Clinical trial NCT02859454
Conditions: Recurrent Respiratory Papillomatosis Juvenile Laryngeal Papilloma Laryngeal Papilloma, Recurrent Respiratory Papillomatosis Human Papilloma Virus
Keywords: PD-L1 Expression Human Papilloma Virus (HPV) Juvenile-onset Disease Papillomatous Lesions Monoclonal Antibody
Sponsor: National Cancer Institute (NCI)
Start date: 2016-08-06; Completion date: 2021-09-15
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Recurrent respiratory papillomatosis (RRP) is a rare disease caused by human papillomavirus. It can cause voice changes, airway compromise, pulmonary lesions, and cancers. Programmed death-ligand 1 (PD-L1) is a protein on cells. It may be able to stop or decrease the immune system s response to viruses such as human papillomavirus. The drug Avelumab interferes with the activity of PD-L1. Researchers want to see if Avelumab treats RRP and study its side effects.

Objective:

To see if Avelumab works in treating RRP and is safe.

Eligibility:

People ages 18 and older with aggressive RRP that has not responded to available treatments

Design:

Participants will be screened with:

Medical history

Previously collected tumor tissue

Physical exam

Blood, urine, and heart tests

Endoscopy procedure: A small tube with a camera is used to look in the nose, throat, larynx, and upper windpipe.

Before starting treatment, participants will have:

Endoscopy under anesthesia. A sample of papilloma will be taken.

Voice handicap questionnaire

Computed tomography (CT) scans

Apheresis: An intravenous (IV) is inserted into an arm vein. White blood cells are separated from the rest of the blood and stored for research. The rest of the blood is returned through the same IV or one in the other arm.

Participants will get the study drug by IV every 2 weeks for up to 12 weeks.

Participants will repeat the previous tests throughout the study.

If they respond to treatment, participants will be evaluated every 6 weeks (3 times), then every 12 weeks (3 times), then every 26 weeks (2 times) until their disease progresses.

Participants will be evaluated 30 days after their last infusion. They will then be contacted annually.

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 require repeated interventional procedures for disease control.
* Study of a small number of RRP samples has shown programmed death-ligand 1 (PD-L1) expression by inflammatory mononuclear cells and by papilloma epithelial cells.
* This clinical trial will evaluate the activity of a PD-L1-targeted drug, avelumab, in the treatment of RRP. 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 avelumab 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

* Phase II clinical trial
* Simon optimal two-stage design with initial enrollment of 12 patients and expansion to 37 patients if one or more complete response(s) is/are observed in the initial patients.

Arms: arm 1: Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses.
Interventions: intervention 1: Avelumab
Intervention descriptions: intervention 1: Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses.

Protocol documents:
Prot_SAP_002.pdf: 
Abbreviated Title: Avelumab in RRP  
 
 
Version Date: 12/1/2020 
Abbreviated Title: Avelumab for RRP  
NIH Protocol #: 16C0160 
NCT #: NCT02859454 
Version Date: 12/1/2020 
 
Title: A Phase II Study of Avelumab in Subjects with Recurrent Respiratory Papillomatosis 
 
NCI Principal Investigator:       Scott Norberg, DO 
 
Genitourinary Malignancies Branch (GMB)  
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: 
Avelumab 
IND Number: 
130884 
Sponsor: 
Center for Cancer Research  
Manufacturer: 
EMD Serono 
Commercial Agents:  None 
 
 


Abbreviated Title: Avelumab in RRP  
 
 
Version Date: 12/1/2020 
     
 
 
2 
 
PRÉCIS  
Background 
x Recurrent respiratory papillomatosis (RRP) is a rare papillomatous disease of the aerodigestive 
tract that is caused by the Human Papilloma Virus (HPV). 
x RRP can progress to cause airway compromise, fatal pulmonary lesions, and invasive cancers. 
x There is no effective systemic therapy for RRP. Patients require repeated interventional 
procedures for disease control. 
x Study of a small number of RRP samples has shown PD-L1 expression by inflammatory 
mononuclear cells and by papilloma epithelial cells. 
x This clinical trial will evaluate the activity of a PD-L1-targeted drug, avelumab, in the 
treatment of RRP.  This drug was selected for its demonstrated activity in a variety of cancers 
and for its acceptable safety profile. 
 
Objective 
x Determine the complete response rate for avelumab in the treatment of patients with RRP. 
 
Eligibility 
x Histologically confirmed diagnosis of RRP. 
x 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. 
x Age 18 years or greater. 
x Eastern Oncology Cooperative Group Performance Score of 0 or 1. 
 
Design 
x Phase II clinical trial 
x Simon optimal two-stage design with initial enrollment of 12 patients and expansion to 37 
patients if one or more complete response(s) is/are observed in the initial patients. 


Abbreviated Title: Avelumab in RRP  
 
 
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TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
1 
INTRODUCTION .................................................................................................................. 5 
1.1 
Study Objectives .............................................................................................................. 5 
1.2 
Background and Rationale ............................................................................................... 5 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 10 
2.1 
Eligibility Criteria .......................................................................................................... 10 
2.2 
Screening Evaluation...................................................................................................... 13 
2.3 
Baseline Evaluation ........................................................................................................ 14 
2.4 
Participant Registration and Status Update Procedures ................................................. 14 
3 
STUDY IMPLEMENTATION ............................................................................................ 14 
3.1 
Study Design .................................................................................................................. 14 
3.2 
Drug Administration ...................................................................................................... 17 
3.3 
On-study assessments ..................................................................................................... 17 
3.4 
Dose Modifications/Delay.............................................................................................. 20 
3.5 
Study Calendar ............................................................................................................... 23 
3.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 26 
3.7 
Stopping Rule ................................................................................................................. 26 
4 
BIOSPECIMEN COLLECTION .......................................................................................... 27 
4.1 
Correlative Studies For Research ................................................................................... 27 
5 
DATA COLLECTION AND EVALUATION ..................................................................... 31 
5.1 
Data Collection ............................................................................................................... 31 
5.2 
Response Criteria ........................................................................................................... 32 
5.3 
Toxicity Criteria ............................................................................................................. 35 
6 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .... 35 
6.1 
Definitions ...................................................................................................................... 35 
6.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 35 
6.3 
NCI Clinical Director Reporting .................................................................................... 35 
6.4 
NIH Required Data and Safety Monitoring Plan ........................................................... 35 
7 
SPONSOR PROTOCOL/SAFETY REPORTING ............................................................... 36 


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7.1 
Definitions ...................................................................................................................... 36 
7.2 
Assessment of Safety Events.......................................................................................... 37 
7.3 
Reporting of Serious Adverse Events ............................................................................ 38 
7.4 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 38 
7.5 
Reporting Pregnancy ...................................................................................................... 39 
7.6 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 39 
8 
CLINICAL MONITORING ................................................................................................. 39 
9 
STATISTICAL CONSIDERATIONS.................................................................................. 40 
10 COLLABORATIVE AGREEMENT ................................................................................... 40 
10.1 
Cooperative Research and Development Agreement ................................................. 40 
10.2 
Material Transfer Agreement ..................................................................................... 40 
11 HUMAN SUBJECTS PROTECTIONS ............................................................................... 40 
11.1 
Rationale For Subject Selection ................................................................................. 40 
11.2 
Participation of Children ............................................................................................ 41 
11.3 
Participation of Pregnant Women............................................................................... 41 
11.4 
Evaluation of Benefits and Risks/Discomforts ........................................................... 41 
11.5 
Consent  Process and Documentation ........................................................................ 42 
12 PHARMACEUTICAL INFORMATION ............................................................................. 42 
12.1 
Avelumab IND#  130884 ........................................................................................... 42 
13 REFERENCES ..................................................................................................................... 45 
14 APPENDICES ...................................................................................................................... 47 
14.1 
Appendix A: Performance Status Criteria .................................................................. 47 
14.2 
Appendix B: Voice Handicap Index-10 ..................................................................... 48 
14.3 
Appendix C: Management of Immune-Related Adverse Events ............................... 49 
14.4 
Appendix D: Derkay Staging for RRP ....................................................................... 55 
 


