat dose of 1,200 mg IV 
on days 1 and 15. 
Subjects will receive M7824 via IV infusion over 1 hour (-10 minutes / +20 minutes, that is, over 
50 to 80 minutes) once every 2 weeks. M7824 will be administered as a "flat" dose of 1,200 mg 
independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 
0.2 micron in-line filter. 
In order to mitigate potential infusion-related reactions, premedication with an antihistamine and 
with acetaminophen (for example, 25-50 mg diphenhydramine and 500-650 mg acetaminophen) 
may be given within approximately 30 to 60 minutes prior to dosing of M7824.  Steroids as 
premedication are not permitted. If hypersensitivity reaction occurs, the subject should be treated 
according to the best available medical practice. 
• 
Risk for cutaneous keratocanthoma/squamous cell carcinoma with administration of 
M7824 
All cases of skin lesions suspicious for the above will be preferably referred to Dermatology at 
the NIH. In cases where patients are unable to follow up with Dermatology at the NIH, 
keratoacanthomas may be managed by an outside dermatologist. Patients will then undergo 
routine follow-up skin exams and treatment as deemed appropriate by the Dermatologist. 
3.2.3 Adenoviral vaccines 
ETBX 011, 051 and 061 will be given as subcutaneous injections, on day 1 of treatment to 
subjects in Arms B and C. 
ETBX-011, ETBX-051 and ETBX-061 will be administered by subcutaneous injection in the 
upper arm or anterolateral upper thigh after preparation of the site with alcohol. A 1 to 1⁄2 inch, 
20- to 25- gauge needle should be used for each individual administration. It is preferred to 
administer ETBX-011, ETBX-051 and ETBX-061 in separate limbs. The limb of administration 
should be documented in the medical record. When administered in the same thigh, injection 
sites should be separated by at least 5 cm. 
3.2.4 N-803  
N-803 will be given via subcutaneous injection to subjects in Arm C at a dose of 15 mcg/kg on 
day 1. N-803 dosing will be calculated using a weight obtained within 5 days prior to the first 
dose.  


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Injection should occur in the abdomen. Depending on the injection volume required, the dose of 
N-803 may be administered as a single injection or multiple injections at the discretion of the 
investigator. 
Doses of N-803 can be administered on an outpatient basis. Patients should be monitored for 30 
minutes post dose. N-803 will not be self-administered.  
• 
Skin Rash in Association with Subcutaneous Administration of N-803 
Based on current experience, localized skin rashes are common with subcutaneous 
administration. If a rash occurs and the rash area surrounding the N-803 injection site is > 6 cm 
and symptomatic (painful and/or itchy), it may be treated (at the discretion of the treating 
physician) with topical 0.05% clobetasol propionate (i.e. 0.05% Cormax) or 0.1% triamcinolone 
(i.e., Kenalog) cream. Diphenhydramine may be administered pre- (25-50 mg TID orally) and 
post-dosing (25-50 mg TID orally x 2 days) of N-803 at the discretion of the treating physician. 
Diphenhydramine should be eliminated if not tolerated. Other agents may be administered at the 
discretion of the treating physician.  
3.2.5 Sequence and Monitoring of Dose Administration 
When administering concurrent investigational agents on the same day, the following sequence 
of administration is preferred. Acetaminophen 650 mg and Benadryl 50 mg by mouth (or another 
equivalent antihistamine) may be given within 30 to 60 minutes prior to M7824 infusion. 
Vaccines are preferred to be given within this time frame prior to M7824 infusion. Patients will 
be monitored for symptoms of delayed M7824 infusion reaction for 10 minutes. N-803 
administration is preferred to occur after an interval of at least 10 minutes, but no longer than 5 
hours, following M7824 infusion completion.  
3.3 
DOSE MODIFICATIONS 
No dose modifications are allowed. 
3.3.1 Suggested evaluation of suspected bleeding or hemorrhage events and treatment 
modification  
• 
For anemia or hemorrhage events assessed as treatment-related, items queried may 
include but are not limited to detailed relevant past medical and treatment history, 
bruising tendency, history of blood transfusions and/or dependency, and a request for an 
updated participant history including details such as concomitant medications, all 
laboratory data, updated dosing information and recent tumor evaluation scans.  
• 
In this protocol, anemia may be due to M7824 (documented in 29% of patients) and/or 
SX-682. For M7824 anemia is an important identified risk (see Investigators’ 
Brochure). Notably, there are many reasons for hemorrhage and/or anemia in patients 
with advanced cancer, and Hb level of at least 10 g/dL is required for this study. A 
thorough investigation of new anemia cases of unspecified etiology is recommended: 
• 
Participants must enter the study with Hgb values at least 10 g/dL and baseline anemia 
evaluation is conducted per recommendations below.  
• 
Consider hematology consult for severe and or refractory anemias.  


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• 
All relevant hematologic testing for treatment related anemias should be done prior to 
blood transfusion, if clinically feasible. 
• 
Transfusion should be performed at the discretion of the investigator, based on clinical 
assessment and considered when participant experiences significant anemia.  
• 
Guidance for evaluation of baseline anemia or suspected treatment-related anemias is 
provided below. Investigators may consider the following laboratory evaluations in 
participants with anemia.  
o Hb and CBC with differential (e.g. MCV, RDW, ANC, hematocrit, reticulocytes 
counts) 
o Peripheral blood smear for cell morphological assessment 
o Complete metabolic panel including liver panel-LFTs, bilirubin, LDH, renal 
function, and serum folate, B12 values and other chemistries 
o Coagulation factors (PT, PTT, INR) 
o Urinalysis including culture 
o Iron panel (TIBC, ferritin, Fe) 
• 
Discuss further management with Principal Investigator for clinically significant 
treatment related anemias.  
3.3.2 Immune-related adverse events 
Management of irAEs attributed should include consideration of published guidelines [24] and 
the investigator’s discretion.  
o In addition to above referenced guidelines, the following recommendations should 
be considered when managing irAEs: 
• Permanent treatment discontinuation is required in case of immune-related 
Grade 4 rash/inflammatory dermatitis, nephritis, autoimmune hemolytic 
anemia, 
hemolytic 
uremic 
syndrome, 
aplastic 
anemia, 
immune 
thrombocytopenia, 
acquired 
thrombotic 
thrombocytopenic 
purpura 
inflammatory arthritis, myositis and polymyalgia-like syndrome.  
• For Grade 4 immune-related lymphopenia, permanent treatment 
discontinuation will be required, if lymphopenia is considered immune-
related in nature, no clear alternative explanation exists for the event, and 
it does not resolve within 14 days. Permanent treatment discontinuation is 
not required when the AE is manifested by a single laboratory value out of 
normal range without any clinical correlates. In this case, treatment should 
be held until the etiology is determined. If the event is not considered 
immune-related and resolves to Grade ≤ 1, restarting treatment may be 
considered.  
• For Grade 1 immune-related pneumonitis: continue treatment. If clinically 
indicated, monitor participants weekly or more frequently as needed with 


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history, physical examination and pulse oximetry. If symptoms appear 
and/or changes in the physical exam are noted, treat as Grade 2.  
•  For myositis: in case of management with rituximab, treatment should be 
discontinued.  
• For Grade 3 or 4 endocrinopathies: withhold until clinically stable or 
permanently discontinue depending on severity.  
• For hepatitis with no tumor involvement of the liver: withhold if total 
bilirubin increases to more than 1.5 and up to 3 times ULN, permanently 
discontinue if more than 3 times ULN  
3.3.3 Discontinuation 
Treatment will be discontinued in case of following events if occur within the DLT evaluation 
period: 
• Any Grade 4 adverse drug reactions (ADRs), as defined by CTCAE v5 and assessed as 
related to any study agent by the Investigator, except for laboratory values that are 
determined to not be clinically significant or single laboratory valued that resolve to Grade ≤ 
1 or baseline grade within 7 days with adequate medical management. 
• Any Grade 3 ADRs except for any of the following: 
o Transient flu-like symptoms or fever, which is controlled with medical management.  
o Transient fatigue, local reactions, headache, nausea, emesis which is controlled with 
medical management. 
o Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor. 
o Any drug-related amylase or lipase abnormality that is not associated with symptoms or 
clinical manifestations of pancreatitis.  
o Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood transfusions or 
erythroid growth factor use does not require treatment discontinuation.  
o Keratoacanthoma and squamous cell carcinoma of the skin.  
o Any endocrinopathy that can be medically managed with hormone replacement 
o Those which in the opinion of the investigator is not clinically relevant or can be 
medically managed with minimal risk to the patient (e.g. placement of a pleurx catheter 
for recurrent inflammatory pleural effusions)  
3.3.4 Dose hold  
Dose hold determined to be necessary by the investigator is permitted. If a patient misses the 2nd 
dose of M7824 that patient does not need to be replaced on that study arm. For conditions 
determined to be transient by the principal investigator, treatment may be delayed by up to 3 
days. 
N-803 dosing should be held for hypotension (defined as systolic blood pressure less than 90 mm 
Hg) if in the presence of any clinically significant symptoms (in the opinion of the treating 
physician), until the systolic blood pressure reading is stable. If mild dehydration is suspected, an 
IV 
fluid 
bolus 
may 
be 
used 
per 
standard 
of 
care.


