Conditions: Recurrent Respiratory Papillomatosis Respiratory Papillomatosis Laryngeal Papilloma, Recurrent Human Papilloma Virus
Keywords: Human Papilloma Virus (HPV) Monoclonal Antibody PD-L1 Expression
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
Background:

Programmed cell death protein 1 (PD-L1) is a protein on the surface of cells. It regulates if a cell can be killed by immune system cells. It is thought to be able to affect the immune system response to diseased cells like those infected with a virus. The molecule M7824 interferes with the activity of PD-L1. It could help the immune system kill cells infected with a virus . Since recurrent respiratory papillomatosis is caused by a virus infection, this molecule could help.

Objective:

To see if M7824 works in treating recurrent respiratory papillomatosis.

Eligibility:

Adults ages 18 years or older with recurrent respiratory papillomatosis

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and pregnancy tests

Endoscopy procedure in clinic. A small tube with a camera will look at the inside of the nose, throat, larynx, and upper windpipe.

Some participants will also be screened with a chest scan.

At the start of the study, participants will:

Have a sedated endoscopy procedure where biopsies will be taken.

Have blood tests.

Have apheresis. Blood will be collected by a tube in an arm vein. A machine will remove white blood cells. The rest of the blood will be returned into an arm vein.

Fill out a voice questionnaire.

Participants will get the study molecule into a vein over about 1 hour. They will get it every other week for up to 12 weeks.

Participants will repeat screening and starting procedures throughout the study. They will also review side effects and any medicine they are taking.

When they are done with the study treatment, participants will be evaluated by repeating the study procedures. They may be evaluated periodically until their disease progresses.

Detailed description:
Background

* Recurrent respiratory papillomatosis (RRP) is a rare papillomatous disease of the aerodigestive tract that is caused by the Human Papilloma Virus (HPV).
* RRP can progress to cause airway compromise, fatal pulmonary lesions, and invasive cancers.
* There is no effective systemic therapy for RRP. Patients typically require repeated interventional procedures for disease control.
* A recently completed phase II clinical trial investigating avelumab in subjects with aggressive RRP demonstrated an acceptable safety profile from Avelumab and a high rate of partial responses.
* RRP is characterized by frequent expression of PD-L1 and transforming growth factor beta (TGF)-beta in the tumor microenvironment.
* This clinical trial will evaluate the activity of M7824, a novel bifunctional fusion protein composed of a fully human Immunoglobulin G1 (IgG1) monoclonal antibody against human PD-L1 (avelumab) fused, via a flexible glycine-serine linker, to the soluble extracellular domain of human TGF- B receptor II (Transforming growth factor, beta receptor II (TGF-BRII), which functions as a TGF-B trap. This drug was selected for its demonstrated activity in a variety of cancers and for its acceptable safety profile.

Objective

\- Determine the complete response rate for M7824 in the treatment of patients with RRP.

Eligibility

* Histologically confirmed diagnosis of RRP.
* One of the following:

  * A Derkay anatomic score of 10 or greater and a history of two or more endoscopic interventions in the last 12 months for control of RRP.
  * Pulmonary RRP with pulmonary disease that is measurable by computed tomography scan.
  * Tracheal involvement with RRP that has required either two or more endoscopic interventions in the last 12 months or a tracheostomy.
* Age 18 years or greater.
* Eastern Oncology Cooperative Group Performance Score of 0 or 1.

Design

* This is a phase II clinical trial with two cohorts that will enroll simultaneously.
* Cohort 1 will consist of subjects who have not been treated previously with an immune checkpoint inhibitor. Cohort 2 will consist of subjects whose disease has been treated previously with andrefractory to an immune checkpoint inhibitor. Each cohort will have a Simon optimal two-stage design with initial enrollment of 12 patients and expands 21 patients if one or more complete response(s) is/are observed in the initial patients. With amendment D, dated 7/24/2019, cohort 2 will be closed to further enrollment.

Arms:
arm 1: Patients will receive 1200 mg intravenous (IV) of M7824 on day 1 of a 14 day cycle, every other week, for up to 12 weeks total treatment (6 cycles).

Interventions: intervention 1: M7824
Intervention descriptions: intervention 1: Patients will receive 1200 mg intravenous (IV) of M7824 on day 1 of a 14 day cycle, every other week, for up to 12 weeks total treatment (6 cycles).

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 (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
Page 1 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
INSTITUTE/CENTER:  National Cancer Institute 
PRINCIPAL INVESTIGATOR:  Christian Hinrichs, MD 
STUDY NUMBER:  19-C-0002 
 
STUDY TITLE:  A Phase II Study of M7824 in Subjects with Recurrent Respiratory 
Papillomatosis 
IRB Approval Date: 09/20/2019 
Cohort: Treatment  
Consent Version:  7/24/2019  
 
 
WHO DO YOU CONTACT ABOUT THIS STUDY?  
Principal Investigator: Christian Hinrichs, MD 
 
Phone:  240-760-6059 
 
Email:  Hinrichs@nih.gov  
 
Study Coordinator: 
Erin Ferraro, RN 
 
Phone:  240-760-6163 
 
Email:  Erin.Ferraro@nih.gov 
 
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). 
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. Taking part in research at the NIH is your choice. 
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 
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.   


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
Page 2 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
WHY IS THIS STUDY BEING DONE? 
The main purpose of this study is to see if M7824 works in treating recurrent respiratory 
papillomatosis (RRP).    
M7824 is an investigational drug, which means that the Food and Drug Administration (FDA) has 
not approved it for sale or for marketing for recurrent respiratory papillomatosis. This study is a 
Phase 2 clinical trial.  Phase 2 trials test the effectiveness (if the drug works) and safety of an 
investigational drug.   
M7824 belongs to a family of molecules called anti-PD-L1 antibodies. PD-L1 is a protein on the 
surface of cells that regulates whether that cell can be killed by immune system cells. PD-L1 is 
thought to be able to stop or decrease the response of the immune system to different kinds of 
diseased cells, such as cancer cells or cells infected with a virus. M7824 interferes with the activity 
of PD-L1 and is thought to have an effect on the immune system (in particular white blood cells) 
that may cause an immune response or increase the effectiveness of the response.  
M7824 has been tested at different dose levels to see which dose is safe and well tolerated when 
given once every two weeks. Based on this information it was determined that 1200 mg drug 
strength would be used in this research trial.  
Another purpose of the trial is to find out whether M7824 can reduce papillomas. Another goal of 
the study is to learn more about your disease and your response to this investigational drug. To do 
this, we will draw blood and collect tissue to measure certain “biomarkers”. “Biomarkers” refer to 
different types of markers found in the blood and tissue that are associated with the disease and/or 
your response to the investigational drug. For this, samples of your blood and papilloma may be 
collected. The purpose of this research is to find out if there are any disease-related markers which 
may help in predicting how subjects respond to M7824. This is described in more detail below.  
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY? 
You are being asked to take part in this trial because you have aggressive recurrent respiratory 
papillomatosis that has not yet been treated, or your disease may not have responded adequately 
to available treatments. 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
Up to 26 patients will be enrolled on this trial. 
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?   
Before you begin the study 
Before receiving the investigational drug, you will have several tests performed to check whether 
the trial is suitable for you. Your doctor will review your medical history and the drugs that you 
are currently taking as well as the previous treatments of your disease to determine whether you 
can participate in this trial. A small part of tumor tissue that was previously collected from you 
may be used to confirm the diagnosis of recurrent respiratory papillomatosis. Some of these tests 
or procedures are part of regular care and may be done even if you are not being considered to join 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
Page 3 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
the study.  If you have had some of these tests or procedures recently, they may or may not have 
to be repeated.  The following tests and procedures will be performed prior to starting treatment: 
1. 
Complete history and physical examination. 
2. 
Routine blood tests and viral studies 
3. 
For females of child-bearing potential, a pregnancy test will be done. You will not be 
able to participate if you are pregnant. 
4. 
CT scan of chest (if necessary) to evaluate any papillomas in your lungs 
5. 
An endoscopy procedure in the clinic called flexible nasopharyngolaryngoscopy. For this 
procedure, the doctor uses a flexible endoscope (a small tube with a built-in camera) to 
look at the structures inside the nose, throat, larynx (voice box) and upper windpipe. This 
is a procedure to assess your throat and larynx; you will likely have already had this 
procedure before.  
6. 
Evaluation of the veins in your arms to determine if your veins are large enough to allow 
your blood to be collected during an apheresis procedure (see #4 under “Before 
Treatment” for a description of procedure). 
During the study 
Before Treatment  
If you are determined eligible to be in the study, you will have the following additional tests that 
will be performed for research purposes only: 
1. Endoscopy procedure under anesthesia (sedation or general anesthesia). This procedure 
allows us to make sure we know where all of your papilloma disease is located, to make sure 
that your airway will be open enough to undergo the experimental treatments and to get 
biopsies of your papilloma. If we are concerned that your papilloma may cause breathing 
issues while you receive the experimental treatment, we may remove some of the papilloma 
to make your breathing safer. This pre-treatment biopsy is required because it will confirm 
the diagnosis and provide information that is critical to the goals of this study.  
The biopsy will be studied in the research laboratory to evaluate additional proteins and 
characteristics in your papilloma.  You will not receive results of the research testing because 
they are being conducted in a research lab and are not valid for treatment purposes.  The 
research testing on the biopsy may include growing cell lines (cells which keep dividing and 
growing in the laboratory, sometimes for years allowing us to continually study those cells).   
In addition, a portion of the biopsy will be reviewed by the pathologist at your study site to 
confirm your diagnosis of benign papilloma.  You will receive the results of this review.  
2. You will have blood collected (approximately 7.5 tablespoons for research testing).  You will 
not receive results of the research testing. One of the laboratory tests help us determine 
certain immune elements present in your blood.  
3. You will be asked to complete the Voice Handicap Index-10 assessment questionnaire. This 
will tell us the extent to which RRP is affecting your voice. We will have you complete the 
same questionnaire later on in the study to see if this changes.   


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
4. You may have an apheresis procedure for research. The apheresis procedure involves 
inserting a catheter (tube) into your vein to allow your blood to be collected.  White blood 
cells will be separated from the rest of your blood and stored until the time they are used for 
research and the rest of the blood will be returned to you through the same catheter it came 
out of or through second needle in your other arm.  We will try to use IV catheters already in 
place, but may need to give you an additional IV catheter.  You will be asked to sign a 
separate consent for this procedure, and may decline to have this procedure.  If you decide 
not to have the apheresis, it will not affect your participation in this study. 
After the research samples have been collected, you will begin treatment.  Your participation in 
the Study Treatment Period may continue for as long as you are receiving benefit and you do not 
meet any of the withdrawal criteria. 
During treatment 
M7824 will be administered at a dose of 1200 mg every other week (Day 1 of a 14-day cycle 
(weeks 1, 3, 5, 7, 9 and 11)) for up to 12 weeks total (6 cycles), which are broken down into two 
courses.  Each course has three cycles.  You will only proceed to course 2 if you have had a partial 
response to M7824.  If you have a partial response after course 2, you can choose to receive up to 
2 more courses of therapy. M7824 will be given as an infusion through a vein (IV) over 
approximately a 60-minute period. 
You will be monitored closely while you are participating in this trial.  You will need to inform 
your study doctor about any prescription and non-prescription medications you are taking. Your 
doctor will help determine whether you should continue these drugs, whether you need to change 
the way you are taking these drugs, or whether you need to switch to another medication.  
Some of the tests done before starting treatment will be repeated 6 and 12 weeks after starting 
treatment to check on how the treatment is working.  
Every 2 weeks while receiving study treatment:  
x Physical examination which may include flexible nasopharyngolaryngoscopy in the clinic. 
x Vital signs and weight.  
x Pregnancy test in women of childbearing potential. 
x Routine blood tests 
x Blood collection (approx. 3-4 tablespoons) for research testing.  
x Review of side effects that you have experienced and medications that you are taking. 
x Voice Handicap Index-10 assessment questionnaire. 
x Infusion of M7824.  
Additional studies at a single time point two weeks after the initial dose 
x Endoscopy procedure under anesthesia (sedation or general anesthesia) to see if there are 
clinical signs of inflammation in your airway or if there is blockage of your airway and to 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
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obtain biopsies which will be used for research purposes to evaluate how your disease is 
responding to the treatment. 
x Optional apheresis procedure to collect white blood cells (also called leukocytes) which will 
be used for research. 
Every 6 weeks while receiving study treatment: 
x Physical examination.  
x Flexible nasopharyngolaryngoscopy in the clinic. 
x Voice Handicap Index-10 assessment questionnaire.  
x CT scan of chest (if used for response assessment) to evaluate your RRP status. 
When you are finished taking the study treatment: 
x Endoscopy procedure under anesthesia (sedation or general anesthesia) to either perform a 
biopsy to verify that your papilloma is gone if you had a complete response to the treatment, 
or to remove all visible papilloma with normal surgery techniques if you do not have a 
complete response to the treatment.  
x If you respond to the treatment, you will be evaluated every 6 weeks (3 times), then every 12 
weeks (3 times), then every 26 weeks (two times) or until you experience disease 
progression.  
x You will be evaluated 42 days after the last dose of M7824 if you do not experience a 
response to treatment. 
x If you do not experience a response to treatment you will be contacted annually to document 
additional disease recurrence and treatments that you have received. 
x Evaluations will include: 
o Physical Exam 
o Pregnancy test in women of childbearing potential 
o Vital signs.  
o Flexible nasopharyngolaryngoscopy in the clinic. 
o Blood tests (about 1 tablespoon) to check your blood counts, blood chemistries and 
other tests to monitor your health.  
o Blood collection (approx. 3-4 tablespoons) for research testing.  
o Review of side effects that you have experienced and medications that you are taking. 
o Voice Handicap Index-10 assessment questionnaire. 
BIRTH CONTROL 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
Page 6 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
we don’t know how this medicine would affect your baby or your unborn child. If you are a woman 
who can become pregnant, or if your partner is capable of becoming pregnant and you wish to 
participate in this study, and you have not had your prostate or testicles removed, or you are not 
receiving continuous hormone therapy, then you must use a medically acceptable method of birth 
control and refrain from donating sperm while you are receiving the study drug and for a period 
of at least 4 months after your last dose of the study drug.  
If your partner becomes pregnant during the course of treatment, you must inform your doctor 
immediately. Your doctor will ensure that you and your partner receive information about options 
available to you in relation to pregnancy and that you and your partner are fully supported in 
whichever option you chose.  Acceptable birth control options for you and your partner include: 
x Intrauterine device (IUD) 
x Approved hormonal contraceptives or therapies (birth control pills, Depo-Provera, or 
Lupron Depot)  
x Surgical Sterilization (you and/or your partner) 
x Barrier methods (such as a condom or diaphragm) used with a spermicide 
Embryofetal toxicity 
Based on how the study drug works, there is also a risk of embryofetal toxicity (risks to your 
unborn baby).  
Risks to an Unborn Child and Sexual Partner 
Your study doctor will discuss the risks to unborn children for drugs used in this study. The effects 
of the study drugs, if any, on unborn children are unknown.  
RISKS OR DISCOMFORTS OF PARTICIPATION 
What side effects or risks can I expect from being in this study?  
What could be the side effects of the study drug? 
In a clinical study like this one, every risk or side effect cannot be predicted. Each person’s reaction 
to a study drug, device or procedure may be different. You may have a side effect or be at risk for 
symptoms, illnesses and/or complications that could not be predicted by your study doctor or the 
sponsor of this clinical study.  If such side effects occur, you must inform your study doctor 
immediately. 
Based on animal studies and previous studies in humans, the following possible side effects could 
occur: 
Infusion-related reactions including hypersensitivity (allergic reactions to the drug infusion) 
Allergic reactions or reactions in the context with the infusions might occur during treatment. 
Although the study drug is a fully human protein the risk cannot be completely excluded. 
Infusion-related reactions have already been observed under treatment with a similar drug 
which is currently in the clinical development at the Sponsor. Infusion-related reactions may 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
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File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
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be mild to moderate such as nausea, vomiting or dizziness, but could also be severe to life-
threatening (anaphylactic reaction) and even fatal reactions might occur, which require 
advanced cardiac life support. Severe to life-threatening symptoms could be bronchospasm, 
dyspnea (difficulty in breathing), low blood pressure, irregular heart or cardio-vascular 
collapse/cardio-respiratory arrest.  
For the prevention of infusion-related adverse effects and possible allergic reactions you may 
receive a premedication of an antihistamine drug (Benadryl® or similar) and acetaminophen 
(Tylenol®) 30 to 60 minutes before every infusion. In addition, as a preventive measure, you 
will undergo an overnight stay at the hospital for observation after the first two infusions of 
the study drug.  For other doses, you will be asked to remain in the study center for at least 2 
hours after the end of the infusion. 
Immune-related Adverse Events (irAEs)/Autoimmune Disorders  
Immune-related adverse events (irAEs)/autoimmune disorders (illnesses caused by an over 
activity of your body’s immune-system that normally protects you from infections). Immune-
mediated side effects have been observed with other drugs which are similar to one component 
of the study drug. These similar drugs comprise a drug which is currently in the clinical 
development at the Sponsor and other drugs which are already on the market. 
Symptoms/illnesses such as arthralgia (joint/joints pain), arthritis (inflammatory disease of 
the joint), pneumonitis (inflammation of the lung tissue), hypothyroidism (decreased function 
of the thyroid gland), hyperthyroidism (increased function of thyroid gland), autoimmune 
hepatitis (inflammation of the liver caused by the body’s immune system), iritis (inflammatory 
eye disease), diabetes mellitus (high blood sugar levels), adrenal insufficiency (decreased 
function of the adrenal glands), myositis (inflammation of a muscle characterized by pain and 
tenderness), myocarditis (inflammation of muscle of the heart) or inflammation of other 
organs and autoimmune disorder (body’s immune system approaches its own cells and 
causing destruction) might occur. The potential side effects listed above may be temporary, 
long term, permanent or result in death. However, based on the experience with the other 
drugs most of these potential side effects are usually manageable and reversible. That means 
they will stop once the drug is discontinued.  One immune-related adverse event of colitis 
(inflammation of the bowel tissue) with subsequent bleeding and anemia has been observed 
with the use of this drug. The colitis might present with no or limited symptoms. It is important 
that you notify your treating physician immediately if you experience mild abdominal pain, 
blood in your stools, or mild diarrhea. Rarely nerve inflammation may also be seen leading to 
temporary or in extremely rare cases permanent nerve damage. This may present in a number 
of ways including localized weakness, changes in vision or hearing and nausea and vomiting. 
Anemia 
Anemia, a reduction of your red blood cell number is considered a potential risk as it has been 
observed in animal studies with the study drug. During the study, your red blood cell count 
will be closely monitored. In case of a significant decrease, your study doctor will stop 
treatment with the study drug as appropriate and apply adequate medicinal treatment which 
may include blood transfusions.   


