Clinical trial NCT02875613
Conditions: Nasopharyngeal Cancer
Keywords: Nasopharyngeal PD-L1 monoclonal antibody Epstein-barr virus
Sponsor: Assuntina Sacco, M.D.
Start date: 2017-01-01; Completion date: 2019-04-01
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether avelumab, an investigational antibody against programmed death-ligand (PD-L1), has an effect on recurrent nasopharyngeal cancer. Avelumab is designed to block the interaction between programmed cell death protein 1 (PD-1), a known immune checkpoint, and PD-L1. By blocking this interaction, the immune system may be stimulated, allowing it to more effectively recognize and attack the cancer.

Detailed description:
This is a prospective, multi-center, open-label, single-arm phase II trial to evaluate the efficacy of Avelumab for patients with recurrent/metastatic, Epstein-Barr virus (EBV)-related nasopharyngeal carcinoma.

Upon study entry, all patients will receive Avelumab 10 milligrams per kilogram (mg/kg) intravenously (IV) on days 1 and 15 of each 28-day cycle. Treatment will be given until disease progression, unacceptable toxicity, investigator decision or patient withdrawal. Dose interruptions may occur per pre-specified criteria for grade 3 or higher toxicity.

Arms: arm 1: Avelumab 10mg/kg IV infusion on days 1 and 15 of 28-day cycle
Interventions: intervention 1: Avelumab
Intervention descriptions: intervention 1: Avelumab 10mg/kg IV on days 1 and 15 of each 28-day cycle. Treatment will be given until disease progression, unacceptable toxicity, investigator decision or patient withdrawal.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version 1.3 
 
 
 
 
 
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An Open-label, Single-arm, Multi-institutional Phase II Trial of Avelumab for Recurrent, 
Metastatic Nasopharyngeal Carcinoma 
 
 
 
Study Chair (Sponsor-Investigator) 
Assuntina G. Sacco, M.D. 
Department of Medicine 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0658 
La Jolla, CA 92093 
Phone: (858) 822-5210 
Fax: (858) 822-5724 
E-mail: agsacco@ucsd.edu 
 
Research Coordinating Center 
UCSD Moores Cancer Center 
3855 Health Sciences Drive #0698 
La Jolla, CA 92093-0698 
Clinical Research Coordinator: TBD 
Phone: TBD 
Fax: TBD 
Email: TBD 
 
 
 
Protocol Number: 160114 
IND Number:  130626 
Study Agent: 
Avelumab 
IND Holder Name:  
Assuntina G. Sacco, M.D. 
 
 
Protocol 
Date 
Original (v 1.3) 
05/17/2016 
 
 
 


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LIST OF INVESTIGATORS 
 
 
UCSD Moores Cancer Center 
Assuntina G. Sacco, M.D., Study Chair, Hematology-Oncology, agsacco@ucsd.edu 
 
Co-investigators: 
Ezra Cohen, M.D., Hematology-Oncology, ecohen@ucsd.edu 
Gregory Daniels, M.D., Hematology-Oncology, gdaniels@ucsd.edu 
Scott Lippman, M.D., Hematology-Oncology, slippman@ucsd.edu 
Kathryn Gold, M.D., Hematology-Oncology, kagold@ucsd.edu 
Robert Weisman, M.D., Head and Neck Surgical Oncology, rweisman@ucsd.edu 
Kevin Brumund, M.D., Head and Neck Surgical Oncology, kbrumund@ucsd.edu 
Charles Coffey, M.D., Head and Neck Surgical Oncology, cscoffey@ucsd.edu 
Brian Sutton, P.A., Hematology-Oncology, bsutton@ucsd.edu 
Tiffany Turpin, P.A., Hematology-Oncology, t6brown@ucsd.edu 
Maechelle Espiritu, N.P., Hematology-Oncology, maespiritu@ucsd.edu 
Geline Tamayo, R.N, Hematology-Oncology, gjtamayo@ucsd.edu 
Joshua Carter, R.N., Hematology-Oncology, jocarter@ucsd.edu 
 
Biostatistician: 
Karen Messer, Ph.D., Family Medicine and Public Health, kmesser@ucsd.edu 
 
 
Collaborating Sites 
Site 
 
 
 
Stanford Cancer Institute 
PI 
 
 
 
A. Dimitrios Colevas, M.D. 
Email  
 
 
colevas@stanford.edu 
 
Site 
 
 
 
University of California, Los Angeles, Jonsson Cancer Center 
PI 
 
 
 
Deborah Wong, M.D., Ph.D. 
Email  
 
 
dewong@mednet.ucla.edu 
 
Site 
 
 
 
University of California, Irvine, Chao Cancer Center 
PI 
 
 
 
Chaitali Nangia, M.D. 
Email  
 
 
cnangia@uci.edu 
 
Site 
 
 
 
University of Southern California, Norris Cancer Center 
PI 
 
 
 
Jorge Nieva, M.D. 
Email  
 
 
jorge.nieva@med.usc.edu 
 
 


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Site 
 
 
 
Providence Cancer Center 
PI 
 
 
 
Rom Leidner, M.D. 
Email  
 
 
Rom.Leidner@providence.org 
 
Site 
 
 
 
Dana-Farber Cancer Institute 
PI 
 
 
 
Nicole Chau, M.D. 
Email  
 
 
Nicole_Chau@dfci.harvard.edu 
 


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Protocol Date 05/17/2016 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
UCSD Principal Investigator / Study Chair 
 
 
_____________________________ 
Printed Name 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
 
 
 
 
 
Participating Site Principal Investigator 
 
 
_____________________________  
_____________________________ 
Printed Name  
 
 
 
Institution 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................................................................ 7 
STUDY SUMMARY ................................................................................................................................................ 10 
1.0 
BACKGROUND AND RATIONALE ................................................................................................................. 14 
1.1 
DISEASE BACKGROUND ................................................................................................................................... 14 
1.2 
ROLE OF EBV INFECTION ON PD-L1 EXPRESSION ................................................................................................. 14 
1.3 
RATIONALE FOR PD-L1 INHIBITION WITH AVELUMAB ........................................................................................... 14 
1.4 
NON-CLINICAL PHARMACOLOGY ....................................................................................................................... 15 
1.5 
CLINICAL EFFICACY ......................................................................................................................................... 16 
1.6 
CLINICAL SAFETY ........................................................................................................................................... 17 
1.7 
CLINICAL DATA OF PD-1/PD-L1 AXIS INHIBITION IN RECURRENT NASOPHARYNGEAL CARCINOMA ............................... 18 
1.8 
RATIONALE FOR STUDY ................................................................................................................................... 18 
2.0 
STUDY OBJECTIVES ..................................................................................................................................... 18 
2.1 
PRIMARY OBJECTIVES ..................................................................................................................................... 18 
2.2 
SECONDARY OBJECTIVES ................................................................................................................................. 18 
2.3 
ENDPOINTS .................................................................................................................................................. 18 
3.0 
PATIENT ELIGIBILITY ................................................................................................................................... 19 
3.1 
INCLUSION CRITERIA ....................................................................................................................................... 19 
3.2 
EXCLUSION CRITERIA ...................................................................................................................................... 20 
4.0 
TREATMENT PLAN ...................................................................................................................................... 22 
4.1 
STUDY DESIGN .............................................................................................................................................. 22 
4.2 
TREATMENT DOSAGE AND ADMINISTRATION ...................................................................................................... 23 
4.3 
TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ....................................................................................... 23 
4.4 
PRE-MEDICATIONS ........................................................................................................................................ 28 
4.5 
PERMITTED CONCOMITANT THERAPY ................................................................................................................. 28 
4.6 
PROHIBITED CONCOMITANT THERAPY ................................................................................................................ 28 
4.7 
OTHER CONSIDERATIONS ................................................................................................................................ 28 
4.8 
PATIENT WITHDRAWAL/DISCONTINUATION FROM STUDY TREATMENT .................................................................... 29 
4.9 
END OF STUDY TREATMENT AND FOLLOW UP ..................................................................................................... 30 
4.10 
PATIENT WITHDRAWAL/DISCONTINUATION FROM STUDY CRITERIA ........................................................................ 30 
5.0 
STUDY PROCEDURES ................................................................................................................................... 30 
5.1 
DEFINITIONS OF STUDY ASSESSMENTS ............................................................................................................... 30 
5.2 
SCREENING/BASELINE PROCEDURES .................................................................................................................. 32 
5.3 
PROCEDURES DURING TREATMENT ................................................................................................................... 33 
5.4 
FOLLOW-UP PROCEDURES ............................................................................................................................... 34 
5.5 
CORRELATIVE STUDIES .................................................................................................................................... 34 
6.0 
MEASUREMENT OF EFFECT ......................................................................................................................... 37 
6.1 
SAFETY/TOLERABILITY ..................................................................................................................................... 37 
6.2 
ANTITUMOR EFFECT ....................................................................................................................................... 37 
7.0 
ADVERSE EVENTS ........................................................................................................................................ 37 
7.1 
ADVERSE EVENT MONITORING ......................................................................................................................... 38 
7.2 
SEVERITY ...................................................................................................................................................... 38 
7.3 
SERIOUSNESS ................................................................................................................................................ 39 
7.4 
RELATIONSHIP ............................................................................................................................................... 39 
7.5 
PRIOR EXPERIENCE ......................................................................................................................................... 39 


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7.6 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS .............................................................................................. 39 
8.0 
AGENT INFORMATION ................................................................................................................................ 41 
8.1 
AVELUMAB ................................................................................................................................................... 41 
9.0 
STATISTICAL CONSIDERATIONS ................................................................................................................... 43 
9.1 
STUDY POPULATIONS ..................................................................................................................................... 43 
9.2 
SAMPLE SIZE AND PRIMARY ANALYSIS ............................................................................................................... 43 
9.3 
ACCRUAL ..................................................................................................................................................... 44 
9.4 
SECONDARY EFFICACY ANALYSES ...................................................................................................................... 44 
9.5 
SECONDARY SAFETY ANALYSES ......................................................................................................................... 44 
9.6 
ANALYSIS OF BIOMARKERS .............................................................................................................................. 44 
10.0 
STUDY MANAGEMENT....................................................................................................................... 44 
10.1 
CONFLICT OF INTEREST ................................................................................................................................... 44 
10.2 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT ............................................................................ 44 
10.3 
REQUIRED DOCUMENTATION FOR MULTI-SITE STUDIES ........................................................................................ 45 
10.4 
PATIENT REGISTRATION .................................................................................................................................. 45 
10.5 
SUBJECT DATA PROTECTION ............................................................................................................................ 45 
10.6 
DATA AND SAFETY MONITORING/AUDITING ....................................................................................................... 45 
10.7 
ADHERENCE TO THE PROTOCOL ........................................................................................................................ 46 
10.8 
AMENDMENTS TO THE PROTOCOL .................................................................................................................... 46 
10.9 
RECORD RETENTION ....................................................................................................................................... 46 
10.10 
OBLIGATIONS OF INVESTIGATORS ...................................................................................................................... 47 
11.0 
REFERENCES ...................................................................................................................................... 48 
12.0 
APPENDICES ...................................................................................................................................... 50 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
ALT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
EBV 
Epstein-Barr Virus 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Ethylenediaminetetraacetic acid 
HIV 
Human Immunodeficiency Virus 
HRPP 
Human Research Protections Program 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
I.V 
Intravenous 
LFT 
Liver function test 
LLN 
Lower Limit Normal 
MoAb 
Monoclonal Antibody 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NK 
Natural Killer 
NSAIDs 
Non-steroidal Anti-inflammatory Drugs 
NSCLC 
Non-small Cell Lung Cancer 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PD-1 
Programmed Death-1 
PD-L1 
Programmed Death Ligand-1 
PET 
Positron Emission Tomography 
PFS 
Progression-free Survival 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
TSH 
Thyroid Stimulating Hormone 
UPR 
Unanticipated Problems involving Risk to subjects or 
others 
WBC 
White Blood Cells 
 