Abbreviated Title: Avelumab in RRP  
 
 
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1 
 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
To determine the complete response rate for avelumab in the treatment of patients with recurrent 
respiratory papillomatosis (RRP). 
1.1.2 Secondary Objectives 
x Exploratory analyses to assess: 
o PD-L1 expression as a potential biomarker of response.  
o HPV type as a potential biomarker of response. 
o Induction of HPV-specific T cells responses. 
o Clearance of HPV infection from normal appearing mucosa.  
x Determine the effect of treatment with avelumab on Derkay and Voice Handicap Index-10 
scores. 
x Determine the partial response rate for avelumab 
x Determine the duration of clinical responses to avelumab 
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 
[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 persistent 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-Į and local injection of anti-viral and antiangiogenic 


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agents [5]. Study results have been inconsistent, and no single adjuvant approach has been 
widely adopted or accepted as the standard of care.  
1.2.2
Avelumab 
Avelumab is a fully human monoclonal antibody (HuMAb; immunoglobulin G1 [IgG1]) that 
targets programmed death-ligand 1 (PD-L1). Programmed death-1 (PD-1) is a negative 
regulatory molecule expressed by activated T and B lymphocytes. Binding of PD-1 to its ligand, 
PD-L1, results in the down-regulation of lymphocyte activation (Figure 1). Inhibition of the 
interaction between PD-1 and PD-L1 promotes activation of adaptive immunity and antigen-
specific T-cell responses to both foreign antigens as well as self-antigens. Avelumab is produced 
using standard mammalian cell cultivation and chromatographic purification technologies.  
Figure 1 
Pardoll, Nat Rev Cancer, 2012 
The clinical use of monoclonal antibodies that block T-cell inhibitory receptors has provided 
transformative information on the nature of the immune system and cancer.  An emerging picture 
suggests that endogenous immune responses can mediate effective tumor regression and/or 
improved survival even in patients with large volume tumors resistant to other forms of therapy.  
Some of the unique features of this type of therapy, based largely on experience in advanced 
melanoma, include:  improved overall survival (OS) with or without radiographic responses or 
improved progression-free survival (PFS); responses that may be delayed or occur after 
radiographic disease progression; combinations of immune modulators with enhanced or novel 
activities (in the example of anti-CTLA4 and anti-PD-1 agents); and toxicity that is almost 
exclusively immune or inflammatory in nature.  It is not yet clear what factors determine 


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responses and which components of the immune system are needed for this to occur.  It seems 
likely that both memory helper and effector cells would be needed to sustain long-term 
responses. Increasing emphasis has been placed on understanding the relationships of the tumor, 
cellular infiltrate, and immunologic milieu surrounding each tumor.   
PD-1, a 55-kDa type 1 transmembrane protein, is a member of the CD28 family of T-cell co-
stimulatory receptors that include Ig super family member CD28, CTLA-4, inducible co-
stimulator (ICOS), and B and T lymphocyte attenuator (BTLA).[8]  PD-1 is transiently but 
highly expressed on activated T cells functioning to limit immune effectors at the site of 
activation.  Chronic stimulation may prevent the re-methylation of the PD-1 gene leading to 
continuous expression and characterizes a state of “exhausted” T cells that lose function and 
proliferative capacity while enhancing a suppressive tumor microenvironment.  PD-1 may act 
together with other T-cell modulating molecules, including CTLA-4, TIM-3, lymphocyte-
activation gene 3 (LAG-3) as well as indoleamine-pyrrole 2,3-dioxygenase 1 (IDO-1), cytokines, 
and transforming growth factor beta (TGF-beta).   
Two ligands specific for PD-1 have been identified:  PD-ligand 1 (PD-L1, also known as B7-H1 
or CD274, expressed on tumor, antigen-presenting cells [APCs], and dendritic cells [DCs]) and 
PD-L2 (also known as B7-DC or CD273, expressed on endothelial cells).  The interaction of PD-
1 with PD-L1 and PD-L2 results in negative regulatory stimuli that down-modulate the activated 
T-cell immune response through SHP-1 phosphatase.   
PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis (C57BL/6) and 
cardiomyopathy (BALB/c).  In transplantable tumor models that expressed PD-1 and LAG-3 on 
tumor-infiltrating CD4+ and CD8+ T cells dual anti-LAG-3/anti-PD-1 antibody treatment cured 
most mice of established tumors that were largely resistant to single antibody treatment.[9]  
Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual 
knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, 
leading to eventual lethality. 
PD-L1 expression is found on a number of tumors, and is associated with poor prognoses based 
on OS in many tumors, including melanoma,[10] renal,[11-13] bladder, esophageal,[14] 
gastric,[15] ovarian,[16] pancreatic,[17] lung,[18] and other cancers.[8] 
The PD-1/PD-L1 axis plays a role in human infections, particularly in hepatitis C virus (HCV) 
and human immunodeficiency virus (HIV).  In these cases, high expression levels of PD-1 were 
found in viral-specific CD8+ T cells that also display a non-responsive or exhausted phenotype.  
Non-responsive PD-1-high T cells were observed in simian immunodeficiency virus (SIV) 
infection in rhesus macaques.  Treatment of SIV-infected macaques with an anti-PD-1 mAb (3 
mg/kg x4) resulted in decreased viral loads and increased survival along with expanded T cells 
with increased T-cell functionality.   
1.2.2.1 Nonclinical Development of Avelumab 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, avelumab alone was 
well tolerated (change this reference to the avelumab IB)[8]. Avelumab bound specifically to 
monkey PD-L1 with an affinity constant of 1.1 nM.  In monkeys, a no-observed-adverse-effect-
level was observed at a dose of avelumab significantly higher (140 mg/ml) than that selected for 
clinical development (10 mg/ml). Avelumab monotherapy increased survival time in MC38 


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(colon carcinoma) and PANC02 (pancreas adenocarcinoma) tumor-bearing mice in a CD8 T-cell 
dependent fashion and appeared to induce NK-cell mediated antibody dependent cellular 
cytotoxicity in some tumors.  
1.2.2.2 Clinical Development of avelumab 
Avelumab is an investigational fully-human monoclonal antibody (IgG1) that specifically targets 
PD-L1. It has demonstrated clinical activity in a variety of solid tumor types including NSCLC, 
merkel-cell carcinoma, gastric, ovarian and bladder cancer. Similar to other checkpoint 
inhibitors, many responses have been durable lasting beyond the duration of active therapy. Over 
700 patients have been treated in initial MTD and expansion cohort phase I trials, with a phase II 
trial in metastatic merkel-cell carcinoma and a phase III trial in recurrent NSCLC underway. The 
clinical activity and safety information presented here focuses primarily on data obtained from 
EMR100070-001 (Phase I, open label trial in primarily Caucasian patients) and MER100070-002 
(Phase I, open label trial in Asian patients). 
Nine of 53 (16.9%) LQLWLDOSDWLHQWVH[SHULHQFHGJUDGH$(VSRWHQWLDOO\UHODWHGWRDYHOXPDE
including immune-related AEs. None of the subjects treated with doses up to 10 mg/kg 
experienced a DLT, thus 10 mg/kg q2 weeks dose of avelumab was considered a safe and well-
tolerated dose for further investigation in the expansion cohorts 
Expansion cohorts in breast, NSCL, gastric, ovarian and urothelial cancer were administered 10 
mg/kg every 2 weeks. Of 717 patients treated with this dose and schedule, 498/717 (69%) 
experienced treatment-UHODWHG$(VRIDQ\JUDGHDQGH[SHULHQFHGJUDGH$(V
The most common grade 3 reactions included infusion side related reactions, (134, 18.7%), 
fatigue (130, 18.1%), nausea (74, 10.3%), diarrhea (49, 6.8%), chills (48, 6.7%0 and decreased 
appetite (37, 5.2%). The 14 subjects reporting Grade 4 treatment-related TEAEs included 7 
subjects (3.8%) in the NSCLC expansion cohort with the PTs of infusion-related reaction (2 
subjects), amylase increased, embolic stroke, frontal lobe epilepsy, monoplegia, syncope, 
dyspnea, pneumonitis, and autoimmune neutropenia (each in 1 subject). Further Grade 4 
treatment-related TEAEs were seen in 5 subjects of the metastatic breast cancer (MBC) 
expansion cohort (3.0%) with the PTs of gamma-glutamyltransferase increased, hypokalemia, 
respiratory failure, anemia, neutropenia, thrombocytopenia, and cardiac arrest (each in 1 subject). 
The other 2 subjects who reported Grade 4 treatment-related TEAEs were 1 subject in the 
mesothelioma expansion cohort (blood creatine phosphokinase increased) and 1 subject in the 
urothelial carcinoma expansion cohort (myositis). 
The 4 subjects who experienced Grade 5 treatment-related TEAEs were 2 subjects in the NSCLC 
expansion cohort (radiation pneumonitis [Subject ID 172-0004] and acute respiratory failure 
[Subject ID: 168-0004]) and 2 subjects in the MBC expansion cohort (respiratory distress 
[Subject ID 139-0004] and acute hepatic failure [Subject ID: 120-0014]). 
The NSCLC and ovarian carcinoma expansion cohorts from the EMR100070-001 trial have 
demonstrated objective response rates of 13.6% and 10.7%, respectively. Within the NSCLC 
expansion cohort, progression free survival was extended from 5.9 weeks to 12 weeks and 
overall survival was extended from 4.6 months to 8.9 months.  