 
PATIENT IDENTIFICATION 
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Version Date: 7/24/2019 
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Alterations in wound healing or repair of tissue damage 
This is a potential risk considering how the drug works. If you have a wound or tissue damage, 
there may be a delay/alteration in the healing of that wound.  Please make your doctor aware 
if you plan to undergo any kind of surgery while you are participating in this study.  
Rash  
You may experience a rash that appears as a red flat area on the skin with small raised bumps.  
Rash with skin thickening/keratoacanthoma/skin cancer 
Taking into account experience with other investigational drugs, which are similar to one 
component of the study drug, additional possible side effects include skin rash with excessive 
skin thickening, a certain type of a benign skin tumor that can form a dome-shaped lump 
(keratoacanthoma) and a certain type of skin cancer. Your study doctor will carefully monitor 
your skin for any of these changes.  If a suspicious skin rash or lesion is detected, your study 
doctor may take a skin biopsy (small piece of tissue) for analysis in a laboratory.  You may 
also be asked to see a skin specialist (dermatologist) for further assessment and testing.  The 
skin lesion may need to be surgically removed. We recommend limiting your sun exposure 
during treatment due to the known association between TGF-β inhibitors and skin tumors. 
Bleeding 
Bleeding has been frequently observed in patients receiving the drug M7824. Patients may 
experience bleeding including, but not limited to: gum bleeding, nose bleeds, blood in their 
urine, blood in their stool, or coughing up blood. Occasionally, this bleeding can be serious 
and potentially life threatening. If you experience any bleeding on this trial, please tell the 
study team immediately. Tell your doctor if you’ve had a life-long problem of frequent or 
excessive bleeding or bruising, or if you take aspirin or prescription medication to thin your 
blood. 
Less common side effects: 
x Inflammation in the lungs (pneumonitis that can be fatal) 
x Inflammation of the colon (colitis) which can lead to abdominal pain and diarrhea with 
or without blood. If left untreated, this may lead to a tear in the wall of the intestine 
which can be serious and life threatening.  
x Inflammation of the liver called hepatitis, that can cause liver failure and death 
x Inflammation of the thyroid (thyroiditis) 
x Feeling faint, joint and abdominal pain, salt craving, skin darkening like a suntan  
x Weight gain 
x Anxious, angry 
x Can’t sleep 
x Increased sweating 


 
PATIENT IDENTIFICATION 
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x Hair loss 
x Muscle pain, tenderness and/or weakness 
x Inflammation of the heart (myocarditis) (May cause your heart to have difficulty 
pumping blood throughout your body, which can cause chest pain, difficulty breathing, 
swelling in your legs.  You may also experience a fast or irregular heartbeat that can 
cause dizziness or fainting.  Sometimes this condition can lead to death.) 
x  Skin changes (rash, itchiness, redness) 
x Allergic reactions, causing: 
o swelling of the face, lips and throat 
o breathing difficulties which might be serious 
o hives or nettle-like rash 
o change in blood pressure 
The side effects listed above may or may not be caused by problems with your lungs, colon, 
liver, thyroid, adrenal gland, muscles, heart, and skin.  They may be temporary, long term, 
permanent or result in death. However, most of these side effects are reversible. That means they 
will stop once the drug is discontinued.  
Other immune-related events were observed with similar drugs in this class, such as type I 
diabetes mellitus, pituitary dysfunction, inflammation of the kidney, inflammation of the eyes, 
inflammation of the joint, inflammation of the brain, inflammation of the pancreas and 
inflammation of the nervous system. 
Allergic reactions or reactions in the context with the infusions might occur during treatment. 
Infusion related reactions have been observed under treatment with the study drug, as seen for 
other similar drugs. In general, these reactions are mild to moderate and can be handled with 
appropriate drugs, but in rare cases, life-threatening and even fatal reactions might occur, which 
require advanced cardiac life support.  
For the prevention of infusion-related adverse effects and possible allergic reactions you will receive 
a premedication of an antihistamine drug and paracetamol (acetaminophen) before every infusion. 
There is a chance the study drug could lead to Tumor Lysis Syndrome (TLS) due to tumor 
shrinkage.  TLS is when cancer cells break down and the body has to get rid of the broken-up 
cell parts. Sometimes your body can’t remove the cell parts quickly enough and the levels of 
some products in your blood, such as salts and acids, can rise. This can happen especially in 
participants with large tumors or a high number of white cells in the blood. TLS can lead to 
serious problems, such as effects on your kidney and heart (including abnormal heart rhythms) 
or seizures. These side effects can result in needing kidney dialysis (a special machine to remove 
toxins from the blood) or be fatal. Your study doctor knows to watch out for signs of this 
condition and how to treat this condition should it occur. 


 
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Any side effects or other health issues occurring during the study will be followed up by the study 
doctor. 
Other side effects linked to medical procedures during the trial  
Blood samples  
Each time a blood sample is needed, a needle will be put into a vein in your arm (or into your 
central venous catheter, if you have one).  You may feel pain when the needle goes through the 
skin.  Other side effects associated with drawing your blood for blood tests may include infection, 
bruising, redness, discomfort or bleeding at the site of the needle stick, and possible 
lightheadedness and fainting. 
Electrocardiogram (ECG) 
An electrocardiogram or ECG is a test that records the electrical activity of the heart.  It is used to 
measure the rate and regularity of heartbeats as well as the size and position of the heart chambers, 
and the presence of any damage to the heart.  For this test, you will be asked to lie down, and small 
patches that have an adhesive edge with a gel in the middle, called electrodes, will be placed on 
your arms, legs, and chest.  The areas where the electrodes are placed will be cleaned and, if 
needed, some hair may be shaved or clipped to allow for better attachment of the electrodes.  The 
adhesive from the patches may irritate your skin. 
CT scan 
During a CT scan, you're briefly exposed to much more radiation than you would be during a plain 
X-ray. Radiation exposure potentially increases your risk of developing cancer. Although rare, the 
intravenous (IV) contrast material involved in some CT scans causes medical problems or allergic 
reactions in some people. Most reactions are mild and result in hives or itchiness. In rare instances, 
an allergic reaction can be serious and potentially life threatening. Make sure to tell your study 
doctor if you've ever had a prior reaction to contrast material during medical tests.  
Papilloma biopsy under anesthesia 
You are required to have general anesthesia three times for this protocol – before treatment starts, 
two weeks after treatment has started, and after completing treatment. Although rare, serious risks 
associated with general anesthesia include an adverse drug reaction, stroke, heart attack or death. 
You will be asked to sign a separate consent prior to each procedure involving anesthesia. Aside 
from the risk of anesthesia, this procedure carries a risk of post-operative tongue or throat 
discomfort that may last for several days and a very small risk of a chipped tooth from the 
instruments in your mouth. We use special tooth guards to prevent this from happening.  
Flexible nasopharyngolaryngoscopy 
Complications are very uncommon; but may include tearing, gagging, coughing, and, less 
frequently, nose bleeding due to the scope being passed through the nose. 
Apheresis 
The most common side effects from this procedure are pain and bruising at the catheter site.  You 
may also experience tingling of the lips and fingers due to the medicine used to keep blood from 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
Page 11 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
clotting.  You may feel faint or light-headed during or after the procedure.  Rarely this procedure 
may cause bleeding or infection at the catheter site. 
Other 
It is possible that other side-effects could occur which are not described in this consent form.  It is 
also possible that you could have a side effect that has not occurred before. 
POTENTIAL BENEFITS OF PARTICIPATION 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental treatment will cause your papilloma to shrink.   
We do not know if you will receive personal, medical benefit from taking part in this study.  These 
potential benefits could include shrinking of your papilloma or lessening of your papilloma-
associated symptoms.  Because there is not much information about the drug’s effect on your 
disease, we do not know if you will benefit from taking part in this study, although the knowledge 
gained from this study may help others in the future who have papilloma and other types of growths 
caused by viruses or cancers.   
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY?  
Instead of being in this study, you have these options: 
x Getting treatment or care for your papilloma without being in a study 
x Taking part in another study 
Please talk to your doctor about these and other options. 
STOPPING THERAPY  
Your doctor may decide to stop your therapy for the following reasons: 
x if he/she believes that it is in your best interest 
x if your papilloma progresses  
x if you need to use medication that is not allowed on the study 
x if you have side effects from the treatment that your doctor thinks are too severe 
x if new information shows that another treatment would be better for you 
x if the sponsor, the FDA, the Institutional Review Board or your doctor decides to stop or 
interrupt the study 
x If you become pregnant 
x If you cannot or do not come to your clinic visits or do not follow the study procedures 
In this case, you will be informed of the reason therapy is being stopped. 
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. 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
Page 12 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
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 or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed. 
CONFLICT OF INTEREST 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide.   You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.  
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using a drug, developed 
by EMD Serono through a joint study with your researchers and the company. The company also 
provides financial support for this study. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH 
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect, use them for future research and 
share them with other researchers. We will not contact you to ask about each of these future uses.  
These specimens and data will be stripped of identifiers such as name, address or account number, 
so that they may be used for future research on any topic and shared broadly for research purposes.  
Your specimens and data will be used for research purposes only and will not benefit you. It is 
also possible that the stored specimens and data may never be used.  Results of research done on 
your specimens and data will not be available to you or your doctor.  It might help people who 
have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
Page 13 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
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. 
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.  
x If some tests and procedures performed outside the NIH Clinical Center, you 
may have to pay for these costs if they are not covered by your insurance 
company. 
x Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center. 
x Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center. 
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   
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 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include: 
x The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people. 
x National Institutes of Health Intramural Institutional Review Board 
x The study Sponsor (Center for Clinical Research) or their agent(s) 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
Page 14 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
x Qualified representatives from EMD Serono, the pharmaceutical company who produces 
M7824. 
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act.  
Certificate of Confidentiality 
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.   
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.   
The Certificate does not protect your information when it:   
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or  
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA);  
3. is for other research; 
4. is disclosed with your consent.  
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research.  
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent. 
Privacy Act 
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
Page 15 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting,  to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act. 
POLICY REGARDING RESEARCH-RELATED INJURIES   
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action. 
PROBLEMS OR QUESTIONS 
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Christian 
Hinrichs, MD, hinrichs@nih.gov, 240-764-6059. Other researchers you may call are: Erin 
Ferraro, RN, at 240-760-6163 or Scott Norberg, DO, at 240-858-3303. You may also call the NIH 
Clinical Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 
301-402-3713, if you have a research-related complaint or concern. 
CONSENT DOCUMENT  
Please keep a copy of this document in case you want to read it again. 
 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (2) 
Version Date: 7/24/2019 
Protocol Number: 19-C-0002 
Page 16 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study. 
 
 
 
 
 
Signature of Research Participant 
 
Print Name of Research Participant 
 
Date 
 
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study. 
 
 
 
 
 
Signature of LAR 
 
Print Name of LAR 
 
Date 
 
Investigator: 
 
 
 
 
 
Signature of Investigator 
 
Print Name of Investigator 
 
Date 
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation. 
 
Witness: 
 
 
 
 
 
Signature of Witness* 
 
Print Name of Witness 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER: 
 
 
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated 
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness. 
 
 
 
 
 
 
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated 
the administration of informed consent but did not serve as a witness. The name or ID code of the person  
providing interpretive support is: 
 
. 
 

Prot_SAP_002.pdf: 
Abbreviated Title: M7824 in RRP 
Version Date: 12/1/2020 
 
1 
 
Abbreviated Title: M7824 for RRP  
NIH Protocol #: 19C0002 
NCT #: NCT03707587 
Version Date: 12/1/2020 
 
Title: A Phase II Study of M7824 in Subjects with Recurrent Respiratory Papillomatosis 
 
NCI Principal Investigator:       Scott Norberg, DO 
 
Genitourinary Malignancies Branch (GMB)  
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
10 Center Drive, Room 6B09 
Bethesda, MD 20892 
Phone: 301-275-9668 
Email: scott.norberg@nih.gov 
 
 
Investigational Agent:     
Drug Name: 
M7824 
IND Number: 
138835 
Sponsor: 
Center for Cancer Research  
Manufacturer: 
EMD Serono 
 
Commercial Agents:  None 
 
 


Abbreviated Title: M7824 in RRP 
Version Date: 12/1/2020 
 
2 
 
PRÉCIS  
Background 
• Recurrent respiratory papillomatosis (RRP) is a rare papillomatous disease of the 
aerodigestive tract that is caused by the Human Papilloma Virus (HPV). 
• RRP can progress to cause airway compromise, fatal pulmonary lesions, and invasive 
cancers. 
• There is no effective systemic therapy for RRP. Patients typically require repeated 
interventional procedures for disease control. 
• A recently completed phase II clinical trial investigating avelumab in subjects with 
aggressive RRP demonstrated an acceptable safety profile from avelumab and a high rate of 
partial responses. 
• RRP is characterized by frequent expression of PD-L1 and TGF-beta in the tumor 
microenvironment. 
• This clinical trial will evaluate the activity of M7824, a novel bifunctional fusion protein 
composed of a fully human IgG1 monoclonal antibody against human PD-L1 (avelumab) 
fused, via a flexible glycine-serine linker, to the soluble extracellular domain of human TGF-
β receptor II (TGF-βRII), which functions as a TGF-β “trap.” This drug was selected for its 
demonstrated activity in a variety of cancers and for its acceptable safety profile. 
Objective 
• Determine the complete response rate for M7824 in the treatment of patients with RRP. 
Eligibility 
• Histologically confirmed diagnosis of RRP. 
• One of the following: 
o A Derkay anatomic score of 10 or greater and a history of two or more endoscopic 
interventions in the last 12 months for control of RRP. 
o Pulmonary RRP with pulmonary disease that is measurable by computed tomography 
scan. 
o Tracheal involvement with RRP that has required either two or more endoscopic 
interventions in the last 12 months or a tracheostomy. 
• Age 18 years or greater. 
• Eastern Oncology Cooperative Group Performance Score of 0 or 1. 
Design 
• This is a phase II clinical trial with two cohorts that will enroll simultaneously. 
• Cohort 1 will consist of subjects who have not been treated previously with an immune 
checkpoint inhibitor. Cohort 2 will consist of subjects whose disease has been treated 
previously with and refractory to an immune checkpoint inhibitor. Each cohort will have a 
Simon optimal two-stage design with initial enrollment of 12 patients and expansion to 21 


Abbreviated Title: M7824 in RRP 
Version Date: 12/1/2020 
 
3 
 
patients if one or more complete response(s) is/are observed in the initial patients. With 
amendment D, dated 7/24/2019, cohort 2 will be closed to further enrollment.  