 
 


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Avelumab 
10 mg/kg IV on 
Days 1 and 15 
(28—day cycle) 
E 
N 
R 
O 
L 
L 
M 
E 
N 
T 
 
Discontinue 
Treatment,  
Survival 
Follow-up 
  
  
Continue 
Treatment 
STUDY SCHEMA 
CR 
complete response 
PR 
partial response 
SD 
stable disease 
PD 
progressive disease 
  
CR 
PR 
SD 
  
PD 
Unacceptable toxicity 
Physician/Patient Discretion 


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STUDY SUMMARY 
Title 
An Open-label, Single-arm, Multi-institutional Phase II Trial of 
Avelumab for Recurrent, Metastatic Nasopharyngeal Carcinoma 
Short Title 
Phase II trial of Avelumab for Recurrent/Metastatic Nasopharyngeal 
Carcinoma 
Phase 
2 
Methodology 
Open-label, Single-Arm, Multi-institutional 
Study Duration 
3 years 
Study Center(s) 
University of California, San Diego;  
Stanford Cancer Institute; 
University of California, Los Angeles; 
University of California, Irvine; 
University of Southern California; 
Providence Portland Medical Center; 
Dana-Farber Cancer Institute 
Objectives 
Primary Objective 
1. To determine the clinical activity of Avelumab in the 
management of R/M nasopharyngeal carcinoma. 
Secondary Objective 
2. To determine duration of response 
3. To determine progression-free survival at 6 and 12 months 
4. To determine overall survival 
5. To assess safety and tolerability of Avelumab 
6. To evaluate correlation between molecular markers and 
disease outcome 
7. To determine clinical activity using immune-related RECIST. 
 
Number of Subjects 
39 
Diagnosis and Main 
Inclusion Criteria 
Diagnosis/Main Inclusion Criteria 
• 
Histologically/cytologically confirmed, non-
keratinizing/undifferentiated, EBV-related nasopharyngeal 
carcinoma, not amenable to curative intent therapy 
• 
At least one prior line of chemotherapy 
• 
Measurable disease per RECIST v1.1 
• 
Newly obtained tumor specimen for correlative analysis 
• 
ECOG 0-2 
• 
Adequate hematologic, renal, hepatic function 
• 
Willingness to use appropriate contraception 
Key Exclusion Criteria: 
• 
Prior immunotherapy with inhibitors of PD1/PDL1 axis 
• 
Chemotherapy, RT or major surgery within 4 weeks 
• 
Active CNS metastases (stable permitted) 
• 
Uncontrolled HIV, Active Hepatitis B/C 
• 
Active autoimmune disease 
• 
Uncontrolled intercurrent illness 
• 
Chronic use of steroids or other immunosuppressive agents 


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• 
Clinically significant cardiac disease 
Study Product(s), Dose, 
Route, Regimen 
Avelumab 10mg/kg on days 1 and 15 of 28-day cycle 
Duration of administration 
Avelumab will be continued until disease progression, unacceptable 
toxicity, investigator decision or patient withdrawal. 
Reference therapy 
None 
Statistical Methodology 
Safety population: all patients who have received at least one dose 
of Avelumab. 
 
Intention-to-Treat (ITT) population: all patients who have enrolled to 
the study. 
 
Sample Size/Primary Analysis 
Simon’s optimal two-stage design, primary endpoint of overall 
response (complete and partial responses) at 6 months, based on 
RECIST. 
 
If the overall response rate is ≤15%, we will consider the treatment 
as not meeting the threshold of going further. We will test the null 
hypothesis H0: p≤15% against the alternative hypothesis H1: 
p>15%, where p is the overall response rate after six months of 
study treatment. The two-stage design proposed below will have an 
80% power to reject the null hypothesis and conclude that the true 
overall response rate is above 15%, if the observed overall 
response rate is ≥30%, at 10% significance level. The study design 
is described in detail is as follows: 
 
Stage 1: 19 subjects will be accrued; accrual will be held until the 
progression results for all the 19 subjects are known for the first six 
months. The trial will be terminated at Stage 1 if ≤ 3 of the 19 
subjects have any CR/PR by 6 months; otherwise it will continue to 
Stage 2.  
 
Stage 2: 20 more patients will be accrued. We will reject the therapy 
if, among all the 39 (19+20) subjects, the number of patients who 
have an overall response is ≤8; if ≥9 patients have a defined 
response by RECIST, the treatment will be successful. It will be 
concluded that our study treatment is associated with an overall 
response in more than 15% of patients.   
 
Early stopping probability: Under this design, if the null hypothesis is 
true, the probability of stopping the trial early will be 68.4%.  
 
 
 


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SCHEDULE OF EVENTS 
Procedure 
Screen/ Baseline 
(≤ 21 days, unless 
otherwise noted) 
Treatment Cycles (28-day cycles) 
End of 
Treatment 
(28 (± 7) days 
after last dose) 
Follow-up 
(q3 months) 
Cycle 1 
(± 3 days) 
Cycle 2 
(± 3 days) 
Cycle 3 
(± 3 days) 
Cycle 4 
(± 3 days) 
Each Additional 
Cycle 
(± 3 days) 
Informed Consent 
Within 28 days 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Concomitant Medications 
Assessment 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam1 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs & Height 
X 
X 
X 
X 
X 
X 
X 
 
ECOG 
X 
X 
X 
X 
X 
X 
X 
 
CBC with Diff2 
Within 7 days 
X 
X 
X 
X 
X 
X 
 
CMP3 
Within 7 days 
X 
X 
X 
X 
X 
X 
 
TSH4 
Within 7 days 
 
X 
 
X 
 
X 
 
Pregnancy test5 
Within 72 hours 
 
 
 
 
 
 
 
Urinalysis6 (dipstick) 
X 
 
 
 
X 
 
X 
 
HIV (as clinically indicated) 
X 
 
 
 
 
 
 
 
Hepatitis B & C (as clinically 
indicated) 
X 
 
 
 
 
 
 
 
EBV DNA plasma level7 
X 
 
 
 
X 
 
X 
 
Tumor tissue collection8  
Within 42 days 
 
 
 
 
 
X 
 
Blood Collection for Correlative 
studies9  
X 
 
 
 
X 
 
 
 
CT, MRI, or PET/CT10 
Within 28 days 
 
 
 
X 
 
 
 
Avelumab administration 
X 
X 
X 
X 
X 
 
 


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Survival contact 
 
 
 
 
 
 
X 
Cycles are 28 days in length. 
1. 
Full physical exam at baseline; targeted physical exam at other time points. 
2. 
CBC with Diff: Complete blood count with differential. 
3. 
CMP: Comprehensive metabolic panel (bicarbonate, calcium, chloride, creatinine, glucose, potassium, sodium BUN, albumin, bilirubin total, alkaline 
phosphatase, total protein, ALT, AST).  For patients with known hepatic metastases at time of study entry, liver function tests (including ALT, AST, total 
bilirubin, and alkaline phosphatase) must be performed once weekly for 7 weeks upon treatment initiation. 
4. 
TSH monitoring will occur at baseline, cycle 2, cycle 4, then every 3 cycles thereafter (ie. Cycle 7,10 etc.), and at the end of treatment.  For patients with 
asymptomatic TSH elevation, please refer to Section 4.3.1 for further evaluation.  Specifically, 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. 
5. 
Pregnancy test for females of child-bearing potential only. 
6. 
Urinalysis (dipstick) will be performed at baseline, every 3 cycles following initiation of treatment (ie. Cycle 4, 7 and 10 etc.), and at the end of treatment. Urine 
microscopic examination should be performed if dipstick is abnormal. 
7. 
EBV DNA plasma levels will be measured at baseline, every 3 cycles following initiation of treatment (ie. Cycle 4, 7, 10 etc.), and at end of treatment. 
8. 
Newly obtained tumor tissue collection is mandatory upon study entry: See Section 5.5 for specifications.  The study chair may grant exceptions to the 
mandatory biopsy should the treating physician deem that a biopsy is not feasible or unsafe for the patient, and archival tissue is available and provided for 
study purposes. A conversation with the study chair is required to obtain an exception. At time of disease progression, a repeat biopsy is encouraged but 
optional.  
9. 
Blood for correlative studies should be collected at the same time blood is drawn for CBC and CMP if possible. 30 ml blood to be collected at baseline, at 12 
weeks after treatment initiation (± 7 days). See Section 5.5. 
10. Imaging for radiographic disease assessment will be performed every 12 weeks following treatment initiation (± 7 days). The same imaging modality should be 
used throughout the study when feasible. For patients who are clinically stable, a repeat scan will be required 4 weeks (±7 days) after initial radiographic 
findings of disease progression as a confirmatory assessment.    For CT or MRI, neck and chest should be evaluated; abdomen/pelvis as indicated. If a 
PET/CT is utilized, CT must be diagnostic quality.


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Nasopharyngeal carcinoma (NPC), with approximately 80,000 cases worldwide, has distinct 
racial and geographic distributions.1  While NPC is a leading cancer in endemic areas such as 
southern China, SE Asia, and Middle East/North Africa, it is much less common in the United 
States and Western Europe (incidence of 0.5 to 2 per 100,000).1-2  Epstein-Barr virus (EBV) has 
been recognized as the primary causative agent in the pathogenesis of nasopharyngeal 
carcinoma, particularly in cases classified as non-keratinizing carcinomas, which are further 
subdivided by the World Health Organization (WHO) as differentiated (type II) and 
undifferentiated (type III).  The majority of patients (~70%) present with locally advanced stage 
III/IV disease, and NPC has a predilection for early systemic dissemination (including lung, liver 
and bone).3  For those patients who develop recurrent or metastatic NPC, curative intent 
therapy is rarely possible and treatment-related morbidity is high with poor survival. While first-
line, platinum-based regimens have resulted in response rates as high as 60-70%, these 
responses are not durable as progression-free survival is still on the order of 5-6 months and 
median overall survival is typically 19-21 months.4 Apart from gemcitabine (which has 
demonstrated clinical activity after platinum-failure in a small series), there is no well-defined 
paradigm for second line therapies or beyond.5 
1.2 
Role of EBV infection on PD-L1 expression 
Enhanced PD-L1 expression has been demonstrated in a variety of EBV-driven processes, 
including EBV-associated Hodgkin lymphoma, EBV-associated B-cell lymphomas and EBV-
associated post-transplant lymphoproliferative disease (PTLD).6-7 
  
Based on pre-clinical data, Fang et al have proposed two mechanisms by which EBV results in 
increased PD-L1 expression in NPC.8 The innate immune resistance of EBV-induced latent 
membrane protein 1 (LMP1) correlates with upregulated PD-L1 expression.  Secondly, the 
adaptive immune resistance in response to Interferon-gamma represents a distinct but 
synergistic mechanism of PD-L1 regulation in EBV-associated NPC.  Interestingly, Fang et al 
were also able to demonstrate in multivariate analysis that PD-L1 expression was an 
independent poor prognostic factor in EBV-associated NPC; increased PD-L1 expression 
correlated with significantly shorter disease-free survival. 
1.3 
Rationale for PD-L1 Inhibition with Avelumab 
Because of the known role of programmed death ligand 1 (PD-L1) in the suppression of T cell 
responses and the strong correlation between PD-L1 expression and prognosis in cancer, the 
blockade of the PD-L1/programmed death 1 (PD-1) interaction presents a highly promising 
strategy for cancer immunotherapy. 
 
