A Phase II, Open-label, Single Arm, Multicenter Study of Avelumab With Hypofractionated Radiation in Adult Subjects With Transformed IDH Mutant Glioblastoma
Phase: PHASE2
Conditions: Glioblastoma
Sponsor: NYU Langone Health

  
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
 
 
 
A phase II, open-label, single arm, multicenter study of Avelumab with 
hypofractionated re-irradiation in adult subjects with transformed IDH mutant 
glioblastoma 
 
Regulatory Sponsor/Overall 
Principal Investigator: 
Sylvia Kurz, MD, PhD 
Laura and Isaac Perlmutter Cancer Center 
NYU Langone Medical Center 
240 East 38th Street, 19th Floor 
New York, NY 10016 
Tel: 212-731-6267 
Fax: 646-754-9696 
Email: Sylvia.Kurz@nyulangone.org 
 
Funding Sponsor: 
EMD Serono/Merck KGaA 
Study Product: 
Avelumab (MSB0010718C) 
NYU Protocol Number: 
s16-01179 
NCT Number: 
NCT02968940 
IND Number: 
132960 
EMD Serono Study Number: 
MS100070-0077 
 
Co-Investigators: 
Joshua Silverman, MD, PhD 
 
Department of Radiation Oncology 
 
NYU Langone Medical Center 
 
Email: Joshua.S.Silverman@nyumc.org 
 
 
Matija Snuderl, MD, 
 
Department of Pathology 
 
NYU Langone Medical Center 
 
Email: Matija.Snuderl@nyumc.org 
 
Biostatistician: 
Judith D. Goldberg, ScD 
 
Departments of Population Health and Environmental Medicine 
 
New York University School of Medicine 
 
Email:  jd.goldberg@nyumc.org 
 
Participating Sites: 
Dana-Farber/Harvard Cancer Center (Massachusetts General 
Hospital, Dana-Farber Cancer Institute, Beth Israel Deaconness 
Medical Center), Boston, MA 
 
 
University of California, San Francisco 
 
University of California, Los Angeles 
 
Initial version: 12/28/2016 
Amendment 1: 1/26/2017 
Amendment 2: 3/14/2017 
Amendment 3: 4/24/2017 
Amendment 4:  7/11/2017 
Amendment 5:  1/13/2018 
Amendment 6:  10/30/2018 
Clinical Research Protocol 

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Table of Contents 
STUDY SUMMARY ....................................................................................................................................... 1 
1 
INTRODUCTION ................................................................................................................................... 3 
1.1 
BACKGROUND................................................................................................................................. 3 
1.1.1 
Study Disease .......................................................................................................................... 3 
1.1.2 
Rationale for PD-L1 Inhibitor in IDH-mutant transformed GBM............................................... 3 
1.1.3 
Rationale for PD-L1 Inhibitor + Hypofractionated Radiotherapy (HFRT) in transformed IDH 
mutant GBM .......................................................................................................................................... 4 
1.1.4 
Rationale for Radiation Treatment Scheme and Schedule with Avelumab ............................. 5 
1.1.5 
Rationale for Study Design and Safety Lead-In:...................................................................... 5 
1.1.6 
Summary of Background and Rationale .................................................................................. 6 
1.2 
AVELUMAB...................................................................................................................................... 6 
1.2.1 
General Information ................................................................................................................. 6 
1.2.2 
Physical, chemical, and pharmaceutical properties and formulation....................................... 7 
1.2.3 
Instructions for Storage ............................................................................................................ 7 
1.2.4 
Handling of the Dosage Forms ................................................................................................ 7 
1.2.5 
Nonclinical pharmacology ........................................................................................................ 8 
1.2.6 
Nonclinical pharmacokinetics and metabolism ........................................................................ 8 
1.2.7 
Nonclinical toxicology ............................................................................................................... 9 
1.2.8 
Clinical safety ........................................................................................................................... 9 
1.2.9 
Clinical Efficacy ...................................................................................................................... 10 
1.3 
PRECLINICAL DATA ....................................................................................................................... 11 
1.3.1 
Preclinical Efficacy of Avelumab ............................................................................................ 11 
1.3.2 
Preclinical efficacy of PD-1 inhibition and radiation therapy in gliomas ................................ 11 
1.4 
DOSE RATIONALE ......................................................................................................................... 12 
1.5 
RESEARCH RISKS & BENEFITS ...................................................................................................... 14 
1.5.1 
Risk of Avelumab administration ............................................................................................ 14 
1.5.2 
Risk with Radiation Therapy (RT) .......................................................................................... 14 
1.5.3 
Potential Overlapping Toxicities with Avelumab and Re-Irradiation ...................................... 15 
1.5.4 
Other Risks of Study Participation ......................................................................................... 15 
1.5.5 
Potential benefits .................................................................................................................... 16 
2 
STUDY OBJECTIVES ........................................................................................................................ 16 
3 
STUDY DESIGN ................................................................................................................................. 16 
3.1 
GENERAL DESIGN ......................................................................................................................... 16 
3.1.1 
Study Schema ........................................................................................................................ 16 
3.1.2 
General Study Design ............................................................................................................ 17 
3.2 
PRIMARY STUDY ENDPOINTS ......................................................................................................... 18 
3.3 
SECONDARY STUDY ENDPOINTS.................................................................................................... 19 
3.4 
PRIMARY SAFETY ENDPOINTS ....................................................................................................... 20 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 21 
4.1 
INCLUSION CRITERIA ..................................................................................................................... 21 
4.2 
EXCLUSION CRITERIA .................................................................................................................... 23 
4.3 
SUBJECT RECRUITMENT AND SCREENING ...................................................................................... 24 
4.3.1 
Informed Consent ................................................................................................................... 25 
4.3.2 
Documentation of Consent .................................................................................................... 25 
4.3.3 
Multi-Site Surveillance............................................................................................................ 25 
4.3.4 
Patient Informed Consent at Additional Sites ........................................................................ 26 
4.4 
REGISTRATION PROCEDURES ........................................................................................................ 26 
4.4.1 
General Guidelines ................................................................................................................ 26 
4.4.2 
Patient Registration at Other Participating Institutions .......................................................... 27 
4.5 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................... 28 
4.5.1 
When and How to Withdraw Subjects.................................................................................... 28 