Abbreviated Title: M7824 in RRP 
Version Date: 12/1/2020 
 
4 
 
TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
STATEMENT OF COMPLIANCE ................................................................................................ 7 
1 
INTRODUCTION .................................................................................................................. 7 
1.1 
Study Objectives .............................................................................................................. 7 
1.2 
Background and Rationale ............................................................................................... 7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 13 
2.1 
Eligibility Criteria .......................................................................................................... 13 
2.2 
Screening Evaluation...................................................................................................... 15 
2.3 
Baseline Evaluation ........................................................................................................ 16 
2.4 
Participant Registration and Status Update Procedures ................................................. 16 
3 
STUDY IMPLEMENTATION ............................................................................................ 17 
3.1 
Study Design .................................................................................................................. 17 
3.2 
Drug Administration ...................................................................................................... 20 
3.3 
On-study assessments ..................................................................................................... 21 
3.4 
Dose Modifications/Delay.............................................................................................. 21 
3.5 
Study Calendar ............................................................................................................... 24 
3.6 
Cost and Compensation .................................................................................................. 28 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 28 
3.8 
Stopping Rule ................................................................................................................. 29 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 29 
4.1 
Supportive care ............................................................................................................... 29 
4.2 
Prohibited therapies ........................................................................................................ 29 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 30 
5.1 
Correlative Studies For Research ................................................................................... 31 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 35 
6.1 
Data Collection ............................................................................................................... 35 
6.2 
Data Sharing Plans ......................................................................................................... 36 
6.3 
Response Criteria ........................................................................................................... 37 
6.4 
Toxicity Criteria ............................................................................................................. 39 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .... 39 


Abbreviated Title: M7824 in RRP 
Version Date: 12/1/2020 
 
5 
 
7.1 
Definitions ...................................................................................................................... 39 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 39 
7.3 
NCI Clinical Director Reporting .................................................................................... 39 
7.4 
NIH Required Data and Safety Monitoring Plan ........................................................... 40 
8 
SPONSOR SAFETY REPORTING ..................................................................................... 40 
8.1 
Definitions ...................................................................................................................... 40 
8.2 
Assessment of Safety Events.......................................................................................... 41 
8.3 
Reporting of Serious Adverse Events ............................................................................ 42 
8.4 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 42 
8.5 
Reporting Pregnancy ...................................................................................................... 42 
8.6 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 43 
9 
CLINICAL MONITORING ................................................................................................. 43 
10 STATISTICAL CONSIDERATIONS.................................................................................. 43 
10.1 
Statistical Hypotheses ................................................................................................. 43 
10.2 
Statistical Analyses ..................................................................................................... 44 
11 COLLABORATIVE AGREEMENT ................................................................................... 45 
11.1 
Cooperative Research and Development Agreement ................................................. 45 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................... 46 
12.1 
Rationale For Subject Selection ................................................................................. 46 
12.2 
Strategies/Procedures for Recruitment ....................................................................... 46 
12.3 
Participation of Children ............................................................................................ 46 
12.4 
Participation of Pregnant Women............................................................................... 46 
12.5 
Evaluation of Benefits and Risks/Discomforts ........................................................... 46 
12.6 
Consent Process and Documentation ......................................................................... 48 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 48 
13.1 
Study Discontinuation and Closure ............................................................................ 48 
13.2 
Quality Assurance and Quality Control ...................................................................... 49 
13.3 
Conflict of Interest Policy........................................................................................... 49 
13.4 
Confidentiality and Privacy ........................................................................................ 49 
14 PHARMACEUTICAL INFORMATION ............................................................................. 50 
14.1 
Description of the Investigational Product (IND: 138835) ........................................ 50 
15 REFERENCES ..................................................................................................................... 53 


Abbreviated Title: M7824 in RRP 
Version Date: 12/1/2020 
 
6 
 
16 APPENDICES ...................................................................................................................... 56 
16.1 
Appendix A: Performance Status Criteria(33) ........................................................... 56 
16.2 
Appendix B: Voice Handicap Index-10 (34, 35) ........................................................ 57 
16.3 
Appendix C: Management of Immune-Related Adverse Events ............................... 58 
16.4 
Appendix D: Derkay Staging for RRP ....................................................................... 64 
 


Abbreviated Title: M7824 in RRP 
Version Date: 12/1/2020 
 
7 
 
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. 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• To determine the complete response rate for M7824 in the treatment of patients with 
recurrent respiratory papillomatosis (RRP). 
1.1.2 Secondary Objective 
• Determine the partial response rate for M7824. 
• Determine safety of M7824 in patients with RRP. 
1.1.3 Exploratory Objectives 
• Determine the effect of treatment with M7824 on Derkay and Voice Handicap Index-10 
scores. 
• PD-L1 and/or TGF-β expression as a potential biomarker of response.  
• Determine the duration of clinical responses to M7824. 
• HPV type as a potential biomarker of response. 
• Induction of HPV-specific T cell responses. 
• Clearance of HPV infection from normal appearing mucosa.  
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Recurrent respiratory papillomatosis (RRP) 
RRP is a rare but difficult-to-treat and sometimes fatal neoplastic disease of the aerodigestive 
tract. RRP is caused by infection with human papillomavirus (HPV) type 6 or 11, or more rarely 
type 16 (1). Approximately 1,500 new cases of RRP are diagnosed each year in the United States 


Abbreviated Title: M7824 in RRP 
Version Date: 12/1/2020 
 
8 
 
(2). RRP is classified based on age of onset as juvenile or adult. Juvenile-onset disease has an 
incidence of 4/100,000 and tends to have an aggressive clinical course. Adult-onset RRP has an 
incidence of 2-3/100,000 and tends to have a more indolent clinical course. RRP morbidity and 
mortality results from papilloma mass effects on the vocal cords, airways, or lungs. This may 
cause voice changes, stridor, airway occlusion, loss of lung volume, and/or pneumonia (3). 
Repeated procedures are required to debulk and monitor the disease, which exposes patients to 
anesthetic and surgical risk, and emotional distress. It is estimated that the economic cost of RRP 
is $150M in the United States each year (2). Although rare (one to three percent of cases) RRP 
can transform into invasive squamous cell carcinoma (4). Subsequent mortality is based upon the 
clinical stage of the malignancy at the time of diagnosis. 
There is no cure for RRP. The mainstay of treatment is endoscopic debulking with ablation or 
excision of papillomatous lesions. Surgical principles dictate that, to minimize morbidity from 
treatment, papillomatous disease but not normal appearing epithelium is removed. It is thought 
that latent HPV viral particles persist in an inactive state in the clinically-normal mucosa and 
subsequently become reactivated leading to RRP recurrence (5). Patients with juvenile-onset 
RRP require on average 20 surgeries over their lifetime to control their disease (6). Patients with 
adult-onset RRP generally require fewer interventions; nonetheless greater than 50% will require 
5 or more procedures to control symptoms (7). Adjuvant systemic therapies have been tested in 
clinical trials, including systemic interferon-α and local injection of anti-viral and antiangiogenic 
agents (5). Study results have been inconsistent, and no single adjuvant approach has been 
widely adopted or accepted as the standard of care.  
RRP is caused by HPV infection.  HPV infections are common, but most individuals clear the 
virus without manifesting papillomas, dysplasia, or invasive cancers (8).  Why some 
immunocompetent individuals are unable to eliminate the virus and therefore develop 
papillomatosis is not understood.  Local therapies fail to eradicate the disease apparently due to 
chronic persistence of latent virus in normal appearing mucosa. This notion is supported by a 
study demonstrating the presence of HPV DNA in the clinically healthy mucosa of patients with 
RRP (9, 10). Efforts to study systemic immunotherapy for RRP have been limited.  Adjuvant 
IFN-α after papilloma treatment was shown to increase short-term time to recurrence but did not 
demonstrate long-term benefit (11).  
Programmed death ligand 1 (PD-L1) expression on tumor cells has been associated strongly with 
poor prognosis in a variety of human cancers. (12) In recent years, a number of agents targeting 
the programmed death 1 (PD-1)/PD-L1 pathway have received regulatory approval, 
demonstrating impressive durations of response for multiple tumor types, including melanoma, 
non-small cell lung cancer, renal cell cancer, and head and neck cancer (13-17). Notably, 
atezolizumab, durvalumab and avelumab are all anti–PD-L1 antibodies with proven efficacy and 
regulatory approval. Study of a small number of RRP samples by our group has shown PD-L1 
expression by inflammatory mononuclear cells and by papilloma epithelial cells (18). In 
response to this data, we recently completed a phase II study investigating the role of avelumab 
in patients with aggressive RRP. We found that while the majority of patients demonstrated 
partial responses to single agent avelumab (Figure 1), no complete responses were achieved. 
Toxicities were generally mild and comparable to previous safety data with avelumab.  


Abbreviated Title: M7824 in RRP 
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Figure 1: Clinical responses to phase II study of avelumab in patients with aggressive RRP 
 
1.2.2 TGF-β/ TGFβR1 signaling pathway 
In an effort to increase the rate of response to these therapies, clinical trials are evaluating anti–
PD-1/PD-L1 agents in combination with other immunotherapies (19). Importantly, combined 
inhibition of PD-L1 and TGF-β is a promising therapeutic strategy because these key pathways 
have independent immunosuppressive functions.  
Transforming growth factor β (TGF-β) is a pleiotropic cytokine. In patients with cancer, TGF-β 
is associated with malignant progression, evasion of immune surveillance, invasion, and 
metastasis (20, 21). TGF-β Receptor 1 (TGFβR1) pathway signalling and overexpression have 
also been found to be significantly associated with HPV+ cancers (22). Based on two genome 
wide association studies (GWAS) which compared patients with upper aero-digestive (n= 2091) 
and cervical cancers (n=617) to cancer free patients (8,334 and 512 respectively), an integrative 
computational analysis (including single-gene, gene-interconnectivity, protein–protein 
interaction, gene expression, and pathway analysis) looked to identify immune genes and 
pathways significantly associated with HPV+ cervical and oropharyngeal cancer. They found 
that TGFβR1 expression and downstream signalling was significantly increased in HPV+ 
cervical cancer and head and neck cancers (22). Similarly, TGF-β has been shown to be 
significantly expressed in the microenvironment of RRP specimens (23). 
 
The direct effects of TGF-β on T cells include decreases in perforin, granzymes, interferon 
gamma, Fas ligand, and natural killer group 2D (NKG2D). It can also decrease NKG2D and 
major histocompatibility complex (MHC) class I polypeptide sequence A (MICA) in natural 
killer (NK) cells (24). Elevated levels of TGF-β have been found to correlate with poor outcomes 
in many different human cancers (25). Antibodies (e.g., fresolimumab) and small-molecule 
inhibitors (e.g., galunisertib) targeting the TGF-β pathway have entered clinical development, 
where they have shown promise in hepatocellular carcinoma, pancreatic cancer, and melanoma 
(26). 


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1.2.3 M7824 
M7824 is a novel bifunctional fusion protein composed of a fully human IgG1 monoclonal 
antibody against human PD-L1 fused, via a flexible glycine-serine linker, to the soluble 
extracellular domain of human TGF-β receptor II (TGF-βRII), which functions as a TGF-β 
“trap.” The anti-D-L1 moiety of M7824 is based on avelumab (MSB0010718C), which is 
currently in Phase III clinical trials in multiple tumor types and was recently FDA approved for 
metastatic Merkel cell Carcinoma and urothelial carcinoma (27, 28). Preclinical studies have 
shown its ability to simultaneously bind PD-L1 and TGF-β, as well as appropriately block PD-
L1 signaling and TGF-β signaling in vitro. M7824 was shown to have better antitumor efficacy 
than anti-PD-L1 or TGF-β trap control (a mutated antibody that doesn't bind to PD-L1, linked 
with the TGF-β trap) in both MC38 and EMT-6 tumor models in both wild-type mice and B cell 
deficient mice. Because M7824 is very immunogenic in mice, due to the fully human antibody 
and its immunostimulatory mechanism of action, host anti-drug antibodies preclude continued 
dosing. In an orthotopic EMT-6 breast cancer model using B cell-deficient Jh mice M7824 
showed much better activity than either anti-PD-L1 antibody alone or TGF-β trap control 
(Figure 2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2: Preclinical studies using B cell-deficient Jh mice with subcutaneous EMT-6 breast cancer 
tumors showing significantly reduced tumor volume with M7824 (anti-PD-L1/TGFβ) compared with 
either anti-PDL1 antibody or TGF-β trap alone.  
At tumor re-challenge, 13/13 mice previously cured with M7824 treatment had complete 
protection. Furthermore, M7824 therapy extended survival in a dose dependent manner. Similar 
results were also observed in the MC38 colorectal carcinoma model. Furthermore, depletion 
studies in MC38 model demonstrated that both CD8+ cytotoxic T cells and NK cells are required 
for tumor rejection (Figure 3). 


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Figure 3:  Antibody-based, selective depletion of immune effector cell subsets showed that both CD8+ 
cytotoxic T cells and NK cells are required for tumor rejection with M7824 (Anti-PD-L1/TGFβ Trap) in 
MC38 model. 
 
In in vivo studies, not only did M7824 decrease TGF-β in the serum and bind PDL1 within the 
tumor, it also substantially increased CD8+ T-cell and NK cell infiltration within the tumor, 
while decreasing myeloid-derived suppressor cell (MDSC) infiltration, compared with an anti–
PD-L1 antibody control. 
Based on these preclinical data, a Phase I 3+3 dose-escalation study was completed to evaluate 
the pharmacokinetics (PK), safety, tolerability, and biological and clinical activity of M7824 in 
patients with advanced solid tumors (NCT02517398).  
Sixteen heavily pretreated patients received M7824 at 1, 3, 10, or 20 mg/kg once-every-2-weeks. 
M7824 was shown to saturate peripheral PD-L1 at doses ≥ 3 mg/kg and sequester plasma TGF-
β1, -β2, and -β3 (Figure 4) throughout the dosing period at ≥1 mg/kg. The only DLT observed 
was colitis with associated anemia (20 mg/kg). No MTD was reached. Grade 3 treatment-related 
adverse events occurred in 3 patients (skin infection secondary to localized bullous pemphigoid 
(3 mg/kg), asymptomatic lipase increase (20 mg/kg), and colitis (20 mg/kg) with associated 
anemia). These toxicities are on par with other PD-1/PD-L1 inhibitors. The only added toxicity 
seen over traditional PD-1/PD-L1 inhibitors was the occurrence of keratoacanthomas which have 
been described previously with TGFβ inhibitors (29).  Keratoacanthomas appear in 
approximately 10% of treated patients, but usually resolve with discontinuation of therapy. There 
were no treatment-related grade 4–5 events. Based upon this safety data the decision was made 
to treat subsequent patient cohorts with a dose of 1,200 mg IV once every 2 weeks. This dose has 
been used in several phase Ib expansion cohorts treating more than 500 patients. This dose has 
been recommended for all phase II trials using M7824. 