Avelumab (also referred to as MSB0010718C) is a fully human IgG1 antibody directed against 
PD-L1. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-
1 and B7.1. This removes the suppressive effects of PD-L1 on anti-tumor CD8+ T cells, 
resulting in the restoration of cytotoxic T cell response.  The PD-1 receptor is expressed on 
activated CD4+ and CD8+ T cells. By interaction with its ligands, PD-L1 and PD-L2, PD-1 
delivers a series of strong inhibitory signals through its cytoplasmic tail to inhibit T cell 
functions.9-11 PD-L1 (also called B7-H1 and CD274) can be detected on resting and activated T 
cells, B cells, macrophages, dendritic cells, and mast cells; PD-L1 expression is greatly up-
regulated after activation or interferon treatment.10 Numerous results from in vitro cellular 


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assays have demonstrated that blockade of the PD-1/PD-L1 interaction enhances T cell 
responses, such as increases in proliferation and cytokine production.12-18 In PD-1–/– mice both 
T and/or B cells responses are unregulated resulting in an array of autoimmune pathologies.19-20 
Breaking tolerance through, blocking PD-1 interaction with its ligands, and thus PD-1 signaling, 
can be applied to enhance T cell activity towards chronic pathologies such as cancer.21 
 
External20 and internal immunohistochemistry studies have demonstrated that PD-L1 is also 
expressed by a variety of human tumors, both by the tumor cells, as well as by the immune cells 
that are present in the tumor microenvironment. In contrast to very strong expression on 
syncytiotrophoblasts in the placenta and in cancer cells, low levels of PD-L1 expression were 
detected in some normal tissues including fetal cardiac tissue.14 High levels of PD-L1 
expression have been found to be associated with disease progression, increased metastasis, 
poor response to treatment, and decreased survival in a number of human cancers.20  
Importantly anti-PD-L1 blockade has demonstrated therapeutic efficacy in a variety of murine 
tumor models as monotherapy and has shown synergistic effect in combination therapy 
setting13, 22-27. 
 
The antitumor activity of avelumab has been investigated in various murine tumor models. 
Inhibition of the PD-1/PD-L1 interaction is proposed to exert a therapeutic effect by restoring 
anti-tumor CD8+ T cell responses. 
 
To circumvent the need for a surrogate antibody, the lead candidate antibody was specifically 
selected for cross-reactivity to murine PD-L1, and, as consequence all of the nonclinical studies 
were conducted in syngeneic murine tumor models in which the immune system of the host is 
fully intact. It was demonstrated that the inhibition of the PD-1/PD-L1 interaction restores 
antitumor CD8+ T cell responses, which results in an anti-tumor activity. 
 
Avelumab has demonstrated significant nonclinical activity as a monotherapy and in various 
combination therapy settings. In general, the anti-tumor immunotherapy via blockade of the 
PD-1/PD-L1 axis seems not to be limited to any specific tumor types, but there is recent 
evidence that PD-L1 tumor expression is a pre-requisite to achieve an objective response upon 
blockade of the PD-1/PD-L1 axis.28 The clinical relevance of PD-1/PD-L1 blockade has been 
demonstrated in Phase I trials performed with antibodies targeting either PD-L1 or PD-1.28-29 
 
Given the important role of PD-L1 in the suppression of T-cell responses, and the mode of 
action of avelumab which blocks the interaction between PD-L1 and its receptors, avelumab is 
being developed as a potential therapy for subjects with various tumors. 
1.4 
Non-clinical Pharmacology 
The nonclinical pharmacology studies have shown that avelumab functionally enhances T cell 
activation in vitro and significantly inhibits the growth of PD-L1 expressing tumors in vivo. 
 
Avelumab binds to human PD-L1 with a high affinity of 0.7 nM and not to any other B7 family 
proteins, and competitively blocks the interaction of PD-L1 with PD-1. The in vitro study results 
have shown that by binding to PD-L1, avelumab effectively enhances T cell activation as 
measured by interleukin (IL)-2 or interferon-gamma (IFN-γ) production. In addition, as a fully 
human IgG1 antibody, avelumab has the potential to trigger the antibody-dependent cell-
mediated cytotoxicity (ADCC) against target cells expressing PD-L1. 
 
As a monotherapy, avelumab has demonstrated anti-tumor activity against murine MC38 colon 
carcinoma tumors that are characterized by a high level of PD-L1 expression. A dose 


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dependent trend was observed, and 400 μg per dose (20 mg/kg, approximately) was identified 
as the optimally effective dose when given every third day for 3 total doses.  
 
The in vivo anti-tumor effects were found to be primarily mediated by CD8+ T cells as 
evidenced by the observation that in vivo depletion of this cell type completely abrogated the 
anti-tumor efficacy of avelumab. The contribution of ADCC as a potential mechanism of anti-
tumor activity was further demonstrated in vivo using a deglycosylated version of avelumab to 
abrogate fragment crystalline (Fc) receptor binding or via the systemic depletion of natural killer 
(NK) cells. In both settings, loss of in vivo ADCC potential significantly reduced the anti-tumor 
activity. 
 
The combination of avelumab with commonly used cancer treatments, such as cytotoxic agents 
and radiation therapy, resulted in an improved anti-tumor activity. Chemotherapy with 
combination therapy (with folinic acid, 5-fluorouracil, and oxaliplatin [FOLFOX], and radiation 
therapy showed the better tumor growth inhibition. In particular, radiation therapy was found to 
be a highly synergistic combination with avelumab capable of causing complete regression of 
established tumors probably through generating anti-tumor immune memory. 
 
Various immunomonitoring assays were incorporated into the in vivo studies. Treatment with 
avelumab resulted in a consistent increase in the percentage of CD8+PD-1+ T cells and an 
increased frequency of CD8+ T cells with an effector memory (TEM) phenotype as determined 
by flow cytometry. Furthermore, these changes correlated with the anti-tumor effect. Increases 
in tumor antigen-specific T cell responses, as measured by enzyme-linked immunosorbent spot 
and pentamer immunoassays, were evident following treatment with avelumab and these 
responses were enhanced when combined with FOLFOX or radiation. Hence, increases in 
CD8+PD-1+ T cells, CD8+ TEM cells, and antigen-specific T cell responses, may be leveraged 
as pharmacodynamics (PD) biomarkers with translational relevance to the clinical setting. 
1.5 
Clinical Efficacy 
 
Clinical Phase I/II trials with MoAbs targeting either PD-L1 or PD-1 have shown promising hints 
for clinical efficacy, i.e., objective tumor response in indications such as NSCLC, melanoma, 
and ovarian cancer.28-30 
 
Avelumab has two main mechanisms of action for exerting its anti-tumor effects: 
1. PD-L1 on tumor cells can interact with PD-1 or B7-1 on activated T cells. These 
interactions have been shown to significantly inhibit T cell activities. Therefore, blocking 
PD-L1 interaction with PD-1 or B7-1 by anti-PD-L1 can release T cells from 
immunosuppression, and lead to elimination of tumor cells by T cells. 
2. Tumor cells may express high levels of PD-L1 on their surface compared with normal 
tissues. As a fully human IgG1 MoAb, avelumab has ADCC potential. Upon binding to 
PD-L1 on tumor cells and binding with their Fc part to Fc-gamma receptors on 
leukocytes, avelumab can trigger tumor-directed ADCC. 
 
The clinical efficacy information includes data from the NSCLC and ovarian cancer expansion 
cohorts of the ongoing Phase I Trial EMR 100070-001, and for 20 subjects in the gastric cancer 
expansion cohort of the ongoing Phase I Trial EMR 100070-002. 
 
The NSCLC expansion cohort in the ongoing Phase I Trial EMR 100070-001 had a cutoff date 
of 15 January 2015, 6 months after start of avelumab treatment of the last subject in this 


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expansion cohort (a total of 184 treated subjects). The objective response rate (ORR) based on 
confirmed and unconfirmed responses for subjects treated in the NSCLC expansion cohort was 
13.6% (25 of 184 NSCLC subjects). Progression free survival (PFS) and overall survival (OS) 
were all evaluated for all NSCLC subjects treated in the expansion phase. As of 15 January 
2015, the median PFS and OS for the NSCLC treatment expansion cohort were 11.6 weeks and 
8.4 months, respectively. 
 
The clinical activity of avelumab was also evaluated by subjects’ tumor PD-L1 expression status 
in the NSCLC expansion cohort. An objective response was observed in 19 of 122 subjects 
(15.6%) who were PD-L1 positive (defined as having at least 1% PD-L1 positive tumor cells) 
compared with 2 of 20 subjects (10.0%) who were considered PD-L1 negative (defined as 
having less than 1% PD-L1 positive tumor cells). A longer median PFS (12.0 vs 5.9 weeks) and 
OS (8.9 vs 4.6 months) were both observed in PD-L1 positive compared to PD-L1 negative 
subjects. 
 
The ovarian cancer expansion cohort had a data cutoff of 13 February 2015, approximately 
13 weeks after the start of avelumab treatment on the last subject who was included in this pre-
planned interim analysis on this expansion cohort. The ORR based on confirmed and 
unconfirmed responses for subjects treated in the ovarian cancer expansion cohort was 10.7% 
(8 of 75 subjects). The median PFS for the ovarian cancer expansion cohort was 11.4 weeks 
(95% CI: 6.3 to 12.0 weeks). 
 
The preliminary efficacy data for the ongoing Phase I Trial EMR 100070 002 are based on a 
data cutoff of 11 March 2015. As of the data cutoff, 3 of 20 subjects responded to trial treatment 
(all responses were partial responses (PRs) and all responses were confirmed responses), and 
the best overall response (BOR) was 15.0% (95% CI: 3.2% to 37.9%). The median PFS of this 
group was 11.9 weeks (95% CI: 6.0 to 12.3 weeks). 
1.6 
Clinical Safety 
As of the safety cutoff date of 01 June 2015, 770 subjects have received at least one dose of 
avelumab at doses ranging from 1.0 to 20 mg/kg in the Phase I Trial EMR 100070-001, and 
were followed for at least 4 weeks. Overall, 717 subjects have received the proposed dose of 10 
mg/kg in the expansion cohorts, of which 184 subjects have NSCLC, 120 subjects have gastric 
cancer, 75 subjects have ovarian cancer and 44 subjects have urothelial carcinoma. 
 
In the dose escalation portion of the Trial EMR 100070-001, there was no evidence of 
differences in the safety profile across all administered dose levels from 1 mg/kg to 20 mg/kg. 
The MTD was not reached. Ongoing review of the safety data by the SMC suggests an 
acceptable safety profile of avelumab administered at the 10 mg/kg every 2 weeks dose and 
schedule. Treatment-related treatment emergent adverse events (TEAEs) were observed in 498 
(69.5%) subjects in the pooled expansion cohort. The most frequently observed treatment 
related TEAE was infusion-related reaction reported in 134 subjects (18.7%), followed by fatigue 
reported in 130 subjects (18.1%) and nausea reported in 74 subjects (10.3%). Grade ≥ 3 
treatment-related TEAEs were observed in 77 subjects (10.7%) in the pooled expansion cohort, 
of which 13.0%, 9.2%, 6.7%, and 4.5% occurred in the NSCLC, gastric cancer, ovarian cancer, 
and urothelial carcinoma expansion cohorts, respectively. Infusion-related reactions including 
hypersensitivity reactions and immune-mediated adverse reactions have been identified as 
expected adverse drug reactions of avelumab. The safety profile is consistent with findings 
reported for other anti-PD-1 or anti-PD-L1 antibodies. 
 