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4.5.2 
Data Collection and Follow-up for Withdrawn Subjects ......................................................... 28 
5 
STUDY DRUG ..................................................................................................................................... 29 
5.1 
DESCRIPTION................................................................................................................................ 29 
5.2 
TREATMENT REGIMEN ................................................................................................................... 29 
5.2.1 
Safety Lead-In ........................................................................................................................ 31 
5.2.2 
Phase II Trial .......................................................................................................................... 35 
5.2.3 
Dose Modification and Study Treatment Discontinuation Rules............................................ 36 
Table 3: General Treatment Hold Guidelines for Immune-Related Adverse Events (irAEs).............. 38 
5.3 
PREPARATION AND ADMINISTRATION OF STUDY DRUG.................................................................... 41 
5.4 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 43 
5.5 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 43 
5.5.1 
Concomitant Medications ....................................................................................................... 43 
5.5.2 
Acceptable Concomitant Medications .................................................................................... 43 
5.5.3 
Prohibited Medications ........................................................................................................... 44 
5.6 
PACKAGING .................................................................................................................................. 44 
5.7 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 45 
5.7.1 
Receipt of Drug Supplies ....................................................................................................... 45 
5.7.2 
Storage ................................................................................................................................... 45 
5.7.3 
Dispensing of Study Drug ...................................................................................................... 46 
5.7.4 
Return or Destruction of Study Drug ...................................................................................... 46 
6 
STUDY PROCEDURES ...................................................................................................................... 46 
6.1 
SCREENING PROCEDURES ............................................................................................................ 46 
6.2 
CYCLE 1, DAY 1 (C1D1) ............................................................................................................... 48 
6.3 
CYCLE 1, DAY 8 (C1D8) ............................................................................................................... 49 
6.4 
CYCLE 1, DAY 15 (C1D15) AND ALL SUBSEQUENT MID-CYCLE (I.E., DAY 15) VISITS ......................... 50 
6.5 
CYCLE 2, DAY 1 (C2D1) AND ALL SUBSEQUENT DAY 1 CYCLE VISITS (I.E., C3D1, C4D1) ................ 50 
6.6 
CYCLE 3, DAY 1 (C3D1) AND THEN EVERY 8 WEEKS THEREAFTER .................................................. 51 
6.7 
END OF TREATMENT PROCEDURES................................................................................................ 52 
6.8 
POST TREATMENT PROCEDURES ................................................................................................... 52 
6.9 
EFFICACY PROCEDURES ............................................................................................................... 53 
6.10 
RESEARCH SPECIMEN PROCEDURES ............................................................................................. 54 
6.10.1 
Archival Tumor Specimen.................................................................................................. 54 
6.10.2 
Research Blood Samples .................................................................................................. 54 
6.10.3 
Optional Tumor Biopsy for Research ................................................................................ 55 
7 
STATISTICAL PLAN .......................................................................................................................... 55 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 55 
7.1.1 
Background for Statistical Plan: ............................................................................................. 55 
7.1.2 
Safety Lead-In sample size determination ............................................................................. 56 
7.1.3 
Phase II trial sample size determination ................................................................................ 56 
7.2 
STATISTICAL METHODS ................................................................................................................. 57 
7.2.1 
Safety Lead-In ........................................................................................................................ 57 
7.2.2 
Phase II trial ........................................................................................................................... 57 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 57 
7.3.1 
Safety Lead-In Population ...................................................................................................... 57 
7.3.2 
Phase II Trial Efficacy Analysis Population ............................................................................ 58 
7.3.3 
Safety Analysis Populations ................................................................................................... 58 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 58 
8.1 
DEFINITIONS ................................................................................................................................. 58 
8.2 
EVALUATION OF SEVERITY AND CAUSALITY .................................................................................... 61 
8.2.1 
Evaluation of Severity ............................................................................................................ 61 
8.2.2 
Evaluation of Causality........................................................................................................... 61 
8.3 
RECORDING OF ADVERSE EVENTS ................................................................................................. 61 
8.4 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS.................................. 62 

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8.4.1 
Investigator reporting: notifying the study sponsor, NYULMC IRB, Perlmutter Cancer Center 
Clinical Trials Office, and EMD Serono/Merck KGaA ......................................................................... 63 
8.4.2 
Investigator reporting: notifying the IRB ................................................................................. 64 
8.4.3 
Sponsor reporting: Notifying the FDA .................................................................................... 66 
8.4.4 
Sponsor Reporting: Notifying EMD Serono ........................................................................... 66 
8.4.5 
Sponsor reporting: Notifying participating investigators ........................................................ 67 
8.5 
STOPPING RULES ......................................................................................................................... 67 
8.6 
MEDICAL MONITORING .................................................................................................................. 67 
8.6.1 
Data and Safety Monitoring Committee ................................................................................. 67 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 68 
9.1 
CONFIDENTIALITY.......................................................................................................................... 68 
9.1.1 
Leftover Research Samples (Tissue and Blood) ................................................................... 68 
9.2 
CONFIDENTIALITY AND HIPAA ....................................................................................................... 69 
9.3 
SOURCE DOCUMENTS ................................................................................................................... 69 
9.4 
DATA AND SOURCE DOCUMENTATION ............................................................................................ 70 
9.5 
RECORDS RETENTION ................................................................................................................... 70 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................... 70 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 70 
10.2 
AUDITING AND INSPECTING ............................................................................................................ 71 
11 
ETHICAL CONSIDERATIONS ........................................................................................................... 71 
12 
STUDY FINANCES ............................................................................................................................. 72 
12.1 
FUNDING SOURCE ........................................................................................................................ 72 
12.2 
CONFLICT OF INTEREST ................................................................................................................. 72 
12.3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................ 72 
13 
PUBLICATION PLAN ......................................................................................................................... 72 
14 
REFERENCES .................................................................................................................................... 72 
15 
ATTACHMENTS ................................................................................................................................. 77 
15.1 
ATTACHMENT 1: SCHEDULE OF EVENTS ........................................................................................... 1 
15.2 
ATTACHMENT: 2 .............................................................................................................................. 4 
KARNOFSKY PERFORMANCE STATUS SCALE ................................................................................................. 4 
15.3 
ATTACHMENT: 3 .............................................................................................................................. 5 
IRANO (IMMUNOTHERAPY RESPONSE ASSESSMENT IN NEURO-ONCOLOGY) CRITERIA ..................................... 5 
15.4 
ATTACHMENT: 4 ............................................................................................................................ 10 
DOSE MODIFICATION OR DISCONTINUATION AND SUPPORTIVE CARE GUIDELINES FOR SPECIFIC DRUG-
RELATED ADVERSE EVENTS ....................................................................................................................... 10 
15.5 
ATTACHMENT: 5 ............................................................................................................................ 17 
FACTORS TO CONSIDER IN ASSESSING THE RELATIONSHIP OF AES TO AVELUMAB OR INFUSION PROCEDURE, 
STUDY PROCEDURE, OR COMBINATION TREATMENT .................................................................................... 17 
15.6 
ATTACHMENT: 6 ............................................................................................................................ 18 
TECHNICAL SPECIFICATIONS AND STRUCTURAL CONSIDERATIONS FOR ........................................................ 18 
PLANNING RADIOTHERAPY ......................................................................................................................... 18 
15.7 
ATTACHMENT: 7 ............................................................................................................................ 22 
RESEARCH BIOMARKER/CORRELATIVE STUDIES: BACKGROUND AND RATIONALE .......................................... 22 
 