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Figure 4: Total TGF-β1, -β2, and -β3 plasma concentrations following intravenous 
administration of M7824. 
In addition, in the ongoing Phase I study of M7824 (NCT02517398), substantial clinical 
evidence has been seen in 4 of 9 subjects (44%) with HPV-associated malignancies, including 2 
of 5 patients (40%) with metastatic cervical cancer, 1 of 2 patients (50%) with metastatic anal 
cancer and 1 of 2 patients (50%) with metastatic P16+ head and neck cancer have had substantial 
clinical benefit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 5: This 56-year-old woman with initially locally advanced cervical cancer status post 
(s/p) cisplatin/RT developed metastases to lung within 3 months of initial treatment. Then went 
on to receive topotecan/taxol plus bevacizumab and was enrolled on phase I of M7824 with 
enlarging right-sided lung masses (arrows in left side of figure). She received 2 doses of M7824 
at 20 mg/kg but then developed colitis necessitating drug discontinuation. Despite this her 
restaging scan at 12 weeks showed marked reduction in disease volume (right side of figure).  
This includes a subject with metastatic cervical cancer with a 25% reduction (by long axis 
measurement) in her disease at 3 months (Figure 5), a subject with metastatic P16+ head and 
neck cancer with an unconfirmed partial response 6 weeks after starting treatment, a patient with 
metastatic anal cancer with normalization of tumor markers and an ongoing durable partial 
response 9 months after starting treatment and a patient with metastatic cervical cancer with 
normalization of tumor markers and an ongoing durable complete response for more than a year.     
This early data from a small cohort of subjects with HPV-associated malignancies in this phase 1 
trial of M7824 suggests that this agent, which targets both PD-L1 and TGF-β pathways, may 
produce responses at a higher rate as compared with other single agent PD-1/PD-L1 inhibitors. 
Here, we aim to assess the clinical response rate following treatment with M7824 in subjects 
with aggressive RRP. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 RRP criteria 
• Histological diagnosis of RRP confirmed by pathology report from a CLIA-certified 
laboratory. 
• One of the following: 
o A Derkay anatomic score of 10 or greater (See Section 13.4) and a history of two or 
more endoscopic interventions in the last 12 months for control of RRP. 
o Pulmonary RRP with pulmonary disease that is measurable by computed tomography 
scan and evaluated by RECIST Criteria. 
o Tracheal involvement with RRP that has required either two or more endoscopic 
interventions in the last 12 months or a tracheostomy. 
2.1.1.2 Greater than or equal to 18 years of age. 
2.1.1.3 Able to understand and sign the Informed Consent Document. 
2.1.1.4 Clinical performance status of ECOG 0 or1.  See section 13.1 
2.1.1.5 Willing to undergo endoscopic evaluation with biopsies in compliance with this 
protocol. 
2.1.1.6 No systemic therapy for RRP for at least 3 half-lives of the prior drug(s).   
2.1.1.7 Screening laboratory values must meet the following criteria and should be obtained 
within 14 days prior to first dose: 
o WBC > 2000/μL 


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o Neutrophils > 1000/μL 
o Platelets > 75 x103/μL 
o Hemoglobin > 9.0 g/dL 
o Serum Creatinine < 1.5 x ULN OR eGFR > 30 mL/min (measured or calculated 
using the MDRD equation). 
o AST/ALT ≤ 2.5 x ULN 
o Total Bilirubin ≤ 1.5 x ULN  
o PT/INR and PTT ≤ ULN 
2.1.1.8 Sexually active subjects (men and women) of reproductive potential must agree to use 
two methods of contraception: one highly effective and one other effective method 
throughout M7824 treatment and for at least 120 days after M7824 treatment. Highly 
Effective Methods are defined as: Intrauterine device (IUD), hormonal (birth control 
pills, injections, implants), tubal ligation and partner’s vasectomy; Other Effective 
Methods are defined as: latex condom, diaphragm and cervical cap. 
2.1.1.9 Seronegative for HIV antibody.  The experimental treatment being evaluated in this 
protocol depends on an intact immune system.  Patients who are HIV seropositive can 
have decreased immune function and thus are likely less responsive to the experimental 
treatment. 
2.1.1.10 Seronegative for hepatitis B antigen, positive hepatitis B tests can be further evaluated 
by confirmatory tests (Hep B DNA Quant, HBV Viral Load), and if confirmatory tests 
are negative, the patient can be enrolled. 
2.1.1.11 Seronegative for hepatitis C antibody unless antigen negative.  If hepatitis C antibody 
test is positive, then patients must be tested for the presence of antigen by  Hep C RNA 
Quant, HCV Viral Load and be HCV RNA negative. 
2.1.2 Exclusion criteria  
2.1.2.1 Any severe acute or chronic medical or psychiatric conditions including recent (within 
the past year) or active suicidal ideation or behavior, liver disease, lung disease (with 
the exception of what is specified in inclusion criteria in section 2.1.1.1) , or laboratory 
abnormalities that, in the opinion of the investigators, may increase the risk associated 
with study participation or study drug administration, impair the ability of the subject to 
receive protocol therapy, or interfere with the interpretation of study results and in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.  Patients with mild to moderate asthma or chronic obstructive pulmonary disease 
(COPD) well controlled with oral or inhaled medications are permitted to enroll. 
2.1.2.2 Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement, or psoriasis not requiring systemic treatment, are permitted to enroll. 
2.1.2.3 Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 
days of study drug administration.  Inhaled, topical intranasal or intro-ocular steroids, 


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15 
 
and adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease. 
2.1.2.4 Prior organ transplantation, including allogeneic stem cell transplantation.  
2.1.2.5 Patients who are receiving any other investigational agents 
2.1.2.6 Pregnant or breast feeding. Women of childbearing potential must have a negative 
pregnancy test at screening.  Women of childbearing potential include women who have 
experienced menarche and who have not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not 
postmenopausal.  Post-menopause is defined as amenorrhea ≥12 consecutive months.  
Note: women who have been amenorrheic for 12 or more months are still considered to 
be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, 
anti-estrogens, ovarian suppression or any other reversible reason. 
2.1.2.7 History of allergy to study drug components. 
2.1.2.8 History of severe hypersensitivity reaction to any monoclonal antibody (Grade ≥ 3 
NCI-CTCAE v 5.0), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or 
more features of partially controlled asthma). 
2.1.2.9 Clinically significant (i.e., active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months 
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart 
Association Classification Class II), or serious cardiac arrhythmia requiring medication. 
2.1.2.10 Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 5.0; however, 
alopecia, sensory neuropathy Grade ≤ 2 or other Grade ≤ 2 AEs not constituting a safety 
risk based on investigator's judgment are  acceptable. 
2.1.2.11 Known alcohol or drug abuse. 
2.1.2.12 Vaccination within 4 weeks of the first dose of M7824 and 4 weeks after the last dose 
of M7824 are prohibited. 
2.1.2.13 HPV vaccination within one year of the first dose of M7824   
2.1.2.14 With amendment D, patients that received prior PD-1 based immunotherapy will be 
excluded. 
2.2 
SCREENING EVALUATION 
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion 
criteria at screening before study treatment administration. Screening evaluations may be 
performed as part of an NIH Screening protocol. This does not include the baseline correlative 
studies that will only be performed after the patient has signed the consent form for this protocol. 
2.2.1 Within 14 days prior to subject enrollment, unless otherwise indicated below: 
2.2.1.1 Complete history and physical examination, including ECOG status, weight, vital signs, 
and oxygen saturation by pulse oximetry at rest and after exertion. 
2.2.1.2 Confirmation of the diagnosis of RRP by pathology report from a CLIA-certified 
laboratory (no time limit).  


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2.2.1.3 Clinic-based flexible nasopharyngolaryngoscopy and/or tracheoscopy to document 
disease to the extent that can be evaluated without sedation or general anesthesia. This 
will include standard bright light endoscopy and may include videostroboscopy. 
Endoscopy may be omitted in patients with disease that is not endoscopically 
accessible. This examination will allow determination of a Derkay score that will 
determine if the patient meets inclusion criteria.  
2.2.1.4 Computed tomography scan of the neck and/or chest if patients have known or 
suspected pulmonary RRP.  This examination could also be used to determine if the 
patient meets inclusion criteria. 
2.2.1.5 Hepatitis and HIV testing as detailed in sections 2.1.1.9 - 2.1.1.11 (within 90 days prior 
to subject enrollment).   
2.2.1.6 PT/INR and PTT  
2.2.1.7 Venous Assessment (per department of transfusion medicine (DTM) guidelines) 
2.2.2 Within 3 days prior to subject receiving the first dose of study drug the following 
assessments will be done:  
• CBC w/differential, chemistry panel including: LDH, AST, ALT, ALP, T.Bili, BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, glucose, amylase, lipase, TSH, free T4, 
free T3  
• Pregnancy test in women of childbearing potential. 
• Review of medications 
2.3 
BASELINE EVALUATION 
After consenting to enrollment in this study, baseline evaluation will include exam under 
anesthesia (sedation or general anesthesia) including rigid and/or flexible endoscopy to 
thoroughly assess airway patency and the extent of disease, rule out invasive cancer, debulk 
lesions that pose a major risk of airway obstruction, and obtain papilloma and normal mucosa 
tissue for research. Baseline imaging studies will be done if clinically indicated. For other 
baseline evaluations please refer to the Study Calendar (Section 3.5). 
2.4 
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 here. 
2.4.1 Treatment Assignment and Randomization/Stratification Procedures for Registration 
Purposes Only 
Cohorts 
Number 
Name 
Description 
1 
Cohort 1 
Patients with RRP who are checkpoint inhibitor naïve. 


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2 
Cohort 2 (closed to accrual) 
Patients with RRP who are refractory to checkpoint inhibition. 
Arms 
Number 
Name 
Description 
1 
Arm 1 
Patients will receive 1200 mg IV of M7824 on day 1 of a 14 day 
cycle, every other week, for up to 12 weeks total treatment (6 
cycles). 
Stratification 
Not applicable to this protocol. 
Randomization 
Patients in Cohorts 1 and 2 will be directly assigned to Arm 1. With amendment D, cohort 2 will 
be closed to further enrollment.  
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
3.1.1 General study plan   
This protocol is a phase II study of M7824. The protocol will enroll subjects with an RRP 
disease burden that requires repeated surgical procedures for management.  Patients with a 
pathologically confirmed diagnosis of RRP will be screened for this protocol.  Patients who 
appear to be eligible for treatment will be examined via flexible nasopharyngolaryngoscopy 
and/or tracheoscopy by the Otolaryngology Service. Patients that meet the eligibility criteria will 
be enrolled onto the study. This study will have two cohorts: (1) patients who are checkpoint 
inhibitor naive, and (2) patients whose RRP disease is refractory to checkpoint inhibition. After 
enrollment, patients will undergo exam under anesthesia (EUA) staging of RRP with biopsies to 
confirm baseline staging, debulk disease that poses an impending airway risk and rule out 
invasive cancer. Patients will complete the Voice Handicap Index-10 at this time. The voice 
handicap index-10 (VHI-10) is a patient-based self-assessment tool that quantifies a patients’ 
perception of their voice handicap. It consists of 10 questions that cover three domains: 
functional, physical and emotional aspects of voice disorders. There is a positive correlation 
between improvement in anatomic Derkay score and mean VHI-10 score (35).  
With amendment D, cohort 2 will be closed to enrollment. Two patients were enrolled and 
treated on this cohort with no response. Due to the lack of perceived clinical benefit seen thus far 
in this patient cohort and in previous clinical trials testing M7824 in patients with metastatic 
HPV-associated cancers that were refractory to checkpoint inhibitors, the checkpoint refractory 
cohort will be closed to further enrollment.  
An optional leukapheresis will be performed prior to the first dose of M7824 (see Section 5.1.1).  
If patients are willing, they will also be enrolled on protocol 16C0061 for banking of 
biospecimens. During EUA, samples for research will be obtained from those patients who enroll 
on protocol 16C0061 for banking of biospecimens.  


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M7824 will be administered at a dose of 1200 mg flat dose IV every 2 weeks (+/- 3 days).  EUA 
and endoscopy will be performed to assess airway, RRP lesion inflammation and to obtain 
research biopsies 2 weeks after the first dose of M7824 (9-17 days after the first dose). An 
optional leukapheresis will also be obtained at this time point. These procedures should occur 
before the second dose of M7824. Disease response will first be assessed six weeks after the first 
dose of M7824 (+/- 10 days), which corresponds to the end of the first course (3 doses) of 
M7824, by clinic-based endoscopic examination, Voice Handicap Index-10 and imaging if 
appropriate.  These procedures should occur before the Course 2 Cycle 1 Day 1 dose of M7824, 
if applicable. If patients have a complete response or no response or Disease progression, 
treatment will be discontinued at that time. If patients have a partial response, treatment will be 
continued for up to 6 additional weeks (12 weeks total treatment) or until disease progression or 
complete response. If subjects demonstrate a partial response and receive an additional 6 weeks 
of treatment their responses will again be measured after completing this additional treatment 
(+/- 10 days). Patients that have a partial response at the end of course 2 can choose to receive 
more courses of therapy (maximum of 2) or conclude therapy. Patients will be assessed after 
each course. At the conclusion of treatment all patients will undergo EUA and endoscopy with 
either standard of care surgical debulking of their disease or biopsies to confirm complete 
regression of papillomatous disease. The primary endpoint of this study is complete response to 
treatment, but patients will be followed long-term after completion of treatment to assess timing 
and frequency of future interventions.   
If a patient’s condition precludes safe performance of any protocol-driven biopsy, apheresis or 
other research procedure, the procedure may be delayed for an additional two weeks or canceled 
at the discretion of the investigator. This will not be considered a protocol deviation.  Endoscopy 
may be omitted in patients with disease that is not endoscopically accessible. 
 


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3.1.2 Protocol Schema 
 
 
 
 
 
 
 
M7824 1200 mg IV x 1 
Screening and baseline evaluations including:  
Clinic-based examinations, EUA, operative endoscopy, biopsy,  optional 
leukapheresis, and imaging 
2 week EUA, operative endoscopy, biopsy, and optional 
leukapheresis H&P, clinic-based endoscopy, and Voice Handicap 
Index-10  
Treatment discontinuation: EUA, operative endoscopy, biopsy (if 
CR) or surgical debulking (if NR) 
M7824 1200 mg IV every other 
week for 3 doses (6 weeks) 
6 week response assessment: H&P, clinic-based endoscopy, Voice 
Handicap Index-10 and imaging 
Continue treatment only for a PR 
12 week post-treatment evaluation, including: EUA, operative 
endoscopy with surgical debulking (if residual disease) or biopsy 
(if CR). Patients with partial response can choose to receive 
more therapy (up to 2 cycles). If so, response assessment will 
not occur until 12 weeks post additional treatment.  
 
Response assessment: H&P, clinic-based endoscopy, Voice 
Handicap Index-10 and imaging 
M7824 1200 mg IV x q 2 weeks x 2 
No response or complete response 
Partial response 
Patient chooses more therapy 
M7824 1200 mg IV every other 
week for 3 doses (6 weeks) 


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3.2 
DRUG ADMINISTRATION 
3.2.1 M7824 
M7824 will be administered via peripheral IV at a dose of 1200 mg IV every other week for up 
to 12 weeks total (6 cycles).  All patients will be pre-treated with an antihistamine and 
acetaminophen approximately 30-60 minutes prior to each dose (for example, 25-50 mg 
diphenhydramine and 500-650 mg acetaminophen). M7824 is to be diluted as described in 
section 11.1.4. It is not to be administered as an IV push or bolus injection.   
M7824 will be infused at 60 mL/hour for 10 minutes; if no infusion reaction observed then rate 
will be increased to 120 mL/hour for 10 minutes; if no infusion reaction observed then rate will 
be increased to 250 mL/hour for the remainder of the infusion. If infusion reactions are observed, 
the infusion rate may be decreased to the previous rate at which it was tolerated. At the end of 
the infusion, flush the line with a sufficient quantity of normal saline.  See Section 3.4.4 for 
infusion reaction guidance. 
M7824 will be infused in the NIH Clinical Center Day Hospital or on an inpatient oncology 
ward. Vital signs (blood pressure, pulse, respiration, temperature) will be assessed before 
infusion, at each rate change, at completion of infusion, and every 1 hour (+/- 15 minutes) or 
more frequently as clinically indicated for 2 hours after completion of the infusion or until stable.   
Medications readily available for the emergency management of anaphylactoid reactions should 
include: epinephrine (1:1000, 1 mg/mL) for subcutaneous injection, diphenhydramine 
hydrochloride for intravenous injection, and resuscitation equipment. 
3.2.1.1 Overall summary of the treatment plan 
18 week response assessment: H&P, clinic-based 
endoscopy, Voice Handicap Index-10 and imaging 
Continue treatment only for a PR 
M7824 1200 mg IV every other 
week for 3 doses (6 weeks) 
Progressive disease or complete 
response 
Continued partial response 
Treatment discontinuation: EUA, operative endoscopy, biopsy (if 
CR) or surgical debulking (if NR) 
24 week post treatment evaluation including EUA, 
operative endoscopy with surgical debulking (if 
residual disease) or biopsy (if CR).   
 