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1.2.2.3 Pharmacokinetics 
Pharmacokinetics (PK) of avelumab was linear in the range of 1 to 20 mg/kg, with dose-
proportional increases in maximum serum concentration (Cmax) and area under the 
concentration-time curve from time zero to infinity (AUC0-), with low to moderate inter-subject 
variability observed at each dose level (insert avelumab IB here)[8].  Clearance of avelumab is 
independent of dose in the dose range (1-20 mg/kg).  Body weight normalized dosing showed 
approximately constant trough concentrations over a wide range of body weights.  The mean 
terminal elimination half-life of avelumab is 5 days. 
1.2.3 PD-1-targeted therapy for RRP 
RRP is caused by HPV infection.  HPV infections are common, but most individuals clear the 
virus without manifesting papillomas, dysplasia, or invasive cancers [19].  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 [20].[21][21][21]. Efforts to study systemic immunotherapy for RRP have been limited.  
Adjuvant IFN-Į after papilloma treatment was shown to increase short-term time to recurrence 
but did not demonstrate long-term benefit [22].  
Clinical trials with new immunotherapeutic agents such as checkpoint inhibitors that block the 
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), or programmed cell death 1 (PD-1) 
receptors or their ligands such as PD-L1, have not been reported for the treatment of RRP. PD-1 
expression has been observed by flow cytometric analysis of T cells infiltrating respiratory 
papillomas, and PD-L1 mRNA expression in papillomas has been observed by RT-PCR [23].  
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 (Table 1 and Figure 2).  
Expression of PD-L1 by tumor-infiltrating immune cells or by the tumor cells themselves has 
positively correlated with tumor response in clinical trials of drugs PD-1/PD-L1-targeted drugs 
[24].  This clinical trial will evaluate the activity of a PD-L1-targeted drug, avelumab, in the 
treatment of RRP.  This drug was selected for its demonstrated activity in a variety of cancers 
and for its acceptable safety profile. 
Table 1 PD-L1 expression on RRP 
 
N  
(30 samples tested) 
% 
Epithelial cell membranous or 
infiltrating hematopoietic cells 
24 
80 
Epithelial cell membranous 
18 
60 
Infiltrating hematopoietic cell 
22 
73 
Epithelial cell membranous and 
infiltrating hematopoietic cells 
16 
53 
 


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Figure 2 
 
1.2.4
Summary of risks and potential benefits 
This clinical trial is being performed to evaluate avelumab 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 avelumab. 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.  
2 
 ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1
Inclusion Criteria 
2.1.1.1
RRP criteria 
PD-L1 expression by a respiratory 
papilloma. Blue arrows point to 
mononuclear inflammatory cells 
demonstrating 
strong 
PD-L1 
expression on their surface.  Purple 
arrows 
point 
to 
squamous 
epithelium of the papilloma with 
PD-L1 expression.   200x, original 
magnification. 


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x Histological diagnosis of RRP confirmed by pathology report from a CLIA-certified 
laboratory. 
x One of the following: 
o A Derkay anatomic score of 10 or greater (See Section 12.4)  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. 
o Tracheal involvement with RRP that has required either two or more endoscopic 
interventions in the last 12 months or a tracheostomy. 
x Greater than or equal to 18 years of age. 
2.1.1.2 Able to understand and sign the Informed Consent Document. 
2.1.1.3 Clinical performance status of ECOG 0 or1.  See section 12.1 
2.1.1.4 Willing to undergo endoscopic evaluation with biopsies in compliance with this 
protocol. 
2.1.1.5 No systemic therapy for RRP for four weeks prior to treatment. 
2.1.1.6 Screening laboratory values must meet the following criteria and should be obtained 
within 14 days prior to first dose: 
o :%&!ȝ/ 
o 1HXWURSKLOV!ȝ/ 
o Platelets > 100 x103ȝ/ 
o Hemoglobin > 9.0 g/dL 
o Serum creatinine < 1.5 x ULN or creatinine clearance (CrCl) > 30 mL/min 
(measured or calculated using the Cockcroft-Gault formula below): 
Female CrCl:  (140 - age in years) x weight in kg x 0.85  
72 x serum creatinine in mg/dL 
Male CrCl:     (140 - age in years) x weight in kg x 1.00  
72 x serum creatinine in mg/dL 
o AST/ALT  2.5 x ULN; for subjects with documented metastatic disease to the 
OLYHU$67DQG$/7OHYHOVî ULN 
o Total Bilirubin  1.5 x ULN  
2.1.1.7 Sexually active subjects (men and women) and all subjects of reproductive potential 
must agree to use two methods of contraception: one highly effective and one other 
effective method  for at least 28 days prior, throughout  the avelumab treatment and for 
at least 60 days after avelumab 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. 


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2.1.1.8 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. 
2.1.1.9 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. 
2.1.1.10 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, 
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 Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or immune 
checkpoint pathways. 
2.1.2.6 Patients who are receiving any other investigational agents 
2.1.2.7 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-PHQRSDXVHLVGHILQHGDVDPHQRUUKHDFRQVHcutive months.  
Note: women who have been amenorrheic for 12 or more months are still considered to 


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13 
 
be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, 
anti-estrogens, ovarian suppression or any other reversible reason. 
2.1.2.8 History of allergy to study drug components. 
2.1.2.9 History of severe hypersensitivity reaction to any monoclonal antibody *UDGH
NCI-CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or 
more features of partially controlled asthma). 
2.1.2.10 Clinically significant (i.e., active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months 
SULRUWRHQUROOPHQWXQVWDEOHDQJLQDFRQJHVWLYHKHDUWIDLOXUH1HZ<RUN+HDUW
Association Classification Class II), or serious cardiac arrhythmia requiring medication. 
2.1.2.11 Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however, 
alopecia, VHQVRU\QHXURSDWK\*UDGH RURWKHU*UDGH$(VQRWFRQVWLWXWLQJDVDIHW\
risk based on investigator's judgment are  acceptable. 
2.1.2.12 Known alcohol or drug abuse. 
2.1.2.13 Vaccination within 4 weeks of the first dose of avelumab and while on trial is 
prohibited except for administration of inactivated vaccines. 
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).  
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 2.1.1.8 - 2.1.1.10 (within 90 days prior 
to subject enrollment). 