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List of Abbreviations 
 
ADA 
Anti-drug antibody 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine Aminotransferase  
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase  
BID 
Twice Daily 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed-Tomography 
CTL 
Cytotoxic T cell 
CTO 
Clinical Trials Office 
CXR 
Chest X-ray  
DLT 
Dose Limiting Toxicity 
DR 
Duration of Response 
DSMC 
Data and Safety Monitoring Committee 
ECG 
Electrocardiogram  
ECHO 
Echocardiogram 
FDA 
Food and Drug Administration  
FFPE 
Formalin-fixed, paraffin-embedded 
FISH 
Fluorescence in situ Hybridization 
GBM 
Glioblastoma 
GCPs 
Good Clinical Practices  
Gy 
Gray (unit) 
H1 
Histamine H1 receptor 
HCT 
Hematocrit 
HFRT 
Hypofractionated radiotherapy 
HGB 
Hemoglobin 
HGG 
High-grade glioma 
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
IC50 
Concentration of 50% Inhibition  
ICH 
International Conference on Harmonization 
IDH 
Isocitrate dehydrogenase 
IEC 
Independent Ethics Committee 
irAEs 
Immune-related adverse events 
IRB 
Institutional Review Board 
KPS 
Karnofsky Performance Status 
LGG 
Low-grade glioma 
LLN 
Lower Limit of Normal 
mAb 
Monoclonal Antibody 
MDSC 
Myeloid-derived suppressor cell 
MG 
Malignant Glioma 
MHC 
Major histocompatibility complex 

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MMR 
Mismatch repair  
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 
NSCLC 
Non-small cell lung cancer 
NYULMC 
New York University Langone Medical Center 
OR 
Objective Response 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral blood mononuclear cells 
PCC 
Perlmutter Cancer Center 
PCV 
Procarbazine, lomustine (CCNU), vincristine chemotherapy regimen 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic  
PD 
Pharmacodynamic 
PD-1 
Programmed cell death protein 1 
PD-L1  
Programmed death-ligand 1 
PFS6 
6-month progression-free survival 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PR 
Partial Response 
PTV 
Planning Target Volume 
QD 
Once Daily 
iRANO 
Immunotherapy Response Assessment for Neuro-Oncology 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
RT 
Radiation Treatment 
SAE 
Serious Adverse Event 
SD 
Stable Disease  
SGOT 
Serum Glutamic-Oxaloacetic Transaminase (also known as AST)  
SGPT 
Serum Glutamic-Pyruvic Transaminase (also known as ALT)  
T1/2 
Half-Life of the Terminal Disposition Rate Constant 
TCR 
T cell receptor 
TIL 
Tumor-infiltrating lymphocytes 
TO 
Target Occupancy 
Treg 
Regulatory T cell 
ULN 
Upper Limit of Normal 
WB 
Whole Blood  
WBC 
White Blood Cell 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 
 
 
 
 
 
 
 

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Study Summary 
Title 
A phase II, open-label, single arm, multicenter study of Avelumab with 
hypofractionated re-irradiation (HFRT) in adult subjects with transformed IDH 
mutant glioblastoma (GBM) 
Short Title 
Phase II trial of Avelumab with HFRT in adult transformed IDH mutant GBM 
Protocol Number 
s16-01179 
Phase 
Phase 2 
Methodology 
Multicenter, open-label, single arm, 2 stage phase II study with a safety lead-
in. 
Study Duration 
Approximately 24 months from start of screening to last subject processed and 
finishing the study) 
Study Center(s) 
Multicenter. Four sites:  
1) Perlmutter Cancer Center (PCC) at New York University Langone Medical 
Center (NYULMC) 
2) Dana-Farber/Harvard Cancer Center (DF/HCC), which includes 
Massachusetts General Hospital, Dana-Farber Cancer Institute and Beth Israel 
Deaconness Medical Center 
3) University of California, San Francisco (UCSF) 
4) University of California, Los Angeles (UCLA) 
Objectives 
Primary Objectives:  
• 
To assess the safety and toxicities of, and recommended phase 2 dose 
(RP2D) of Avelumab when administered with HFRT in adults with IDH 
mutant gliomas that have transformed to GBM after temozolomide or PCV 
chemotherapy. There will be a Safety Lead-In cohort of 6 patients followed 
by an expansion cohort in which the primary objective will be; 
• 
To estimate the 6-month progression-free survival (PFS6) of Avelumab + 
HFRT in adults with IDH mutant gliomas that have transformed to GBM 
after temozolomide or PCV chemotherapy; 
Secondary Objectives: 
• Assess the safety, toxicities and tolerability of Avelumab + HFRT in adults 
with IDH mutant gliomas that have transformed to GBM after temozolomide 
or PCV chemotherapy; 
• Estimate the 12-month OS, median PFS, Response Rate, and median 
duration of response; 
• Explore the association of PFS6 with: hypermutation phenotype; proportion 
of predicted mutation-associated neoantigens among all somatic mutations; 
tumor PD-L1 expression; baseline and change in regulatory T cell (Treg) and 
myeloid-derived suppressor cell (MDSC) levels 
Number of Subjects 
A minimum of 12 subjects and a maximum of 61 subjects will be registered 
Diagnosis and Main 
Inclusion Criteria 
Adults with a previously diagnosed lower grade (WHO grade II or III) IDH1/2 
mutant glioma that has transformed to glioblastoma (GBM, WHO grade IV) 
after treatment with temozolomide, CCNU or PCV chemotherapy. 
Refer to Section 4 for complete Inclusion and Exclusion Criteria. 