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3.4 
STUDY CALENDAR 
Procedure 
Screening 
Baseline1 D1 
D8 
D15 
D21-
2821 
D49 
D29-
10414 
D10515 
Long 
Term 
FU16 
NIH Advance Directive Form2 
 
X 
 
 
 
 
 
 
 
 
Evaluations 
Physical exam, weight and 
ECOG 
X 
X 
 
 
X18 
 
X17 
 
X 
 
Radiologic Evaluation3 
X 
X 
 
 
 
X 
 
 
 
 
Histologic confirmation of dx 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
X18 
 
X17 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
EKG 
 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
 
X18 
 
X17 
 
X 
 
Biopsies 
Pre-treatment 
biopsy 
(mandatory)5 
 
X 
 
 
 
 
 
 
 
 
Post-treatment 
biopsy 
(optional)6 
 
 
 
 
 
X 
 
 
 
 


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Procedure 
Screening 
Baseline1 D1 
D8 
D15 
D21-
2821 
D49 
D29-
10414 
D10515 
Long 
Term 
FU16 
Clinic-based 
flexible 
nasopharyngo-laryngoscopy 
and/or tracheoscopy19 
X 
X 
 
 
X 
X 
 
 
X 
 
Study Agents 
M78247 
 
 
X 
 
X 
 
 
 
 
 
ETBX 011, 051, and 0618 
 
 
X 
 
 
 
 
 
 
 
N-8039 
 
 
X 
 
 
 
 
 
 
 
Taken 
off 
treatment 
for 
definitive surgical resection* 
 
 
 
 
 
X 
 
 
 
 
Laboratory tests 
CBC w/differential, PT, PTT  
X 
X 
 
 
X18 
X20 
X17 
 
X 
 
Chemistry10 
X 
X 
 
 
X18 
 
X17 
 
X 
 
Amylase, lipase, LDH, GGT,  
 
X 
 
 
X18 
 
X17 
 
X 
 
CK, Uric Acid, Total Protein, 
CRP 
 
X 
 
 
X18 
 
X17 
 
X 
 
Thyroid tests-TSH, free T3 & 
T4 
 
X 
 
 
X18 
 
X17 
 
X 
 
TBNK phenotyping  
 
X 
 
 
 
 
 
 
 
 


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Procedure 
Screening 
Baseline1 D1 
D8 
D15 
D21-
2821 
D49 
D29-
10414 
D10515 
Long 
Term 
FU16 
HIV, 
Hepatitis 
B 
and 
C 
serology and/or viral load 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test11 
X 
X 
 
 
 
 
 
 
 
 
HLA Class I 12 
 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
X18 
 
 
 
X 
 
Correlative Studies (Please refer to section 5.1 for details) 
Research blood 13 
 
 
X 
X 
X 
X 
 
 
X 
 
Follow-up and others 
Adverse event evaluation 
 
X 
 
 
X 
 
 
 
X 
X 
Concomitant meds 
 
X 
 
 
X 
 
 
 
X 
X 
Phone call or e-mail every two 
weeks 
 
 
 
 
 
 
 
X 
 
 
Phone call or e-mail every 3 
months17 
 
 
 
 
 
 
 
 
 
X 
*Resection will be planned and performed under the care of surgeons as per standard of care once patients are 
taken off of study treatment. The records from outside providers administering standard of care surgery and anti-
cancer therapies will be requested in reviewed. For patients that have surgery outside of the NIH Clinical Center, tissue 


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blocks and/or slides will be obtained from the institution where the patient underwent surgery after the patient signs that 
institution’s release document.  
1. Baseline evaluations do not need to be repeated if performed within given time frame.  
2. As indicated in section 12.3, all subjects will be offered the opportunity to complete an NIH Advance Directive form. 
This should be done preferably at baseline but can be done at any time during the study as long as the capacity to do so 
is retained. The completion of the form is strongly recommended but is not required. 
3. CT of neck and chest. In cases where a CT is not clinically appropriate, other imaging modalities such as MRI may be 
used as clinically appropriate. 
4. Vital signs will be obtained routinely as part of ‘physical’ exam. Additionally, on D1 and D15 (treatment days) vital 
signs will be obtained at the beginning of and at the end of M7824 infusion.   
5. Mandatory biopsy performed within 5 days prior to day 1 of treatment 
6. Optional research biopsy performed if patient not having surgery at NIH Clinical Center or Suburban Hospital. If 
patient having surgery at NIH or Suburban hospital, tissue samples will be obtained from the OR.  
7. 1,200 mg of M7824 via IV infusion on day 1 and day 15. For the prevention of possible allergic reactions, patients may 
receive an antihistamine such as Benadryl and acetaminophen (Tylenol) before the M7824 infusion. See section  
8. Dosing and administration as described in section 3.2.3. 
9. N-803 (15mcg/kg) subcutaneous injection on day 1 
10. Chemistry: Serum, Acute care panel, Hepatic panel and Mineral panel. Please refer section 2.2 and 2.4 for details. 
11. Applies to females of childbearing potential only (within 3 days prior to enrollment) 
12. Patients who have had HLA Class I typing previously performed at NIH do not require retesting. 
13. For correlative studies: Blood sample will be collected on days 1 and 15 prior giving treatment, Additionally, When no 
treatment is being given, blood will be collected around day 8 (may occur anytime from days 6-10), within day 21-28, 
and around day 105. This could occur +/- 3 days for any time point. Please refer to section 5.1 for details.  Per PI 
discretion additional samples might be collected at the NIH Clinical Center every 12 weeks while on study and at the 
time of taking a patient off treatment.  
14. Will occur +/- 7 days for every two-week mark up to day 105. 
15. Will occur +/- 2 weeks of day 105.  
16. Starting 3 months after the day 105 visit, every 3 months (+/- 1 week), patients will be contacted by phone call or e-
mail for questioning regarding disease progression, adverse events, and survival until the patient is 2 years out from 
surgery. Only AEs considered related to study treatment will be collected as explained in detail under Section 6.1. 


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17. Visit and labs are to be performed on day 49 (+21/- 7 days). Flexibility on timing is provided because, depending on 
tumor location and extent of surgery, patients commonly remain in the hospital for several weeks post-operatively. This 
visit may be skipped per investigator discretion. 
18. Medical history, physical exam and clinical labs may be performed/drawn within 4 days prior to the day 15 treatment 
19. Visualization of tumor with Clinic-based flexible nasopharyngo-laryngoscopy may be deferred in patients whose 
primary tumors are accessible without these procedures.  Nasopharyngo-laryngoscopy done for research purposes may 
also be deferred in cases where institutional facility procedures are prohibitive (e.g., the appropriate clinical setting is 
not available due pandemic-related restrictions).   
20. PTT/PT may be  omitted 
21. Procedures are to be performed once within this timeframe  
 


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3.5 
COST AND COMPENSATION  
3.5.1 Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they 
are not covered by an insurance company.  Medicines that are not part of the study treatment will 
not be provided or paid for by the NIH Clinical Center.     
3.5.2 Compensation 
There will be no compensation provided in this study. 
3.5.3 Reimbursement  
On this study, the NCI will cover the cost for some of the expenses.  Some of the costs may be 
paid directly by the NIH and some may be reimbursed to the subject.  Someone will work with 
subjects to provide more information. 
3.6 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
After completing the study treatment, effort must be made to have all subjects complete the 
scheduled follow up on day 49.  
3.6.1 Criteria for removal from protocol therapy 
• Completion of protocol therapy 
• Participant requests to be withdrawn from active therapy  
• Unacceptable toxicity (see section 3.1.2)  
• Positive pregnancy test or intent to become pregnant 
• Investigator discretion  
• Initiation of alternative anticancer therapy including another investigational agent.  
• Intercurrent illness that prevents further administration of treatment, in the judgement of the 
investigator 
3.6.2 Off-Study Criteria 
• Death 
• Completion of 2-year study follow up period 
• Subject is lost to follow up*  
• Subject requests to be removed from the study  
• Investigator discretion 
• PI decision to close the study 
3.6.3 Lost to Follow-up*  
A participant will be considered lost to follow-up if he or she is unable to be reached after 
reasonable effort is made by the study site staff (for example, 3 telephone calls and, if necessary, 
an IRB approved certified letter to the participant’s last known mailing address or local 


38 
Abbreviated Title: Neoadjuvant IO for HNSCC 
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equivalent methods). These contact attempts should be documented in the participant’s medical 
record or study file. 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
GENERAL GUIDANCE  
Supportive care with blood components, antibiotics, analgesics, general medical therapy, etc., 
will be delivered as required.  
Immunotherapy including interferon, immunosuppressive drugs (for example, chemotherapy or 
systemic steroids except for short term treatment of allergic reactions, endocrine replacement 
therapy or low dose prednisone [≤ 10mg daily] or equivalent, or for the treatment of irAEs or 
other appropriate short-term steroid use), or other experimental pharmaceutical products are 
prohibited. Short term administration of systemic steroid or other immunosuppressant such as 
infliximab or mycophenolate (that is, for allergic reactions or management of irAEs) is allowed. 
Steroids with no or minimal systemic effect (topical, inhalation), are allowed. 
Any live vaccine therapies for the prevention of infectious disease are prohibited. Administration 
of inactivated vaccines is allowed (for example, inactivated influenza vaccine). Locally approved 
COVID vaccines are permitted.  
Antiemetics may be used for the treatment of nausea and vomiting but should not be used 
prophylactically at first dosing. Steroid-based anti-emetics are not allowed.  
4.2 
N-803 
Central nervous system function may be affected with N-803. Caution should be used with 
psychotropic medications. 
Nephrotoxic, myelotoxic, cardiotoxic, or hepatotoxic medications should be avoided if possible 
as they may further increase toxicities that have been associated with N-803. 
Interferon-alfa is prohibited while on study.  
Beta-blockers and other antihypertensives may potentiate the hypotension seen with N-803. 
Therefore, administration of these agents should be avoided during N-803 treatment period, 
unless clinically indicated. If a patient who is to receive N-803 is on a beta-blocker or other 
antihypertensive, that agent may be discontinued starting on the day of the first treatment with N-
803, if the investigator determines that stopping the agent is safe. The beta blocker may be 
resumed 2 weeks following the dose of N-803. Anti-hypertensive management decisions will be 
made on a case by case basis. For example, an anti-hypertensive may be resumed or added at any 
point if the investigator believes it to be clinically indicated e.g. if a patient experiences 
uncontrolled hypertension while receiving N-803 treatment on study. For patients on 
antihypertensives at baseline, the agent will be resumed if clinically indicated by blood pressure 
readings in the days following N-803 treatment cessation. 
If a localized skin rash at the injection site occurs that is >6 cm and symptomatic, it may be 
treated with 0.05% clobetasol propionate or 0.1% triamcinolone cream or similar product at the 
discretion of the treating physician.  


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Administration of additional glucocorticoids is discouraged during the N-803 treatment period as 
the use of systemic steroid medications may result in loss of therapeutic effects of the study drug. 
However systemic steroids may be used to treat an irAE.  
 