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2.2.2 Within 3 days prior to subject receiving the first dose of study drug:  
2.2.2.1 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  
2.2.2.2 Pregnancy test in women of childbearing potential. 
2.2.2.3 Review of concomitant 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 imaging is used for response 
assessment. 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. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
3.1.1 General study plan   
This protocol is a phase II study of avelumab.  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. 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. 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.  Leukapheresis will be performed 
prior to the first dose of avelumab (see Section 4.1.1).   
Avelumab will be administered at a flat dose of 10 mg/kg 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 avelumab (9-17 days after the first dose). 
Leukapheresis will also be obtained at this time point. These procedures should occur before the 
second dose of avelumab. Disease response will first be assessed six weeks after the first dose of 
avelumab (+/- 7 days), which corresponds to the end of the first course (3 doses) of avelumab, 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 avelumab, if 


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applicable. If patients have a complete response or no response, 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 (+/- 7 days). 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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16
3.1.2
Protocol Schema 
Avelumab 10 mg/kg IV x 1 
Screening and baseline evaluations including:  
Clinic-based examinations, EUA, operative endoscopy, biopsy, and 
leukapheresis 
2 week EUA, operative endoscopy, biopsy, and Leukapheresis H&P, 
clinic-based endoscopy, Voice Handicap Index-10 and imaging 
Treatment 
discontinuation: EUA, 
operative endoscopy, 
biopsy (if CR) or surgical 
debulking (if NR) 
Avelumab 10 mg/kg 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). 
Response assessment: H&P, 
clinic-based endoscopy, Voice 
Handicap Index-10 and imaging 
Avelumab 10 mg/kg IV x q 2 weeks x 2 
No response or complete response 
Partial response 


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3.2 
DRUG ADMINISTRATION 
3.2.1 Avelumab 
Avelumab will be administered at a dose of 10 mg/kg IV every other week for up to 12 weeks 
total (6 cycles).  All patients will be pre-treated with an antihistamine and acetaminophen 30-60 
minutes prior to each dose (for example, 25-50 mg diphenhydramine and 500-650 mg 
acetaminophen). Avelumab is to be diluted in 250 mL of 0.45% or 0.9% saline solution (sodium 
chloride injection) and administered as an IV infusion, using a volumetric pump with a 0.2/0.22 
micron in-line filter at the protocol-specified dose. It is not to be administered as an IV push or 
bolus injection.   
Avelumab 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.  
Avelumab 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 
Drug 
Dose  
Days 
Avelumab 
10 mg/kg 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.  
3.3 
ON-STUDY ASSESSMENTS 
If doses are delayed, assessments and research studies will be postponed accordingly.  
3.3.1 Prior to each dose within 3 days of drug administration 
x Targeted physical examination if clinically indicated which may include clinic-based 
flexible nasopharyngolaryngoscopy and/or tracheoscopy with assignment of a Derkay 
score if the Derkay score is being used as the primary response assessment 
x Vital signs and oxygen saturation at rest and after exertion 
x Assess for symptoms of myocarditis (chest pain, shortness of breath, swelling of 
ankles or feet) 
x Pregnancy test in women of childbearing potential 


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x CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH 
with reflexive Free T4, Free T3 
x TBNK  
x Adverse events assessment 
x Research blood:   
• 
6 Cell Preparation Tubes (CPT) (48 mL) will be collected for immunological 
testing and processed as described in section 4.1.1. Attention Jeremy Rose, Bldg. 
10, room 12C216 contact phone: 301-594- 5339.  
• 
1 Serum Separator Tubes (SST) (8 mL) will be obtained for serum collection and 
processed as described in section 4.1.1 .  Attention Jeremy Rose, Bldg. 10, room 
12C216 contact phone: 301-594-5339.  
x Review of concomitant medications 
x Voice Handicap Index-10 assessment questionnaire 
3.3.2 Additional studies at a single time point two weeks after the first dose of avelumab 
x Leukapheresis (see Section 4.1.1) 
x Exam under anesthesia (sedation or general anesthesia) including rigid and/or flexible 
endoscopy with biopsies to assess disease response, clinical signs of inflammation or 
airway compromise, and to obtain biopsies for research. 
3.3.3 Every 6 week (3 cycles) (+/- 7 days) response assessment (performed at 6 and 12 weeks 
after first dose of avelumab) 
x Interval targeted history and physical. 
x Clinic-based flexible nasopharyngolaryngoscopy and/or tracheoscopy. This will 
include standard bright light endoscopy and videostroboscopy, and assignment of a 
Derkay score. This endoscopic examination combined with radiographic examination 
(if radiographically measurable disease is present) will be used to determine response 
to treatment.  
x Voice Handicap Index-10 assessment questionnaire, see Section 12.2. 
x Imaging studies if imaging is used for response assessment. 
3.3.4 Every 1 week between on-site assessments 
x 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) will be 
assessed. 
x Laboratory studies as follows: CBC w/differential, LFTs (ALT, AST, total bilirubin, 
alkaline phosphatase), BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, 
glucose, amylase and lipase.  


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3.3.5 At completion of treatment 
x Targeted physical examination if clinically indicated which may include clinic-based 
flexible nasopharyngolaryngoscopy and/or tracheoscopy 
x Vital signs and oxygen saturation at rest and after exertion 
x Symptoms of myocarditis (chest pain, shortness of breath, swelling of ankles or feet) 
will be assessed 
x Pregnancy test in women of childbearing potential 
x CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH 
with reflexive Free T4, Free T3 
x TBNK  
x Adverse events assessment 
x Research blood:   
• 
6 CPT tubes (48 mL) will be collected for immunological testing and processed as 
described in section 4.1.1. Attention Jeremy Rose, Bldg. 10, room 12C216 contact 
phone: 301-594- 5339.  
• 
1 SST tube (8 mL) will be obtained for serum collection and processed as 
described in section 4.1.1 .  Attention Jeremy Rose, Bldg. 10, room 12C216 
contact phone: 301-594-5339.  
x Clinic-based flexible nasopharyngolaryngoscopy and/or tracheoscopy. This will 
include standard bright light endoscopy and may include videostroboscopy, and 
assignment of a Derkay score if the Derkay score is being used for response 
assessment. This endoscopic examination will be used to assess treatment response. 
x Imaging studies if imaging is used for response assessment. 
x Voice Handicap Index-10 assessment questionnaire. 
x Exam under anesthesia (sedation or general anesthesia) including rigid and/or flexible 
endoscopy with biopsies to perform standard of care papilloma debulking, to obtain 
biopsies for research and to validate complete response or the presence of persistent 
disease. These tests will be done 2 and 6 weeks after the first dose of avelumab for all 
patients. The same tests will be repeated 12 weeks after the first dose for patients that 
demonstrate a partial response and receive an additional 6 weeks of treatment.   
3.3.6 Follow-up studies  
x Patients who experience a complete response or partial response will be evaluated 
every 6 weeks x 3, then every 12 weeks x 3, then every 26 weeks x 2 or until disease 
progression (+/- 10 days for each time point).  After completing the first 2 years’ 
worth of follow up clinic visits, patients will be contacted annually (+/- one month) 


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for 3 years (a total of 5 years follow up) for patient status, dates of disease recurrence 
and interventions to treat recurrent disease. 
x 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. 
x Evaluations will include: 
• 
Interval directed history and physical 
• 
CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN 
or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, 
TSH with reflexive Free T4, Free T3 
• 
TBNK  
• 
Vital signs and oxygen saturation at rest and after exertion 
• 
Clinic-based flexible nasopharyngolaryngoscopy and/or tracheoscopy including 
standard bright light endoscopy and videostroboscopy with assignment of a 
Derkay score 
• 
Voice Handicap Index-10 assessment questionnaire. 
• 
Research blood:  At each clinic visit and at subsequent time points at the 
discretion of the patient and the investigators: 
• 
6 CPT tubes (48 mL) will be collected for immunological testing and 
processed as described in section 4.1.1. Attention Jeremy Rose, Bldg. 10, 
room 12C216 contact phone: 301-594- 5339.  
• 
1 SST tube (8 mL) will be obtained for serum collection and processed as 
described in section 4.1.1 .  Attention Jeremy Rose, Bldg. 10, room 12C216 
contact phone: 301-594-5339. 
• 
Adverse events will be followed until return to baseline or stabilization of event. 
• 
Imaging studies if imaging is used for response assessment. 
• 
Patients will be contacted 42 days (+/- 10 days) after the last dose of avelumab to 
check on patient’s status. 
3.4 
DOSE MODIFICATIONS/DELAY 
Dose modifications are not permitted.  
3.4.1 Doses will be delayed for the following: 
x 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 
x Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication.   
x Algorithms for management of toxicities are provided in Section 12.3. 


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3.4.2 Resuming treatment 
Subjects may resume treatment with avelumab under any of the following circumstances: 
x Any grade 2 event that resolves to grade 1 or less within 14 days without systemic 
steroid treatment 
x Grade 3/4 rash that improves to Grade 1/2 with treatment 
x Grade 2/3/4 endocrinopathy that responds to treatment/replacement therapy  
3.4.3 Discontinuing treatment 
Treatment should be permanently discontinued for the following: 
x Any Grade 3 or 4 drug-related adverse event with the exception of criteria listed in 
3.4.2 
3.4.4 Avelumab infusion reactions 
Since avelumab 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. All Grade 3 or 4 infusion reactions 
should be reported within 24 hours to the sponsor and reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE (version 4.0) guidelines. 
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 d 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 
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 


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initial improvement; hospitalization 
indicated for other clinical sequelae  [e.g., 
renal impairment, pulmonary infiltrates]). 
Grade 4: (life-threatening; pressor or 
ventilator support indicated). 
 