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Study Product, Dose, 
Route, Regimen 
• 
Avelumab (MSB0010718C) 10 mg/kg intravenously (IV) every 2 weeks  
• 
Hypofractionated radiation therapy to a total dose of 25 Gy, delivered in 5 
Gy per fraction for 5 consecutive daily fractions 
Duration of 
administration 
Avelumab therapy will continue for up to 2 years if tolerated and or until 
disease progression, unacceptable toxicity, or withdrawal of consent, 
whichever comes first. 
Reference therapy 
The reference therapies are bevacizumab monotherapy and hypofractionated 
radiation therapy, each of which is a standard single-modality therapy for 
recurrent GBM. 
Statistical 
Methodology 
Primary Efficacy Analysis: Forty three (43) patients will be enrolled and 
treated in the phase II portion of this trial. With an optimum 2 stage Simon 
Phase II design, we can test the null hypothesis that PFS6 ≤0.40 versus the 
alternative that PFS6 ≥0.60 with alpha = 0.05 (actual alpha =0.047) and power 
of 80% (actual is 82.7%) with a total of 43 patients. If 7 or fewer subjects 
achieve PFS6 among 18 patients, the study will conclude at the end of stage 
1; if 8 or more subjects achieve PFS6, the trial will continue for up to 43 
patients. If 23 or more subjects achieve PFS6 in the total of 43 patients, the 
therapy will be considered interesting for further study. 
 

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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted in accordance with 
US government research regulations, and applicable international standards of Good Clinical Practice, 
and institutional research policies and procedures. 
1.1 Background 
1.1.1 Study Disease 
Gliomas harboring mutations in isocitrate dehydrogenase (IDH) 1 (IDH1) or IDH2 are associated 
with relatively longer survival compared to wildtype IDH gliomas.1,2  However, all IDH mutant 
glioma patients eventually develop secondary glioblastoma (GBM) and the vast majority of 
patients die from their disease. IDH mutant gliomas are particularly devastating as they occur 
most frequently in the second and third decades of life yet median overall survival times range 
from as low as 2.1 years to 10 years in large scale studies.3-6  No effective salvage therapy exists 
for IDH mutant gliomas that have progressed after standard radiation and chemotherapy.  Median 
survival from the time of transformation to secondary GBM is dismal and equivalent to survival of 
IDH wildtype GBM at first recurrence (7-9 months).7,8 
1.1.2 Rationale for PD-L1 Inhibitor in IDH-mutant transformed GBM 
Cancer immunotherapy agents have emerged as highly effective for the treatment of several 
cancer types, inducing durable and extensive tumor regressions in otherwise fatal metastatic 
diseases for some patients.  One immunotherapy strategy that has proven effective for several 
cancer types is enhancement of the anti-tumor immune response using agents that target T cell 
inhibitory checkpoint receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and 
programmed death 1 (PD-1, CD279).  
  
Under chronic stimulation, T cells lose effector function and proliferative capacity often due to 
signal down-regulation as a result of increased expression of immune checkpoint receptors such 
as PD-1.  PD-1 is an Ig superfamily member related to CD28 and CTLA-4 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  The ligands 
PD-L1 (also known as B7-H1 and CD274) and PD-L2 can be detected on resting and activated T 
cells, B cells, macrophages, dendritic cells, and mast cells and its expression is greatly up-
regulated after activation or interferon treatment. PD-L1 is often expressed on tumor cells, and 
binding of PD-1 transmits inhibitory signals to the T cell and down-modulates the anti-tumor T cell 
response.11  Under normal conditions, PD-1 is expressed on the cell surface of activated T-cells 
and down-modulate unwanted or excessive immune responses, including autoimmune reactions.  
 
The PD-1/PD-L1 receptor-ligand axis is hijacked by tumors to suppress immune control and 
mediate tumor immune evasion.  PD-1 is expressed on activated peripheral CD4+ and CD8+ T-
cells, B-cells, Tregs and Natural Killer cells.12  Healthy organs express little (if any) PD-L1, whereas 
a number of cancers including GBM constitutively and abundantly express PD-L1 and PD-L2.12,13  
More than 70% of recurrent GBMs have prominent diffuse/fibrillary expression of PD-L1,14 a 
frequency higher than that observed in melanoma, non-small cell lung cancer (NSCLC) and renal 
cell carcinoma (RCC).15-17  GBMs also upregulate PD-L1 expression in circulating monocytes and 
tumor-associated macrophages (TAMs).18  Thus, immune checkpoint pathways such as the PD-
1/PD-L1 axis are highly attractive target for therapeutic intervention.  Indeed, inhibition of the 
immune checkpoints using antibodies against CTLA-4, PD-1 and PD-L1 have resulted in durable 
regressions of several types, leading to recent US FDA approvals of several systemic agents.19-22 
 

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Although remarkably durable responses have been observed in several cancer types, immune 
checkpoint therapy has been effective in only subsets of patients with these cancer types, while 
non-responding patients receive no benefit from these agents. Recently, higher nonsynonymous 
mutation burden has been associated with clinical benefit to immune checkpoint inhibitors, 
including PD-1 inhibitors.23-25  Notably, a recent study demonstrated that hypermutation 
phenotype resulting from mismatch repair (MMR)-deficiency predicted response to anti-PD-1 
therapy in colorectal cancers. 23  In this study, only hypermutant cancers had objective 
responses. In addition, two biallelic MMR deficiency syndrome pediatric patients with recurrent 
multifocal GBM were recently reported to have durable responses to anti-PD-1 therapy.26  Both 
GBM patients had driver mutations in POLE and >20,000 somatic mutations per exome in their 
tumors.   
 