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1.7 
Clinical Data of PD-1/PD-L1 Axis Inhibition in Recurrent Nasopharyngeal 
Carcinoma 
Promising interim results from a phase 1b study evaluating the use of a PD-1 inhibitor in solid 
tumors, including patients with PD-L1 positive, advanced (unresectable and/or metastatic) NPC, 
was recently presented at the 2015 European Cancer Congress.31 Twenty-seven patients with 
NPC were enrolled on study, with 92.5% of patients receiving prior treatment for R/M disease 
and 33.3% of patients being heavily pre-treated (at least 5 lines of prior therapy).  One complete 
response and 6 partial responses were noted in addition to 14 patients experiencing stable 
disease.   The overall response rate (confirmed and unconfirmed) was 25% (95%CI, 11.1–46.3).  
This preliminary signal for clinical efficacy in R/M NPC is encouraging, thus meriting further 
investigation. 
1.8 
Rationale for Study 
Building on the aforementioned findings, we thus propose a prospective phase II open-label trial 
to evaluate the clinical efficacy of PD-L1 inhibition with Avelumab in patients with R/M 
nasopharyngeal carcinoma.  We hypothesize that PD-L1 inhibition will represent an attractive 
treatment approach given that EBV upregulates PD-L1 activity, and nasopharyngeal cancer 
(WHO II, III) is primarily EBV-driven. This therapeutic approach could translate into a clinically 
meaningful benefit for a patient population with otherwise significantly limited treatment options. 
Further, demonstration of clinical activity with Avelumab could ultimately lead to registration 
trials for its use in the management of R/M nasopharyngeal carcinoma. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
To determine the clinical activity of Avelumab in the management of R/M nasopharyngeal 
carcinoma. 
2.2 
Secondary Objectives  
1. To determine duration of response 
2. To determine progression-free survival at 6 and 12 months 
3. To determine overall survival 
4. To assess safety and tolerability of Avelumab 
5. To evaluate correlation between molecular markers and disease outcome 
6. To determine clinical activity using immune-related RECIST. 
2.3 
Endpoints 
 
Primary Endpoint: 
1. Overall response rate (defined as complete or partial response) at 6 months based on 
RECIST.  
 
Secondary Endpoints: 
1. Duration of response, defined as time from documentation of tumor response to disease 
progression 
2. Progression-free survival, defined as the time start of Avelumab until disease 
progression or death 
3. Overall survival, defined as the time from start of Avelumab to death from any cause 


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4. Toxicity (grade 3 or higher), as defined by CTCAE 4.03.   
5. Exploratory correlatives: 
o Tissue (new biopsy required upon study entry prior to therapy; repeat biopsy at time 
of progression will be encouraged but optional): 
 
PDL1 expression by immunohistochemistry (ABC technique [Vector labs], 
using rabbit mAb 1:200 [Cell Signaling]) 
 
Immunophenotyping by flow cytometry: 
• 
T cell subsets (CD4, CD8, FOXP3) 
• 
 Macrophages (CD68) 
 
Cytokeratin 5/6 (by immunohistochemistry) 
o Peripheral blood (comparison of baseline and 12 week post-treatment samples, 
unless otherwise denoted) 
 
TCR and BCR sequencing 
 
T cell subsets (CD3, CD4, CD8, CD25, FOXP3) 
 
B cells (CD19, CD20) 
 
Macrophage I/II and myeloid-derived suppressor cells (MDSC) (CD16, CD68, 
CD206) 
 
Natural killer cell activity (CD56, CD16) 
 
EBV DNA plasma levels (will be performed at baseline, every 12 weeks after 
treatment initiation and at end of treatment) 
6. Clinical activity of Avelumab as defined by overall response rate will also be measured 
utilizing immune-related RECIST. 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Patients must meet all of the inclusion criteria to participate in this study. 
 
1. Patient has the ability to understand and the willingness to sign a written informed consent. 
 
2. Patient has histologically/cytologically confirmed, non-keratinizing/undifferentiated, EBV-
related nasopharyngeal carcinoma, not amenable to curative intent therapy. EBV testing 
may be completed per institutional standards. 
 
3. Patient must have at least one measurable site of disease as defined by RECIST v1.1, 
determined by investigator review 
 
4. Patient has received at least one prior line of systemic therapy in the recurrent/metastatic 
setting. 
 
5. Patient is willing to undergo a fresh tumor biopsy (core or excisional) for correlative analyses 
(ie. PD-L1 expression). The study chair may grant exceptions to the mandatory biopsy 
should the treating physician deem that a biopsy is not feasible or unsafe for the patient, and 
archival tissue is available and provided for study purposes. A conversation with the study 
chair is required to obtain an exception. 
 
6. Age ≥ 18 years. 
 
7. Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2. 


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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. 
 
8. Patient has adequate organ and marrow function as defined below: 
• 
Absolute Neutrophil Count 
≥ 1.0 x 109/L 
• 
Platelet count 
≥ 75 x 109/L 
• 
Hemoglobin 
≥ 8.0 g/dL 
• 
Total bilirubin 
≤ 1.5 x institution’s upper limit of normal  
• 
AST/SGOT and ALT/SPGT 
≤ 2.5 X institutional upper limit of normal 
• 
Albumin 
≥ 2.0 g/dL 
• 
Serum creatinine 
≤ 1.5 x institution’s ULN, or creatinine 
 
clearance ≥ 60 ml/min  
 
9. Female patient of childbearing potential has a negative serum or urine pregnancy within 72 
hours prior to receiving the first dose of study medication. 
 
10. Female patient of childbearing potential agrees to use 2 methods of birth control or be 
surgically sterile, or abstain from heterosexual activity for the course of the study through 
120 days after the last dose of study medication (Reference Section 4.6.2). 
Note: Females of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for > 1 year. 
 
11. Male patient with a partner of childbearing potential agrees to use an adequate method of 
contraception starting with the first dose of study therapy through 120 days after the last 
dose of study therapy. 
 
3.2 
Exclusion Criteria 
Patients meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 
1. Patient is currently receiving or has received another investigational agent within 4 weeks 
prior to Day 1 of study.  
 
2. Patient has received chemotherapy or radiotherapy within 4 weeks prior to Day 1 of study.  
Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least 
one measurable lesion that has not been radiated. 
 
3. Patient has received prior immunotherapy with inhibitors of PD-1/PD-L1 axis. 
 


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4. Patient has had major surgery or insufficient recovery from surgical-related trauma or wound 
healing within 14 days of Study Day 1. 
 
5. Patient has had a prior Grade ≥ 3 immune-related adverse event (irAE) while receiving any 
previous immunotherapy agent, or any unresolved irAE > Grade 1. 
 
6. Patient has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin 
that has undergone potentially curative therapy or in situ cervical cancer. 
 
7. Patient has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  
 
Note: Patients with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging for at least four weeks prior to the first 
dose of trial treatment and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases, and are not using steroids for at least 7 
days prior to trial treatment. This exception does not include carcinomatous meningitis which 
is excluded regardless of clinical stability. 
 
8. Patient has an active autoimmune disease that has required systemic treatment in the past 
2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). 
Notes:  
• 
Patients with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment 
within the past 2 years are not excluded. 
• 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
  
9. Patient has a diagnosis of immunodeficiency, or is receiving systemic steroid therapy 
(>10mg prednisone daily, or steroid equivalent) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of avelumab. 
 
10. Patient has a known history of active TB (Baccillus Tuberculosis). 
 
11. Patient has a known history of, or any evidence of active, non-infectious pneumonitis. 
 
12. Patient has a known history of chronic interstitial lung disease. 
 
13. Patient has an active infection requiring systemic therapy. 
 
14. Patient has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 
 
15. Patient has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the trial. 
 


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16. Patient is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial. 
 
17. Patient has known active Hepatitis B infection (defined as presence of HepB sAg and/ or 
Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known 
Human Immunodeficiency Virus (HIV). 
 
• 
Patients with HIV who have a normal CD4 count (≥ 200) and an undetectable viral load 
are not excluded.  
 
18. Patient has received a live vaccine within 30 days of study Day 1. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
 
4.0 
TREATMENT PLAN 
4.1 
Study Design 
This is a prospective, multi-center, open-label, single-arm phase II trial to evaluate the efficacy 
of Avelumab for patients with recurrent/metastatic, EBV-related nasopharyngeal carcinoma.  A 
total of 39 patients will be eligible to enroll.  Patients will be enrolled at 7 sites: UC San Diego 
Moores Cancer Center, Stanford Cancer Institute, UC Los Angeles Jonsson Comprehensive 
Cancer Center, UC Irvine Chao Cancer Center, University of Southern California Norris 
Comprehensive Cancer Center, Providence Cancer Center, and Dana-Farber Cancer Institute.  
 
All patients providing informed consent will be screened for eligibility.  Baseline assessments 
will include vital signs, physical exam, ECOG performance status evaluation, blood hematology 
and chemistries, urinalysis and tumor imaging. Upon study entry, all patients will receive 
Avelumab 10mg/kg IV on days 1 and 15 of each 28-day cycle.  Treatment will be given until 
disease progression, unacceptable toxicity, investigator decision or patient withdrawal.  Dose 
reductions and/or interruptions may occur per pre-specified criteria for grade 3 or higher toxicity. 
 
History and physical examination, adverse event assessment and routine bloodwork will be 
performed prior to every cycle.  For patients with known hepatic metastases at time of study 
entry, liver function tests (including ALT, AST, total bilirubin, and alkaline phosphatase) must be 
performed once weekly for 7 weeks upon treatment initiation.  All patients will undergo imaging 
(CT, MRI, or PET/CT [CT must be diagnostic quality]) within 4 weeks prior to study entry, 12 
weeks after treatment initiation (+/- 7 days), and then every 12 weeks thereafter (+/-7 days).  
Response will be assessed using RECIST.  For patients who are clinically stable, a repeat scan 
will be required 4 weeks (+/- 7 days) after initial radiographic findings of disease progression as 
a confirmatory assessment.   
 
A newly obtained tumor specimen will be obtained prior to study entry (unless it is not feasible 
or deemed unsafe for the patient, archival tissue is available, and study chair has granted an 
exception) for the purposes of measuring PD-L1 expression, T cell subsets etc.  Patients will 
also provide blood samples at baseline and 12 weeks after treatment initiation for correlative 
studies, including PBMCs, T and B-cell subsets, frequency and clonality.  Peripheral blood will 
be collected at baseline, and then every 12 weeks after treatment initiation as well as at end of 
treatment for serial measurement of EBV plasma DNA levels. Additionally, at time of disease 


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progression, patients will be encouraged but not mandated to undergo a second biopsy for 
study purposes to permit further correlative studies. 
 
An end of treatment visit for clinical evaluations and safety assessments will be performed 
approximately 28 days (± 7 days) after the last dose of study drug. Patients discontinuing study 
treatment will be followed every 3 months for disease and survival outcomes. 
4.2 
Treatment Dosage and Administration 
4.2.1 Preparation and Administration of Avelumab 
Specific instructions for the preparation infusion fluid and administration of infusion solution are 
provided in the Pharmacy Manual. 
 
Avelumab is administered on an outpatient basis. Avelumab 10mg/kg body weight, diluted with 
0.45% or 0.9% saline solution, will be administered as a 60 minute intravenous (IV) infusion 
every 2 weeks.  
 
4.2.2 Monitoring of Dose Administration 
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Events. 
 
Patients will be monitored for the presence of infusion-related reactions. Dose modification and 
toxicity management for infusion-related reactions are outlined in the dose modification section 
(Section 4.3). 
 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit subjects to an intensive care unit if necessary. 
4.2.3 Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient is without ongoing Grade 3 non-
hematologic or Grade 4 hematologic toxicities attributable to study treatment. 
4.3 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient 
will be assessed for the development of toxicity according to the NCI Common Toxicity Criteria 
for Adverse Events (CTCAE), version 4.03. 
 