 
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 avelumab 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 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 avelumab 
IV infusion.  Alternative treatments for fever (for example, paracetamol) may be given to 
subjects at the discretion of the Investigator. 
3.4.6 Tumor Lysis Syndrome 
In addition, since avelumab 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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3.5 
STUDY CALENDAR   
Procedures 
Screening 
Baseline 
Course 1 
Course 2 
(if indicated) 
 
 
 
 
 
 
Cycle 1  
Day 1 
 
Cycle 2  
Day 1 
  
Cycle 3  
Day 1 
 
End of 
Course 1 
Cycle 1  
Day 1o 
 
Cycle 2  
Day 1 
  
Cycle 3  
Day 1 
 
End of 
Treatment a 
Follow-up q,r 
History and PEb 
Xf 
Xc,e 
Xc,e 
Xc 
Xc 
Xm 
Xc 
Xc 
Xc 
X 
X 
Vital signs, weight, O2 
saturation 
Xf 
Xc,e 
Xc,e 
Xc 
Xc 
 
Xc 
Xc 
Xc 
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 
Xm 
Xc 
Xc 
Xc 
X 
X 
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 
T3c 
Xc,e 
Xc,e 
Xc,e 
Xc 
Xc 
Xm 
Xc 
Xc 
Xc 
X 
X 
Antibody screen for 
Hepatitis B and C; HIVp 
Xp 
 
 
 
 
 
 
 
 
 
 


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Procedures 
Screening 
Baseline 
Course 1 
Course 2 
(if indicated) 
 
 
 
 
 
 
Cycle 1  
Day 1 
 
Cycle 2  
Day 1 
  
Cycle 3  
Day 1 
 
End of 
Course 1 
Cycle 1  
Day 1o 
 
Cycle 2  
Day 1 
  
Cycle 3  
Day 1 
 
End of 
Treatment a 
Follow-up q,r 
Pregnancy testc 
Xc,e 
Xc,e 
Xc,e 
Xc 
Xc 
 
Xc 
Xc 
Xc 
X 
 
TBNKc  
 
Xc,e 
Xc,e 
Xc 
Xc 
X 
Xc 
Xc 
Xc 
X 
X 
Imaging 
 
Xe,f 
 
 
 
Xa,m,n 
 
 
 
Xm,n 
Xm,n 
ECG 
 
X 
 
 
 
 
 
 
 
 
 
Clinic-based Flexible 
nasopharyngolaryngoscop
y and/or tracheoscopy 
with Derkay score 
Xf 
 
Xc,e 
Xi 
Xj 
Xk 
Xc 
Xc 
Xc 
Xm 
X 
Voice Handicap Index-10 
 
 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
X 
Exam under anesthesia 
with biopsies and possible 
debulking 
 
 
Xh 
Xi 
 
Xk 
 
 
 
Xl 
 
Research Bloodc 
 
Xc 
Xc 
Xc 
Xc 
X 
Xc 
Xc 
Xc 
X 
X 
Adverse Eventsc 
 
 
 
Xc 
Xc 
X 
Xc 
Xc 
Xc 
X 
Xd 
Concomitant Medicationsc  
 
Xe 
Xc 
Xc 
Xc 
X 
Xc 
Xc 
Xc 
X 
 
Leukapheresis 
 
 
Xh 
Xi 
 
 
 
 
 
 
 
Avelumab 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
a End of Treatment studies will be performed 42 days (+/- 10 days) after the final Avelumab 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 procedures must be performed within 3 days before each dose of avelumab while on treatment. 


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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 avelumab 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 avelumab 
i 9-17 days after first dose of avelumab and before second dose of avelumab 
j 9-17 days after second dose of avelumab and before third dose of avelumab 
k 9-17 days after third dose of avelumab and before the Course 2 Cycle 1 Day 1 dose, if applicable 
l 9-17 days after last dose of avelumab  
m +/- 10 days 
n If imaging is used for response assessment  
o Tests performed for End of Course 1 time point that were completed within 7 days prior to the Course 2 Cycle 1 Day1 dose of avelumab do not 
need to be repeated for Course 2 Cycle 1 Day 1.  
p within 90 days prior to subject enrollment 
q Patients who experience a complete response or partial response will be evaluated every 6 weeks 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, 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 the 
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. 
s As indicated in section 9.3, 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. 


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3.6 
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. 
3.6.1 Criteria for removal from protocol therapy 
Patients will be taken off treatment for the following: 
x Completion of protocol therapy 
x Participant requests to be withdrawn from active therapy 
x The patient receives any other treatment for RRP or requires the use of any 
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive 
medications.   
x 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.  
x Any Grade 3/4 drug-related adverse events with the exceptions as detailed in section 3.4. 
x Disease progression 
x Participant becomes pregnant 
3.6.2 Duration of Follow up 
Patients who do not experience a complete response will be contacted 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 will be contacted 
annually for three years after completing the first 2 years’ worth of follow up clinic visits (for a 
total of approximately five years of follow up). The dates of disease recurrence and interventions 
to treat recurrent disease will be recorded. 
3.6.3 Off-Study Criteria 
Patients will be taken off study for the following: 
x The patient voluntarily withdraws 
x There is significant patient noncompliance 
x The investigators decide it is in the patient’s best interest 
x The patient completes follow-up 
x Death 
3.7 
STOPPING RULE 
3.7.1 All protocol treatment will be temporarily stopped to allow for review of data and 
consultation with the FDA and IRB if either of the following events occur:  
x Any treatment-related death 
x 7KUHH*UDGHUnexpected Serious Adverse Events  


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3.7.2 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 
BIOSPECIMEN COLLECTION 
Biospecimen collection on this protocol will consist of blood draws, leukapheresis products, and 
biopsies of papillomas and adjacent tissue.   
4.1 
CORRELATIVE STUDIES FOR RESEARCH 
4.1.1 Biospecimen collection before the start of avelumab  
x Patients will also be invited to enroll on protocol 16C0061 for which patients must 
consent separately.  
x Blood will be collected for research purposes.  A total of 12 CPT tubes (8 mL each of 
blood) will be collected prior to the first dose of avelumab. This is a total of 96 mL of 
blood. This blood will 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 
avelumab. One CPT tube will be used to collect plasma which will be frozen in a 
4mL vial. PBML from the remainder of the CPT tubes will be frozen in aliquots of 10 
x 106 cells/vial.  Send to ETIB’s Pre-Clinical Core lab; Attention Jeremy Rose, Bldg. 
10, room 12C216 contact phone: 301-594-5339. 
x 16 mL of blood will be drawn to obtain serum for research purposes (2 SST tubes, 8 
mL per tube) within 14 days prior to the first dose of avelumab.  This will be 
processed in ETIB Pre-Clinical Core and frozen in aliquots of 0.5-1mL/vial. Send to 
ETIB’s Pre-Clinical Core lab; Attention Jeremy Rose, Bldg. 10, room 12C216 contact 
phone: 301-594-5339. 
x A research apheresis sample will be collected prior to first dose of avelumab. 
Apheresis collection will be 5 L volume (as close to 5 L as possible). Apheresis will 
only be performed on patients with adequate peripheral venous access. Cells will be 
transferred to ETIB 's 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 avelumab. 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 be obtained and sent to Dr. Hinrichs’ laboratory. Send to Dr. Hinrichs’ lab; 
Building 10, Room 4B04. 