Recently, we and others have characterized the molecular events that drive the malignant 
transformation to secondary GBM in IDH mutant glioma.27-32  A subset of tumors acquire 
mutations in the Rb pathway27 concomitant with DNA demethylation and activation of RB/cell 
cycle pathway genes.29,30  Subsets of tumors also acquire receptor tyrosine kinase 
amplifications,28,29 Akt/PI3K pathway mutations,27-29 MYC pathway mutations,28,29 and P16 
deletions.29  More recent data has demonstrated that therapy significantly influences the genetic 
landscape associated with malignant transformation in IDH mutant glioma.  Chemotherapy and 
radiation are both associated with acquisition of significantly more mutations at progression,29 and 
notably, a subset of glioma patients develop the particularly malignant hypermutation phenotype 
after treatment with temozolomide or PCV chemotherapy, the most common present-day 
chemotherapies used for glioma therapy.27,33-35  A majority of lower grade (WHO grade II or III) 
IDH mutant glioma patients treated with temozolomide or PCV develop a hypermutation 
phenotype at recurrence,27,29,31,32 and nearly all IDH mutant gliomas that transform into GBM 
(WHO grade IV) after temozolomide or PCV therapy are hypermutant.27,31,32  Ultimately, 
temozolomide or PCV therapy of lower grade IDH mutant gliomas results in selection of clones 
that have acquired somatic mutations in DNA mismatch repair genes (80-90% of cases acquire 
MSH6 mutations), and these MMR mutant, hypermutated clones subsequently dominate later 
recurrences which are invariably fatal.27,31,32  These data provide considerable rationale for anti-
PD-1/PD-L1 therapy in IDH mutant gliomas that have transformed to GBM after temozolomide or 
PCV chemotherapy, a population highly enriched for hypermutant tumors.27,31,32 
1.1.3 Rationale for PD-L1 Inhibitor + Hypofractionated Radiotherapy (HFRT) in 
transformed IDH mutant GBM 
Although there appears to be considerable rationale for the use of immune checkpoint inhibitors 
in gliomas, GBM tumors have a dominant immune suppressive microenvironment that may 
mediate intrinsic resistance.36,37  These mechanisms include secretion of immunosuppressive 
factors, expression of cell surface immunosuppressive factors such as PD-L1, and presence of 
immune cells that mediate immunosuppression such as tumor-associated macrophages of the 
M2 lineage and myeloid-derived suppressor cells (MDSCs).36,37  Indeed, highly variable efficacy 
has been reported with single agent immune checkpoint inhibitors in preclinical GBM models, with 
some studies reporting no efficacy.38-44 
 
One strategy to reverse the suppression of tumor immune responses involves the use of radiation 
therapy (RT), which has been shown to augment anti-cancer immune responses and enhance 
the efficacy of immune therapies in systemic cancer preclinical models and patients.43-49  
Preclinical studies examining combined radiotherapy and checkpoint inhibition indicate that each 
activate mostly non-redundant immune stimulating mechanisms and the major contribution of 
radiotherapy appears to be increasing T-cell receptor (TCR) diversity.48  RT induces major 
histocompatibility complex (MHC) class I presentation, increases antigen presentation, and 
increases cytotoxic T cell (CTL) recognition of irradiated cells50,51 and enhances the diversity of 
the TCR repertoire of the expanded peripheral T cell clones.48  A recent study also demonstrated 
that fractionated radiotherapy leads to CD8+ T-cell–dependent adaptive upregulation of tumor 
cell PD-L1 expression.49 

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In preclinical GBM models, the combination of immune checkpoint inhibition and a short course of 
RT has demonstrated impressive efficacy.  RT induces a proinflammatory response to enhance 
the antitumor efficacy of immunotherapy.  RT upregulates surface MHC class I expression, 
thereby enhancing the presentation of normally suppressed tumor-associated antigens, while 
also increasing ICAM-1 expression and CXCL16 secretion.43,52,53  RT also increases tumor-
infiltrating lymphocytes (TILs), including 4 fold increases in total CD4+ and 4.5 fold increases in 
total CD8+ cells, and also mildly increases Natural Killer cell infiltration.52  Additionally, RT alone 
can decrease intratumoral Treg levels, and RT + anti-PD1 therapy synergize to increase cytotoxic 
T cell (CTL) infiltration and significantly increase the CTL to Treg ratio in the tumors.43  In 
orthotopic, syngeneic murine glioma models, combined immune checkpoint inhibitor and short 
course RT therapy cured a significant fraction of mice, generating robust antitumor immune 
responses, tumor regressions, long-term survival and antitumor immunity.43,44   
1.1.4 Rationale for Radiation Treatment Scheme and Schedule with Avelumab 
The specific radiation fractionation scheme utilized to stimulate an immune response has also 
been shown to affect tumor responses to immune checkpoint inhibitor in preclinical studies of 
melanoma. A three or five fraction regimen of radiation (8 Gy x 3 fractions or 6 Gy x 5 fractions in 
consecutive days) in one study resulted in superior responses at the primary tumor site compared 
to a single fraction radiation regimen (20 Gy) when combined with an anti-CTLA4 antibody.46  In 
addition, in this preclinical study the three and five fraction regimens induced an "abscopal effect", 
which resulted in regression in non-irradiated metastases that was not observed with the single 
fraction regimen.  
 
Per numerous studies and extensive clinical experience, HFRT in regimens similar to that used in 
this protocol (25-35 Gy x 5 fractions) has a well-established and acceptable tolerability and safety 
profile in recurrent GBM patients.54-61  In a recent phase I study, HFRT (30 Gy delivered in 5 
fractions) combined with pembrolizumab (an anti-PD1 antibody) and bevacizumab had an 
acceptable toxicity profile in patient with recurrent high-grade glioma.62  In patients with 
melanoma brain metastasis, HFRT combined with immune checkpoint therapy has been reported 
to be well tolerated and demonstrated preliminary evidence of synergistic activity.63  An additional 
potential advantage of using HFRT is that a shorter course of radiation could potentially avoid the 
sustained immunosuppression that has been reported with prolonged weekly fractionation 
schedules typically given for adjuvant therapy of high-grade gliomas.64,65 
 
The optimal schedule for combining radiotherapy and immune checkpoint inhibitors is currently 
unclear. No significant differences in efficacy have been observed when immune checkpoint 
inhibitor was given prior to, concurrent with, or 7 days after RT in glioma and melanoma in vivo 
models.44,48  However, in one preclinical mouse study using colon cancer xenografts, significant 
improvements in overall survival were only observed when an anti-PD-L1 antibody was given at 
day 1 or 5 of a five-day fractionated radiotherapy cycle whereas anti-PD-L1 antibody given 7 days 
after completion of radiotherapy was completely ineffective at increasing overall survival 
compared with radiotherapy alone.49 
1.1.5 Rationale for Study Design and Safety Lead-In:  
Hypofractionated Radiotherapy (HFRT) in the schedule used for this trial (25 Gy delivered in 5 
fractions) has a well-established safety profile in recurrent GBM (see above Section 1.1.4 and 
reference [56]), and similar regimens have been safely provided concurrently with anti-PD-1 
antibody therapy in recurrent high-grade glioma patients in a phase I study62 and in patients with 
melanoma brain metastases.63  Therefore, Avelumab is expected to be well tolerated when 
combined with HFRT.  Nevertheless, a 6 subject Safety Lead-In will be conducted to further 
define the safety and determine the recommended phase II dose (RP2D) of Avelumab when 
combined with HFRT.  The dose of Avelumab administered during the Safety Lead-In will not 

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exceed the established recommended phase II dose of Avelumab when administered as 
monotherapy.   
 