Adverse events (both non-serious and serious) associated with avelumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Avelumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as listed in Sections 4.3.1-4.3.3.  
 
4.3.1 Management of Immune-Related Adverse Events 
Gastrointestinal irAEs 
Severity of diarrhea/Colitis 
(NCI-CTCAE v4) 
Management 
Follow-up 


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Grade 1 
Diarrhea: < 4 stools/day over  
baseline; 
Colitis: asymptomatic 
Continue avelumab therapy 
 
Symptomatic treatment (e.g. 
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; i.v. 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 > 5-7 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 ¾ 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; i.v. 
fluids ≥ 24 h; 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 
methlyprednisolone i.v. 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 recur 
after improvement: 
Add infliximab 5mg/kg (if no 
contraindication), 
Note: infliximab should not be used 
in cases of perforation or sepsis 
Dermatologic irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 to 2 
Covering ≤ 30% body surface 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 0.5-1.0 mg/kg/day 
methylprednisolone i.v. 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 i.v. or i.v. 
equivalent 
If improves to Grade 1: 
Taper steroids over at least 1 month 
and add 
prophylactic antibiotics for 
opportunistic 
infections 
Resume avelumab therapy 


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Pulmonary irAEs 
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 
i.v. or oral equivalent 
 
Consider bronchoscopy, lung 
biopsy 
 
Re-image every 1 to 3 days 
 
If improves: 
When symptoms return to near 
baseline, trapper 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 i.v. or i.v. 
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, i.v. 
immunoglobulin, or mycophenolate 
mofetil) 
Hepatic irAEs 
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 3-4 
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x 
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 > 5-7 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 


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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 i.v. 
or i.v. 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 
Endocrine irAEs 
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 i.v. 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 i.v. steroids with mineralocorticoid activity 
I.V. fluids 
Consult endocrinologist 
If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathy 
ADL: activities of daily living; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CT: computerized 
tomography; irAE: immune-related adverse event; i.v.: intravenous; LFT: liver function test; LLN: lower limit of normal; 
MRI: magnetic resonance imaging; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse 
Event; NSAIDs: nonsteroidal anti-inflammatory drugs; T4: free thyroxine; TSH: thyroid-stimulating hormone; ULN: 
upper limit of normal. 
4.3.2 Management of Infusion-Related Reactions 
Treatment Modification for Symptoms of Infusion-Related Reactions Caused by Avelumab 
 
NCI-CTCAE Grade 
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening 
 


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The total infusion time for avelumab should not 
exceed120 minutes 
Grade 2 – moderate 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (for example, 
antihistamines, NSAIDs, narcotics, i.v. fluids); 
prophylactic medications indicated for ≤ 24 h 
Stop avelumab infusion 
 
Resume infusion at 50% of previous rate once infusion-
related reaction has resolved or decreased to at least 
Grade 1 in severity, and monitor closely for any 
worsening 
Grade 3 or Grade 4 – severe or life-threatening 
• 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae 
• 
Grade 4: Life-threatening consequences; 
urgent intervention indicated 
Stop the avelumab infusion immediately and disconnect 
infusion tubing from the subject 
 
Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any further 
avelumab treatment 
i.v.: 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 the subject has a 
second infusion-related reaction Grade ≥ 2 on the slower infusion rate, the infusion should be 
stopped and the subject should be removed from avelumab treatment. If a subject experiences 
a Grade 3 or 4 infusion-related reaction at any time, the subject must discontinue avelumab. If 
an infusion reaction occurs, all details about drug preparation and infusion must be recorded. 
 
4.3.3 Severe Hypersensitivity Reactions and Flu-Like Symptoms 
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf. Subjects should be instructed to report any 
delayed reactions to the investigator immediately. 
 
A. Symptoms 
• 
Impaired airway 
• 
Decreased oxygen saturation (< 92%) 
• 
Confusion 
• 
Lethargy 
• 
Hypotension  
• 
Pale/clammy skin 
• 
Cyanosis 
 
B. Management 
• 
Epinephrine injection and dexamethasone infusion 
• 
Subject should be placed on monitor immediately 
• 
Alert intensive care unit for possible transfer if required 
 
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 i.v. 
infusion. Alternative treatments for fever (for example, paracetamol) may be given to subjects at 
the discretion of the investigator. 


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4.4 
Pre-Medications 
To mitigate infusion-related reactions, premedication with an antihistamine and with 
acetaminophen, per institutional standards, is mandatory prior to each dose of avelumab.  
 
Management of infusion-related reactions should follow guidelines set forth in Section 4.3.2. 
4.5 
Permitted concomitant therapy 
Concomitant medication also includes all prescription, over-the-counter (OTC), herbal 
supplements, blood transfusions, and IV medications. The patient needs to notify the 
investigational site about any new medications he/she takes after the start of the study drug. 
 
All concomitant medications received within 7 days before the first dose of trial treatment and 28 
days after the last dose of trial treatment should be recorded in the patient’s medical record.   
4.6 
Prohibited concomitant therapy 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy. 
• 
Immunotherapy not specified in this protocol. 
• 
Chemotherapy not specified in this protocol. 
• 
Investigational agents other than avelumab. 
• 
Radiation therapy. 
o Note: Radiation therapy to a symptomatic lesion or to the brain may be allowed 
at the investigator’s discretion.   
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
adverse event of suspected immunologic etiology. 
 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the treatment 
portion of the study. Patients may receive other medications that the investigator deems to be 
medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
4.7 
Other Considerations 
4.7.1 Contraception 
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 methods 
of birth control or are considered highly unlikely to conceive. Highly unlikely to conceive is 
defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥ 45 years of age and 
has not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study. The two birth control methods can be 2 
barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Patients 
should start using birth control from study Visit 1 throughout the study period up to 120 days 
after the last dose of study drug.  
 


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The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. To participate in the study they 
must adhere to the contraception requirement (described above) for the duration of the study 
and during the follow-up period as defined above. If there is any question that a patient will not 
reliably comply with the requirements for contraception, that patient should not be entered into 
the study. 
4.7.2 Pregnancy and Lactation  
Pregnancy 
Pregnancy must be excluded before the initiation of and during avelumab therapy, and 
prevented by the use of reliable contraception during treatment. 
 
If a patient inadvertently becomes pregnant while on treatment with avelumab, the patient will 
immediately be removed from the study. The site will contact the patient at least monthly and 
document the patient’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the Study Chair and to Pfizer without delay and 
within 24 hours to the Study Chair and within 2 working days to Pfizer if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn).   
 
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Study Chair. If a male patient 
impregnates his female partner the study personnel at the site must be informed immediately 
and the pregnancy reported to the Study Chair and to Pfizer and followed as described above.  
 
Lactation 
It is unknown if avelumab is secreted in breast milk.  Breast-feeding must be discontinued 
during treatment with avelumab. 
 
4.7.3  Overdose 
Symptoms 
Experience with overdose of avelumab is not available. 
 
Management 
Treatment is directed to symptoms. 
 
4.8 
Patient Withdrawal/Discontinuation from Study Treatment 
In the absence of treatment delays due to adverse events, study treatment may continue until: 
• 
Disease progression 
• 
The patient experiences unacceptable adverse event(s) or those events listed in the 
dose modification guidelines that require discontinuation; 
• 
The patient exhibits an inter-current illness that prevents further administration of study 


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treatment,  
• 
The patient has a confirmed positive serum pregnancy test; 
• 
The patient or legal representative withdraws consent; 
• 
The patient is noncompliant with trial treatment or procedure requirements; 
• 
The patient is lost to follow-up; 
• 
The patient dies; 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator; 
• 
Administrative reasons. 
 
4.9 
End of Study Treatment and Follow Up 
After the last dose of study treatment, each patient will be followed for 28 days for adverse 
event monitoring (serious adverse events will be collected for 90 days after the end of treatment 
as described in Section 7.1). Patients removed from treatment for unacceptable adverse events 
will be followed until resolution or stabilization of the adverse event.  
 
Patients who discontinue for reasons other than progressive disease will have post-treatment 
follow-up approximately every 3 months for disease status until disease progression, initiation of 
a non-study cancer treatment, withdrawal of consent or lost to follow-up. 
 
After documented disease progression, each patient will be followed approximately every 3-6 
months by review of medical records, telephone, or review of the Social Security Index for 
overall survival until death, withdrawal of consent, or the end of the study, whichever occurs 
first. 
4.10 
Patient Withdrawal/Discontinuation from Study Criteria 
Patients may be removed from study participation for the following reasons: 
• 
The patient or legal representative withdraws consent for follow-up; 
• 
The patient is lost to follow-up; 
• 
The patient dies; 
• 
It is the decision of the investigator. 
 
5.0 
STUDY PROCEDURES 
Refer to the study Schedule of Events for procedures. 
 
All patients will be closely monitored for safety and tolerability during all cycles of therapy, at 
study treatment completion/early study treatment discontinuation, and during the follow-up 
period. 
5.1 
Definitions of Study Assessments 
a. Medical history 
A medical history and details regarding the disease for which the patient has enrolled in 
this study will be obtained by the investigator or qualified designee. Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Any clinically significant 


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changes from Screening (e.g. worsening severity or abnormal findings) are considered 
to be adverse events (AEs). 
 
b. Demographics 
The patient’s demographic profile of date of birth, gender, race, and ethnicity will be 
obtained unless the patient declines. 
 
c. Review of eligibility criteria 
Review of eligibility criteria as described in Section 3 to ensure patient qualification for 
study entry and adjuvant study treatment. 
 
d. Concomitant Medication 
All concomitant therapy, including anesthetic agents, vitamins, homeopathic/herbal 
remedies, nutritional supplements, received by patients from seven days prior to the first 
day of study treatment until 28 days after the last study dose (or until the start of a new 
treatment, whichever comes first) will be recorded in the patient’s medical record. If a 
reportable adverse event deemed related to study intervention (see Section 7) occurs 
within 28 days after last study dose and the patient has not started a new treatment, 
recording of concomitant medications related to the treatment of that adverse event 
should continue until resolution of the adverse event. 
 
e. Physical exam 
The investigator or qualified designee will perform a complete physical examination 
during screening, which should include the evaluation of general appearance; evaluation 
of head, eyes, ears, nose, and throat (HEENT); and cardiovascular, pulmonary, 
abdominal, musculoskeletal, skin, lymph nodes, and neurological systems. Subsequent 
exams may be directed as appropriate. 
 
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as adverse events if 
clinically significant. 
 
f. Vital Signs and height 
Vital signs should include temperature, pulse, blood pressure and weight. Height will 
only be collected at screening.  
 
g. Performance status 
Performance status is evaluated by the ECOG scale. 
 
h. Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See Section 7 for 
Adverse Event monitoring and reporting. 
 
i. Laboratory Assessments 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 
5-1. 
 