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5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
Study 
Test Name 
Lab Name  
Sample 
Time Points 
Volume/type 
Tube* 
Visualization of immune cells and analysis of 
immune cell localization 5.1.1 
Multiplex 
immunofluore
scence 
TIML, GMB, Dr. 
Houssein Sater 
D1 
and 
D21-28 or at 
surgery 
Fixed tumor tissue 
N/A 
T cell receptor (TCR) sequencing 5.1.2 
Deep-TCR 
sequencing 
Frederick 
Genomic 
Core 
Facility, 
Dr. 
Xiaolin Wu 
D1 
and 
D21-28 or at 
surgery 
Fixed tumor tissue 
N/A 
Assessment of antigen-specific responses in TIL 
5.1.3  
RNA-Seq  
Sample 
Preparation 
in 
Allen 
Lab 
and 
sequencing 
at 
Nant 
D1 
and 
D21-28 or at 
surgery 
Fresh tumor tissue 
N/A 
Exome sequencing, RNA sequencing and neoantigen 
prediction 5.1.3  
DNA 
and 
RNA 
sequencing 
Nant 
D1 
and 
D21-28 or at 
surgery 
Fixed tumor tissue 
N/A 
Biomarker analysis related to wound healing 5.1.4 
Expression 
analysis 
Allen Lab 
D1 
and 
D21-28 or at 
Snap frozen tumor, 
normal mucosa and 
N/A 


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surgery 
skin tissue may also 
be sampled 
Sorting and expansion of B cells to be used as 
antigen presenting cells for assays 5.1.3 
FACS sorting 
Allen Lab 
D1, 8, 15, 
21-28, D105 
Whole 
blood 
for 
PBMC 
8 
(10 
mL) 
sodium 
heparin 
green 
top 
tubes 
Assessment 
of 
antigen-specific 
responses 
in 
peripheral T cells. 5.1.5 
Intracellular 
cytokine 
staining assay 
Dr. 
Duane 
Hamilton, 
LTIB, 
NCI 
D1, 8, 15, 
21-28, D105  
Whole 
blood 
for 
PBMC 
Study of peripheral immune cell accumulation and 
function by flow cytometry 5.1.6 
Flow 
cytometry 
Dr. 
Renee 
Donahue, 
LTIB, 
NCI 
D1, 8, 15, 
21-28,  
D105 
Whole 
blood 
for 
PBMC 
Analysis of cytokine concentrations 5.1.7 
ELISA 
or 
multiplexed 
assays 
(e.g. 
Mesoscale, 
Luminex, 
cytokine bead 
array). 
Dr. James Hodge, 
LTIB, NCI 
D1, 8, 15, 
21-28,  
D105 
Serum 
2 
(8 
mL) 
SST 
tubes 
*Please note that tubes and media may be substituted based on availability with the permission of the PI or laboratory investigator. 


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The amount of blood that may be drawn from adult patients for research purposes shall not 
exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week period. 
Blood samples will be processed and stored through the Clinical Services Program with Leidos 
Biomedical research, Inc. (CSP) and will be shipped to different labs for research analysis as 
required. Blood will be collected on days 1 and 15 prior giving treatment, Additionally, when no 
treatment is being given, blood will be collected on day 8 and within day 21-28, and day 105. 
This could occur +/- 3 days for any time point.    
Tumor tissue (and also normal mucosa and skin tissue may be collected) biopsies will be 
collected on Day 1 and within Day 21-28 or at surgery. Day 1 tissues will be collected via biopsy 
in the clinic under local anesthesia for accessible tumors. This pre-treatment biopsy is mandatory 
for all patients. If tumors are not accessible in the clinic or a biopsy in the clinic is deemed 
unsafe by the investigator, Day 1 biopsies may be performed in the operating room under general 
anesthesia. For post-treatment biopsy (on day 21-28 biopsies), if the surgery is performed at the 
NIH Clinical Center or at Suburban Hospital, the tissue will be acquired from the operating room 
while the patient is under general anesthesia. If the surgery will be performed at an outside 
academic institution other than Suburban Hospital, then biopsies will be performed in the clinic 
setting under local anesthesia at the NIH Clinical Center. This could occur +/- 3 days for any 
time point and is optional. When not possible or safe to obtain biopsies in the clinic, post-
treatment biopsies will not be obtained.  
Primary tumor biopsies are limited to 10 per patient per time point; normal mucosa biopsies are 
limited to 2 per patient per time point; skin biopsies are limited to 1 per patient per time point. 
All tissue samples required for the Hamilton, Donahue and Hodge labs will be stored in the 
Allen lab as described later in section 5.2.2 and distributed when they are ready to perform 
assays.  
Tissue and blood samples will be assessed for correlative changes related to development of 
antigen-specific anti-tumor immunity, general immune activation, and potential alterations in 
wound healing.  
5.1.1 To define immune infiltrate and localization using Multiplex immunofluorescence 
Multi-parameter (multi-plex) immunofluorescence using the Perkin-Elmer Opal System will be 
used to assess tumor samples for infiltration and location of selected immune cell subsets, 
including effector T cells, regulatory T cells and myeloid cells. This will be done in collaboration 
with the Tumor Immune Microenvironment Laboratory (TIML) in the Genitourinary 
Malignancies Branch, NCI managed by Dr. Houssein Sater. Dr. Sater’s laboratory is located 
directly across the hallway from Dr. Allen’s laboratory and formalin-fixed parrafin-embedded 
(FFPE) tissue blocks or cut slides will be delivered by hand from Dr. Allen to Dr. Sater 
5.1.2 To determine T cell receptor (TCR) clonality  
DeepTCR sequencing will be performed via the Adaptive ImmunoSeq Platform by the Frederick 
Genomic Core Facility managed by Dr. Xiaolin Wu. This analysis will be performed on FFPE 
tissue blocks or cut slides. This is a service provided by an NCI Core Facility. Requests for this 


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service will be made online through the NCI at Frederick Access System, which will then 
provide instructions on shipping and receiving.  
5.1.3 Assessment of antigen-specific responses in TIL and antigens predicted from exome and 
RNA sequencing  
Standardized protocols developed in the NCI TIL Laboratory will be used to culture tumor 
infiltrating lymphocytes (TIL) form tumor fragments. Briefly, tumor will be minced into 1-2 mm 
fragments and plated in T cell supportive mediate supplemented with human IL-2. Following 3 
weeks of culture, T cells will be sorted via negative magnetic selection and assessed for antigen 
specific responses by ELISpot. Samples stimulated with Ionomycin, phorbol-myristate-acetate 
(PMA/Iono) will be used as a positive control. Autologous B cells expanded from PBMC will be 
used as antigen-presenting cells. Messenger RNA (mRNA) encoding genes of interest will be in 
vitro transcribed (IVT) from expression vectors engineered to express genes harboring potential 
antigens. mRNA will be electroporated into B cells. TIL will be screened for responses against 
naturally processed and presented MHC class I restricted epitopes from MUC-1, CEA, or 
brachyury, or predicted neoepitopes. This work will be performed in the Allen Lab, NIDCD. 
Prediction of neoepitopes requires exome sequencing, RNA sequencing and prediction pipeline 
bioinformatics. This work will be perfomed by Nant. Nant will use Illumina's HiSeq and 
NovaSeq platforms for sequencing. All samples will be run according to clinical sequencing 
quality standards, as regulated by CLIA/CAP, by clinical laboratory scientists with specific 
certifications as Clinical Genetic Molecular Biologist Scientists Bioinformatic analysis will be 
performed by both Nant and NCI investigators.    
5.1.4 Biomarker analysis related to wound healing.  
Expression analysis of genes related to wound dealing and TGFβ signaling may we assessed. 
Hypotheses related to the role of immunotherapy-induced inflammation, TGFβ signaling and 
wound healing will be studied by immunohistochemistry, immunofluorescence, and focused 
PCR arrays on FFPE or frozen tissues. This work will be performed in the Allen Lab, NIDCD. 
5.1.5 Assessment of antigen-specific responses in peripheral T cells.  
PBMCs may be analyzed for tumor antigen-specific immune responses to MUC-1, CEA, and 
Brachyury using an intracellular cytokine staining assay. PBMCs will be stimulated in vitro with 
overlapping 15-mer peptide pools encoding the tumor-associated antigens listed above; control 
peptide pools will involve the use of human leukocyte antigen peptide as a negative control and 
CEFT peptide mix as a positive control. CEFT is a mixture of peptides of CMV, Epstein-Barr 
virus, influenza, and tetanus toxin. Post-stimulation analyses of CD4 and CD8 T cells will 
involve the production of IFN-γ, IL-2, TNF, and the degranulation marker CD107a. If sufficient 
PBMCs are available, assays may also be performed for the development of T cells to other 
tumor-associated antigens. A detailed description of this assay has been previously reported [21]. 
This work will be performed in collaboration with the Laboratory of Dr. Duane Hamilton, LTIB, 
NCI. When ready to analyze, samples will be requested from Theresa Burks, CSP – Leidos, who 
will arrange for same day courier delivery of samples on dry ice. These will be received directly 
br Dr. Duane Hamilton. 


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5.1.6 Study of peripheral immune cell accumulation and function by flow cytometry  
Suspensions of PBMC will be subjected to standard flow cytometry techniques to assess for the 
accumulation and activation of select immune sell subsets. Antibody panels will test specific 
hypotheses related to T cell immune checkpoint expression, as well as Treg and MDSC function 
and mechanisms of trafficking into tumor. This work will be performed in collaboration with the 
Laboratory of Dr. Renne Donahue, LTIB, NCI. When ready to analyze, samples will be 
requested from Theresa Burks, CSP – Leidos, who will arrange for same day courier delivery of 
samples on dry ice. These will be received directly br Dr. Renae Donahue. 
5.1.7 Analysis of cytokine concentrations.  
Sera may be analyzed for changes in cytokines (IFN-γ, IL-10, IL-12, IL-2, IL-4, TGFβ, etc.), 
chemokines, antibodies, tumor-associated antigens, and/or other markers using ELISA or 
multiplexed assays (e.g. Mesoscale, Luminex, cytokine bead array). This work will be performed 
in the Laboratory of James Hodge, LTIB, NCI. When ready to analyze, samples will be 
requested from Theresa Burks, CSP – Leidos, who will arrange for same day courier delivery of 
samples on dry ice. These will be received directly br Dr. James Hodge 
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
5.2.1 Frederick Genomic Core Facility, Leidos 
Blood samples will be processed and stored through the Clinical Services Program with Leidos 
Biomedical research, Inc. (CSP).  
Clinical Services Program - Leidos Biomedical Research, Inc. 
Attn: Theresa Burks 
1050 Boyles Street 
Bldg. 469/Room 121 
Frederick, MD 21702 
On days samples are drawn, Jen Bangh at CSP (part of NCI Frederick Central Repositories) 
should be notified (phone: [301] 846-5893; fax [301] 846-6222). She will arrange same-day 
courier delivery of the specimens. 
• The Clinical Support Laboratory, Leidos Biomedical Research, Inc.-Frederick, processes 
and cryopreserves samples in support of IRB-approved, NCI clinical trials.  All 
laboratory personnel with access to patient information annually complete the NIH online 
course in Protection of Human Subjects.  The laboratory is CLIA certified for anti-IL15 
and certain cytokine measurements, and all laboratory areas operate under a Quality 
Assurance Plan with documented Standard Operating Procedures that are reviewed 
annually.  Laboratory personnel are assessed for competency prior to being permitted to 
work with patient samples.  Efforts to ensure protection of patient information include: 
• The laboratory is located in a controlled access building and laboratory doors are kept 
locked at all times. Visitors to the laboratory are required to be accompanied by 
laboratory staff at all times.   