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x Patients with papillomas that cannot be biopsied by endoscopy may participate in the 
trial. All tissue specimen collection except papilloma biopsies will be performed. 
x Specimens will be cataloged and stored in ETIB’s Pre-Clinical Core lab. Assays will 
be performed retrospectively. 
4.1.2 Biospecimen collection during treatment and follow-up  
x Patients will return to the Clinical Center every two weeks for avelumab dosing.  
Blood and serum for research and TBNK testing will be obtained prior to each dose 
of avelumab.  Blood for research will consist of: 
• 
6 CPT tubes of Research Blood (48 mL) will be collected for immunological 
testing and processed as described in section 4.1.1. Attention Jeremy Rose, Bldg. 
10, room 12C216 contact phone: 301-594- 5339.  
• 
1 SST tube (8 mL) of Research Blood will be obtained for serum collection and 
processed as described in section 4.1.1 .  Attention Jeremy Rose, Bldg. 10, room 
12C216 contact phone: 301-594-5339. 
x Papilloma and adjacent tissue samples will be collected by biopsy 2 weeks after the 
first dose of avelumab (9-17 days after the first dose). This should occur prior to 
second dose of avelumab. Repeat biopsies will be collected again two weeks after the 
third dose of avelumab (9-17 days after the third dose), which corresponds to the end 
of the first course (3 doses) of avelumab. These procedures should occur before 
Course 2, if applicable. Biopsies will again be collected at the time of completion 
debulking for patients who do not experience a complete tumor response. 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: 
Stacey Doran, MD 301-451-6957. 
x A research apheresis sample will be collected 2 weeks after the first dose of avelumab 
(9-17 days after the first dose). This apheresis should occur before the second dose of 
avelumab. Apheresis will only be performed on patients with adequate peripheral 
venous access. Cells will be transferred to ETIB 's 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.If patients experience a 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 will be collected at these time points as described above.  
4.1.3 Research studies 
x Biospecimens will be collected for research to identify biomarkers of response, 
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x Research studies will be considered exploratory analyses and will include all or some of 
the following: assessment of PD-L1 expression by papillomas and papilloma-infiltrating 
immune cells, testing of papillomas and normal appearing mucosa for HPV, 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 [25].  
Generation and isolation of T cells 
Papilloma-infiltrating T cells will be generated from papilloma biopsy specimens by 
culture of 2 mm tissue fragments in culture media with IL-2. Lymphocyte cultures 
will 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 will 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 will be autologous 
immature dendritic cells (DCs) generated from apheresis samples. The DCs will 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 [25]. 
HPV detection and genotyping  
Testing will be performed by Dr. Hinrichs’ laboratory using PCR-based type-specific 
HPV detection and quantification assays [25]. 
Generation of papilloma cell lines. 
When feasible, papilloma biopsy specimens will be sent to Richard Schlegel’s 
laboratory for the generation of papilloma cell lines for use in research at Georgetown 
University Medical Center. The specimens will be provided in a tube of sterile saline 
or similar sterile buffer. The specimens will be deidentified. The source of the 
specimens will be known to the NIH investigators but not the Georgetown University 
investigators.  
Richard Schlegel  M.D., Ph.D. 
Professor and Oscar B. Hunter Chair 
Chair, Department of Pathology 
Director, Center for Cell Reprogramming 
Research Building, Room W500 
Georgetown University Medical School 
3900 Reservoir Road, NW 
Washington, DC 20057 
Telephone:  202-687-1655 


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Transportation to Dr. Schlegel’s laboratory will be provided by courier.  The courier 
will be Washington Express.  The contact information for Washington Express is:   
www.washingtonexpress.com 
800-939-5463 
4.1.4 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.   
4.1.5 Sample Storage, Tracking and Disposition 
Preclinical Development and Clinical Monitoring Facility 
x 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 the ETIB PDCMF’s Microsoft Excel databases on frozen cells and plasma. These 
databases are stored on the NCI group drive in the ETIB ‘PRECLINSERVICE’ folder. 
Access to this folder is limited to PDCMF staff and ETIB clinical staff, requiring individual 
login and password. All staff in the PDCMF laboratory receives annually updated NIH/CIT 
training and maintains standards of computer security. 
x 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. 
x 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. 
x  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. 


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x 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. 
x These freezers are located onsite at the PDCMF laboratory (12C216) or in ETIB common 
equipment space (CRC/3-3273). 
4.1.5.1 Hinrichs laboratory 
x Samples may be transferred from Preclinical Development and Clinical Monitoring 
Facility to the Hinrichs laboratory for the research studies indicated in 4.1.3. 
x Samples transferred to the Hinrichs laboratory will be barcoded and tracked with 
LabMatrix. 
x Laboratory research data will be stored on the NCI secure server in the Hinrichs 
laboratory folder with secure access by laboratory personnel only. 
4.1.6 Protocol Completion/Sample Destruction  
x Once research objectives for the protocol are achieved, researchers can request access to 
remaining samples, providing they have both approval of the Principal Investigator of the 
original protocol under which the samples or data were collected and either an IRB 
approved protocol and patient consent or the OHSRP Exemption Form stipulating that the 
activity is exempt from IRB review. 
x 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. 
Reporting will be per the requirements of section 6.2. 
5 
DATA COLLECTION AND EVALUATION  
5.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
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. 
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. Patients 
will be followed for adverse events for minimum of 30 days after removal from study treatment 
or until off-study, whichever comes first. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 


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x 
Results in discontinuation from the study 
x 
Is associated with clinical signs or symptoms  
x 
Requires treatment or any other therapeutic intervention 
x 
Is associated with death or another serious adverse event, including hospitalization.  
x 
Is judged by the Investigator to be of significant clinical impact 
x 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 6.2.1.   
5.1.1 Concomitant medications recording:  
Only medications used to treat adverse events related to the study medication will be recorded in 
the data base.  
5.1.2 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. 
5.1.3 Collection of Adverse Events following surgery/procedure 
Grade 1 or 2 adverse events that are clearly attributable to surgery/procedure will not be 
recorded.  
5.1.4 Collection of Adverse Events during Follow-up 
Adverse Events that occur during the follow-up period will only be recorded if they are 
considered related to the avelumab. 
5.2 
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 [16]. 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 


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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) [26].  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. 
5.2.1 Baseline assessment 
x All accessible disease will be examined by physical exam and/or endoscopy to establish a 
baseline. 
x Only lesions visualized by clinic-based flexible nasopharyngolaryngoscopy and/or 
tracheoscopy will be included in the baseline objective Derkay score. 
x Imaging studies will be performed if appropriate and baseline measurements determined 
using RECIST 1.1 criteria. 
5.2.2 Definition of measurable disease 
x Any papilloma that can be visualized via clinic-based endoscopy and assigned a score 
using the Derkay system 
x Any papilloma that can be measured by imaging using RECIST 1.1 criteria. 
5.2.3 Definition of disease response 
5.2.3.1 Complete Remission (CR)  
All criteria must be met. 
x No evidence of papillomas on physical exam and/or clinic-based flexible 
nasopharyngolaryngoscopy and/or tracheoscopy. 
x No evidence of papillomas by exam under anesthesia (sedation or general anesthesia) 
with endoscopy and biopsies. 
x Absence of disease by imaging if lesions are assessed by imaging. 
5.2.3.2 Partial response (PR) 
Either criterion may be met. 
x Decrease in Derkay anatomic score of 30 percent or greater 
x Partial tumor response by imaging using RECIST 1.1 criteria 


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5.2.3.3 Progressive disease (PD) 
Any criterion may be met.  
x Increase in objective Derkay anatomic score of 50 percent or greater 
x Disease progression by imaging using RECIST 1.1 criteria 
x New or worsening symptoms attributable to growth of papillomas or new papillomas. 
5.2.3.4 Stable disease 
x Not meeting criteria for CR, PR, or PD. 
5.2.4 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 
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. 


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*** 
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. 
5.3 
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 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
6 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
6.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
6.2 
 OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
6.2.1 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. 
6.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
6.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP 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. 
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. 
6.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
6.4.1 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.  