The Safety Lead-In also incorporates a de-escalation of Avelumab dosing if unexpected dose-
limiting toxicity is observed in the first 6 subjects that follows a 3+3 phase I design for the dose 
de-escalation. Avelumab will initially be administered at 10 mg/kg intravenously (IV) every 2 
weeks, which is the RP2D established for monotherapy administration. The first 6 subjects will be 
considered the Safety Lead-In and observed for dose-limiting toxicities (DLTs) for an evaluation 
period of 28 days (see DLT definitions in Section 5.2.1.2). If 2 unexpected DLTs are observed in 
the first 6 subjects, the Safety Lead-In will enter a dose de-escalation phase with subjects 
enrolled at lower dose levels in groups of 3 in a 3+3 design (see Safety Lead-In study design, 
Section 5.2.1). 
1.1.6 Summary of Background and Rationale  
There is a significant rationale for combining anti-PD-L1 therapy with HFRT for therapy in IDH 
mutant GBM patients who have transformed after temozolomide or PCV chemotherapy, a 
population that is highly enriched for clonal hypermutant tumors.  Although gliomas have a highly 
immunosuppressive tumor microenvironment, the extremely high number of somatic mutations 
present within these genetically-defined tumors are more likely to stimulate an anti-tumor immune 
response, possibly due to the concomitantly higher number of potential mutation-associated 
neoantigens.  A brief course of radiation therapy may increase the presentation of these potential 
neoantigens by increasing MHC class I presentation and increasing TCR diversity and would also 
synergize with anti-PD-L1 therapy given their non-redundant mechanisms of anti-tumor immune 
stimulation.   
 
Preclinical modeling indicates that the optimal dose of radiotherapy to enhance immune 
checkpoint therapy is a brief course of fractionated radiotherapy (e.g. HFRT) rather than a single 
fraction of radiation or prolonged fractionated radiation prescriptions given over many weeks.  
With regards to scheduling, the administration of immune checkpoint therapy either prior to 
initiation of radiotherapy or concurrent with radiotherapy appears superior to immune checkpoint 
therapy given after the completion of radiotherapy.  
1.2 Avelumab 
1.2.1 General Information 
The active pharmaceutical ingredient in Avelumab (MSB0010718C) is a fully human antibody of 
the IgG1 isotype that specifically targets and blocks the ligand (PD-L1) for PD-1.  
 
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.   
 
The calculated molecular weight of the molecule is 143,832 Dalton. The antibody is produced by 
mammalian cell culture in a serum-free growth medium. The antibody is purified by affinity, ion-
exchange, and mix-mode chromatography. The process also includes specific viral inactivation 
and removal steps. The antibody is then transferred into formulation buffer and brought to the 
desired concentration. 
 
Avelumab will be provided to patients enrolled on this study by EMD Serono/Merck KGaA. 
 
Complete background information on Avelumab and the Avelumab development program can be 
found in the Investigator's Brochure and the Pharmacy Manual.  

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1.2.2 Physical, chemical, and pharmaceutical properties and formulation 
Avelumab drug product is a sterile, clear, colorless and non-pyrogenic concentrate for solution 
presented at concentration of 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 vial contains 200 mg of avelumab as a preservative-free acetate-buffered 
solution (pH 5.2) containing Mannitol, and Polysorbate 20 (Tween 20).  
 
Avelumab requires further dilution prior to intravenous (IV) infusion. Avelumab infusion solution 
should be prepared by dilution in 0.9% Sodium Chloride (Normal Saline) (or in 0.45% Sodium 
Chloride, only if the first option is not applicable). The verified Avelumab concentration range in 
the infusion solution is 0.016 mg/mL to 8 mg/mL. 
 
For Avelumab drug product, only excipients that conform to the current Ph. Eur. and/or the 
current USP are used. 
1.2.3 Instructions for Storage 
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. 
 
In the event of a temperature excursion: 
 
• 
Inform Fisher Clinical Services immediately by sending a Temperature Excursion Form 
(provided separately) to: AvelumabTemperatureExcursion@thermofisher.com  
 
And 
 
• 
Quarantine vials until further approval for use is received     
1.2.4 Handling of the Dosage Forms 
General Instructions: 
 
To prepare the dilutions, subsequent preparation steps must be accomplished by adequate 
trained personnel to guarantee the sterility of the product to be injected. Only clinical site 
personnel who are appropriately trained on the procedure may perform the preparation and 
administration procedures specified in the Pharmacy Manual. Clinical site personnel 
involved in these procedures must comply with all applicable regulations and standards.   
 
Safety Precautions: 
 
Handling Information:  Recommendation in the Safety Data Sheet (SDS) should be followed.  
The SDS will be provided separately to the study sites.   
 
Safety Equipment Used:  Appropriate gowning and footwear as per local site procedures. 
 
Handling Conditions: 
 

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Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room 
temperature (15-25°C, 59-77°F) preferably for 30-50 min. 
 
Rough shaking of the solution must be avoided. Addition of other medication to the infusion 
containers containing Avelumab must be avoided. No other drug should be added to the 
solution for infusion containing Avelumab. 
1.2.5 Nonclinical pharmacology 
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 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. 
 
Avelumab has 2 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 monoclonal antibody (mAb), 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. 
 
Therefore, blocking PD-L1 inhibitory mechanisms by interactions with not only PD-1 but also the 
other ligand, B7-1, avelumab offers unique therapeutic potential compared with mAbs targeting 
PD-1. 
1.2.6 Nonclinical pharmacokinetics and metabolism 
Avelumab exhibits the expected pharmacokinetic (PK) profile for an antibody binding to a cellular 
target with combined first order catabolic clearance and saturable target-mediated clearance in 
mice and monkeys. Due to the lower KM value for monkey the non-linear pathway is already 
saturated at lower Avelumab concentrations than in mice. Volume of distribution of Avelumab was 
low and in the range of the serum volume. Similar t1/2 of around 60 to 70 hours at doses between 
20 and 140 mg/kg were observed in toxicity studies in mice and monkeys. 
 