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• Hard copy records or electronic copies of documents containing patient information are 
kept in the locked laboratory or other controlled access locations.    
• An electronic database is used to store information related to patient samples processed 
by the laboratory.   
• The database resides on a dedicated program server that is kept in a central, locked 
computer facility.   
• The facility is supported by two IT specialists who maintain up to date security features 
including virus and firewall protection.   
• Program access is limited to specified computers as designated by the laboratory 
director.  Each of these computers has a password restricted login screen.   
• The database sample entry program itself is accessed through a password protected entry 
screen.   
• The database program has different levels of access approval to limit unauthorized 
changes to specimen records and the program maintains a sample history.   
• Upon specimen receipt each sample is assigned a unique, sequential laboratory accession 
ID number.  All products generated by the laboratory that will be stored either in the 
laboratory freezers or at a central repository facility are identified by this accession ID. 
• Inventory information will be stored at the vial level and each vial will be labeled with 
both a sample ID and a vial sequence number.   
• Vial labels do not contain any personal identifier information.    
• Samples are stored inventoried in locked laboratory freezers and are routinely transferred 
to the NCI-Frederick repository facilities for long term storage.   
• Access to stored clinical samples is restricted.  Investigators establish sample collections 
under “Source Codes” and the investigator responsible for the collections, the protocol 
Principal Investigator, specifies who has access to the collection.  Specific permissions 
will be required to view, input or withdraw samples from a collection.  
• Sample withdrawal requests submitted to approved laboratory staff by anyone other than 
the repository source code owner is submitted to the source code owner for approval.  
The repository facility will also notify the Source Code holder of any submitted requests 
for sample withdrawal.   
• It is the responsibility of the Source Code holder (the NCI Principal Investigator) to 
ensure that samples requested and approved for withdrawal are being used in a manner 
consistent with IRB approval.   
• The Clinical Support Laboratory does perform testing services that may be requested by 
clinical investigators including, but not limited to, immunophenotyping by flow 
cytometry and cytokine testing using ELISA or multiplex platforms.   
• When requests are submitted by the NCI investigator for shipment of samples outside of 
the NIH it is the policy of the laboratory to request documentation that a Material 
Transfer Agreement is in place that covers the specimen transfer. At a minimum, the lab 
needs confirmation that one has been executed or an exception was granted from an 
office authorized to make such exceptions, e.g. NCI Technical Transfer Center.   
• The laboratory does not provide patient identifier information as part of the transfer 
process but may, at the discretion of the NCI investigator, group samples from individual 
patients when that is critical to the testing process.    


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• The NCI investigator responsible for the sample collection is responsible for ensuring 
appropriate IRB approvals are in place and that a Material Transfer Agreement has been 
executed prior to requesting the laboratory to ship samples outside of the NIH.   
5.2.2 Translational Tumor Immunology Program Laboratory (TTIPL), NIDCD-Allen Lab 
All samples are physically stored in Dr. Allen’s laboratory in secure, limited-access facilities 
with sufficient security, backup, and emergency support capability and monitoring to ensure 
long-term integrity of the specimens for research. Samples are logged, barcoded and tracked 
using Freezerworks Summit. This data storage software allows secure tracking of specimens that 
are completely de-identified, coded linked and tracked with barcodes only. Freezerworks has the 
capacity to fully audit all individual specimen processes such as location, aliquoting, thawing 
and shipping. Acquired samples are immediately transported to the NIDCD tissue core where 
they are processed and barcoded. The patient sticker that was used for transport is immediately 
destroyed. Unique barcodes generated for each individual sample are linked to patient 
identification numbers given to laboratory staff by NIDCD research nurses. These unique patient 
numbers correspond to patient information that is stored in CTDM. Protected patient information 
in CTDM will be recorded by NIDCD Research Nurses. Aside from the patient label that is 
immediately destroyed after specimen transport, laboratory staff will not have access to protected 
patient information. 
Investigators are granted view, input, and withdrawal authority only for their specimens. They 
may not view specimen data or access specimens for which they have not been authorized. 
Access to specimen storage is confined to repository staff. Visitors to the repositories are 
escorted by repository staff at all times 
Tissue biopsies will be ordered in CRIS and any linked protected patient data will be stored in 
the Clinical Trial Data Management (CTDM) system. Should a CRIS screen not be available, the 
CRIS downtime procedures will be followed. All tissue biopsies collected will be coded and 
stored in the NIDCD Biospecimen Tissue Bank.  
Contact information: 
Biospecimen Tissue Bank Manager: 
Paul Clavijo, PhD 
Building 10, Room 7S244 
Phone: 301-594-6091 
Cell: 240-449-6724 
Dr. Clavijo will be notified the week before each sample acquisition at our weekly tissue 
procurement meeting (Thursdays at 2pm in the NIDCD Conference Room, Building 10, Room 
7S233). All pre-treatment biopsies will be performed at the NIH Clinical Center. Post-treatment 
biopsies will be performed at either the NIH Clinical Center or Johns Hopkins Suburban 
Hospital. Dr. Friedman will be responsible for obtaining the samples from the OP5 clinic or 
operating room at the NIH and from Suburban Hospital. 


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• 
Storage, Logging, Access to and Sample Destruction upon Completion  
Waste tissues will be stored in the NIDCD tissue bank at the NIH Clinical Center. In addition, 
limited samples may be collected under this protocol as described above. Following enrollment, 
subjects will be registered and assigned a code in CTDB under which the limited demographic 
and clinical information will be stored. Only the code will be used on the specimens to 
electronically log the specimens using a task-specific bar-code technology software which has 
full security and audit functions consistent with NIH requirements. Samples and the limited 
demographic and clinical information will not contain PII. Data should be entered within 2 
weeks of patient enrollment onto the protocol. The access to the code keys will be limited to 
those designated by the Primary Investigator and will be kept in a secured, locked location.  
Samples will be stored in freezers, liquid nitrogen containers or tissue cartridge shelves in the 
NIDCD Core laboratory, located in building 10 on the NIH campus, secured by locked doors.  
Access to samples from a protocol for research purposes will be by permission of the Principal 
Investigator of that protocol in order to be used (1) for research purposes associated with 
protocol objectives for which the samples were collected, or (2) for a new research activity 
following submission and IRB approval of a new protocol and consent, or (3) for use only as 
unlinked or linked samples under the Office of Human Subjects Research Protections (OHSRP) 
Exemption Form guidelines stipulating that the activity is exempt from IRB review. The use of 
all samples will be fully tracked and audit lists of when each sample was used and who used it 
can be generated upon need or request.  
Samples, and associated data, will be stored permanently unless the patient withdraws consent. If 
researchers have samples remaining once they have completed all studies associated with the 
protocol and patient consent has not been withdrawn, samples may be kept permanently for 
possible use in future IRB approved investigations.  
Once research objectives for the protocol are achieved, researchers can request access to 
remaining samples, providing they have both approval of the Principal Investigator of the 
original protocol under which the samples or data were collected and either an IRB approved 
protocol and patient consent or the OHSRP Exemption Form stipulating that the activity is 
exempt from IRB review.  
5.2.3 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described above. 
Samples from consenting subjects will be stored until they are no longer of scientific value or if a 
subject withdraws consent for their continued use, at which time they will be destroyed. If the 
patient withdraws consent, the participant’s data and specimens will be excluded from future 
distributions, but data and specimens that have already been distributed for approved research 
use will not be able to be retrieved.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will 
be made per the requirements of section 7.2. 


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5.3 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
5.3.1 Description of the scope of genetic/genomic analysis 
Using blood and tissue samples, we will perform next generation sequencing (NGS) of DNA and 
RNA. This will be performed by Nant. Nant will use Illumina's HiSeq and NovaSeq platforms 
for sequencing. 
 The primary purpose of this sequencing is to perform bioinformatic prediction of neoepitopes. 
However, clinically actionable gene variants may be discovered as a result of exome sequencing. 
Refer to section 5.1.3 .  
5.3.2 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
Initially the samples of each patient will be barcoded. At no time will patient’s names be used on 
the blood and tissue samples. Sometimes, because a group collaboration or journal policy 
requires it, a subject’s genetic data will be deposited in a database such as dbGaP. Although there 
is controlled access to such a database, such a submission carries theoretical risks of revealing 
the identity of the subject. This is discussed in the consent. 
5.3.3 Management of Results 
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. (A list of current guidelines is 
maintained 
on 
the 
CCR 
intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 
Subjects 
will be contacted at this time with a request to provide a blood sample to be sent to a CLIA 
certified laboratory. If the research findings are verified in the CLIA certified lab, the subject 
will be offered the opportunity to come to NIH (at our expense) to have genetic education and 
counseling to explain this result. If the subject does not want to come to NIH, a referral to a 
local genetic healthcare provider will be provided (at their expense). 
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
5.3.4 Genetic counseling 
The costs of CLIA testing will be paid for by the Principal Investigator. If the health history, 
family history, or tumor diagnosis suggests that the participant might benefit from genetic 
testing, we will discuss this with him/her. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 


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data manager will assist with the data management efforts. All data obtained during the conduct 
of the protocol will be kept in secure network drives or in approved alternative sites that comply 
with NIH security standards. Primary and final analyzed data will have identifiers so that 
research data can be attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention, study day 1, through 30 days after the subject 
received the last product administration. After 90 days, only adverse events which are grade 3 or 
higher and possibly related to the study investigational agent need to be recorded. An abnormal 
laboratory value will be recorded in the database as an AE only if the laboratory abnormality is 
characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows  
• Coded, linked data in an NIH-funded or approved public repository. 
• Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
• Identified or coded, linked data with approved outside collaborators under appropriate 
agreements. 
How and where will the data be shared? 
• An NIH-funded or approved public repository: clinicaltrials.gov, dbGaP 
• BTRIS (automatic for activities in the Clinical Center) 
• Approved outside collaborators under appropriate individual agreements. 
• Publication and/or public presentations. 