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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 6.2.1 will be submitted 
within the appropriate timelines.   
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7 
SPONSOR PROTOCOL/SAFETY REPORTING 
7.1 
DEFINITIONS 
7.1.1 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)) 
7.1.2 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: 
x 
Death, 
x 
A life-threatening adverse event (see section 7.1.3) 
x 
Inpatient hospitalization or prolongation of existing hospitalization  
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
x 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
x 
A congenital anomaly/birth defect 
x 
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. 
7.1.3 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) 
7.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.0. 
7.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
x 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. 
x Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
7.1.6 Adverse Events of Special Interest (AESI) 
Myocarditis or other serious autoimmune AEs (even if such events are expected) that occur will 
be reported by the PI and/or study coordinator. These AEs will be submitted to the FDA Division of 
Antiviral Products (DAVP) by the sponsor. 
7.2 
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: 
x 
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. 
x 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 


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x 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor.  
7.3 
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 section 7.2. 
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. 
7.4 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
Reporting will be per the collaborative agreement.  
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described 
below. 
7.4.1 Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
Definition: A suspected adverse reaction to study treatment that is both serious and unexpected. 
SUSARs will be reported within 24 hours of learning of the event to EMD Serono’s parent 
company, Merck via Fax: 781-681-2961 or email: ICSR_CT_GPS@merckgroup.com. 
7.4.2 Serious Adverse Event (SAE) 
Definition: See Section 6.1.5. SAEs will be reported within 24 hours of learning of the event to 
EMD Serono’s parent company, Merck via Fax: 781-681-2961 or email: 
ICSR_CT_GPS@merckgroup.com. 
7.4.3 Pregnancy 
The Investigator 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. 


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7.4.4 Annual Report 
7.5 
THE SPONSOR WILL PROVIDE A COPY OF THE FDA ANNUAL REPORT TO EMD 
SERONO/MERCK AT THE TIME OF SUBMISSION TO THE FDA.REPORTING PREGNANCY  
7.5.1 Maternal exposure 
If a participant 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 becomes known. 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 7.1.2) 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. 
7.5.2 Paternal exposure 
Male participants should refrain from fathering a child or donating sperm during the study and 
for 60 days after the last dose of avelumab. 
Pregnancy of the participant’s partner is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 60 days after the last 
dose should, if possible, be followed up and documented. 
7.6 
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. 
8 
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: 
x Informed consent process 
x Eligibility confirmation 


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x Drug administration and accountability 
x Adverse events monitoring 
x 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.   
9 
STATISTICAL CONSIDERATIONS   
The trial will be conducted using a Simon optimal 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).   
The design will use alpha=0.10 (10% chance of accepting a poor agent) and beta=.10 
(corresponding to 90% power--and 10% 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 37 evaluable 
patients have enrolled. If there are 1 to 3 complete responses in 37 patients, this would be 
considered unacceptably low, while if 4 or more patients have complete responses in 37 patients, 
then the results will be considered sufficiently promising for further evaluation. Under the null 
hypothesis (5% complete response rate), the probability of early termination is 54.0%.  
It is anticipated that up to 2 patients per month may enroll onto this trial; thus, up to 2 years may 
be required to complete accrual. The trial would require up to 37 total evaluable patients; the 
accrual ceiling will be set at 40 patients to allow for a small number of inevaluable patients. 
10 COLLABORATIVE AGREEMENT 
10.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT 
x The study drug avelumab will be provided under a CRADA (EMD Serono, Inc – NCI 
CRADA# 02666/NCI MTA # 41332-16) between the manufacturer, EMD Serono, and 
the Center for Cancer Research, National Cancer Institute. 
10.2 MATERIAL TRANSFER AGREEMENT 
x An MTA is in place with Georgetown University Medical School (NCI MTA# 42132-17) 
for the samples discussed in section 4.1.3 
11 HUMAN SUBJECTS PROTECTIONS  
11.1 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 


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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. 
11.2 PARTICIPATION OF CHILDREN 
Because no dosing or adverse event data are currently available on the use of avelumab in 
patients <18 years of age, children are excluded from this study, but will be eligible for future 
pediatric trials.   
11.3 PARTICIPATION OF PREGNANT WOMEN 
Based on its mechanism of action and data from animal studies, avelumab can cause fetal harm 
when administered to a pregnant woman. Human IgG1 is known to cross the placental barrier 
and avelumab is an immunoglobulin G1 (IgG1); therefore, avelumab 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 
for at least 28 days prior, throughout the avelumab treatment and for at least 60 days after 
avelumab treatment. 
11.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The experimental treatment has a chance to provide clinical benefit though this is unknown. The 
safety profile of avelumab has been established in treatment of over 700 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 
also contribute to our knowledge of the mechanism of action of avelumab and the biology or 
RRP that will help to advance treatment of RRP and other diseases. 
11.4.1 Study drug risks 
The risks associated with the study product are discussed in Section 10.1.4. 
11.4.2 EUA and Biopsy Risks 
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 


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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. 
11.4.3 Risks associated with blood sampling 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
11.4.4 Risks associated with leukapheresis 
Risks may involve bleeding at the apheresis site and lightheadedness. Decrease in blood pressure 
is considered a less common risk. 
11.4.5 Risks associated with CT scans 
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. If a CT scan is used, there will also be a 
risk of exposure to radiation from up to 3 CT scans. The amount of radiation received in this 
study is 0.43 rem which is below the guideline of 5 rem (or 0.5 rem in children) per year allowed 
for research subjects by the NIH Radiation Safety Committee. 
11.5 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.  
12 PHARMACEUTICAL INFORMATION   
12.1 AVELUMAB IND#  130884 
Amino Acid Sequence:  4 polypeptide chains, which include 2 identical heavy chains with 440 
amino acids and 2 identical light chains. 
Other Names: MSB0010718C 
Classification: Anti-PD-L1MAb 
M.W.:  143,832 daltons 


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12.1.1 Mode of Action  
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. 
12.1.2 Description   
Avelumab drug product is a sterile, clear, and colorless concentrate for solution intended for 
intravenous (i.v.) administration. The drug is presented at the concentrations of 10 mg/mL and 
20 mg/mL in single-use glass vial containing 80 mg and 200 mg of avelumab, respectively. 
12.1.3  Source 
Avelumab is an investigational agent that will be supplied to the NIH Pharmacy by EMD Serono. 
12.1.4 Toxicities 
As of 01 June 2015, safety data of 717 subjects who were treated with 10 mg/kg of avelumab 
every 2 weeks and followed up for at least 4 weeks in the pooled tumor expansion cohort of Trial 
EMR 100070-001 were evaluated. 
The most frequently observed treatment-related TEAEs (with an incidence of  2%) of any grade 
in the pooled expansion cohort were infusion-related reaction, fatigue , nausea, diarrhea, chills, 
and decreased appetite. Other frequently seen treatment-related TEAEs with an incidence < 5% 
but  2% included arthralgia, pyrexia, hypothyroidism, pruritus, vomiting, influenza-like illness, 
rash, anemia, AST increased, myalgia, asthenia, headache, ALT increased, dyspnea, and 
constipation.  
Note:  On this protocol, dry mouth has been observed with greater frequency than previously 
observed, from a CTCAE grade 1-2 intensity, and may be attributable to avelumab.  This has 
been noted in the informed consent document. 
12.1.5 Preparation  
Avelumab 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 
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 avelumab 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 avelumab 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 
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12.1.6 Storage and Stability 
Avelumab drug product must be stored at 2°C to 8°C until use, and it must not be frozen. Rough 
shaking of avelumab product must be avoided. Avelumab drug product must be diluted with 0.45% 
or 0.9% saline solution. It is recommended that the diluted avelumab solution is used immediately. 
12.1.7 Administration procedures 
Avelumab is to be administered as an IV infusion, using a volumetric pump with a 0.2/0.22 
micron in-line filter at the protocol-specified dose. It is not to be administered as an IV push or 
bolus injection.  At the end of the infusion, flush the line with a sufficient quantity of normal 
saline. 
12.1.8 Potential Drug Interactions 
   