Table 5-1. Laboratory tests 
Hematology 
• 
Complete Blood Count (CBC) with differential 
o 
hemoglobin,  


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o 
hematocrit,  
o 
platelet count,  
o 
white blood cell count,  
o 
percentage or absolute differential count 
Chemistry 
• 
Comprehensive metabolic panel (CMP) 
o 
albumin  
o 
alkaline phosphatase  
o 
aspartate aminotransferase (ALT) 
o 
alanine aminotransferase (AST) 
o 
bicarbonate (CO2) 
o 
blood urea nitrogen (BUN)  
o 
calcium  
o 
chloride 
o 
creatinine 
o 
glucose  
o 
potassium  
o 
sodium 
o 
total protein 
o 
total bilirubin  
• 
Thyroid stimulating hormone (TSH) 
Pregnancy Test 
• 
Urine human chorionic gonadotropin (HCG) or serum βHCG 
Urinalysis 
o 
Blood,  
o 
Glucose,  
o 
Protein,  
o 
Specific gravity 
o 
Microscopic exam (if abnormal) 
If clinically 
indicated 
• 
Hepatitis B: HepB sAg and/ or Hep B DNA 
• 
Hepatitis C: Hep C RNA PCR  
• 
HIV 
 
j. Blood collection for correlative studies 
See Section 5.5 for details. 
 
k. Tumor assessment 
Radiologic assessment is performed by MRI with gadolinium or CT with contrast (neck 
and chest; abdomen/pelvis as indicated) or PET/CT.  If a PET/CT is performed, the CT 
must be of diagnostic quality. The same radiographic technique should be used 
throughout the study. However, a patient who develops a contraindication to undergo an 
MRI scan during study treatment may remain on study and undergo contrast enhanced 
CT scans.  
 
l. Tumor biopsy and tissue collection 
See Section 5.5 for details. 
 
5.2 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
All screening procedures must be performed within 21 days prior to registration unless 
otherwise stated. The screening procedures include: 
• 
Written informed consent (within 28 days). 
• 
Review of inclusion and exclusion criteria. 


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• 
Complete medical/oncology history. 
• 
Demographics. 
• 
Documentation of concomitant medications. 
• 
Complete physical examination, including vital signs and height. 
• 
Performance status assessment. 
• 
Laboratory tests (within 7 days; pregnancy test within 72 hours).  
• 
Blood collection for EBV DNA plasma levels and correlative studies. 
• 
Documentation of tumor staging (imaging completed within 28 days). 
• 
Tumor biopsy tissue collection for correlative studies (within 42 days).  
5.3 
Procedures During Treatment 
5.3.1 Cycle 1 Day 1 (±3 days) 
• Focused physical exam, including vital signs, ECOG performance status 
assessment and weight  
• Assess for adverse events 
• Update concomitant medications  
• Collect blood samples for CBC with differential, CMP 
• 
For patients with known hepatic metastases at time of study entry, liver function 
tests (including ALT, AST, total bilirubin, and alkaline phosphatase) must be 
performed once weekly for 7 weeks upon treatment initiation. 
5.3.2 Each Additional Cycle, Day 1 (±3 days) 
• Focused physical exam, including vital signs, ECOG performance status 
assessment and weight  
• Assess for adverse events 
• Update concomitant medications  
• Collect blood samples for CBC with differential, CMP 
5.3.3 Thyroid studies and Urinalysis (±3 days) 
• Collect blood sample for TSH at cycle 2, cycle 4, then every 3 cycles thereafter (ie. 
cycle 7, 10 etc). Obtain urinalysis (dipstick) every 3 cycles following treatment 
initiation (ie. cycle 4, 7, 10 etc).  Urine microscopic examination should be 
performed if dipstick abnormal. 
 
5.3.4 Additional Blood Collection for Correlative Studies (±7 days) 
• Collect blood sample to measure EBV DNA plasma levels every 3 cycles (ie. cycle 
4, 7, 10 etc) and at end of treatment. 
• Collect blood sample for additional correlative studies at 12 weeks after treatment 
initiation (ie. cycle 4).  
5.3.5 Imaging (every 12 weeks ±7 days after treatment initiation)  
• MRI, CT (neck and chest; abdomen/pelvis when indicated) or PET/CT (CT must be 
diagnostic quality) 
• For patients who are clinically stable, a repeat scan will be required 4 weeks (±7 
days) after initial radiographic findings of disease progression as a confirmatory 
assessment.    
5.3.6 End of Treatment Visit (28 days after last dose, ± 7 days) 


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• Focused physical exam, vital signs, ECOG performance status, weight 
• Documentation of concomitant medications and adverse events. 
• Collect blood samples for CBC with differential, CMP, TSH, EBV DNA plasma level. 
• Collect urine sample for urinalysis. 
• Optional tumor biopsy for patients who developed disease progression as reason 
for end of treatment 
5.4 
Follow-up Procedures 
Patients discontinuing study treatment will be followed every three months after the last dose of 
study treatment until death with: 
• 
Tumor assessments if they discontinued from study treatment without disease 
progression- until disease progression or initiation of a new anti-cancer therapy, and  
• 
Survival contacts via medical record review, telephone call, or review of the Social 
Security Index. 
5.5 
Correlative Studies 
The goal of the planned laboratory correlative studies is to examine the relationship between 
presence of EBV infection and PD-L1 expression, to gain a better understanding of the impact 
of avelumab on the tumor’s immunophenotype, and explore potential biomarkers which may 
correlate with response to avelumab. 
5.5.1 Sample Collection Guidelines 
Specimens should be collected as outlined below and ALL samples should be labeled with the 
following: 
• 
Protocol number 
• 
Institution 
• 
Patient’s de-identified study number  
• 
Date of biopsy or surgery 
5.5.1.1 Newly obtained tumor tissue  
Newly obtained tumor tissue will be collected, preferably from a diagnostic core biopsy, within 
42 days of initiating study treatment.  
 
Samples collected for research will be obtained from only material in excess of that needed for 
routine clinical care as determined by a staff pathologist. 
 
When possible, 4 core biopsies should be taken for lesions > 1.5 cm, otherwise 2 cores should 
be taken.  
• 
If 4 cores are obtained, 1 core should be fresh frozen and the rest should be formalin-
fixed paraffin embedded (FFPE).  
 
• 
If < 4 cores are obtained, tissue for research should be FFPE after being divided into the 
research and diagnostic documentation blocks according to the Pathology staff’s 
specifications. 
 
Ten (10) unstained sections (4-5 micron slices) or one (1) 20 micron roll-ups from FFPE tissue 
are desired. 
 
Fresh frozen samples should be stored in liquid nitrogen and FFPE samples at room 
temperature until shipment. 


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5.5.1.2 Peripheral Blood Mononuclear Cells (PBMCs) 
Blood for PBMCs will be collected prior to study treatment at screening (may be collected at the 
same time as blood drawn for routine laboratory tests). 
 
Blood samples will be collected in two heparin green top tubes (approximately 20 ml).  
 
Additional blood sample collections will be performed at: 
• 
Twelve weeks after treatment initiation (+/- 7 days) 
 
Samples should be processed the day of collection according to the PBMC isolation protocol in 
the Laboratory Manual. 
 
PBMCs should be stored at -80°C until shipment. 
5.5.1.3 Buffy Coat 
Blood samples will be collected in one EDTA purple top tube (approximately 10 ml) prior to 
study treatment at screening (may be collected at the same time as blood drawn for routine 
laboratory tests).  
 
Additional blood samples will be collected in one EDTA purple top tube (approximately 10 ml) 
at:  
• 
time of first radiographic disease assessment 12 weeks after treatment initiation,  (± 7 
days) 
 
Samples should be processed the day of collection according to the buffy coat isolation protocol 
in the Laboratory Manual. 
 
Samples should be stored at -80°C until shipment. 
5.5.2 Specimen Shipping 
Samples should be batched and shipped overnight for receipt on weekdays only during normal 
business hours to the Coordinating Site UCSD laboratory at the following address: 
 
Attn:  Sharmeela Kaushal 
 
Moores Cancer Center, 3345/3G, GG 
 
3855 Health Sciences Drive 
 
La Jolla, CA 92093-0819 
 
Phone: 858-822-7661 
 
PBMC and buffy coat samples should be shipped on dry ice. FFPE tumor tissue (archived or 
newly obtained) can be shipped at room temperature. Please notify the Study Coordinator prior 
to shipment so it can be expected. 
5.5.3 Specimen Analyses 
Analyses will be performed at the direction of the study chair, Dr. Sacco.  
 
Tumor specimens will be evaluated by immunohistochemistry (IHC) for such biomarkers as:  
• 
PD-L1 expression  
• 
T cell subsets (CD4, CD8, FOXP3) 
• 
Macrophage (CD68) 


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• 
Cytokeratin 5/6 
 
PBMCs will be analyzed by flow cytometry for the following immune cell markers: 
• 
T cell subsets (CD3, CD4, CD8, CD25, FOXP3) 
• 
B cells (CD 19, CD20)  
• 
Macrophage I/II and myeloid-derived suppressor cells (MDSC) (CD16, CD68, CD206),  
• 
Natural killer cell activity (CD56, CD16) 
 
Buffy coat samples will be analyzed for T cell receptor (TCR) and B cell receptor (BCR) 
sequencing.  
 
EBV DNA plasma levels will be evaluated in peripheral blood at baseline, then every 12 weeks 
after treatment initiation and at end of treatment. 
 
Fresh frozen core biopsies (when available) will undergo whole exome sequencing for 
neoantigen discovery. 
 
Additional biomarkers may be examined as new information arises. 
5.5.4 Specimen Banking 
Patient samples collected for this study will be retained in the UCSD Moores Cancer Center 
Biorepository for analysis and future cancer research. Specimens will be stored indefinitely or 
until they are used up. Samples will be labeled with the protocol number, subject’s de-identified 
study number and collection date. The link between study number and medical record number 
will be viewed over a password secured encrypted server-client. 
 
The study research coordinator at each local site will review their subject's medical record for 
demographic and clinical information pertaining to the subject's general medical history, 
diagnosis, and outcomes of any treatments received. This information will be transmitted to and 
retained by the Coordinating Site UCSD. Samples and data extracted from the subject's medical 
record will be coded with a de-identified study number so that the subject's name and identifying 
information will be removed. A log that links the subject's name and identifiers to the study 
number will be maintained in a secure database distinct from the secure database into which 
the subject's clinical information will be entered by study personnel. 
 
Dissemination of specimens for research is at the discretion of the Study Chair, Dr. Sacco. 
Potential research collaborators outside of UCSD who approach the Moores Cancer Center for 
clinical specimens will be required to complete an agreement (Material Transfer Agreement or 
recharge agreement) stating that the specimens will only be released for use in disclosed 
research, and any specimen left over from research will either be returned to the Cancer Center 
or destroyed. Any data obtained from the use of clinical specimen will be the property of UCSD 
for publication and any licensing agreement will be strictly adhered to. These outside 
collaborators may include for-profit biotechnology corporations interested in collaborating with 
UCSD investigators in research diagnostic, prognostic assays and drug development. 
 
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value. The Informed Consent form contains this information and informs the subject that there is 
the potential for financial gain by UCSD, the investigator or a collaborating researcher or entity.  
 


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If patients later decide they do not want their specimens collected to be used for future 
research, they may tell this to the local site principal investigator, who will inform the Study Chair 
Dr. Sacco. Dr. Sacco will use her best efforts to stop any additional studies and to destroy the 
specimens. Samples stored in the Biorepository will be destroyed; for samples that have been 
disseminated outside of the Biorepository, Dr. Sacco will contact the recipient to notify them of 
the need to halt further research and destroy specimens. 
 
6.0 
Measurement of Effect 
6.1 
Safety/tolerability 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE version 4.03 (http://ctep.cancer.gov/reporting/ctc.html) for reporting of 
adverse events.  
6.2 
Antitumor Effect 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria. See Appendix A. 
6.2.1 Best Overall Response 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation. 
6.2.2 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
until objective tumor progression or death. 
6.2.3 Time to Progression 
Time to progression is defined as the duration of time from start of treatment until 
objective tumor progression. 
6.2.4 Overall Survival 
Overall survival is defined as the duration of time from start of treatment to death. 
 
7.0 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention. Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the investigational agent, is also an AE. 
 
Progression of the cancer under study or events which are unequivocally due to disease 
progression should not be reported as an AE during the study (unless it is considered to be drug 
related by the investigator). 


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7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care.  
 