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When will the data be shared?  
• Before publication. 
• At the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
RESPONSE CRITERIA 
For the purposes of this study, patients will be followed-up every 3 months +/- 1 week. Patients 
will be contacted by phone call or e-mail for questioning regarding disease progression, adverse 
events, and survival every 3 months until the patient is 2 years out from surgery. 
Primary outcome response measures will be obtained by comparing pre-treatment clinical 
staging determined by imaging according to Response Evaluation Criteria in Solid Tumors 
RECIST) guideline (version 1.1) guidelines to the post-treatment pathologic staging obtained 
from pathologic analysis of the surgically resected specimen. The screening/baseline imaging 
will be used to determine the pre-treatment TNM classification and stage. Both primary endpoint 
criteria are based upon results from pathologic analysis of surgically resected tissues. For 
patients that have surgery outside of the NIH Clinical Center, tissue blocks and/or slides will be 
obtained from the institution where the patient underwent surgery after the patient signs that 
institution’s release document. These tissue blocks and/or slides will be reviewed by the NCI 
Laboratory of Pathology. Outside pathology reports may also be obtained from the 
corresponding institution after the patient sign’s that institution’s medical release document. In 
cases where there is discordance between the pathologic staging as determined by an outside 
institution and the NCI Laboratory of Pathology, we will use the pathologic staging as 
determined by the NCI Laboratory of Pathology to determine the primary outcome measures.  
Secondary outcome response measures will be obtained by comparing CT or MRI of chest and 
neck obtained at screening/baseline and D21-28. Response or progression when comparing pre- 
and post-treatment imaging will be evaluated in this study using the new international criteria 
proposed by RECISTv1.1 guidelines[25]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.  
6.3.1 Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as:  
• By chest x-ray: >20 mm;  
• By CT scan:  
o Scan slice thickness 5 mm or under: as >10 mm 
o Scan slice thickness >5 mm: double the slice thickness  
• With calipers on clinical exam: >10 mm. 


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All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.3.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 


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Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 


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Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive 
CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.3.3 Response Criteria 
6.3.4 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 


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smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
6.3.5 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
6.3.6 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 


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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 


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Non-Target Lesions 
New Lesions 
Overall Response 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised 
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).   
7 
NIH REPORTING REQUIREMENTS/DATA SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found  at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.2 
 OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 
Non-Compliance 
Human 
Subjects 
Research 
found 
at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem will need to be reported per these 
policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.  
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.  
In addition to those reports, all deaths that occur within 30 days after receiving a research 
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To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA 
7.4.1 Serious Adverse Event Reports to IBC 
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-
threatening experience associated with the use of BN-Brachyury as soon as possible but in no 
event later than 7 calendar days of initial receipt of the information. Serious adverse events that 
are unexpected and associated with the use of the BN-Brachyury, but are not fatal or life-
threatening, must be reported to the NIH IBC as soon as possible, but not later than 15 calendar 
days after the investigator’s initial receipt of the information. Adverse events may be reported by 
using the FDA Form 3500a. 
7.4.2 Annual Reports to IBC 
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below. Alternatively, the IRB 
continuing review report can be sent to the IBC in lieu of a separate report. Please include the 
IBC protocol number on the report. 
7.4.3 Clinical Trial Information  
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information:  
• the title and purpose of the trial  
• clinical site 
• the Principal Investigator 
• clinical protocol identifiers;  
• participant population (such as disease indication and general age group, e.g., adult or 
pediatric);  
• the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons  
• the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed,  
• if the trial has been completed, a brief description of any study results.  
7.4.4 Progress Report and Data Analysis  
Information obtained during the previous year's clinical and non-clinical investigations, 
including:  


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• a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system 
• a summary of all serious adverse events submitted during the past year 
• a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications 
• if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death 
• a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability.  
7.5 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet weekly when patients are being actively treated on the trial 
to discuss each patient. Decisions about opening study arms to enrollment will be made based on 
the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator.  
Events meeting requirements for expedited reporting as described in section 7.2.1 will be 
submitted within the appropriate timelines.   
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 Safety Monitoring Committee (SMC) 
This protocol will be periodically reviewed by an intramural Safety Monitoring Committee. 
Initial review will occur as soon as possible after the annual NIH Intramural IRB continuing 
review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly 
meeting schedule permits or more frequently as may be required by the SMC based on the risks 
presented in the study.  
For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within 
the review period. 
The SMC review will focus on unexpected protocol-specific safety issues that are identified 
during the conduct of the clinical trial. 
Written outcome letters will be generated in response to the monitoring activities and submitted 
to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 


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7.5.3 Independent Monitoring Committee  
A committee of two NIH physician investigators who are not affiliated with the Genitourinary 
Malignancies Branch and are not listed as key study personnel on the study will convene every 
3-4 months for adverse event review of new subjects, in addition to the annual Safety Monitoring 
Committee. Meeting minutes will be generated and submitted to the Principal investigator and 
Clinical Director or Deputy Clinical Director, CCR, NCI. These will be submitted to IRB at the 
time of continuing review or sooner based on the risks presented in the study.    
 
8 
SPONSOR PROTOCOL/SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (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 (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 


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appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view 
of either the investigator or sponsor, its occurrence places the patient or subject at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. (21CFR312.32) 
8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
• Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.1.6 
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(s) and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events to characterize and 
understand them in association with the use of these investigational products.  
Only AESIs that match the definition of SAE will be reported as other SAEs within 7 days from 
the knowledge of event. Other non-SAE AESIs should not be reported to OSRO but only 
collected in the clinical database. 
The adverse events related to mucosal bleeding, regardless of site, will be collected as an AESI 
to enable evaluation of potential risk factors, such as site/past radiation/associated infection at 
site/recent instrumentation and other variables such as time to onset, exposure history, grade of 
bleeding, anatomical sites, etc. can be collected. 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution. 


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SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 
• 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section 6.1.  All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4..  
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets a protocol-defined serious criteria or meets the definition of Adverse Event 
of Special Interest that require expedited reporting must be submitted immediately (within 24 
hours of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the 
expedited reporting requirements are found in section 8.4. 
All SAE reporting must include the elements described in 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and 
instructions 
can 
be 
found 
at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
WAIVER OF EXPEDITED REPORTING TO CCR  
As death due to disease progression is part of the study objectives (OS), and captured as an 
endpoint in this study, it will not be reported in an expedited manner to the sponsor. However, if 
there is evidence suggesting a causal relationship between the study drug and the event, report 
the event in an expedited manner according to section 8.3. 
8.5 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
Reporting will be per the collaborative agreements.  
8.6 
REPORTING PREGNANCY  
All 
required 
pregnancy 
reports/follow-up 
to 
OSRO 
will 
be 
submitted 
to: 
OSROSafety@mail.nih.gov. 
 
Forms 
and 
instructions 
can 
be 
found 
here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions. 
8.6.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 


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when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known, 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (8.1.2) should be reported as SAEs.  
The outcome of all pregnancies should be followed up and documented. 
8.6.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 2 
months after the last dose of any investigational drug on this protocol, whichever occurs later. 
Pregnancy of the patient’s partner is not considered to be an AE. The outcome of all pregnancies 
occurring from the date of the first dose until 2 months after the last dose should, if possible, be 
followed up and documented. Pregnant partners may be offered the opportunity to participate in 
an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to 
provide data about the outcome of the pregnancy for safety reporting purposes. 
8.7 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
8.8 
SPONSOR PROTOCOL DEVIATION REPORTING 
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial. 
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. In addition, any deviation to the protocol should 
be documented in the participant’s source records and reported to the reviewing IRB per their 
guidelines. OSRO required protocol deviation reporting is consistent with E6(R2) GCP: 
Integrated Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 
Noncompliance; and ICH E3 16.2.2 Protocol deviations. 
 


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9 
CLINICAL MONITORING  
Clinical site monitoring is conducted to ensure that the rights of the participants are protected, 
that the study is implemented per the approved protocol, Good Clinical Practice and standard 
operating procedures, and the quality and integrity of study data and data collection methods are 
maintained.   
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements. 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.  
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV). 
Some monitoring activities may be performed remotely, while others will take place at the study 
site(s).  Monitoring visit reports will describe visit activities, observations, and associated action 
items or follow-up required for resolution of any issues, discrepancies, or deviations.  Monitoring 
reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, 
coordinating center (if applicable) and the Sponsor regulatory file. 
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR 
Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as 
applicable per institutional and IRB guidance. 
10 STATISTICAL CONSIDERATIONS 
10.1 STATISTICAL HYPOTHESIS 
10.1.1 Primary Endpoint(s): 
The primary endpoint of this study is to determine if by using any of the three proposed 
treatments: M7824 alone, M7824 plus TriAd vaccine, or M7824 plus TriAd vaccine plus N803, 
there is a sufficiently high success rate in patients with head and neck cancer. Success is defined 
as pathologic complete response (pCR) or clinical to pathologic downstaging in each patient. 
10.1.2 Secondary Endpoint(s): 
• Estimate the rate of grade 3 or 4 immune related adverse events (irAEs) 