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13 REFERENCES 
1. 
Mounts, P., K.V. Shah, and H. Kashima, Viral etiology of juvenile- and adult-onset 
squamous papilloma of the larynx. Proc Natl Acad Sci U S A, 1982. 79(17): p. 5425-9. 
2. 
Derkay, C.S., Task force on recurrent respiratory papillomas. A preliminary report. Arch 
Otolaryngol Head Neck Surg, 1995. 121(12): p. 1386-91. 
3. 
Silver, R.D., et al., Diagnosis and management of pulmonary metastasis from recurrent 
respiratory papillomatosis. Otolaryngol Head Neck Surg, 2003. 129(6): p. 622-9. 
4. 
Dedo, H.H. and K.C. Yu, CO(2) laser treatment in 244 patients with respiratory 
papillomas. Laryngoscope, 2001. 111(9): p. 1639-44. 
5. 
Derkay, C.S. and B. Wiatrak, Recurrent respiratory papillomatosis: a review. 
Laryngoscope, 2008. 118(7): p. 1236-47. 
6. 
Armstrong, L.R., C.S. Derkay, and W.C. Reeves, Initial results from the national registry 
for juvenile-onset recurrent respiratory papillomatosis. RRP Task Force. Arch 
Otolaryngol Head Neck Surg, 1999. 125(7): p. 743-8. 
7. 
Kashima, H.K., et al., A comparison of risk factors in juvenile-onset and adult-onset 
recurrent respiratory papillomatosis. Laryngoscope, 1992. 102(1): p. 9-13. 
8. 
 Nivolumab Investigator Brochure, BMS-936558, MDX1106. 2013. 
9. 
Woo, S.R., et al., Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate 
T-cell function to promote tumoral immune escape. Cancer Res, 2012. 72(4): p. 917-27. 
10. 
Taube, J.M., et al., Colocalization of inflammatory response with B7-h1 expression in 
human melanocytic lesions supports an adaptive resistance mechanism of immune 
escape. Sci Transl Med, 2012. 4(127): p. 127ra37. 
11. 
Thompson, R.H., et al., Costimulatory B7-H1 in renal cell carcinoma patients: Indicator 
of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A, 
2004. 101(49): p. 17174-9. 
12. 
Thompson, R.H., et al., Costimulatory molecule B7-H1 in primary and metastatic clear 
cell renal cell carcinoma. Cancer, 2005. 104(10): p. 2084-91. 
13. 
Thompson, R.H., et al., Tumor B7-H1 is associated with poor prognosis in renal cell 
carcinoma patients with long-term follow-up. Cancer Res, 2006. 66(7): p. 3381-5. 
14. 
Ohigashi, Y., et al., Clinical significance of programmed death-1 ligand-1 and 
programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res, 
2005. 11(8): p. 2947-53. 
15. 
Wu, C., et al., Immunohistochemical localization of programmed death-1 ligand-1 (PD-
L1) in gastric carcinoma and its clinical significance. Acta Histochem, 2006. 108(1): p. 
19-24. 
16. 
Dong, H. and L. Chen, B7-H1 pathway and its role in the evasion of tumor immunity. J 
Mol Med (Berl), 2003. 81(5): p. 281-7. 


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17. 
Nomi, T., et al., Clinical significance and therapeutic potential of the programmed death-
1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res, 
2007. 13(7): p. 2151-7. 
18. 
Zitvogel, L., A. Tesniere, and G. Kroemer, Cancer despite immunosurveillance: 
immunoselection and immunosubversion. Nat Rev Immunol, 2006. 6(10): p. 715-27. 
19. 
Venkatesan, N.N., H.S. Pine, and M.P. Underbrink, Recurrent respiratory 
papillomatosis. Otolaryngol Clin North Am, 2012. 45(3): p. 671-94, viii-ix. 
20. 
Smith, E.M., et al., Human papillomavirus infection in papillomas and nondiseased 
respiratory sites of patients with recurrent respiratory papillomatosis using the 
polymerase chain reaction. Arch Otolaryngol Head Neck Surg, 1993. 119(5): p. 554-7. 
21. 
Dudley, M.E., et al., Randomized selection design trial evaluating CD8+-enriched versus 
unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with 
melanoma. Journal of clinical oncology: official journal of the American Society of 
Clinical Oncology, 2013. 31(17): p. 2152-2159. 
22. 
Healy, G.B., et al., Treatment of recurrent respiratory papillomatosis with human 
leukocyte interferon. Results of a multicenter randomized clinical trial. N Engl J Med, 
1988. 319(7): p. 401-7. 
23. 
Hatam, L.J., et al., Immune suppression in premalignant respiratory papillomas: 
enriched functional CD4+Foxp3+ regulatory T cells and PD-1/PD-L1/L2 expression. 
Clin Cancer Res, 2012. 18(7): p. 1925-35. 
24. 
Topalian, S.L., C.G. Drake, and D.M. Pardoll, Immune checkpoint blockade: a common 
denominator approach to cancer therapy. Cancer Cell, 2015. 27(4): p. 450-61. 
25. 
Stevanovic, S., et al., Complete regression of metastatic cervical cancer after treatment 
with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol, 2015. 
33(14): p. 1543-50. 
26. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
 
 
 
 


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14 APPENDICES 
14.1 APPENDIX A: PERFORMANCE STATUS CRITERIA 
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. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 


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14.2  APPENDIX B: VOICE HANDICAP INDEX-10 
 
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 as “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:  
 
 
 
As published in: 
Journal of Voice. Arffa RE, Krishna P, Gartner-Schmidt J, Rosen CA. Normative values for the 
Voice Handicap Index-10. J Voice. 2012;26:462-465 
Otolaryngology-Head and Neck Surgery: Kupfer R, Tatar E, Barry J, Allen C and Merati A. 
Anatomic derkay score is associated with voice handicap in laryngeal papillomatosis in adults. 
Otolaryngology-Head and Neck Surgery.  In Press. 
 
 


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14.3 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 
14.3.1 Gastrointestinal irAEs 
Gastrointestinal irAEs 
Severity of Diarrhea / Colitis 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue avelumab 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 avelumab therapy 
Symptomatic treatment 
If improves to Grade 1:  
Resume avelumab 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 avelumab therapy per 
protocol. 
If worsens or persists > 3 to 5 days with oral 
steroids: 
Treat as Grade 3 to 4 
Grade 3 to 4 
'LDUUKHD*UDGHVWRROVSHU
day over Baseline; incontinence; IV 
IOXLGV 24 hrs; interfering with 
ADL 
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs 
Grade 4:  life-threatening, 
perforation 
Discontinue avelumab 
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  
 
 


Abbreviated Title: Avelumab in RRP  
 
 
Version Date: 12/1/2020 
     
 
 
50 
 
14.3.2 Dermatological AEs 
Dermatological AEs 
Grade of Rash 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 to 2  
&RYHULQJERG\VXUIDFH
area  
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
Continue avelumab 
therapy 
If persists > 1 to 2 weeks or recurs:  
Consider skin biopsy  
Delay avelumab 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 avelumab therapy 
If worsens:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Covering > 30% body surface 
area; life threatening 
consequences  
Delay or discontinue 
avelumab 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 avelumab therapy 
 
 
 


Abbreviated Title: Avelumab in RRP  
 
 
Version Date: 12/1/2020 
     
 
 
51 
 
14.3.3 Pulmonary AEs 
Pulmonary AEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Radiographic changes only  
Consider delay of avelumab 
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 avelumab 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 avelumab 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 avelumab 
therapy 
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)  
 
 
 


Abbreviated Title: Avelumab in RRP  
 
 
Version Date: 12/1/2020 
     
 
 
52 
 
14.3.4 Hepatic AEs 
Hepatic AEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
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 avelumab therapy 
Continue liver function monitoring  
If worsens:  
Treat as Grade 2 or 3 to 4  
Grade 2 
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and / or total bilirubin > 1.5 WR[
ULN  
Delay avelumab therapy 
Increase frequency of 
monitoring to every 3 days  
If returns to Baseline:  
Resume routine monitoring, resume 
avelumab 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 avelumab therapy 
Grade 3 to 4 
AST or ALT > 5 x ULN and / or 
total bilirubin > 3 x ULN  
Discontinue avelumab 
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  
 
 
 


Abbreviated Title: Avelumab in RRP  
 
 
Version Date: 12/1/2020 
     
 
 
53 
 
14.3.5 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 avelumab 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 avelumab 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 
avelumab. 
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 
 
 
 
 


Abbreviated Title: Avelumab in RRP  
 
 
Version Date: 12/1/2020 
     
 
 
54 
 
14.3.6 Endocrine AEs 
Endocrine AEs 
Endocrine Disorder 
Management 
Follow-up 
Asymptomatic TSH abnormality  
Continue avelumab 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 avelumab 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 avelumab 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 avelumab 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  
 


Abbreviated Title: Avelumab in RRP  
 
 
Version Date: 12/1/2020 
55
14.4 APPENDIX D: DERKAY STAGING FOR RRP 
 
The anatomic score will be used to determine response or progression-see section 5.2 

ICF_003.pdf: 
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