Response assessment: H&P, clinic-based 
endoscopy, Voice Handicap Index-10 and imaging 


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Drug 
Dose  
Days 
M7824 
1200 mg IV  
Day 1 of a 14 day cycle (every 
other week) for up to 12 weeks 
total treatment (6 cycles) 
Response will be assessed by flexible endoscopy with or without imaging studies before 
treatment and 6 and 12 weeks after starting treatment. Patients with a partial response at 12 
weeks can choose to receive more therapy (maximum of 2 courses). See protocol schema for 
details on response assessments (section 3.1.2)  
3.3 
ON-STUDY ASSESSMENTS 
See the section 3.5, Study calendar for details. 
3.4 
DOSE MODIFICATIONS/DELAY 
Dose modifications are not permitted.  
3.4.1 Doses will be delayed for the following: 
• Any Grade 2 or greater drug-related adverse event with the following exceptions: 
o Grade 2 skin rash or fatigue 
o Grade 2 infusion reaction in which the full dose of the drug is safely infused, 
per instructions in section 3.4.4 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication   
• Algorithms for management of toxicities are provided in Section 13.3 
3.4.2 Resuming treatment 
Subjects may resume treatment with M7824 under any of the following circumstances: 
• Any grade 2 event that resolves to grade 1 or less within 14 days without systemic 
steroid treatment 
• Grade 3/4 rash that improves to Grade 1/2 with treatment 
• Grade 2/3/4 endocrinopathy that responds to treatment/replacement therapy  
3.4.3 Discontinuing treatment 
Treatment should be permanently discontinued for the following: 
• Any Grade 3 or 4 drug-related adverse event with the exception of criteria listed in 
3.4.2 
3.4.4 M7824 infusion reactions 
Since M7824 contains only human immunoglobulin protein sequences it is unlikely to be 
immunogenic and induce an infusion or hypersensitivity reaction. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypo- or hypertension, bronchospasm, or other symptoms.  Infusion reactions should be graded 
according to NCI CTCAE (version 5.0) guidelines. 


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NCI-CTCAE Grade  
Treatment Modification for Study Drug 
Grade 1 – mild  
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Remain at bedside and monitor subject until recovery from 
symptoms. 
Decrease the study drug infusion rate by 50% and monitor 
closely for any worsening.  Complete the remainder of the 
infusion at the reduced rate (50% of initial infusion rate). 
The total infusion time for study drug should not exceed 4 
hours. 
Grade 2 – moderate 
Therapy or infusion interruption indicated 
but responds promptly to symptomatic 
treatment (for example, antihistamines, 
NSAIDs, narcotics, corticosteroids, 
bronchodilators, IV fluids); prophylactic 
medications indicated for ≤ 24 hours. 
Stop study drug infusion.  Once infusion-related reaction 
has resolved or decreased to Grade 1 in severity, resume 
infusion at 25% of previous rate for 15 minutes, then 
increase to 50% of previous rate, and monitor closely for 
any worsening. 
The total infusion time for study drug should not exceed 4 
hours. 
Grade 3 or Grade 4 – severe or 
life-threatening; urgent intervention 
indicated. Grade 3: Prolonged (for example, 
not rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae  [e.g., 
renal impairment, pulmonary infiltrates]). 
Grade 4: (life-threatening; pressor or 
ventilator support indicated). 
 
 
Immediately discontinue infusion of study drug. Begin an 
IV infusion of normal saline, and treat the subject as 
follows. Recommend bronchodilators, epinephrine 0.2 to 1 
mg of a 1:1,000 solution for subcutaneous administration or 
0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. 
Subject should be monitored until the investigator is 
comfortable that the symptoms will not recur. Study drug 
will be permanently discontinued. In the case of late-
occurring hypersensitivity symptoms (e.g., appearance of a 
localized or generalized pruritus within 1 week after 
treatment), symptomatic treatment may be given (e.g., oral 
antihistamine, or corticosteroids). Subjects must be 
withdrawn immediately from study drug treatment and 
must not receive any further study drug treatment. 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
Once the M7824 infusion rate has been decreased by 50% or interrupted due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions.  If a subject 
experiences a Grade 3 or 4 infusion-related reaction at any time, the subject must discontinue 
study drug. 
3.4.5 Keratoacanthomas 
Keratoacanthomas are expected to form in a subset of patients on this protocol. They will not be 
considered stopping criteria. Patients will be asked at every NIH visit whether they have 
developed any skin lesions. If they have, the patient will be referred to Dermatology for 


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23 
 
characterization and clinical recommendations. The need for intervention should be assessed on 
a case-by-case basis with input from the primary team, the patient, and the Dermatology consult 
service.   
3.4.6 Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. Subjects should be instructed to report any delayed reactions to the Investigator 
immediately. 
For prophylaxis of flu-like symptoms, 25 mg of indomethacin or comparable nonsteroidal 
anti-inflammatory drug (NSAID) dose (for example, ibuprofen 600 mg, naproxen sodium 
500 mg) may be administered 2 hours before and 8 hours after the start of each dose of M7824 
IV infusion.  Alternative treatments for fever (for example, paracetamol) may be given to 
subjects at the discretion of the Investigator. 
3.4.7 Tumor Lysis Syndrome 
In addition, since M7824 can induce antibody-dependent cell-mediated cytotoxicity, there is a 
potential risk of tumor lysis syndrome.  Should this occur, subjects should be treated per the local 
guidelines.


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24 
 
3.5 
STUDY CALENDAR   
Procedures 
 
 
Screening 
Baseline 
Course 1 
Course 2 
(if indicated) 
Courses 3-4 
(if indicated) 
End of Treatment a 
Follow-up q,r 
Cycle 1 
Day 1 
Cycle 2 
Day 1 
Cycle 3 
Day 1 
End of 
Course m 
Cycle 1 
Day 1o 
Cycle 2 
Day 1o 
Cycle 3 
Day 1o 
End of 
Course m 
Cycle 1 
Day 1o 
Cycle 2 
Day 1o 
Cycle 3 
Day 1o 
End of 
Course m 
History and PEb 
Xf 
Xc,e 
Xc,e 
Xc 
Xc 
X 
X 
X 
X 
X 
X, 
X 
X 
X 
X 
X 
Weight  
Xf 
Xc,e 
Xc,e 
Xc 
Xc 
 
X 
X 
X 
X 
X, 
X 
X 
 
 
 
Vital signs, O2 
Saturation at rest and 
after exertion 
X 
X 
Xt 
Xt 
Xt 
X 
Xt 
Xt 
Xt 
X 
Xt 
Xt 
Xt 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance 
Score 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NIH Advance 
Directives Forms 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential  Xc,e 
Xc,e 
Xc,e 
Xc 
Xc 
X 
X 
X 
X 
X 
X, 
X 
X 
X 
X 
X 
PT/INR and PTT 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry panel 
including: LDH, 
AST, ALT, ALP, 
T.Bili, BUN or 
serum urea level, 
creatinine, Ca, Mg, 
Na, K, Cl, glucose, 
amylase, lipase, 
TSH, free T4, free T3 
Xc,e 
Xc,e 
Xc,e 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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25 
 
Procedures 
 
 
Screening 
Baseline 
Course 1 
Course 2 
(if indicated) 
Courses 3-4 
(if indicated) 
End of Treatment a 
Follow-up q,r 
Cycle 1 
Day 1 
Cycle 2 
Day 1 
Cycle 3 
Day 1 
End of 
Course m 
Cycle 1 
Day 1o 
Cycle 2 
Day 1o 
Cycle 3 
Day 1o 
End of 
Course m 
Cycle 1 
Day 1o 
Cycle 2 
Day 1o 
Cycle 3 
Day 1o 
End of 
Course m 
Antibody screen for 
Hepatitis B and C; 
HIV,  
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Venous assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
Xc,e 
Xc,e 
Xc,e 
Xc 
Xc 
X 
X 
X 
X 
X 
X, 
X 
X 
X 
X 
 
TBNK 
 
X,h 
Xh 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HLA Haplotype 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging 
Xu,f 
Xf 
 
 
 
Xn 
 
 
 
Xn 
 
 
 
Xn 
 
 
ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic-based Flexible 
nasopharyngolaryngo
scopy and/or 
tracheoscopy with 
Derkay score 
Xf 
 
Xc,e 
Xi 
Xj 
Xk 
X 
Xi 
Xj 
X,k 
X 
Xi 
Xj 
Xk 
X 
X 
Voice Handicap 
Index-10 
 
 
Xc 
Xi 
Xj 
Xk 
X 
Xi 
Xj 
Xk 
X 
Xi 
Xj 
Xk 
X 
X 
Exam under 
anesthesia with 
possible debulking 
and biopsies x 
 
 
Xh 
Xi 
 
 Xl 
 
 
 
Xl 
 
 
 
Xl 
 
 
Research Bloodv 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsw 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
Concomitant 
Medications  
 
X 
Xc 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Optional 
Leukapheresis 
 
 
Xh 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedures 
 
 
Screening 
Baseline 
Course 1 
Course 2 
(if indicated) 
Courses 3-4 
(if indicated) 
End of Treatment a 
Follow-up q,r 
Cycle 1 
Day 1 
Cycle 2 
Day 1 
Cycle 3 
Day 1 
End of 
Course m 
Cycle 1 
Day 1o 
Cycle 2 
Day 1o 
Cycle 3 
Day 1o 
End of 
Course m 
Cycle 1 
Day 1o 
Cycle 2 
Day 1o 
Cycle 3 
Day 1o 
End of 
Course m 
M7824 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
a End of Treatment studies will be performed 42 days (+/- 10 days) after the final M7824 treatment.  
b Complete H&P at baseline, directed H&P if clinically indicated before each dose (may include clinic-based flexible nasopharyngolaryngoscopy 
and/or tracheoscopy), directed H&P at response assessment. 
c These tests/procedures/assessments must be performed within 3 days before each dose of M7824 while on treatment. 
d Adverse events will be followed until return to baseline or stabilization of event. 
e If the screening and baseline tests were performed prior to 3 days before the first dose of M7824, they will need to be repeated before the start of 
treatment. Refer to section 2.2 for screening evaluation timing requirements. 
f Within 14 days prior to subject enrollment 
g Within 28 days prior to subject enrollment 
h Within 7 days prior to first dose of M7824 
i 9-17 days after first dose of M7824 (before second dose of M7824) 
j 9-17 days after second dose of M7824 (before third dose of M7824) 
k 9-17 days after third dose of M7824 (before the first dose of the next cycle, if applicable) 
l 9-17 days after last dose of M7824 (if patient does not respond to therapy or has completed all protocol permitted therapy) 
m +/- 10 days 
n If imaging is used for response assessment  
o Tests/procedures/assessments performed for End of Course 1 time point that were completed within 7 days prior to Course 2 Cycle 1 Day1 dose 
of M7824 do not need to be repeated. Tests/procedures/assessments will be performed within 7 days prior to the next cycle for all subsequent 
doses. This also applies to Courses 3 and 4 if patient receives these courses.  
p within 90 days prior to subject enrollment 


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q Patients who experience a complete response or partial response will be evaluated every 6 weeks (following the last dose of study drug) x 3, then 
every 12 weeks x 3, then every 26 weeks x 2  (+/- 10 days for each time point during the first two years) or until disease progression.  After 
completing the first 2 years’ worth of follow up clinic visits, patients will be contacted annually (+/- one month) for 3 years (a total of 5 years 
follow up) via phone or email for patient status, dates of disease recurrence and interventions to treat recurrent disease.  The first follow-up visit 
(end of treatment), which occurs 42 days (+/- 10 days) after last study treatment, will satisfy safety visit requirements as noted in section 3.6. If 
unwilling or unable to travel to the NIH Clinical Center for follow-up visits, patients will be contacted by telephone regarding their status, and may 
be asked to send labs and physical exam reports to fulfill visit requirements. 
r Patients who do not experience a response to treatment will be contacted annually (+/- one month) for 2 years following the last dose of study 
drug to document additional disease recurrence and treatments that they have received. For the safety follow-up visit which should occur 
approximately 42 days (+/- 10 days) after last study treatment (as noted in section 3.6), if unwilling or unable to travel to the NIH Clinical Center, 
patients will be contacted by telephone regarding their status, and may be asked to send labs and physical exam reports to fulfill end of treatment 
safety follow-up visit requirements.  Annual follow-up contact may occur via telephone or email. 
s As indicated in section 10.4, all subjects will be offered the opportunity to complete an NIH advance directives 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. 
t As noted in Section 3.2.1. 
u Computed tomography scan of the neck and/or chest only if patients have known or suspected pulmonary RRP.  See Section 2.2.1.4.  
v See section 5.1 for information on specimen collection timepoints. 
w Adverse events will be assessed prior to each dose of M7824 and every week by telephone between on-site assessments (Telephone 
communication with patient to assess for any symptoms suggestive of an adverse event; this will be performed by physician or research nurse.  
Symptoms of myocarditis (chest pain, shortness of breath, swelling of ankles or feet, bleeding) will be assessed). 
x EUA with possible debulking may be performed at any time if clinically indicated. 


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3.6 
COST AND COMPENSATION  
3.6.1 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 performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company.  Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center.     
3.6.2 Compensation 
Participants will not be compensated on this study. 
3.6.3 Reimbursement  
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.  
3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to documenting removal from study, effort must be made to have all subjects complete a 
safety visit approximately 42 days (+/- 10 days) following the last dose of study therapy. 
3.7.1 Criteria for removal from protocol therapy 
Patients will be taken off treatment for the following: 
• Requirement for therapy prohibited by protocol (see section 4.2) 
• Completion of protocol therapy 
• Participant requests to be withdrawn from active therapy 
• The patient receives any other treatment for RRP or requires the use of any 
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive 
medications  
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment on this study in the judgment of the investigator  
• Any Grade 3/4 drug-related adverse events with the exceptions as detailed in section 3.4 
• Disease progression 
• Participant becomes pregnant 
• Investigator discretion 
3.7.2 Duration of Follow up 
Patients who do not experience a response (See section 6.3.3.1) will be contacted via phone or 
email annually for two years after the 42 day (+/- 10 days) follow up visit to determine the date 
of disease recurrence following completion debulking on this study and the dates and types of 
additional interventional procedures to control RRP. Patients who experience a complete 
response or partial response will be evaluated every 6 weeks (following the last dose of study drug) x 3, 
then every 12 weeks x 3, then every 26 weeks x 2  (+/- 10 days for each time point during the first two 


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years) or until disease progression. After completing the first 2 years’ worth of follow up clinic visits, 
patients will be contacted annually (+/- one month) for 3 years (a total of 5 years follow up) via phone or 
email for patient status, dates of disease recurrence and interventions to treat recurrent disease. The dates 
of disease recurrence and interventions to treat recurrent disease will be recorded. 
3.7.3 Off-Study Criteria 
Patients will be taken off study for the following: 
• The patient voluntarily withdraws 
• There is significant patient noncompliance 
• The investigators decide to end the study 
• The investigators decide it is in the patient’s best interest 
• The patient completes off treatment follow-up 
• Death 
3.8 
STOPPING RULE 
3.8.1 The study will be halted (immediately stop accrual and treatment) if any of the following 
safety conditions are met and we will promptly investigate and submit an amendment to 
the IRB and FDA if necessary: 
• Any treatment-related death 
• Three ≥ Grade 3 Unexpected Serious Adverse Events that are at least possibly related to 
the study drug 
• Any bleeding/hemorrhage leading to a serious adverse event  
3.8.2 All protocol treatment will be temporarily stopped to allow review of interim summary of 
safety and efficacy following completion of the pilot cohort prior to expanding 
enrollment. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
SUPPORTIVE CARE 
Epinephrine (1:1000, 1 mg/m subcutaneous injection), diphenhydramine hydrochloride 
(intravenous injection), and resuscitation equipment may be used during the study in the 
emergency management of anaphylactoid reactions. 
Further supportive per NIH CC Pharmacy guidelines is permitted with the exception of 
interventions appearing in section 4.2. 
4.2 
PROHIBITED THERAPIES 
• Vaccination during treatment is prohibited. 
• Any corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive 
medications.  
 