As avelumab represents a foreign protein to the immune system of animals, anti-avelumab 
antibodies in rodents and non-human primates were observed and have been considered in 
interpreting the nonclinical data. 40.5% to 100% of mice, 22.2% of rats, and up to 100% of 
monkeys treated with the drug developed anti-drug antibodies (ADAs). In animals, the generated 
ADAs seem to have the potential to increase the clearance of the avelumab. It should be 
emphasized that immunogenicity of the human avelumab in animals is not deemed predictive for 
the human situation. 

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1.2.7 Nonclinical toxicology 
The toxicological profile of Avelumab was investigated in vivo in mice, rats, and cynomolgus 
monkeys (Studies RF2710, RF2740, RF4990, RF3310, and T16228). In addition, an in vitro  
cytokine release assays (CRA) in human and cynomolgus monkey whole blood and PBMCs 
(Studies T17985, T17986, and 14-DA471-N0) as well as a tissue cross reactivity study in normal 
human and cynomolgus monkey tissues was performed (Study 20015186 and Study 20015187). 
These studies are described in detail in the Investigator's Brochure. 
 
On the basis on the binding affinity data, the cynomolgus monkey and the mouse were selected 
as relevant species for the nonclinical safety testing of avelumab. However, in the repeat dose-
toxicity studies in CD-1 mice with Avelumab IV bolus injection mortality occurred mainly after the 
third administration. A mechanistic study supported the hypothesis that the mortalities are caused 
by an immune-mediated hypersensitivity reaction, the mechanism of which is highly likely to be 
anaphylaxis (immunoglobulin E [IgE]/IgG mediated reaction). Due to severe hypersensitivity 
reactions after repeated administration in mice and the low binding affinity in rats, rodent species 
are not considered appropriate for nonclinical safety testing of avelumab and therefore, a single 
species approach (cynomolgus monkey only) is envisaged. 
 
Accordingly, repeat dose-toxicity studies of 4 and 13 weeks duration have been conducted in 
cynomolgus monkeys. Neither in the pilot 4-week IV repeat-dose toxicity study nor in the pivotal 
13-week study, clinical signs of hypersensitivity have been seen after repeated treatment with 
avelumab at dose levels of 20, 60, and 140 mg/kg, respectively. For the pilot 4-week study as 
well as for the pivotal 13-week IV repeat-dose toxicity study, a NOAEL of 140 mg/kg for systemic 
toxicity was established. Available toxicokinetic data in monkeys showed a t1/2 of 60 to 70 hours 
and linear kinetics of avelumab in this species. 
 
Initial CRA in human and cynomolgus monkey whole blood and PBMCs revealed no clear-cut 
evidence for release of pro-inflammatory cytokines. However, a subsequent, optimized CRA 
demonstrated evidence of potential cytokine release in PHA pre-stimulated PBMCs. Clinical 
experience has demonstrated that the relative risk of an infusion reaction is low (approximately 
2%) and with premedication drops to a very low level (less than 1%) indicating that the optimized 
CRA substantially overestimates the risk of cytokine release in a clinical setting. 
1.2.8 Clinical safety 
Avelumab is currently in clinical development across Phases I, II, and III. The Avelumab 
Investigator’s Brochure reports safety data from the following 4 clinical trials: 
 
• 
EMR 100070-001: A Phase I, open-label, multiple ascending dose trial to investigate the 
safety, tolerability, pharmacokinetics, biological and clinical activity of avelumab in 
subjects with metastatic or locally advanced solid tumors and expansion to selected 
indications 
• 
EMR 100070-002: A Phase I trial to investigate the tolerability, safety, pharmacokinetics, 
biological and clinical activity of avelumab in Japanese subjects with metastatic or locally 
advanced solid tumors, with expansion part in Asian subjects with gastric cancer 
• 
EMR 100070-003: A Phase II, single arm, open-label, multicenter trial to investigate the 
clinical activity and safety of avelumab in subjects with Merkel cell carcinoma (MCC) 
• 
EMR 100070-004: A Phase III open-label, multicenter trial of avelumab versus docetaxel 
in subjects with non-small cell lung cancer that has progressed after a platinum-
containing doublet 
 
More than 1500 subjects have been enrolled in the EMR 100070-001 trial. The 3 + 3 dose 
escalation algorithm to determine the MTD is complete and a dose of 10 mg/kg once every 2 

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weeks was determined for the tumor expansion cohorts on the basis of safety, PK, and PD 
observations. The treatment expansion part of the trial consists of 16 tumor treatment cohorts. As 
of 05 November 2015 (data cutoff for a pre-planned safety data review by the study Safety 
Monitoring Committee [SMC]), 53 subjects in the dose escalation part had received avelumab (4, 
13, 15, and 21 subjects had received 1.0, 3.0, 10.0, and 20.0 mg/kg of avelumab, respectively) 
and 1300 subjects in the pooled expansion part had received 10 mg/kg avelumab and were 
followed up for at least 4 weeks. 
 
The safety summary from the Investigator’s Brochure summarizes data from 1300 subjects 
treated in the pooled treatment expansion cohort from the ongoing Phase I Trial EMR 100070-
001 (as of 05 November 2015). The pooled data included subjects treated in all tumor expansion 
cohorts, including non-small cell lung cancer (NSCLC), metastatic gastric cancer, breast cancer, 
colorectal cancer, castrate-resistant prostate cancer, adrenocortical carcinoma, melanoma, 
mesothelioma, urothelial carcinoma, ovarian cancer, renal cell carcinoma, and squamous cell 
cancer of the head and neck. Safety data are also summarized for 52 subjects in the ongoing 
Phase I Trial EMR 100070-002 and for 88 subjects in the ongoing Phase II Trial EMR 100070-
003 (as of 17 December 2015). For Trial EMR 100070-004, an overview of the serious adverse 
events (SAEs) is provided. 
 
Most of the observed adverse events (AEs) were either in line with those expected in subjects 
with progressive advanced solid tumors or with class effects of mAb blocking the PD-1/PD-L1 
axis. Infusion-related reactions including drug hypersensitivity reactions and immune-mediated 
adverse reactions have been identified as important risks for avelumab.  
 
For a summary of the clinical safety data observed with the planned Avelumab dosing for this 
trial, see the Clinical Safety Data Related to Dose summary in Section 1.4. 
1.2.9 Clinical Efficacy 
The clinical efficacy information summarized in the Avelumab Investigator’s Brochure 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 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 14.1% (26 
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 20 of 122 subjects 
(16.4%) 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 with 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% 
confidence interval (CI): 6.3 to 12.0 weeks). 