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• Determine the rate of treatment-related adverse events (AE) causing a delay of 4 weeks or 
more beyond planned surgery 
• Estimate the response rate of the primary disease by CT imaging (RECIST) 
• Estimate the one- and two-year recurrence free survival 
• One- and two-year overall survival 
10.2 SAMPLE SIZE DETERMINATION 
Based on prior reports for single agents, no pCRs but an overall 30% success rate may be 
anticipated. Because of uncertainty involving delays in surgery following each treatment arm, the 
following three arms will be enrolled sequentially to permit safety evaluation before adding the 
next agent: 
• M7824 alone 
• M7824 + Vaccine 
• M7824 + Vaccine + N-803 
The trial will begin by enrolling 12 patients to the M7824 alone arm (arm A). For sample size 
estimation purposes, with 12 patients, there would be 81% power for an exact binomial test with 
a one-sided 0.10 significance level to detect the difference between a 20% success rate and a 
50% success rate in this arm. If 0-1 of the 12 patients experiences a dose limiting toxicity, 
accrual will then proceed to the 2nd arm (arm B), and 12 patients will enroll following the same 
criteria. Finally, if 0-1 of 12 patients experiences a dose limiting toxicity while treated in the 
second arm (arm B), accrual will proceed to the 3rd arm (arm C), again with 12 patients enrolled.  
After completion of the 3 arms of 12 patients apiece, the success rates will be evaluated in each 
arm. Because there is no knowledge of what the success rate of M7824 alone will be in this 
setting, a more definitive evaluation will first require these preliminary results to determine 
appropriate parameters for further investigation. Based upon the findings from these 3 limited 
size arms, including both the pCR rate and clinical downstaging, an amendment will detail the 
planned expansion as appropriate for A-C of the arms, using parameters derived from 
information obtained during the 12 patients enrolled initially in the trial.  
It is expected that up to 20 patients may enroll in one year. Thus, with 3 arms of 12 patients 
apiece, up to 36 evaluable patients may enroll. Accrual is expected to be completed within 2 
years. To allow for a small number of inevaluable patients, the accrual ceiling will initially be set 
at 40 patients. 
10.3 POPULATIONS FOR ANALYSIS 
Modified intention to treat. Any patients who receive at least one dose of any of the agents will 
be included in any toxicity or safety data reported. 
Patients who receive at least one dose of each of the intended agents on the three arms will be 
included in the analyses of primary and secondary endpoints. 


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10.4 STATISTICAL ANALYSIS 
10.4.1 General approach 
If the arms can have 0-1 patients with dose limiting toxicity, the number of patients on each arm 
who have a pCR or who have clinical to pathologic downstaging will be determined and reported 
with a confidence interval. 
10.4.2 Analysis of primary endpoints 
For each arm, the number of patients who experience a pCR will be determined and reported. In 
addition, for each arm, the fraction of patients who experience clinical to pathologic downstaging 
will be reported. Finally, for each arm, the fraction of patients who experience either a pCR or 
clinical to pathologic downstaging will be reported. Each of these fractions will be reported 
along with a 90% one-sided confidence interval. 
10.4.3 Analysis of secondary endpoints 
The secondary endpoints and their intended analyses are as follows: 
• To estimate the rate of grade 3 or 4 immune-related adverse events; the actual number of 
patients experiencing these events will be reported separately by arm. 
• To determine the rate of patients whose surgery is delayed 4 weeks or greater beyond 
planned surgery will be reported as the number out of the patients per arm, separately by 
arm. 
• To estimate the response rate of the primary disease by RECIST, the fraction with 
CR+PR out of evaluable patients will be reported along with a 95% confidence interval, 
by arm. 
• To estimate the 1 year and 2-year RFS rates. A Kaplan-Meier curve of RFS will be 
constructed for each arm, with the 1- and 2-year values reported along with 95% 
confidence intervals. 
• To estimate the 1 year and 2-year overall survival. A Kaplan-Meier curve of OS will be 
constructed for each arm, with the 1- and 2-year values reported along with 95% 
confidence intervals. 
10.4.4 Safety analyses 
Data on adverse events for each arm will be obtained and reported: to estimate the rate of grade 3 
or 4 immune-related adverse events; the actual number of patients experiencing these events will 
be reported separately by arm. 
10.4.5 Baseline descriptive analyses 
Descriptive statistics will be determined and reported for patients enrolled onto any of the three 
treatment arms, separately by arm. 
10.4.6 Planned interim analyses 
None. 


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10.4.7 Subgroup analyses 
None. 
10.4.8 Tabulation of individual patient data 
None. 
10.4.9 Analysis of exploratory objectives. 
The following endpoints will be evaluated: 
• Immune infiltrate by flow cytometry and localization using multiplex immunofluorescence 
•  T cell clonality using Deep TCRseq 
• TIL responses to shared antigens and antigens predicted from exome and RNA sequencing  
• Antigen specific responses using peripheral T cell isolation 
• Multiparameter characterization of PBMC by flow cytometry 
• Changes in serum cytokines 
• Changes in TGFβ signaling in tumor, normal mucosa and skin 
These evaluations may result in descriptive statistics or possibly statistical evaluations of effects. 
If any statistical tests are performed, they will be conducted in an exploratory fashion, without 
any adjustment for multiple testing performed but interpreted in the context of the number of 
tests undertaken. 
11 COLLABORATIVE AGREEMENTS  
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
A CRADA (02666) is in place with EMD Serono for the supply of M7824. 
A CRADA (03058) is in place with ImmunityBio (previously NantCell) for the supply of N-803. 
A CRADA (02997) is in place with ImmunityBio (previously NantCell) for the supply of ETBX 
(TriAd) vaccines 
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
Subjects from all racial/ethnic groups and both genders are eligible for this study if they meet the 
eligibility criteria. Efforts will be made to extend accrual to a representative population, but in 
this preliminary study, a balance must be struck between patient safety considerations and 
limitations on the number of individuals exposed to potentially toxic and/or ineffective 
treatments on one hand and the need to explore gender and ethnic aspects of clinical research on 
the other hand. If differences in outcome that correlate with ethnic identity are noted, accrual 
may be expanded, or a follow-up study may be written to investigate those differences more 
fully. Participants who do not accept blood transfusions will be excluded. As there is a risk of 
severe bleeding with this study drug, participants must be willing to receive blood transfusions if 
medically necessary for their own safety. Participants must be able to receive blood transfusions 


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in order to minimize the risks of receiving M7824. Another reason for this is that including these 
patients could compromise the scientific validity of the study. For example, death from blood 
loss could make it difficult to assess other aspects of the investigational immunotherapy’s 
safety—a primary scientific goal in this early-phase immunotherapy trial, which are carried out 
in small numbers of participants. 
12.2 PARTICIPATION OF CHILDREN 
Because no dosing or adverse event data are currently available on the use of each individual 
agent in patients <18 years of age, children are excluded from this study.  
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 12.4), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate. For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIH HRPP Policy 403 for 
appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed. 
12.4 RISK/BENEFITS ASSESSMENT 
Patients will receive evaluation of their disease at the National Cancer Institute’s Clinical Center. 
This protocol may or may not benefit an individual, but the results may help the investigators 
learn more about the disease and develop new treatments for patients with this disease. 
Potential adverse reactions attributable to the administration of the treatments utilized in this trial 
are discussed in section 14. All care will be taken to minimize side effects, but they can be 
unpredictable in nature and severity. Patients will be examined and evaluated prior to enrollment. 
All evaluations to monitor the treatment of patients will be recorded in the patient chart.  
The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor 
which may or may not have favorable impact on symptoms and/or survival. 
Potential risks related to treatment on the window trial include unexpected or expected toxicity 
that may delay or prevent surgical resection, or cause post-operative complications precluding 
or affecting the tolerance of standard of care adjuvant therapy. 
Potential risks and discomforts will also be minimized to the greatest extent possible by using 
procedures such as appropriate training of personnel, monitoring, withdrawal of the subject upon 
evidence of difficulty or adverse event; referral for another treatment, counseling or other 
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We anticipate that a thorough discussion of the study at the time informed consent is obtained 
will minimize any susceptibility to undue influences and unnecessary risks to research subjects. 
Although no compensation is available, any injury will be evaluated and treated in keeping with 
the benefits or care to which patients are entitled under applicable regulations. In all publications 
and presentations resulting from this trial, patients’ anonymity will be protected to the maximum 
extent possible. Authorized personnel from the National Cancer Institute (NCI) and Food and 
Drug Administration (FDA) or other regulatory authorities may have access to research files in 
order to verify that patients’ rights have been safeguarded.  
12.4.1 Known Potential Risks 
• 
Research Blood Collection  
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop.  
• 
Tumor, normal mucosa and skin biopsies 
Risks of tumor biopsy include bleeding, minor discomfort, and infection. Risk of bleeding will 
be minimized with the use of lidocaine with epinephrine local anesthesia and the conservative 
use of electrocautery (if in the operating room) or silver nitrate (if in the clinic). Discomfort is 
not a concern if the patient is under general anesthesia and with be minimized in the clinic with 
the use of injectable local anesthetic per standard-of-care approaches. Risk of injection with 
biopsies is minimal, but short course of oral antibiotics after biopsies may be provided at the 
discretion of the investigator. Biopsies of tumor and normal mucosa will be performed with 
sterilized 1-3 mm cupped biopsy forceps. Skin biopsies will be obtained with 2-4 mm punch 
biopsies. For skin biopsies, edges of wound will be approximated with suture using sterile, 
standard of care technique. Suture closure is not required for tumor or normal mucosal biopsies.  
In addition to the risks detailed in the consent for associated with this protocol, patients will be 
consented for all tumor, normal mucosa and skin tissue biopsies with a clinical consent form for 
either operative intervention under general anesthesia or for clinic-based procedures under local 
anesthesia.  
• 
Risks of the study agents 
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or this protocol document. Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents. 
• 
Risks due to contrast dye used in CT scans 
If contrast dye is used, there is a risk for allergic reaction to the dye. Patients who are allergic to 
or sensitive to medications, contrast dye, iodine, or shellfish should notify their physician. 
Patients with kidney failure or other kidney problems should notify their physician. 
• 
Nasopharyngo-laryngoscopy  
This procedure takes only a few minutes, is painless and does not require any sedation. It is a 
normal part of an ENT exam. 