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30 
 
5 
BIOSPECIMEN COLLECTION 
Biospecimen collection on this protocol will consist of blood draws, leukapheresis products, and 
biopsies of papillomas and adjacent tissue.   
 
Sample 
Collection Details* 
Timepoints 
Location of 
specimen analysis 
Blood Samples 
Whole Blood  
96 mL (12 x 8 mL CPT tubes) 
 
48 mL (6 x 8 mL CPT tubes) 
  
Prior to first dose of M7824 
 
Prior to each M7824 dose, 
End of Treatment, 
Followup 
 
 
Pre-Clinical Core lab 
(Jeremy Rose) 
Serum 
16 mL (2 x 8 mL SST tubes) 
 
 
8mL (1 x 8 mL SST tube) 
Within 14 days prior to first 
dose of M7824 
 
Prior to each M7824 dose, 
End of Treatment, 
Followup 
 
Pre-Clinical Core lab  
(Jeremy Rose) 
Apheresis 
Sample 
(optional) 
100 mL or less 
Prior to first and second 
dose of M7824 during 
Course 1 
Pre-Clinical Core lab 
(Jeremy Rose) 
Tissue Samples 
Papilloma 
Biopsy  
Up to 10 papilloma fragments, 
each 1-3 mm in diameter. 
Up to two fragments of normal 
mucosa, each 1-3 mm in diameter. 
Prior to treatment during 
course 1 on C1D1, C2D1 
(9-17 days after first dose 
of M7824 and before 
second dose of M7824); 
end of Course if non-
responder or completion of 
protocol allowed therapy, 
and if debulking is 
performed 
NCI Laboratory of 
Pathology (for review 
and archiving) 
Processed in 
Christian Hinrichs 
Lab, then transported 
to Pre-Clinical Core 
lab (Jeremy Rose) 
 
 
*Tubes/media may be adjusted at the time of collection based upon materials available.  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. 


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31 
 
Sample 
Collection Details* 
Timepoints 
Location of 
specimen analysis 
NOTE:  Portions of all samples may be banked for future research analyses; prospective consent will be 
obtained during the informed consent process.   
 
5.1 
CORRELATIVE STUDIES FOR RESEARCH 
5.1.1 Biospecimen collection before the start of M7824  
• Patients will also be invited to enroll on protocol 16C0061 for which patients must 
consent separately.  
• Blood will be collected for research purposes.  A total of 12 CPT tubes (8 mL each of 
blood) may be collected prior to the first dose of M7824. This is a total of 96 mL of 
blood. This blood may be used for immunology assays. This blood can be collected 
on different days as long as a total of 12 CPT tubes are collected prior to the first dose 
of M7824. One CPT tube may be used to collect plasma which may be frozen in a 
4mL vial. PBML from the remainder of the CPT tubes may be frozen in aliquots of 
10 x 106 cells/vial.  Send to the Pre-Clinical Core lab; Attention Jeremy Rose, Bldg. 
10, room 12C216 contact phone: 301-594-5339. 
• 16 mL of blood may be drawn to obtain serum for research purposes (2 SST tubes, 8 
mL per tube) within 14 days prior to the first dose of M7824.  This will be processed 
in ETIB Pre-Clinical Core and frozen in aliquots of 0.5-1mL/vial. Send to the Pre-
Clinical Core lab; Attention Jeremy Rose, Bldg. 10, room 12C216 contact phone: 
301-594-5339. 
• TBNK (within 7 days prior to the first dose of M7824) 
• HLA typing will be performed at baseline to facilitate immunotherapy assays.  
• The patient has the option to undergo an approximately 5-liter research apheresis 
(target yield 100 mL).  This will be performed prior to first dose of M7824. Apheresis 
will only be performed on patients with adequate peripheral venous access. Cells will 
be transferred to the Pre-Clinical Core lab, Attention Jeremy Rose, Bldg. 10, room 
12C216, contact phone: 301-594-5339. Aliquots of PBMC and plasma will be 
cryopreserved for immunological monitoring. Cell product will be frozen in 10 vials 
at concentration 100 x106 cells/mL and additional vials at 300 x 106 cells/mL. 
• Papilloma and adjacent tissue samples will be collected by biopsy prior to the first 
dose of M7824. Biopsies will be obtained with rigid or flexible endoscopy under 
sedation or general anesthesia. They will consist of up to 10 papilloma fragments, 
each 1-3 mm in diameter. One fragment may be sent to pathology for permanent 
sections. The other fragments of the biopsy will be sent to Dr. Hinrichs’ laboratory in 
sterile 1.5 mL Eppendorf tubes with a small amount of sterile normal saline. 
Additional tissue that is removed to debulk papillomas may also be collected for 
research.  Up to two fragments of normal mucosa, each 1-3 mm in diameter, will also 


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be obtained and sent to Dr. Hinrichs’ laboratory. Send to Dr. Hinrichs’ lab; Building 
10, Room 4B04; Attention:  Megan Kenyon, CRNP 240-858-3667. 
• Patients with papillomas that cannot be biopsied by endoscopy may participate in the 
trial. All tissue specimen collection except papilloma biopsies will be performed. 
• Specimens will be cataloged and stored in the Pre-Clinical Core lab. Assays will be 
performed retrospectively. 
5.1.2 Biospecimen collection during treatment and follow-up  
• Patients will return to the Clinical Center every two weeks for M7824 dosing.  Blood 
and serum for research and TBNK testing may be obtained prior to each dose of 
M7824, at the End of Treatment visit and at follow-up visits.  Blood for research may 
consist of: 
o 6 CPT tubes of Research Blood (48 mL) may be collected for immunological 
testing and processed as described in section 5.1.1. Attention Jeremy Rose, 
Bldg. 10, room 12C216 contact phone: 301-594- 5339.  
o 1 SST tube (8 mL) of Research Blood may be obtained for serum collection 
and processed as described in section 5.1.1 .  Attention Jeremy Rose, Bldg. 
10, room 12C216 contact phone: 301-594-5339. 
• Papilloma and adjacent tissue samples will be collected by biopsy 9-17 after the first 
dose of M7824. This should occur prior to second dose of M7824. Biopsies will again 
be collected at the time of completion debulking.. Biopsies will be obtained with rigid 
or flexible endoscopy under sedation or general anesthesia. They will consist of up to 
10 papilloma fragments, each 1-3 mm in diameter. One fragment may be sent to 
pathology for permanent sections. The other fragments of the biopsy will be sent to 
Dr. Hinrichs’ laboratory in sterile 1.5 mL Eppendorf tubes with a small amount of 
sterile normal saline. Up to two fragments of normal mucosa, each 1-3 mm in 
diameter, will also be obtained and sent to Dr. Hinrichs’ laboratory. Send to Dr. 
Hinrichs’ lab; Building 10, Room 4B04; Attention: Megan Kenyon, CRNP 240-858-
3667. 
• The patient has the option to undergo an approximately 5-liter research apheresis 
(target yield 100 mL).  This apheresis should occur before the second dose of M7824 
during Course 1 only. Apheresis will only be performed on patients with adequate 
peripheral venous access. Cells will be transferred to the Pre-Clinical Core lab, 
Attention Jeremy Rose, Bldg. 10, room 12C216, contact phone: 301-594-5339. 
Aliquots of PBMC and plasma may be cryopreserved for immunological monitoring. 
Cell product may be frozen in 10 vials at concentration 100 x106 cells/mL and 
additional vials at 300 x 106 cells/mL.  
• If patients experience a partial or complete response, they will continue to be 
followed every 6 weeks x 3, then every 12 weeks x 3, then every 26 weeks x 2. 
Research blood and TBNK may be collected at these time points as described above.  
5.1.3 Research studies 
• Biospecimens will be collected for research to identify biomarkers of response, 
understand the mechanism of action of the treatment, and investigate the biology of RRP.  


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• Research studies will be considered exploratory analyses and may include: assessment of 
PD-L1 expression by papillomas and papilloma-infiltrating immune cells, testing of 
papillomas and normal appearing mucosa for HPV, evaluation of papillomas by 
nanostring and evaluation of papilloma-infiltrating T cell responses against HPV 
antigens. 
• 
Testing of papilloma-infiltrating T cells and peripheral blood T cells for recognition 
of HPV antigens (30).  
Generation and isolation of T cells 
Papilloma-infiltrating T cells may be generated from papilloma biopsy specimens by 
culture of 2 mm tissue fragments in culture media with IL-2. Lymphocyte cultures 
may be split when confluent and cryopreserved when sufficient cells have been 
generated. Flow cytometry may be performed to assess the lymphocyte populations 
using markers such as CD3, CD4, CD8, and CD56 to assess lymphocyte subtypes. T 
cells may be isolated from peripheral blood samples by magnetic bead separation 
using standard techniques from commercially available kits (Miltenyi or similar). 
HPV-specific T cell response assays 
Target cells for assays measuring HPV-specific T cells responses may be autologous 
immature dendritic cells (DCs) generated from apheresis samples. The DCs may be 
loaded with pools of overlapping peptides spanning each of the viral antigens 
encoded by HPV. Reactivity against each antigen will be assessed separately. 
Immunological assays may consist of interferon-gamma ELISPOT, interferon-gamma 
production as determined by ELISA, 4-1BB upregulation, and or intracellular 
cytokine production as described previously (30). 
HPV detection and genotyping  
Testing will be performed by Dr. Hinrichs’ laboratory using PCR-based type-specific 
HPV detection and quantification assays (30). 
5.1.4 Co-Enrollment on 16C0061 / Biobanking 
Samples from patients may be transferred to protocol 16C0061 for biobanking of specimens if 
the patient has consented to that study.   
5.1.5 Sample Storage, Tracking and Disposition 
5.1.5.1 Storage/Tracking in the Preclinical Development and Clinical Monitoring Facility 
(PDCMF) 
• Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management 
system.  Should a CRIS screen not be available, the CRIS downtime procedures will be 
followed.  Samples will not be sent outside NIH without appropriate approvals and/or 
agreements, if required. 
• Samples will be archived by the ETIB Preclinical Development and Clinical Monitoring 
Facility (PDCMF). All data associated with archived clinical research samples is entered 
into LabMatrix. Access to this folder is limited to PDCMF staff and ETIB clinical staff, 


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34 
 
requiring individual login and password. All staff in the PDCMF laboratory receives 
annually updated NIH/CIT training and maintains standards of computer security. 
• The data recorded for each sample includes the patient ID, trial name/protocol number, 
date drawn, treatment cycle/post-transplant time point, cell source (e.g. peripheral blood, 
lymph apheresis, mobilized peripheral blood stem cells, marrow, urine, skin or oral 
biopsy) as well as box and freezer location. Patient demographics that correlate treatment 
outcomes and therapies with the samples can be obtained only through the NCI/ETIB 
clinical records. As of January 2007, all newly received samples receive a unique bar 
code number, which is included in the sample record in the PDCMF database. Only this 
bar code is recorded on the sample vial and the vials will not be traceable back to patients 
without authorized access to the PDCMF database. All non-coded samples previously 
archived will be stripped of identifiers prior to distribution for any use other than as a 
primary objective of the protocol under which they were collected. 
• Samples are stored in locked freezers. All samples will be labeled solely with a bar code 
(which includes the date, and serially determined individual sample identifier). The key 
will be available to a restricted number of ETIB investigators and associate investigators 
on the protocol. Coded samples will be stored frozen at -20°, -80° or liquid nitrogen 
vapor phase according to the stability requirements under the restricted control of the 
PDCM Facility of ETIB. 
• 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 coded samples under the OHSRP Exemption Form 
guidelines stipulating that the activity is exempt from IRB review. Unused samples must 
be returned to the PDCMF laboratory. 
• 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, they must be returned to the PDCMF laboratory. 
• These freezers are located onsite at the PDCMF laboratory (12C216) or in ETIB common 
equipment space (CRC/3-3273). 
5.1.5.2 Hinrichs laboratory 
• Samples may be transferred from Preclinical Development and Clinical Monitoring 
Facility to the Hinrichs laboratory for the research studies indicated in 5.1.3. 
• Samples transferred to the Hinrichs laboratory will be barcoded and tracked with 
LabMatrix. 
• Laboratory research data will be stored on the NCI secure server in the Hinrichs 
laboratory folder with secure access by laboratory personnel only. 
5.1.5.3 Protocol Completion/Sample Destruction  
• 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 


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35 
 
approved protocol and patient consent or the OHSRP Exemption Form stipulating that 
the activity is exempt from IRB review. 
• The PDCMF staff will report to the Principal Investigators any destroyed samples, if 
samples become unsalvageable because of environmental factors (ex. broken freezer or 
lack of dry ice in a shipping container), lost in transit between facilities or misplaced by a 
researcher.  
• 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. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into the C3D electronic system and 
ensuring data accuracy, consistency and timeliness. The principal investigator, associate 
investigators/research nurses and/or a contracted 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. 
End of study procedures: Data will be stored according to HHS, FDA 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.  
6.1.1 Adverse event recording 
• Grade 1 adverse events will not be recorded. 
• Grade 2 adverse events that will be recorded: 
a. Unexpected events that are possibly, probably, or definitely related to the 
research. 
b. Expected events that are probably or definitely related to the study interventions 
will be record only for the first year.  
c. Any serious events that are deemed clinically significant by the PI 
Note: Grade 2 adverse events that are clearly attributable to surgery/procedure will not 
be recorded.  
• Adverse Events that occur during the follow-up period will only be recorded if they are 
considered related to the M7824. 
• All grade 3, 4, and 5 adverse events will be recorded regardless of attribution. 
• All adverse events are recorded in the medical record.  
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.  


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Document AEs from the first administration of the study therapy, Study Day 1, through 42 days 
after the study therapy was last administered.  Beyond 42 days after the last administration, only 
adverse events which are serious and related to the study intervention need to be recorded. 
An abnormal laboratory value will be considered an AE 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. 
6.1.2 Concomitant medications recording 
Only medications used to treat adverse events related to the study medication will be recorded in 
the data base.  
6.1.3 Collection of recurrence and subsequent treatments 
The dates of disease recurrences following completion of treatment and/or debulking on this 
study and the dates and types of additional interventional procedures to control RRP will be 
recorded. 
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: 
  x__ Coded and linked data in an NIH-funded or approved public repository.   
_x__ Coded and linked data in BTRIS (automatic for activities in the Clinical Center) 
_x__ Coded and linked or identified data with approved outside collaborators under appropriate 
agreements. 
How and where will the data be shared?  
Data will be shared through: 
  x__ An NIH-funded or approved public repository.  Insert name or names:ClinicalTrials.gov. 
_x__ BTRIS (automatic for activities in the Clinical Center) 
_x__ Approved outside collaborators under appropriate individual agreements. 
_x__ Publication and/or public presentations. 
When will the data be shared 


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_x__ Before publication. 
_x__ At the time of publication or shortly thereafter. 
 