As far as possible, each adverse event should be evaluated to determine: 
• 
duration (start and end dates) 
• 
severity (grade) 
• 
seriousness 
• 
relationship to study agent 
• 
action taken (i.e., none, study agent modification, medical intervention) 
• 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
Adverse events monitoring begins at the time of initiating study treatment through 90 days 
following the last administration of study treatment or study discontinuation/termination, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to avelumab. 
 
Note: Serious adverse events must be recorded in the case report forms for this 90 day-period; 
however, non-serious adverse events need only be recorded through 28 days post last study 
drug administration. 
 
All patients experiencing an adverse event at least possibly related to study treatment will be 
monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any clinically significant abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
7.2 
Severity 
All adverse events will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. The CTCAE v4.03 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities; 
intervention not indicated. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities; 
minimal, local or noninvasive intervention indicated. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities 
or significantly affects his/her clinical status; intervention indicated. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event; urgent 
intervention indicated. 


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Fatal (grade 5): the event caused death. 
7.3 
Seriousness 
A “serious” adverse event is defined in regulatory terminology as any untoward medical 
occurrence that: 
1. Results in death. 
If death results from (progression of) the disease, the disease should be reported as 
event (SAE) itself. 
2. Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe). 
3. Requires in-patient hospitalization or prolongation of existing hospitalization. 
Note: Hospitalization (including hospitalization for an elective procedure) for a 
preexisting condition which has not worsened does not constitute a serious adverse 
event. 
4. Results in persistent or significant disability or incapacity. Substantial disruption of 
one’s ability to conduct normal life functions. 
5. Is a congenital anomaly/birth defect. 
6. Is an important medical event. 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that may not result in hospitalization; development of drug 
abuse or drug dependency. 
7.4 
Relationship 
Attribution categories for adverse events in relationship to protocol therapy are as follows: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.5 
Prior experience 
Expected events are those that have been previously identified as resulting from administration 
of the agent. An adverse event is considered unexpected, for expedited reporting purposes 
only, when either the type of event or the severity of the event is not listed in the current known 
adverse events listed in the agent clinical experience section of this protocol or the current 
Investigator’s Brochure (or Product Label when applicable). 
7.6 
Reporting Requirements for Adverse Events 
7.6.1 Expedited Reporting 
Serious adverse events, or a follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
study treatment initiation through 90 days following cessation of treatment, or the initiation of 
new anti-cancer therapy, requires expedited reporting as described below. 


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7.6.2 Expedited Reporting to Site Principal Investigator and Study Chair  
The Study Chair and Site Principal Investigator must be notified within 24 hours of learning of 
any serious adverse events (SAEs).  
7.6.3 Expedited Reporting to Pfizer 
Pfizer must be notified within 2 working days of learning of any SAEs or non-serious Events of 
Clinical Interest: 
Name: TBD  
Attn: TBD 
FAX: TBD 
 
The Study Chair will submit a copy of all 15 Day FDA Reports to Pfizer at the time of submission 
to FDA. 
 
7.6.4 Expedited Reporting to Regulatory Authorities 
A. The Institutional Review Board (IRB) of each site must be notified by the site principal 
investigator according to their local policies. 
B. The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to subjects or 
others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated sponsor 
safety report), interim result or other finding that indicates an unexpected change 
to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator. 
C. The FDA must be notified by the Study Chair according to the following timelines: 
• 
within 7 calendar days of any unexpected fatal or life-threatening adverse event with 
possible relationship to study drug, and  
• 
within 15 calendar days of any event that is considered: 1) serious, 2) unexpected, and 
3) at least possibly related to study participation. 
7.6.5   Routine Reporting Requirements for Adverse events 
A. The IRB of each site must be notified by the site principal investigator according to their 
local policies. 


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B. The UCSD HRPP must be notified of any adverse events that are not unanticipated 
problems involving risk to subjects or others (non-UPRs) at the time of the annual 
Continuing Review.  
C. The FDA must be notified by the Study Chair of all non-serious adverse events annually at 
the time of the annual report. 
8.0 
AGENT INFORMATION 
8.1 
Avelumab 
Please refer to the Product Label and Investigator’s Brochure for more comprehensive 
information. 
 
Other names for the drug: MSB0010718C 
 
Mechanism of action (or Product description):   
Avelumab binds PD-L1 and blocks the interaction between PD-L1 and PD-1. This removes the 
suppressive effects of PD-L1 on anti-tumor CD8+ T cells, resulting in the restoration of cytotoxic 
T cell response. 
 
Availability: Clinical supplies are provided by Pfizer, and will be affixed with a clinical label in 
accordance with regulatory requirements. 
 
Dosage Forms and Strengths: 
Avelumab drug product is a sterile, clear, and colorless concentrate for solution presented at 
concentrations of 10 mg/mL and 20 mg/mL in European Pharmacopeia (Ph. Eur.) and United 
States Pharmacopeia (USP) type I glass vials closed with a rubber stopper and sealed with an 
aluminum Flip Off® crimp seal closure. 
 
Each single-use 10 mg/mL vial contains 80 mg of avelumab as a preservative-free acetate-
buffered solution (pH 5.5) containing Mannitol, Methionine, and Polysorbate 20 (Tween 20). 
 
Each single-use 20 mg/mL vial contains 200 mg of avelumab as a preservative-free 
acetate-buffered solution (pH 5.2) containing Mannitol, and Polysorbate 20 (Tween 20). 
 
Preparation:   
Avelumab will be prepared according to the product label unless otherwise directed in the 
Pharmacy Manual. 
 
Avelumab drug product must be diluted with 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. 
 
To prepare the dilutions, subsequent preparation steps must be accomplished by adequate 
trained personnel under a laminar flow box using aseptic techniques: 
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 


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chloride solution into the infusion bag. Gently invert the mixture 10 times. Infusion bags must not 
be shaken, in order to avoid foaming or excessive shearing of the protein solution. The 
preparation must be carefully inspected as it should result in a homogeneous looking clear 
solution, free of visible particles. 
 
For detailed information on the assigned dose levels and the concrete volumes to be replaced 
to prepare the target doses, please refer to the clinical trial protocol or to the manual of 
preparation. 
 
Storage and stability: 
Avelumab drug product must be stored at 2°C to 8°C until use. The storage condition is based 
on data from ongoing long term stability studies with avelumab. 
 
Avelumab drug product stored at room (23°C to 27°C) or higher temperatures for extended 
periods of time might be subject to degradation. Avelumab drug product must not be frozen. 
Rough shaking of the solution must be avoided. 
 
For application in clinical trials, avelumab drug product must be diluted with 0.45% or 0.9% 
saline solution (sodium chloride injection) supplied in an infusion bag. The chemical and 
physical in-use stability for the infusion solution of avelumab in 0.45% or 0.9% saline solution 
has been demonstrated for a total of 24 hours at room temperature. However, from a 
microbiological point of view, the diluted solution should be used immediately and is not 
intended to be stored unless dilution has taken place in controlled and validated aseptic 
conditions. If not used immediately, in-use storage times and conditions prior to administration 
are the responsibility of the user. 
 
No other drugs should be added to the solution for infusion containing avelumab. 
 
Route of administration for this study: Intravenous infusion over 1 hour. 
 
Side effects:  
For the purpose of regulatory reporting requirements during clinical development, the following 
AEs will be considered as expected and met the threshold of casual association (based on 
comprehensive evaluation) defined by the Sponsor: 
 
• 
Infusion-related reactions including hypersensitivity reactions 
• 
Immune-mediated adverse reactions like immune-mediated colitis, immune-mediated 
hepatitis including autoimmune hepatitis, immune-mediated thyroid disorders including 
hyperthyroidism, hypothyroidism, thyroiditis and autoimmune thyroiditis, immune-
mediated pneumonitis, immune-mediated skin reactions including rash, pruritis, rash 
generalized, rash macula-papular, erythema, pemphigoid, other immune mediated 
reactions including myocarditis, adrenal insufficiency, uveitis, iritis, myositis. 
 
8.1.1 Study Drug Accountability and Disposition 
The Study Chair and site Principal Investigators are responsible for ensuring accountability for 
the investigational agent, including reconciliation of materials and maintenance of drug records. 
 
Dispensing and administration of avelumab will be recorded following institutional practices. An 
accurate accounting will be available for verification. Accountability records will include: 
• 
Confirmation of delivery to the site 


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• 
Inventory at the site  
• 
Dispensing for each patient 
• 
Return or alternative disposition of unused study drug 
 
Upon completion or termination of the study, all unused and/or partially used avelumab will 
be destroyed at each site per institutional policy. It is the Principal Investigators’ responsibility to 
arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines 
and procedures, and provided that appropriate records of disposal are kept. 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Populations 
The Safety population will consist of all patients who have received at least one dose of 
Avelumab. 
 
The Intention-to-Treat (ITT) population will consist of all patients who have enrolled to the study. 
 
9.2 
Sample Size and Primary Analysis  
A Simon’s optimal two-stage design will be used for this cohort. The primary endpoint is overall 
response (CR or PR) rate at 6 months based on RECIST. If the overall response rate is ≤15%, we 
will consider the treatment as not meeting the threshold of going further. We will test the null 
hypothesis H0: p≤15% against the alternative hypothesis H1: p>15%, where p is the overall 
response rate after six months of study treatment. The two-stage design proposed below will have 
an 80% power to reject the null hypothesis and conclude that the true overall response rate is above 
15%, if the observed overall response rate is ≥30%, at 10% significance level. The study design is 
described in detail is as follows: 
Stage 1: 19 subjects will be accrued; accrual will be held until the progression results for all the 
19 subjects are known for the first six months. The trial will be terminated at Stage 1 if ≤ 3 of the 
19 subjects have any CR/PR by 6 months; otherwise it will continue to Stage 2.  
Stage 2: 20 more patients will be accrued. We will reject the therapy if, among all the 39 (19+20) 
subjects, the number of patients who have an overall response is ≤8; if ≥9 patients have a 
defined response by RECIST, the treatment will be successful. It will be concluded that our 
study treatment is associated with an overall response in more than 15% of patients.   
Early stopping probability: Under this design, if the null hypothesis is true, the probability of 
stopping the trial early will be 68.4%.  
The sample size calculation was done using PASS version 8.0.16 (released January 27, 2011). 
 
Final efficacy analysis will calculate the UMVUE estimate, p-value and 95% CI for the 
response rates.32-33 The calculation will be performed using R clinfun package (www.r-
project.org). 
 
 


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9.3 
Accrual 
 
A minimum of 6 patients with R/M NPC are evaluated monthly across all 7 institutions included 
in this study.  We therefore anticipate this study would require no more than 12 months to 
accrue. 
9.4 
Secondary Efficacy Analyses 
Secondary analysis will present duration of response, progression-free survival, and overall 
survival. We will estimate median survival times together with their 95% confidence intervals, 
and report number of events, as well as Kaplan Meier plots with 95% confidence bands.   
9.5 
Secondary Safety Analyses 
Analyses will be performed for all patients having received at least one dose of study treatment. 
The proportion of subjects experiencing adverse events, serious adverse events, and treatment 
delays will be summarized. Tolerability will be assessed based on dosage delays and 
discontinuation due to adverse events.   
 