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• 
Risks due to Radiation 
The study will involve radiation from the following sources: 
• Up to 3 CT scans (Neck and Chest) per year for disease assessment 
Subjects in this study may be exposed to approximately 0.99 rem. 
The CT scans exposes to 3.3 years of background radiation.  Most of the time, this amount of 
extra radiation is not harmful to subjects.  However, being exposed to too much radiation can 
cause harmful side effects including a new cancer in about 1 out of every 1000 people who get a 
very large amount of extra radiation. 
• 
Non-Physical Risks of Genetic Research 
12.4.1..1 Risk of receiving unwanted information 
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will 
be clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with patients, family members or health care providers. 
12.4.1..2 Risk related to possibility that information may be released 
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency 
or trait can be released to members of the public, insurers, employers, or law enforcement 
agencies. Although there are no plans to release results to the patients, family members or health 
care providers, this risk will be included in the informed consent document. 
12.4.1..3 Risk to family or relatives 
Family members or relatives may or may not want to be aware of familial tendencies or genetic 
risks of disease which may cause anxiety about possible future health problems. As previously 
noted, patients will be notified of any medically significant and actionable incidental findings. 
Study results will not be shared with patients. 
12.4.2 Known Potential Benefits 
The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor 
which may or may not have favorable impact on symptoms and/or survival. 
12.5 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) (legally authorized representative [LAR] if participant is an 
adult unable to consent) for review prior to consenting.  A designated study investigator will 
carefully explain the procedures and tests involved in this study, and the associated risks, 
discomforts and benefits. In order to minimize potential coercion, as much time as is needed to 
review the document will be given, including an opportunity to discuss it with friends, family 
members and/or other advisors, and to ask questions of any designated study investigator. A 
signed informed consent document will be obtained prior to entry onto the study. 


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The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
local policy, including HRPP Policy 303) per discretion of the designated study investigator and 
with the agreement of the participant/consent designee(s).  Whether in person or remote, the 
privacy of the subject will be maintained. Consenting investigators (and participant/consent 
designee, when in person) will be located in a private area (e.g., clinic consult room). When 
consent is conducted remotely, the participant/consent designee will be informed of the private 
nature of the discussion and will be encouraged to relocate to a more private setting if needed.   
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant. 
Manual (non-electronic) signature on electronic document: 
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures: 
• 
Adobe platform (which is not 21 CFR Part 11 compliant); or,   
• 
iMedConsent platform (which is 21 CFR Part 11 compliant) 
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location, but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or 
mouse.  
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent 
Process for additional information (e.g., verification of participant identity when obtaining 
consent 
remotely) 
found 
at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.  
 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS  
13.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, the Investigational New Drug (IND) sponsor and regulatory authorities.  If the study 
is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform 
study participants, the Institutional Review Board (IRB), and sponsor and will provide the 
reason(s) for the termination or suspension.  Study participants will be contacted, as applicable, 
and be informed of changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
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• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
13.2 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
13.3 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest. 
13.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.  
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The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the Center for Cancer Research (CCR). This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites and by CCR research staff will be secured and 
password protected. At the end of the study, all study databases will be archived at CCR. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants. 
 
14 PHARMACEUTICAL INFORMATION 
14.1 ETBX 011, 051, 061 
The combination ETBX-011, ETBX-051, ETBX-061 vaccine (collectively called as TriAd 
vaccine) regimen refers to the combination of three investigational adenoviral vaccines. All 
utilize the same second generation E1(-), E2 (-) vector. Subjects will each receive the three 
vaccines at the same time, at the same doses, through three separate injections administered in 
different limbs (proximal limb areas) or separate locations.  
ETBX-011 is a CEA-targeting vaccine that comprises the Ad5 [E1-, E2b-] vector and a modified 
CEA (CEA(6D)) gene insert. The investigational product ETBX-061 is a MUC1-targeting 
vaccine that comprises the Ad5 [E1-, E2b-] vector and a modified MUC1 (MUC1c) gene insert. 
The investigational product ETBX-051 is a Brachyury-targeting vaccine that comprises the Ad5 
[E1-, E2b-] vector and a modified Brachyury gene insert.  
14.1.1 Source/Acquisition and Accountability 
TriAd vaccine will be provided by ImmunityBio (previously NantCell) to the investigator. The 
investigator or designee (e.g. pharmacist) will maintain an ongoing inventory of the 
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will be dispensed at the direction of an investigator for administration to a study participant 
enrolled on the clinical trial. Disposal of expired or unused product will be returned to the 
manufacturer or disposed of according to standard site procedures based on agreement between 
the manufacturer and the site. 
14.1.2 Dosage Form:  
Suspension for injection  
Product Name 
ETBX-011 (Ad5 [E1-, E2b-]-CEA(6D) Vaccine)  
Dose  
5 x 1011 VP (standard dose) 
Route of Administration  SC injection  
Physical Description  
ETBX vaccine is supplied as a sterile, clear solution in a 2-mL 
single-dose vial. The vaccine is provided at a concentration of 5 x 
1011 VP per 1 mL and contains ARM formulation buffer (20 mM 
TRIS, 25 mM NaCl, 2.5% glycerol, pH 8.0). Each vial contains 
approximately 1.3 mL of the vaccine. ETBX-011 should be stored 
at ≤ -60°C until ready for use. 
Manufacturer  
Etubics (a wholly owned subsidiary of ImmunityBio Inc., formerly 
known as NantCell, Inc; hereafter referred to as Immunity Bio ) 
Product Name(s):  
ETBX-061 (Ad5 [E1-, E2b-]-MUC1 Vaccine)  
Dosage Form:  
Suspension for injection  
Dose  
5 x 1011 VP (standard dose)  
Route of Administration  
 
SC injection  
Physical Description  
ETBX vaccine is supplied as a sterile, clear solution in a 2-mL 
single-dose vial. The vaccine is provided at a concentration of 5 x 
1011 VP per 1 mL and contains ARM formulation buffer (20 mM 
TRIS, 25 mM NaCl, 2.5% glycerol, pH 8.0). Each vial contains1 
mL of extractable vaccine. The product should be stored at ≤ -60°C 
until ready for use.  
Manufacturer  
ImmunityBio (previously NantCell)  
 Product Name(s):  
ETBX-051 (Ad5 [E1-, E2b-]-Brachyury Vaccine)  


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Dosage Form:  
Suspension for injection  
Dose  
5 x 1011 VP (standard dose),  
Route of Administration  SC injection  
Physical Description  
ETBX vaccine is supplied as a sterile, clear solution in a 2-mL 
single-dose vial. The vaccine is provided at a concentration of 5 x 
1011 VP per 1 mL and contains ARM formulation buffer (20 mM 
TRIS, 25 mM NaCl, 2.5% glycerol, pH 8.0). Each vial contains 1 
mL of extractable vaccine. The product should be stored at ≤ -60°C 
until ready for use.  
Manufacturer  
ImmunityBio (previously NantCell)  
14.1.3 Source 
The manufacturing department of ImmunityBio (previously NantCell) will supply each vaccine 
in 2-mL single-dose vials. Each single-dose vial contains a sterile, clear suspension of the ETBX 
vaccine at 5 x 1011 VP per 1 mL intended for single dose administration and contains ARM 
formulation buffer (20 mM TRIS, 25 mM NaCl, 2.5% glycerol, pH 8.0).  
Upon receipt of the investigational product, the Investigator or delegated designee will verify 
that an appropriate shipping temperature was maintained, conduct an inventory, and sign the 
drug receipt form and send a scanned copy to the Sponsor contact as designated on the form. If a 
temperature excursion occurs, the Sponsor should be notified immediately, and the 
investigational product must be quarantined and maintained under the correct storage conditions 
until further instructions are provided by the Sponsor. The temperature excursion form will need 
to be completed and returned to the Sponsor. The original drug receipt form and packing slip 
must be retained in the Investigator’s pharmacy records.  
14.1.4 Toxicity 
The safety of immunizations (injections) with the ETBX-011, ETBX-051, ETBX-061 has been 
established in a phase I clinical trial. Ten subjects enrolled and no DLTs were observed. 
Common TRAEs were fever and injection site reactions, all grade 1 or 2.  
14.1.5 Formulation and Preparation 
Each vaccine is supplied as a clear colorless liquid filled in a 2-mL amber vial at a concentration 
of 5x1011 total virus particles (VP) per 1.0 mL. Each vial is sealed with a rubber stopper and has 
a white flip off seal. End user of the product will need to flip the white plastic portion of the cap 
up/off with their thumb to expose the rubber stopper, and then puncture the stopper with an 
injection needle to withdraw the liquid. The rubber stopper is secured to the vial with an 
aluminum crimped seal.  


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14.1.6 Stability and Storage 
Individual vials (in the desired number) of vaccine will be packaged in a cardboard box and will 
be shipped over dry ice by overnight courier with a temperature monitoring device included. 
Upon receipt, one will inspect contents of package for any noticeable damages or defects. 
Unpack the shipment contents and place the cardboard box containing vaccine vials into a 
freezer with a monitored temperature control. ETBX-011, ETBX-051 and ETBX-061 vials 
should be stored at ≤ -60°C. Receiver must stop the temperature monitoring device by turning off 
the power switch (instructions for handling and operation of temperature monitoring device will 
be provided with the package).  
14.1.7 ETBX dose preparation and administration 
The dose of ETBX vaccine to be injected is 5x1011 VP per 1mL. Prior to injection, the 
appropriate vial should be removed from the freezer and allowed to thaw at controlled room 
temperature (20–25°C, 68-77°F) for at least 20 minutes and not more than 30 minutes, after 
which it should be kept at 2-8°C (35–46°F). The vaccine is stable in the vial for at least 8 hours 
after removal from the freezer when kept refrigerated at 2-8°C (35-46°F). Once the vaccine has 
been thawed, it must not be refrozen.  
Each vial is sealed with a rubber stopper and has a white flip-off seal. The end user of the 
product will need to flip the white plastic portion of the cap up/off with their thumb to expose the 
rubber stopper and then puncture the stopper with an injection needle to withdraw the liquid. The 
rubber stopper is secured to the vial with an aluminum-crimped seal.  
The thawed vial should be swirled and then, using aseptic technique, the pharmacist or 
pharmacist designee should withdraw the appropriate volume from the appropriate vial using an 
appropriately sized syringe.  
The thawed drug product may be stored at 2 – 8°C in the vial or syringe for a total of up to 8 
hours prior to delivery to the patient, if necessary. Instructions for Dose Preparation – 5 x 1011 
Virus Particles  
Withdraw 1 mL of contents from the vial, prepare the injection site with alcohol, and administer 
to the subject by SC injection without any further manipulation (refer to the vial label for a 
description of the vialed ETBX vaccine concentration).  
14.1.8 Administration 
Please refer to section 3.2.3. 
14.1.9 Other Information 
The Ad5 [E1-, E2b-] vector is non-replicating and its genome does not integrate into the human 
genome. However, since this is a non-replicating recombinant virus, it is recommended that it be 
handled under Biosafety Level-2 conditions. Any vialed ETBX vaccine material that has been 
used in the study should be autoclaved or incinerated after use according to institutional policy 
and according to local, state and federal regulations.  