6.3 
RESPONSE CRITERIA 
Disease stage and response will be determined by flexible nasopharyngolaryngoscopy and/or 
tracheoscopy using the Derkay staging system if the patient does not have pulmonary disease 
and/or by imaging if the patient has pulmonary disease (6). The Derkay staging system has been 
validated with a high degree of inter-rater reliability (31). It incorporates an objective score 
based on the number of sites and bulkiness of papillomas within the pharynx, larynx and trachea 
and a subjective score determined by voice and breathing symptoms.  Physical exam and/or 
clinic-based endoscopy will be used to visualize all accessible papillomas and assign an 
objective score using the Derkay system. Only lesions that can be visualized by clinic-based 
flexible nasopharyngolaryngoscopy and/or tracheoscopy will be included in the baseline score 
used for assessing treatment response.  This score must be 10 or greater for patients to be eligible 
for treatment. If patients have disease that is better visualized or only visualized with an imaging 
study such as CT scan or MRI then imaging studies will be obtained. Preliminary Derkay scores 
and response assessment will be determined by the endoscopist performing the procedure. Final 
reporting of clinical responses will be based on a blinded review of endoscopic video and or 
photos by one or more independent otolaryngologists. 
Response and progression from imaging studies will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) (32).  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria. 
If a subject has disease being assessed by imaging for response and refuses clinic-based flexible 
nasopharyngolaryngoscopy and/or tracheoscopy, no Derkay score will be calculated. This will 
not be considered a protocol deviation. 
6.3.1 Baseline assessment 
• All accessible disease will be examined by physical exam and/or endoscopy to establish a 
baseline 
• Only lesions visualized by clinic-based flexible nasopharyngolaryngoscopy and/or 
tracheoscopy will be included in the baseline objective Derkay score 
• Imaging studies will be performed if appropriate and baseline measurements determined 
using RECIST 1.1 criteria 
6.3.2 Definition of measurable disease 
• Any papilloma that can be visualized via clinic-based endoscopy and assigned a score 
using the Derkay system 
• Any papilloma that can be measured by imaging using RECIST 1.1 criteria 
6.3.3 Definition of disease response 
6.3.3.1 Complete Response (CR)  


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All criteria must be met. 
• No evidence of papillomas on physical exam and/or clinic-based flexible 
nasopharyngolaryngoscopy and/or tracheoscopy 
• No evidence of papillomas by exam under anesthesia (sedation or general anesthesia) 
with endoscopy and biopsies 
• Absence of disease by imaging if lesions are assessed by imaging 
6.3.3.2 Partial response (PR) 
Either criterion may be met. 
• Decrease in Derkay anatomic score of 30 percent or greater 
• Partial tumor response by imaging using RECIST 1.1 criteria 
6.3.3.3 Progressive disease (PD) 
Any criterion may be met.  
• Increase in objective Derkay anatomic score of 50 percent or greater 
• Disease progression by imaging using RECIST 1.1 criteria 
• New or worsening symptoms attributable to growth of papillomas or new papillomas 
6.3.3.4 Stable disease  
• Not meeting criteria for CR, PR, or PD 
6.3.4 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 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 


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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. 
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 AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
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 here. 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 here.  
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI 
Clinical Director.  A separate submission is not necessary as reports in iRIS will be available to 
the Clinical Director. 


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In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet every two weeks when patients are being actively treated on 
the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable 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. 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.  
8 
SPONSOR 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 
• 
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. 
8.2 
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. 
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.  


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8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets  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. 
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/pages/viewpage.action?pageId=157942842 
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 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
8.4.1 To be sent by OSRO Safety: 
8.4.1.1 Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
Definition: A suspected adverse reaction to study treatment that is both serious and unexpected. 
The sponsor must report SUSARs within 2 business days of learning of the event to EMD Serono’s 
parent company, Merck via Fax: 781-681-2961 or email: gds@merckgroup.com. 
8.4.1.2 Serious Adverse Event (SAE) 
Definition: See Section 7.1. The sponsor must report SAEs within 2 business days of learning of 
the event to EMD Serono’s parent company, Merck via Fax: 781-681-2961 or email: 
gds@merckgroup.com. 
8.4.1.3 Pregnancy 
The sponsor must report any pregnancy occurring in a subject treated with the study drug during 
the course of the study. The Investigator shall ensure that the case is followed up to the end of the 
pregnancy and provide all relevant documentation and a final report on the outcome to Merck. 
8.4.1.4 Annual Report 
The sponsor will provide a copy of the FDA Annual Report to EMD Serono/Merck at the time of 
submission to the FDA. 
8.5 
REPORTING PREGNANCY  
8.5.1 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 
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 become 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 (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented. 


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8.5.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 60 
days after the last dose of M7824. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose of M7824 until 60 days after the 
last dose should, if possible, be followed up and documented. 
8.6 
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. 
9 
CLINICAL MONITORING  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.   
10 STATISTICAL CONSIDERATIONS   
10.1 STATISTICAL HYPOTHESES 
10.1.1 Primary Efficacy Endpoints 
The primary efficacy endpoint is the fraction of patients in each cohort who have a complete 
response.   


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10.1.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoint is the fraction of patients in each cohort who have a partial 
response.  
10.1.3 Sample Size Determination 
Patients will be enrolled into one of two cohorts according to whether they are checkpoint 
inhibitor naïve or have RRP disease which is refractory to checkpoint inhibition. In each of the 
two cohorts, the trial will be conducted using a Simon minimax two-stage design; the objective is 
to rule out a 5% complete response rate (p0=0.05) and target a 20% complete response rate 
(p1=0.20).   
With amendment D, cohort 2 will be closed to further enrollment.  
The design will use alpha=0.10 (10% chance of accepting a poor agent) and beta=0.20 
(corresponding to 80% power--and 20% chance of incorrectly rejecting a promising agent). The 
first stage of accrual will consist of 12 evaluable patients. If 0/12 has a complete clinical 
response, then no further patients would be enrolled to that cohort. Should 1 or more patients in 
the first 12 have a complete response, then accrual would continue until a total of 21 evaluable 
patients have enrolled in that cohort. If there are 1 to 2 complete responses in 21 evaluable 
patients in a cohort, this would be considered unacceptably low, while if 3 or more evaluable 
patients have complete responses in 21 patients in a cohort (14.3%), then the results will be 
considered sufficiently promising for further evaluation in that cohort. Under the null hypothesis 
(5% complete response rate), the probability of early termination is 54.0%.  
It is anticipated that up to 1 patient per month may enroll onto this trial; thus, 2 to 3 years may be 
required to complete accrual. The trial would require up to 21 total evaluable patients in cohort 
1; the accrual ceiling will be set at 26 patients to allow for a small number of inevaluable patients 
as well as to accommodate the 2 subjects enrolled in cohort 2 prior to its closure. 
10.1.4 Populations for Analysis 
Modified intention to treat: all patients who receive at least one dose of the agent will be 
included in the statistical analyses performed. 
10.2 STATISTICAL ANALYSES 
10.2.1 General Approach 
Separately by cohort, the proportion of evaluable patients who experience a CR will be reported 
along with a confidence interval; the proportion of patients who experience a PR will also be 
reported along with a confidence interval. 
10.2.2 Analysis of the Primary Efficacy Endpoints 
In each of the two cohorts, the fraction of evaluable patients who experience a complete response 
will be determined and this fraction will be reported along with a 95% confidence interval. 
10.2.3 Analysis of the Secondary Efficacy Endpoints 
In each of the two cohorts, the fraction of evaluable patients who experience a partial response 
will be determined and this fraction will be reported along with a 95% confidence interval. 


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10.2.4 Safety Analyses 
Safety of the agent will be assessed by determining the grade of adverse events noted in each 
patient, and reporting the fraction with grade 3 and grade 4 adverse events. Safety data will be 
presented in summaries, overall and by cohort. The safety data will consist of the reporting of all 
adverse events, and may also include reporting vital signs, physical examination data, and 
laboratory safety data. 
10.2.5 Baseline Descriptive Statistics 
Limited demographic and clinical characteristics of all patients will be reported. 
10.2.6 Planned Interim Analyses 
None will be performed. 
10.2.7 Subgroup Analyses 
Results will be reported according to the cohort in which the patient was enrolled. 
10.2.8 Tabulation of Individual Participant Data 
No individual participant data is intended to be reported. 
10.2.9 Exploratory analyses 
Exploratory analyses may include the following: 
• Evaluation of PD-L1 and/or TGF-β expression as a potential biomarker of response by 
comparing levels of their expression between responders (PR +CR) and non-responders, 
separately within each cohort, using an exact Wilcoxon rank sum test 
• Evaluation of HPV type as a potential biomarker of response by determining if the 
distribution of responders vs. non-responders varies by HPV type using either Fisher’s 
exact test or Mehta’s modification to Fisher’s exact test, depending on the number of 
categories of HPV type being evaluated (2 vs. 3) 
• Descriptive analyses of induction of HPV-specific T cell responses 
• Descriptive analysis of the clearance of HPV infection from normal appearing mucosa  
• Determination of the effect of treatment with M7824 on Derkay and Voice Handicap 
Index-10 scores relative to pre-treatment levels using paired tests such as a Wilcoxon 
signed rank test 
• Determination of the duration of clinical responses to M7824 beginning at the date that a 
clinical response has been identified, using the Kaplan-Meier method 
11 COLLABORATIVE AGREEMENT 
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT 
• The study drug M7824 will be provided under a CRADA (EMD Serono, Inc – NCI 
CRADA# 02666) between the manufacturer, EMD Serono, and the Center for Cancer 
Research, National Cancer Institute 


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12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
The patients to be entered in this protocol have RRP involving multiple anatomic sites and 
requiring repeated procedures for disease control. There is no curative therapy for these patients 
and their disease causes substantial morbidity and occasional mortality. Subjects from both 
genders and all racial/ethnic groups are eligible for this study if they meet the eligibility criteria.  
To date, there is no information that suggests that differences in disease response would be 
expected in one group compared to another.  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 the one hand and the need to explore gender and ethnic aspects 
of clinical research on the other hand.  If differences in outcome that correlate to gender or to 
ethnic identity are noted, accrual may be expanded or a follow-up study may be written to 
investigate those differences more fully. 
There is no effective systemic therapy for patients with RRP. 
RRP causes death by airway compromise, mass effect in the lungs, and transformation into 
invasive cancer. 
12.2 STRATEGIES/PROCEDURES FOR RECRUITMENT 
Patients for this protocol will be recruited via standard CCR mechanisms as well as various 
advertising venues.  All advertisements, letters and other recruitment efforts will be submitted to 
the IRB for approval prior to their implementation.   
12.3 PARTICIPATION OF CHILDREN 
Because no dosing or adverse event data are currently available on the use of M7824 in patients 
<18 years of age, children are excluded from this study, but will be eligible for future pediatric 
trials.   
12.4 PARTICIPATION OF PREGNANT WOMEN 
Based on its mechanism of action and data from animal studies, M7824 can cause fetal harm 
when administered to a pregnant woman. Human IgG1 is known to cross the placental barrier 
and M7824 is an immunoglobulin G1 (IgG1); therefore, M7824 has the potential to be 
transmitted from the mother to the developing fetus. Given these risks, pregnant women will be 
excluded from this study and patients of both genders must be willing to practice contraception 
throughout M7824 treatment and for at least 120 days after M7824 treatment. 
12.5 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The experimental treatment has a chance to provide clinical benefit though this is unknown. The 
safety profile of M7824 has been established in treatment of over 500 patients. The risks are 
well-characterized and the toxicities are generally reversible. RRP carries the risk of repeated 
procedures to control the disease and the potential for airway compromise, lung compression and 
infection, and transformation to invasive cancer. If this study has a positive outcome it will 
provide benefit to not only the patients on the study but also to future patients. This study may 


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also contribute to our knowledge of the mechanism of action of M7824 and the biology or RRP 
that will help to advance treatment of RRP and other diseases. 
12.5.1 Summary of risks and potential benefits 
This clinical trial is being performed to evaluate M7824 for RRP. Only patients with a 
substantial disease burden (Derkay anatomic score of 10 or greater) that requires repeated 
endoscopic interventions (two or more procedures in the last 12 months) will be eligible for 
treatment. While the vast majority of patients with RRP experience an acceptable level of disease 
control with infrequent surgical debulking, a small subset of patients have very aggressive 
disease that requires frequent operative intervention, carries the risk of airway obstruction and 
the need for a tracheostomy, and affects their voice and breathing to a degree that negatively 
impacts their quality of life. The inclusion criteria for this study captures these 5-10% of patients 
most severely affected. Patients with disease that has not met this level of severity will not be 
subjected to the risks of treatment.  The primary protocol risks are the toxicities of M7824. There 
may be additional risks of treatment that are specific to RRP such as swelling or progression of 
papillomas that may lead to worsening symptoms. In addition, there are risks from the general 
anesthesia and procedures to stage and monitor the disease. General anesthesia will be employed 
during an initial evaluation to stage the disease, confirm the diagnosis, and debulk papillomas 
that pose an undue safety risk. It will be used again two weeks after the initiation of treatment at 
which time the airway will be assessed for safety. A final procedure under anesthesia will be 
performed at the completion of treatment to remove residual papillomas if they are present. Rare 
but serious complications can occur with general anesthesia including cardiopulmonary 
compromise, stroke, and death. In this protocol they are offset substantially by the important 
safety information related to airway patency, extent of disease, and in some cases surgical 
removal of disease that is gained by these procedures.  
12.5.2 Study drug risks 
The risks associated with the study product are discussed in Section 11.1.3. 
12.5.3 Exam under anesthesia and biopsy risks 
Exam under anesthesia (EUA) is associated with the risk of sedation or general anesthesia. 
Complications of general anesthesia are rare. Serious risks include allergic reaction to a drug, 
loss of airway control and ventilation, and cardiovascular complications such as hypotension, 
dysrhythmia, or myocardial infarction, and neurological complications such as stroke or brain 
damage. The risks associated with biopsies are pain and bleeding at the biopsy site. Rarely, there 
is a risk of infection at the biopsy site. The anesthesia and biopsies of the initial evaluation have 
the benefit of confirming the diagnosis and the extent of the disease, and permitting debulking of 
disease that poses a major airway risk. Similarly, the anesthesia and biopsies at the completion of 
treatment will either confirm a complete response or will be performed in association with 
papilloma debulking according to standard of care therapy. 
12.5.4 Risks associated with blood sampling 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 


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12.5.5 Risks associated with leukapheresis 
Risks may involve bleeding at the apheresis site and lightheadedness. Decrease in blood pressure 
is considered a less common risk. 
12.5.6 Risks associated with intravenous catheter 
12.5.7 The risks of IV insertion include temporary pain and bleeding or bruising at the site 
where the IV enters the skin.  In placing the IV, there is a small chance of fluid leaking 
into the tissue surrounding the IV and infection, which may cause some swelling and 
discomfort. Rarely, the IV site may become infected, which might require treatment with 
antibiotics.Risks associated with flexible nasopharyngolaryngoscopy 
Complications are very uncommon; but may include tearing, gagging, coughing, and, less 
frequently, nose bleeding due to the scope being passed through the nose. 
12.6 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant 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. 
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) per discretion of the 
designated study investigator and with the agreement of the participant.  Whether in person or 
remote, the privacy of the subject will be maintained. Consenting investigators (and participant, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 
conducted remotely, the participant will be informed of the private nature of the discussion and 
will be encouraged to relocate to a more private setting if needed.   
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, funding agency, the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) 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 
• Demonstration of efficacy that would warrant stopping    


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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 as applicable, Food and Drug Administration (FDA). 
13.2 QUALITY ASSURANCE AND QUALITY CONTROL 
Each 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.  
All research activities will be conducted in as private a setting as possible. 


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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/each 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 transmitted to and stored at the NCI 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 the clinical site(s) and by NCI CCR research staff will be secured 
and password protected. At the end of the study, all study databases will be archived at the NCI 
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 DESCRIPTION OF THE INVESTIGATIONAL PRODUCT (IND: 138835) 
M7824 drug product will be supplied by EMD Serono as a sterile liquid formulation.  
Each vial of Powder for Concentrate for Solution for Infusion (freeze-dried formulation) is 
packaged in United States Pharmacopeia (USP) and European Pharmacopeia (Ph Eur) type I 
glass vials. Each vial is filled with 45 mg of M7824 (45 mg/vial) as preservative-free powder 
containing histidine, trehalose dihydrate, sodium chloride, L-methionine and polysorbate 20 
(Tween 20). The vials are closed with a rubber stopper in lyophilization format complying with 
USP and Ph Eur and sealed with an aluminum plastic crimping cap. Only excipients that 
conform to the current USP and / or Ph Eur are used for M7824 drug product. 
The Concentrate for Solution for Infusion (liquid formulation) is 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 liquid formulation contains histidine, 
trehalose dihydrate, sodium chloride, L-methionine and polysorbate 20 (Tween 20). The vials are 
closed with rubber stoppers within serum format complying with USP and Ph Eur with an 
aluminum crimp seal closure. 