All AEs will be listed, documenting the course, outcome, severity, and relationship to the study 
treatment. Incidence rates of AEs and the proportion of subjects prematurely withdrawn from the 
study due to AEs will be shown. 
9.6 
Analysis of Biomarkers 
 
The Chi-Square (or Fisher's Exact test) will be used to assess the association of categorical 
clinical data with categorical biomarker data. Time-to-event clinical data (PFS, OS) will be 
correlated with biomarker data using Kaplan-Meier methodology and Cox regression models. 
Logistic regression models will also be used to predict binary clinical data with baseline 
biomarker data. Finally, graphical methods and descriptive statistics will be used to summarize 
the data as well. 
 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed according to UCSD conflict of interest policy. 
10.2 
Institutional Review Board (IRB) Approval and Consent  
The IRB should approve the consent form and protocol prior to any study-related activities.  It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 


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include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
10.3 
Required Documentation For Multi-site Studies 
Before the study can be initiated at any site, the following documentation must be provided to 
the UCSD Moores Cancer Center Clinical Trials Office: 
• 
A copy of the official IRB approval letter for the protocol and informed consent. 
• 
A copy of the IRB-approved consent form 
• 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study. 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation. 
(NOTE: this is required if UCSD holds the IND. Otherwise, the affiliate Investigator’s 
signature on the protocol is sufficient to ensure compliance) 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values. 
• 
Executed clinical research contract. 
10.4 
Patient Registration 
All patients must be registered with the UCSD Moores Cancer Center Clinical Trials Office 
before enrollment to the study. Prior to registration, eligibility criteria must be confirmed with the 
UCSD Study Coordinator. To register a patient, call (858)-xxx-xxx Monday through Friday, 
8:00am-4:30pm Pacific Time. Study sites other than UCSD must fax informed consent 
documentation, completed eligibility checklist, and all source documentation for eligibility 
confirmation to the UCSD Clinical Trials Office (Fax: 858-822-5380). 
 
Patients will be given a unique sequential study number at the time of enrollment. UCSD will fax 
the outside study site for confirmation of patient registration, the patient’s study number, and 
ability to start study treatment. 
10.5 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study. 
10.6 
Data and Safety Monitoring/Auditing 
In addition to adverse event monitoring and clinical oversight by the Study Chair, site principal 
investigator and co-investigators, quality assurance of the study will be performed by the UCSD 
Moores Cancer Center Clinical Trials Office internal monitor. Monitoring intervals will be 
dependent upon risk-based assessments.  
 
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring Board 
(DSMB) to provide oversight in the event that this treatment approach leads to unforeseen 


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toxicities. Data from this study will be reported annually and will include: 
 
1) 
the protocol title, IRB protocol number, and the activation date of the study.  
2) 
the number of patients enrolled to date. 
3) 
the date and site of patients’ enrollment. 
4) 
a summary of all adverse events regardless of grade and attribution. 
5) 
a response evaluation for evaluable patients when available. 
6) 
a summary of any recent literature that may affect the ethics of the study.  
10.7 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, investigators are required to conduct their 
research according to the plans reviewed and approved by the IRB.  
10.7.1 Emergency Modifications  
Investigators may implement a deviation from, or a change of, the protocol to eliminate apparent 
immediate hazards/risks to trial subjects without prior IRB approval. Any such emergency 
modification implemented must be noted and reported to the IRB along the lines of a protocol 
deviation or violation, depending on the nature of the modification.  
10.7.2 Protocol Violations  
Any unplanned variance from an IRB approved protocol is considered a violation and must be 
reported to the IRB in a timely fashion. For the UCSD IRB: 
A. Major violations must be reported to the IRB within 10 working days of awareness of the 
violation. 
Major violations include: 
• 
Instances that have harmed or increased the risk of harm to one or more 
research participants. 
• 
Instances that have damaged the scientific integrity of the data collected for the 
study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
B. Minor violations may be reported to the IRB at the time of the continuing review. 
Minor violations have no substantive effect on the risks to participants or on the scientific 
integrity of the research plan or the value of the data collected. 
10.8 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Study Chair. It should also be noted that when an amendment to the 
protocol substantially alters the study design or the potential risk to the patient, a revised 
consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the IRBs at 
each site and submitted to the FDA by the Study Chair for approval prior to implementation. 
10.9 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 


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consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
10.10 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. At the completion of the study, all 
case report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
 
 


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11.0 
REFERENCES 
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3. Agulnik M, Siu LL.  State-of-the-art management of nasopharyngeal carcinoma: current and 
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4. Jin Y, Shi YX, Cai XY, et al.  Comparison of five cisplatin-based regimens frequently used as 
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5. Zhang L, Zhang Y, Huang PY, et al.  Phase II clinical study of gemcitabine in the treatment 
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6. Chen BJ, Chapuy B, Ouyang J, et al.  PD-L1 expression is characteristic of a subset of 
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7. Green MR, Rodig S, Juszczynski P, et al.  Constitutive AP-1 activity and EBV infection 
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9. Chemnitz J, Parry RV, Nichols KE, et al. SHP-1 and SHP-2 associate with immunoreceptor 
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11. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009; 229: 114-25. 
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cell proliferation and interleukin-10 secretion. Nat Med. 1999; 5: 1365-9. 
16. Freeman G, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 
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17. Waeckerle-Men Y, Starke1 A, and Wuthrich RP. PD-L1 partially protects renal tubular 
epithelial cells from the attack of CD8+ cytotoxic T cells. Nephrol Dial Transplant. 2007; 
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18. Blank C, Kuball J, Voekl S, et al. Blockade of PD-L1 (B7-H1) augments human tumor 
specific T cell responses in vitro. Int J Cancer. 2006; 119: 317-27. 
19. Okazaki T and Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends in 
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20. Okazaki T and Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int 
Immunol. 2007; 19: 813-24. 
21. Blank C, Gajewski TF, and Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on 
tumor-specific T cells as a mechanism of immune evasion: implications for tumor 
immunotherapy. Cancer Immunol Immunother. 2005; 54: 307-14. 
22. Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal 
antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005; 65: 1089-96. 
23. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from 
host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad 
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24. Iwai Y, Terawaki S, and Honjo T. PD-1 blockade inhibits hematogenous spread of poorly 
immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 2004; 2: 
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25. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the 
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26. Strome S, Sho M, Akahori T, et al. B7-H1 blockade augments adoptive T-cell 
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responses in a murine acute myeloid leukemia model. Blood. 2009; 114: 1545-52. 
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1 antibody in cancer. N Engl J Med. 2012 Jun 28; 366(26): 2443-54. 
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PD-1) in Melanoma. N Engl J Med. 2013; 369: 134-44. 
31. Hsu C, et al.  Antitumor activity and safety of pembrolizumab in patients with PD-L1-positive 
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32. Jung SH, Kim KM. On the estimation of the binomial probability in multistage clinical trials. 
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12.0 
APPENDICES 
 
Appendix A. Response Evaluation Criteria in Solid Tumors (RECIST) 
Tumor assessments will be made according to the schedule of assessments. Response and 
progression will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 guidelines [Eisenhauer et al. 2009]. 
 
1 
Measurability of Tumor at Baseline 
 
1.1 
Definitions 
At baseline, tumor lesions will be categorized as follows: 
1.1.1 Measurable 
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the 
plane of measurements is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measureable). 
• 
20 mm by chest X-ray. 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph 
node must be >= 15 mm in short axis when assessed by CT scan. At baseline and in follow-up, 
only the short axis will be measured and followed. 
1.1.2 Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodes 
with >= 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions considered 
truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
1.1.3 Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• 
Blastic bone lesions are non-measurable.  
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 


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lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
 
1.2 
Specifications by methods of measurements 
1.2.1 Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
1.2.2 Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 


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tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
 
2 
Tumor Response Evaluation 
 
2.1 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this 
means in instances where patients have only one or two organ sites involved a maximum of two 
and four lesions respectively will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
P15mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagital or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20mm· 30mm has a short axis of 
20mm and qualifies as a malignant, measurable node. In this example, 20mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis P10mm 
but <15 mm) should be considered non-target lesions. Nodes that have a short axis <10mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
2.2  
Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
 


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2.2.1 Evaluation of target lesions 
Complete Response (CR):  
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.  
 
2.2.2  Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10mm on study. This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of 
<10mm. Case report forms or other data collection methods may therefore be designed to have 
target nodal lesions recorded in a separate section where, in order to qualify for CR, each node 
must achieve a short axis <10mm. For PR, SD and PD, the actual short axis measurement of 
the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measure and may report them as 
being ‘too small to measure’. When this occurs it is important that a value be recorded on the 
case report form. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0mm. If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5mm should be assigned (Note: It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size when normal 
and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node 
is believed to be present and is faintly seen but too small to measure, a default value of 5mm 
should be assigned in this circumstance as well). This default value is derived from the 5mm CT 
slice thickness (but should not be changed with varying CT slice thickness). The measurement 
of these lesions is potentially non-reproducible; therefore providing this default value will prevent 
false responses or progressions based upon measurement error. To reiterate, however, if the 
radiologist is able to provide an actual measure, that should be recorded, even if it is below 
5mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 


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instance should be the maximal longest diameter for the ‘coalesced lesion’. 
 
2.2.3 Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
 
Complete Response (CR):  
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis). 
 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression).  
 
2.2.4  Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare. 
When the patient has only non-measurable disease. This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e.an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so, therefore the increase must be substantial.  
 
2.2.5  New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 


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modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the patient’s baseline lesions show partial or complete response. For example, necrosis of 
a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow- up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring at 
that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
 
2.3 
Evaluation of best overall response  
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. Furthermore, depending on the nature of the study and the protocol 
requirements, it may also require confirmatory measurement. Specifically, in non-randomized 
trials where response is the primary endpoint, confirmation of PR or CR is needed to deem 
either one the ‘best overall response’. This is described further below. 
 
2.3.1 Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients 
who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
 
Appendix Table 1. Time point response: patients with target (+/- non-target) disease. 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall 
Response 


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CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Appendix Table 2. Time point response: patients with non-target disease only. 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
Inevaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
2.3.2 Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50mm with three measured lesions and at follow-up 
only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
 
2.3.3 Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
 
Best response determination in trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best response, it 
must also meet the protocol specified minimum time from baseline. If the minimum time is not 
met when SD is otherwise the best time point response, the patient’s best response depends on 
the subsequent assessments. For example, a patient who has SD at first assessment, PD at 
second and does not meet minimum duration for SD, will have a best response of PD. The 
same patient lost to follow-up after the first SD assessment would be considered inevaluable. 
 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 3. 
 
Appendix Table 3. Best overall response when confirmation of CR and PR required. 
Overall response 
 First time point 
Overall response 
Subsequent time point 
BEST overall response 
CR 
CR 
CR 


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CR 
PR 
SD, PD OR PR 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise PD 
CR 
Inevaluable 
SD provided minimum criteria for SD duration 
met, otherwise inevaluable 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise PD 
PR 
Inevaluable 
SD provided minimum criteria for SD duration 
met, otherwise inevaluable 
inevaluable 
Inevaluable 
Inevaluable 
 
2.3.4 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans. This measurement 
should be recorded even though the nodes are normal in order not to overstate progression 
should it be based on increase in size of the nodes. As noted earlier, this means that patients 
with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression. For 
example, in most trials it is reasonable to consider a patient with time point responses of PR-
NE-PR as a confirmed response. 
 
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 objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. The objective response status of such 
patients is to be determined by evaluation of target and non-target disease as shown in Tables 
1–3. 
 
Conditions that define ‘early progression, early death and inevaluability’ are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 


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For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
at the next scheduled assessment, progression is confirmed, the date of progression should be 
the earlier date when progression was suspected. 
 
2.4  
Confirmatory measurement/duration of response 
2.4.1 Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e. in 
randomized trials (phase II or III) or studies where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in studies 
which are not blinded. 
 
In the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
 
2.4.2 Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
 
2.4.3 Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
 
The clinical relevance of the duration of stable disease varies in different studies and diseases. 
If the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between two measurements for determination of stable disease. 
 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity and standard 
practice. However, these limitations of the precision of the measured endpoint should be taken 
into account if comparisons between trials are to be made.