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14.1.10 
 Incompatibilities 
None known  
14.2 M7824 (BINTRAFUSP ALFA, MSB0011359C) 
14.2.1 Source/Acquisition and Accountability 
M7824 is manufactured and supplied for the trial by EMD Serono Research and Development 
Institute. The investigator or designee (e.g. pharmacist) will maintain an ongoing inventory of 
the investigational product supply according to standard site procedures. The investigational 
product will be dispensed at the direction of an investigator for administration to a study 
participant enrolled on the clinical trial. Disposal of expired or unused product will be returned to 
the manufacturer or disposed of according to standard site procedures based on agreement 
between the manufacturer and the site. 
14.2.2 Toxicity 
In a phase 1, open-label 3+3 dose-escalation study of M7824 in 16 patients, 3 patients 
experienced grade 3 drug-related adverse events including skin infection secondary to grade 2 
bullous pemphigoid, lipase increased, and colitis with associated anemia. There was no grade 4 – 
5 treatment related adverse events. Please see table below for details: 
Treatment-related TEAE Leading to Permanent Treatment Discontinuation by System 
Organ Class and Preferred Term in ≥ 2 participants in the Pooled Analysis of Dose 
Expansion Cohorts (Source: Investigator Brochure v6) 


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As of the data cutoff of 24 August 2018, 7 deaths (1.1%) were reported as due to treatment-
related TEAE, however an additional death (primary cause of intra-abdominal hemorrhage, 
assessed as treatment-related) started more than 30 days after the end of treatment and is 
therefore is not included in above count of treatment-related death. In Study EMR200647-001, 3 
participants had a treatment-related death: 1 participant had dyspnea, hemolysis and 
thrombocytopenia, 1 participant had an intracranial tumor hemorrhage and 1 participant had 
pneumonia. In Study MS200647-0008, 4 participants had a treatment-related death: 2 
participants died due to ILD, 1 participant due to sudden death and 1 participant due to septic 
shock. Please refer to IB v 6.0 Section 5.2.2.9 for a summary of the SAEs from the Sponsor’s 
Global Drug Safety database from 25 August 2018 to 31 December 2019 for ongoing studies.   
In addition, at least 2 instances of nodular regenerative hyperplasia have been observed with the 
use of this agent 
 


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Important identified risks have been identified as IRRs including hypersensitivity, irAEs and 
skin lesions with hyperkeratosis, keratoacanthoma, cutaneous squamous cell carcinoma possibly 
due to TGFβ inhibition. The important identified risks with M7824 (bintrafusp alfa) observed to 
date were overall manageable. Anemia, alterations in wound healing or repair of tissue damage, 
and embryofetal toxicity remain as important potential risks. Mucosal bleeding events of mild to 
moderate severity were observed in participants treated with M7824 in ongoing studies and are a 
potential risk for M7824. Events may include epistaxis, hemoptysis, gingival bleeding or 
hematuria amongst others. In general, these reactions resolve without discontinuation of 
treatment.  
In addition, after discussion among NCI investigators on multiple protocols using M7824, 
multiple bleeding events ranging from low grade gingival bleeding and epistaxis to more serious 
hemoptysis, GI bleeding and hematuria have been observed. Some of these events can be 
attributed to bleeding events related to cancer directly and others bleeding events can be 
attributed to colitis or cystitis which is a known toxicity of anti-PD-L1 agents including M7824. 
However, there remains the possibility that M7824 may increase the overall risk of bleeding in 
ways that may not be directly related to direct tumor bleeding or inflammatory bleeding events 
described with checkpoint inhibitors like M7824. It is hypothesized that this possible increased 
bleeding risk may be due to TGF beta inhibition which has an effect on angiogenesis; bleeding 
has also been observed in patients receiving M7824 and may be drug-related (e.g., gum bleeding, 
nose bleeds, coughing up blood, blood in their urine, or blood in the stool).  Accordingly, 
patients will be notified of the same possible risk in the informed consent document for this 
study (e.g., gum bleeding, nose bleeds, coughing up blood, blood in their urine, or blood in the 
stool). 
Several procedures have been performed on patients receiving M7824 at the NCI and no 
bleeding complications have been reported. 
Procedure 
Number of patients  
Percutaneous cholecystostomy 
1 
Nephrostomy tube placement 
1 
Liver biopsy 
5 
Thoracentesis 
1 
Biliary stent placement 
1 
Epidural catheter 
2 
Tracheostomy 
1 
Resection of CNS metastasis 
1 
Endoscopic biopsies under anesthesia 
10 


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(13 biopsies per occurrence) 
Complete debridement of papillomas 
4 
14.2.3 Formulation and Preparation 
M7824 is provided as a sterile liquid formulation and packaged at a 10 mg/mL concentration in 
USP/ Ph Eur type I 50R vials that are filled with drug product solution to allow an extractable 
volume of 60 mL (600 mg/60 mL). The vials are closed with rubber stoppers in serum format 
complying with USP and Ph Eur with an aluminum crimp seal closure. Each single-use vial 
contains 600mg of M7824, formulated as 10mg/mL of active, 6% (w/v) Trehalose, 40 mM NaCl, 
5 mM Methionine, 0.05% (w/v) Tween 20, 10 mM LHistidine at pH 5.5.  
The liquid formulation is diluted directly with 0.9% sodium chloride solution for injection. The 
estimated volumes of delivery are anticipated to be no more than 250mL. The verified 
concentration range in the infusion solution is 0.16 mg/mL to 9.6 mg/mL.  
14.2.4 Stability and storage 
M7824 must be stored at 2℃ to 8℃ until use. Product stored at room temperature for extended 
periods of time might be subject to degradation. M7824 must not be frozen. Rough shaking of 
the reconstituted solution must be avoided.  
The chemical and physical in-use stability for the infusion solution of M7824 in 0.9% sodium 
chloride for injection has been demonstrated for a total of 72 hours at room temperature; 
however, from a microbiological point of view, the diluted solution should be used immediately 
and is not intended to be stored unless dilution has taken place in controlled and validated aseptic 
conditions. No other drugs should be added to the infusion containers containing M7824.  
14.2.5 Administration procedures 
See section 3.2.2. 
14.2.6 Incompatibilities 
None known  
14.3 N-803 (ALT-803) 
14.3.1 Acquisition and Accountability 
N-803 is manufactured and supplied by ImmunityBio (previously NantCell) to the Investigator. 
The investigator or designee (e.g. pharmacist) will maintain an ongoing inventory of the 
investigational product supply according to standard site procedures. The investigational product 
will be dispensed at the direction of an investigator for administration to a study participant 
enrolled on the clinical trial. Disposal of expired or unused product will be returned to the 
manufacturer or disposed of according to standard site procedures based on agreement between 
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14.3.2 Toxicity 
In patients receiving the 10 mcg/kg subcutaneous injection, the following were reported grade 1 
and 2 toxicities: worsening anemia, diarrhea, anorexia, nausea/vomiting, constipation, fatigue, 
fever, peripheral IV infiltration, injection site reactions, pain/aches, sinusitis, hypoalbuminemia, 
hypocalcemia, hypophosphatemia, decreased iron, headaches, dysgeusia, atrial fibrillation, and 
cough. Grade 3 hypertension, atrial fibrillation, neutropenia, and decreased lymphocyte count 
were also reported.  
14.3.3 Formulation and preparation 
N-803 is a soluble complex consisting of two protein subunits of a human IL-15 variant 
associated with high affinity to a dimeric human IL-15 receptor α (IL-15Rα) sushi 
domain/human IgG1 Fc fusion protein. The IL-15 variant is a 114 aa polypeptide comprising the 
mature human IL-15 cytokine sequence with an Asn to Asp substitution at position 72 of helix C 
(N72D). The human IL-15Rα sushi domain/human IgG1 Fc fusion protein comprises the sushi 
domain of the human IL-15 receptor α subunit (IL-15Rα) (aa 1-65 of the mature human IL-15Rα 
protein) linked with the human IgG1 CH2-CH3 region containing the Fc domain (232 amino 
acids). Aside from the N72D substitution, all of the protein sequences are human. Based on the 
amino acid sequence of the subunits, calculated molecular weight of complex comprising two 
IL-15N72D polypeptides and a disulfide linked homodimeric IL-15RαSu/IgG1 Fc protein is 92.4 
kilodaltons (kDa). Each IL-15N72D polypeptide has a calculated molecular weight of 
approximately 12.8 kDa and the IL-15RαSu/IgG1 Fc fusion protein has a calculated molecular 
weight of approximately 33.4 kDa. Both the IL-15N72D and IL-15RαSu/IgG1 Fc proteins are 
glycosylated resulting in an apparent molecular weight of N-803 as approximately 113 kDa by 
size exclusion chromatography. The isoelectric point (pI) determined for N-803 ranges from 
approximately 5.5 to 6.5. Thus, the fusion protein is negatively charged at pH 7. The calculated 
molar extinction coefficient at A280 for N-803 is 116,540 M-1, or 1.26 OD280 for a 1 mg/mL 
solution of N-803, or one OD280 is equivalent to 0.79 mg/mL solution of N-803.  
The biological drug product, N-803, is formulated in a phosphate buffered saline solution. The 
drug substance is produced by a recombinant mammalian cell line and is manufactured using 
protein-free media. 
N-803 is supplied in a 2-mL single-dose/single-use vial containing 0.6 mL of N-803 (extractable 
volume is 0.5 mL) at a concentration of 1 mg/mL or 2 mg/mL.   
14.3.4 Stability and storage 
Study medication is provided in a 2mL vial containing 0.6 mL of ALT 803 at a concentration of 
2 mg/mL. Study medication must be maintained at a temperature between 2℃ and 8℃. The 
duration of time during which the product remains stable at room temperature will be obtained 
from ImmunityBio (previously NantCell). 
14.3.5 Administration procedures 
N-803 is administered subcutaneously. See section 3.2.4 


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14.3.6 Incompatibilities 
None known


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APPENDIX A: -PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, 
no 
complaints, 
no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, 
but 
ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely 
disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% 
bedridden. 
Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very 
sick, 
hospitalization 
indicated. Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.