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The liquid formulation has the same composition in terms of excipients, qualitatively and 
quantitatively, except for the addition of water compared with the freeze-dried formulation, 
which was initially used in the ongoing Phase I study (EMR200647-001). Of note, there is no 
change to the drug substance process. 
For applications in clinical studies, the liquid formulation is diluted directly with 0.9% saline 
solution (sodium chloride injection) supplied in an infusion bag. 
The estimated volumes of delivery are anticipated to be no more than 250 mL, which are 
clinically acceptable. Detailed information on infusion preparation and administration are 
provided in the protocol and manual of preparation. 
14.1.1 Mode of Action  
M7824 is a conjugate comprised of avelumab and the soluble extracellular domain of human 
TGF-β receptor II (TGF-βRII). Avelumab targets the programmed death–ligand 1 (PD-L1). PD-1 
is a negative regulatory receptor expressed by activated T and B lymphocytes. Binding of PD-1 
to its ligand, PD-L1, results in the down-regulation of lymphocyte activation. Avelumab inhibits 
the binding of PD-1 to PD-L1.  Inhibition of the interaction between PD-1 and PD-L1 promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as self-
antigens. The “TGF-β trap” portion of the compound sequesters bioavailable TGF-β from the 
papilloma microenvironment.  
14.1.2 Source 
M7824 is an investigational agent that will be supplied to the NIH Pharmacy by EMD Serono. 
14.1.3 Toxicities 
The important potential risks include hypersensitivity, irAEs/autoimmune disorders, anemia, rash 
with hyperkeratosis/keratoacanthomas/SCC of the skin, embryo-fetal toxicity, and alterations in 
wound healing or repair of tissue damage.  
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. 
14.1.4 Preparation  
M7824 drug product must be diluted in 250 mL of 0.45% or 0.9% saline solution (sodium 
chloride injection) supplied in an infusion bag. Detailed information on infusion bags and 


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medical devices to be used for the preparation of the dilutions and subsequent administration will 
be provided in the manual of preparation. 
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room 
temperature. Use a disposable syringe equipped with a needle of suitable size to remove a 
volume of sodium chloride solution to be replaced by M7824 from the infusion bag and discard 
the removed solution. Use a new disposable syringe equipped with a needle of suitable size to 
inject a volume of M7824 drug product identical to the discarded volume of sodium chloride 
solution into the infusion bag. Gently invert the mixture 10 times. Infusion bags must not be 
shaken, in order to avoid foaming or excessive shearing of the protein solution. The preparation 
must be carefully inspected as it should result in a homogeneous looking clear solution, free of 
visible particles.  
14.1.5 Storage and Stability 
M7824 drug product must be stored at 2°C to 8°C until use, and it must not be frozen. Rough 
shaking of M7824 product must be avoided. M7824 drug product must be diluted with 0.45% or 
0.9% saline solution. It is recommended that the diluted M7824 solution is used immediately. 
14.1.6 Administration procedures 
Please see section 3.2.1. 
14.1.7 Potential Drug Interactions 
   
No formal drug interaction trials have been conducted with M7824 in humans. 


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papilloma of the larynx. Proceedings of the National Academy of Sciences of the United States 
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Derkay CS. Task force on recurrent respiratory papillomas. A preliminary report. 
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Silver RD, Rimell FL, Adams GL, Derkay CS, Hester R. Diagnosis and management of 
pulmonary metastasis from recurrent respiratory papillomatosis. Otolaryngology--head and neck 
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2003;129(6):622-9. 
4. 
Dedo HH, Yu KC. CO(2) laser treatment in 244 patients with respiratory papillomas. The 
Laryngoscope. 2001;111(9):1639-44. 
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Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. The 
Laryngoscope. 2008;118(7):1236-47. 
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Armstrong LR, Derkay CS, Reeves WC. Initial results from the national registry for 
juvenile-onset recurrent respiratory papillomatosis. RRP Task Force. Archives of 
otolaryngology--head & neck surgery. 1999;125(7):743-8. 
7. 
Kashima HK, Shah F, Lyles A, Glackin R, Muhammad N, Turner L, et al. A comparison 
of risk factors in juvenile-onset and adult-onset recurrent respiratory papillomatosis. The 
Laryngoscope. 1992;102(1):9-13. 
8. 
Venkatesan NN, Pine HS, Underbrink MP. Recurrent respiratory papillomatosis. 
Otolaryngologic clinics of North America. 2012;45(3):671-94, viii-ix. 
9. 
Smith EM, Pignatari SS, Gray SD, Haugen TH, Turek LP. Human papillomavirus 
infection in papillomas and nondiseased respiratory sites of patients with recurrent respiratory 
papillomatosis using the polymerase chain reaction. Archives of otolaryngology--head & neck 
surgery. 1993;119(5):554-7. 
10. 
Dudley ME, Gross CA, Somerville RPT, Hong Y, Schaub NP, Rosati SF, et al. 
Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating 
lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol. 
2013;31(17):2152-9. 
11. 
Healy GB, Gelber RD, Trowbridge AL, Grundfast KM, Ruben RJ, Price KN. Treatment 
of recurrent respiratory papillomatosis with human leukocyte interferon. Results of a multicenter 
randomized clinical trial. The New England journal of medicine. 1988;319(7):401-7. 
12. 
Wu P, Wu D, Li L, Chai Y, Huang J. PD-L1 and Survival in Solid Tumors: A Meta-
Analysis. PLoS One. 2015;10(6):e0131403. 
13. 
Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab 
versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 
treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 
2015;16(4):375-84. 


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14. 
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab 
versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-32. 
15. 
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab 
versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 
2015;373(17):1627-39. 
16. 
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. 
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 
2015;373(19):1803-13. 
17. 
Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al. Safety and clinical 
activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of 
the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 
2016;17(7):956-65. 
18. 
Ahn J, Bishop JA, Roden RBS, Allen CT, Best SRA. The PD-1 and PD-L1 pathway in 
recurrent respiratory papillomatosis. The Laryngoscope. 2017. 
19. 
Melero I, Berman DM, Aznar MA, Korman AJ, Perez Gracia JL, Haanen J. Evolving 
synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 
2015;15(8):457-72. 
20. 
Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer 
progression. Nat Genet. 2001;29(2):117-29. 
21. 
Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer 
Metastasis Rev. 2006;25(3):435-57. 
22. 
Levovitz C, Chen D, Ivansson E, Gyllensten U, Finnigan JP, Alshawish S, et al. TGFbeta 
receptor 1: an immune susceptibility gene in HPV-associated cancer. Cancer Res. 
2014;74(23):6833-44. 
23. 
Bonagura VR, Hatam LJ, Rosenthal DW, de Voti JA, Lam F, Steinberg BM, et al. 
Recurrent respiratory papillomatosis: a complex defect in immune responsiveness to human 
papillomavirus-6 and -11. APMIS. 2010;118(6-7):455-70. 
24. 
Massague J. TGFbeta in Cancer. Cell. 2008;134(2):215-30. 
25. 
Teicher BA. Transforming growth factor-beta and the immune response to malignant 
disease. Clin Cancer Res. 2007;13(21):6247-51. 
26. 
Colak S, Ten Dijke P. Targeting TGF-beta Signaling in Cancer. Trends Cancer. 
2017;3(1):56-71. 
27. 
Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, et al. Avelumab 
in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-
group, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374-85. 
28. 
Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and 
Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune 
Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. J Clin Oncol. 
2016;34(26):3119-25. 


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29. 
Lacouture ME, Morris JC, Lawrence DP, Tan AR, Olencki TE, Shapiro GI, et al. 
Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of 
transforming growth factor beta by the monoclonal antibody fresolimumab (GC1008). Cancer 
Immunol Immunother. 2015;64(4):437-46. 
30. 
Stevanovic S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, et 
al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-
targeted tumor-infiltrating T cells. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2015;33(14):1543-50. 
31. 
Dong H, Chen L. B7-H1 pathway and its role in the evasion of tumor immunity. Journal 
of molecular medicine. 2003;81(5):281-7. 
32. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European 
journal of cancer. 2009;45(2):228-47. 
33. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55. 
34. 
Arffa RE, Krishna P, Gartner-Schmidt J, Rosen CA. Normative values for the Voice 
Handicap Index-10. J Voice. 2012;26(4):462-5. 
35. 
Kupfer RA, Cadalli Tatar E, Barry JO, Allen CT, Merati AL. Anatomic Derkay Score Is 
Associated with Voice Handicap in Laryngeal Papillomatosis in Adults. Otolaryngology--head 
and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck 
Surgery. 2016;154(4):689-92.


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16 APPENDICES 
16.1 APPENDIX A: PERFORMANCE STATUS CRITERIA(33) 
ECOG Performance Status Scale* 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
 


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16.2  APPENDIX B: VOICE HANDICAP INDEX-10 (34, 35) 
 
Never 
 
0 
Almost 
never 
1 
Sometimes 
 
2 
Almost 
always 
3 
Always 
 
4 
My voice makes it difficult for 
people to hear me 
 
 
 
 
 
People have difficulty 
understanding me in a noisy room 
 
 
 
 
 
People ask “what’s wrong with 
your voice?” 
 
 
 
 
 
I feel as though I have to strain to 
produce voice 
 
 
 
 
 
My voice difficulties restrict 
personal and social life 
 
 
 
 
 
The clarity of my voice is 
unpredictable 
 
 
 
 
 
I feel left out of conversations 
because of my voice 
 
 
 
 
 
My voice problem causes me to 
lose income 
 
 
 
 
 
My voice problem upsets me 
 
 
 
 
 
My voice makes me feel 
handicapped 
 
 
 
 
 
 
Total Score:  
 
 
 
 
 


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16.3 APPENDIX C: MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS 
Immune-Related Adverse Events 
Since inhibition of PD-L1 stimulates the immune system, immune-related AEs (irAEs) may 
occur.  Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more frequent monitoring 
Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4) 
Grade 3 to 4:  treat with high dose corticosteroids 
 
16.3.1 Gastrointestinal irAEs 
Gastrointestinal irAEs 
Severity of Diarrhea / Colitis 
(NCI-CTCAE v5) 
Management 
Follow-up 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue M7824 therapy 
Symptomatic treatment (for 
example, loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2 or 3/4  
Grade 2 
Diarrhea:  4 to 6 stools per day over 
Baseline; IV fluids indicated < 24 
hours; not interfering with ADL 
Colitis:  abdominal pain; blood in 
stool  
Delay M7824 therapy 
Symptomatic treatment 
If improves to Grade 1:  
Resume M7824 therapy 
If persists > 5 to 7 days or recur: 
0.5 to 1.0 mg/kg/day methylprednisolone or 
equivalent  
When symptoms improve to Grade 1, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume M7824 therapy per 
protocol. 
If worsens or persists > 3 to 5 days with oral 
steroids: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; IV 
fluids ≥ 24 hrs; interfering with 
ADL 
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs 
Grade 4:  life-threatening, 
perforation 
Discontinue M7824 therapy 
per protocol 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade 1, then taper 
over at least 1 month 
If persists > 3 to 5 days, or recurs after 
improvement: 
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab should 
not be used in cases of perforation or sepsis  
 


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16.3.2 Dermatological AEs 
Dermatological AEs 
Grade of Rash 
(NCI-CTCAE v5) 
Management 
Follow-up 
Grade 1 to 2  
Covering ≤ 30% body surface 
area  
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
Continue M7824 therapy 
If persists > 1 to 2 weeks or recurs:  
Consider skin biopsy  
Delay M7824 therapy 
Consider 0.5 to 1.0 mg/kg/day methylprednisolone 
IV or oral equivalent. Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume M7824 therapy 
If worsens:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Covering > 30% body surface 
area; life threatening 
consequences  
Delay or discontinue 
M7824 therapy 
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent  
If improves to Grade 1:  
Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic infections  
Resume M7824 therapy 
 
 
 


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16.3.3 Pulmonary AEs 
Pulmonary AEs 
Grade of Pneumonitis 
(NCI-CTCAE v5) 
Management 
Follow-up 
Grade 1 
Radiographic changes only  
Consider delay of M7824 
therapy  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-image at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4  
Grade 2 
Mild to moderate new symptoms  
Delay M7824 therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily, 
consider hospitalization  
1.0 mg/kg/day methyl-
prednisolone IV or oral 
equivalent  
Consider bronchoscopy, lung 
biopsy  
Re-image every 1 to 3 days  
If improves:  
When symptoms return to near Baseline, 
taper steroids over at least 1 month and then 
resume M7824 therapy and consider 
prophylactic antibiotics 
If not improving after 2 weeks or worsening:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Severe new symptoms; New / 
worsening hypoxia; life-threatening  
Discontinue M7824therapy 
Hospitalize  
Pulmonary and Infectious 
Disease consults 
2 to 4 mg/kg/day 
methylprednisolone IV or IV 
equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Baseline:  
Taper steroids over at least 6 weeks  
If not improving after 48 hours or worsening:  
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil)  
 
 
 


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16.3.4 Hepatic AEs 
Hepatic AEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v5) 
Management 
Follow-up 
Grade 1 
Grade 1 AST or ALT > ULN to 3.0 
x ULN and / or total bilirubin > 
ULN to 1.5 x ULN  
Continue M7824 therapy 
Continue liver function monitoring  
If worsens:  
Treat as Grade 2 or 3 to 4  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and / or total bilirubin > 1.5 to ≤ 3 x 
ULN  
Delay M7824therapy 
Increase frequency of 
monitoring to every 3 days  
If returns to Baseline:  
Resume routine monitoring, resume M7824 
therapy 
If elevations persist > 5 to 7 days or worsen:  
 0.5 to 1 mg/kg/day methylprednisolone or 
oral equivalent and when LFT returns to 
Grade 1 or Baseline, taper steroids over at 
least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and 
resume M7824 therapy 
Grade 3 to 4 
AST or ALT > 5 x ULN and / or 
total bilirubin > 3 x ULN  
Discontinue M7824 therapy  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consult gastroenterologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted  
If returns to Grade 2:  
Taper steroids over at least 1 month  
If does not improve in > 3 to 5 days, worsens 
or rebounds:  
Add mycophenolate mofetil 1 gram (g) twice 
daily  
If no response within an additional 3 to 5 
days, consider other immunosuppressants per 
local guidelines  
 
 
 


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16.3.5 Cardiac AEs 
 
Cardiac irAEs 
Myocarditis 
Management 
Follow-up 
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive of 
myocarditis.  
Withhold M7824 therapy 
Hospitalize.  
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility  
experienced in advanced 
heart failure and arrhythmia 
management. 
Cardiology consult to 
establish etiology and rule-
out immune-mediated 
myocarditis.  
Guideline based supportive 
treatment as per cardiology 
consult.* 
Consider myocardial biopsy 
if recommended per 
cardiology consult. 
If symptoms improve and immune-mediated etiology is 
ruled out, re-start M7824 therapy. 
 
 
 
If symptoms do not improve/worsen, viral myocarditis is 
excluded, and immune-mediated etiology is suspected or 
confirmed following cardiology consult, manage as 
immune-mediated myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue 
M7824. 
Guideline based supportive 
treatment as appropriate as 
per cardiology consult.* 
Methylprednisolone 1 to 2 
mg/kg/day. 
Once improving, taper steroids over at least 1 month and 
add prophylactic antibiotics for opportunistic infections. 
 
If no improvement or worsening, consider additional 
immunosuppressants (e.g. azathioprine, cyclosporine A) 
 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
 
 
 


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16.3.6 Endocrine AEs 
Endocrine AEs 
Endocrine Disorder 
Management 
Follow-up 
Asymptomatic TSH abnormality  
Continue M7824 therapy   
 If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 
2 subsequent measurements: include T4 at subsequent cycles as clinically 
indicated; consider endocrinology consult  
Symptomatic endocrinopathy  
Evaluate endocrine function  
Consider pituitary scan  
Symptomatic with abnormal 
lab / pituitary scan:  
Delay M7824 therapy 
1 to 2 mg/kg/day 
methylprednisolone IV or by 
mouth equivalent  
Initiate appropriate hormone 
therapy  
No abnormal lab / pituitary 
MRI scan but symptoms 
persist:  
Repeat labs in 1 to 3 weeks / 
MRI in 1 month  
If improves (with or without hormone 
replacement):  
Taper steroids over at least 1 month and 
consider prophylactic antibiotics for 
opportunistic infections  
Resume M7824 therapy  
Subjects with adrenal insufficiency may need 
to continue steroids with mineralocorticoid 
component  
Suspicion of adrenal crisis (for 
example, severe dehydration, 
hypotension, shock out of proportion 
to current illness)  
Delay or discontinue M7824 therapy  
Rule out sepsis  
Stress dose of IV steroids with mineralocorticoid activity  
IV fluids  
Consult endocrinologist  
If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathy  
 


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16.4 APPENDIX D: DERKAY STAGING FOR RRP 
 
 
 
The anatomic score will be used to determine response or progression-see section 6.2