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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). 
1.3 Preclinical Data 
1.3.1 Preclinical Efficacy of Avelumab  
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 (refer to Avelumab Investigator's Brochure). 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 anti-tumor 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. 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-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. 
1.3.2 Preclinical efficacy of PD-1 inhibition and radiation therapy in gliomas 

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The combination of immune checkpoint inhibitor therapy and a short course of radiation therapy 
has shown impressive efficacy against orthotopic, immunocompetent murine GBM models (see 
also Section 1.1.4).  In one study using focal single fraction radiation therapy followed by an anti-
PD-1 antibody, significantly improved survival time was observed in mice receiving radiation plus 
anti-PD-1 antibody compared to either treatment alone or no treatment (control).43  Median 
survival was 25-28 days in the control, anti-PD-1 antibody, and radiation arms, and 53 days in the 
radiation plus anti-PD-1 antibody arm (P<.05).  Additionally, long-term survival (>180 days) was 
observed in 15%-40% of mice in the combination therapy arm. Immunologic data on day 21 after 
implantation showed increased tumor infiltration by cytotoxic T cells and decreased Tregs  in the 
combination therapy group compared with the single modality arms.  Furthermore, mice that had 
received combination therapy demonstrated evidence of long-term anti-tumor immunity.  
Combination therapy-treated mice that survived >90 days after implantation were re-challenged 
with the same GBM cell line in the flank and compared with treatment naive mice. While flank 
tumors in naive mice developed large tumors by day 20, none of the mice that had previously 
received combination therapy grew tumors by day 60. 
 
Another study in orthotopic, immunocompetent murine GL-261 GBM models demonstrated that 
the combination of radiation therapy and immune checkpoint inhibition was required to see 
survival benefit over either modality alone.44  In this study, immune checkpoint modulation using 
an anti-CTLA-4 antibody and/or a 4-1BB activating antibody was compared to focal single fraction 
radiation therapy alone and various combinations of all 3 agents. In various experiments, only 
groups that received radiation with immune checkpoint modulation (anti-CTLA-4 with/without 4-
1BB activating antibody) had subsets of mice with long-term survival. Median overall survival was 
significantly increased in groups that received combination therapy with radiation and anti-CTLA-
4 antibody compared to groups receiving no treatment, radiation alone, or immune checkpoint 
modulation alone (anti-CTLA-4, anti-4-1BB, or both antibodies). In addition, mice that received 
combination immune checkpoint inhibition and radiation therapy and survived >100 days after 
implantation demonstrated anti-tumor immunity, as none of these mice developed tumors when 
re-challenged with the same GBM cell line subcutaneously into the flank, while all treatment-naive 
mice developed large tumors.  In this study, the systemic anti-tumor memory was also shown to 
be glioma-tumor specific, as a melanoma cell line injected subcutaneously into the opposite flank 
of both long-term surviving mice and naïve mice developed into tumors in all the mice regardless 
of prior treatment. 
1.4 Dose Rationale 
A dose of 10 mg/kg of Avelumab, intravenous (IV) once every 2 weeks, was selected for the 
expansion cohorts of Phase I trials, the Phase II pivotal trial (EMR 100070-003), and the ongoing 
Phase III trials based on the preliminary pharmacokinetic (PK), target occupancy, and preliminary 
clinical safety data collected in the clinical trials. For complete details, refer to the Avelumab 
Investigator's Brochure (also Section 1.2.5). 
 
Avelumab plasma levels leading to full programmed death ligand 1 (PD-L1) receptor target 
occupancy (TO) on PBMCs resulted in tumor growth inhibition in a murine disease model. 
Therefore, full TO on PBMCs can be considered a PD marker for the ability of Avelumab to act on 
its target and to show clinical activity. 
 
Preliminary PK data from EMR 100070-001 show that the concentration at the end of dose 
interval (Cmin) increased more than proportionally to dose between 1 to 10 mg/kg, but 
proportionally for doses above 10 mg/kg. Consistently the t1/2 also increased with the dose. 
However, the average value was 102 and 120 hours for 10 mg/kg and 20 mg/kg, respectively, 
with no significant difference between these two dose groups. This PK characteristic suggests 
that target mediated drug disposition is involved in the clearance of Avelumab and a high PD-L1 
TO is likely achieved at the trough concentration for doses of 10 mg/kg and 20 mg/kg. 
 

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The in vitro target occupancy data further support that a high TO is likely achieved at 10 mg/kg 
and above. 
 
• 
Target occupancy was measured ex vivo by flow cytometry on peripheral blood CD3+ T 
cells from patients (n=9) treated with Avelumab. After the first dose of the initial dose-
escalation portion of Trial EMR 100070-001, the observed mean TO reached a plateau of 
about 90% on Day 15 pre-dose for dose levels of 3 mg/kg and above. 
• 
In addition, in vitro TO was measured using flow cytometry on peripheral blood CD3+ T 
cells from 8 healthy volunteers after spiking Avelumab over a concentration range of 
0.003 to 10 μg/mL. A 50% TO was observed at a drug concentration (standard deviation 
[StD]) of 0.122 (0.042) μg/mL, and a concentration of 1 μg/mL Avelumab was required for 
> 95% target occupancy. Based on these data and the trough serum levels observed in 
EMR 100070-001, TO was projected to reach or exceed > 95% throughout the entire 
dosing interval for 10/13 subjects at 3 mg/kg, and for all (15/15) subjects at 10 mg/kg 
group from dose escalation group in EMR 1000700-001. 
 
Based on the ex vivo peripheral blood CD3+ T cell and in vitro target occupancy results, the dose 
of 10 mg/kg every 2 weeks is expected to achieve target saturation during the entire dosing 
interval in the majority of patients. 
 
Clinical Safety Data Related to Dose 
 
As of the safety cutoff date of 05 November 2015, 1353 subjects have received at least 1 dose of 
Avelumab at doses ranging from 1.0 to 20 mg/kg in the Phase I Trial EMR 100070-001, of which 
1315 have received the proposed dose of 10 mg/kg (15 in the dose escalation part of the study 
and 1300 subjects in the pooled expansion cohort). 
 
In the dose escalation portion of the Phase I study, 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 Safety Monitoring Committee (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 813 
(62.5%) subjects in the pooled expansion cohort. The most frequently observed treatment 
related TEAEs (incidence >5%) were: 
 
• 
Fatigue (212 subjects, 16.3%) 
• 
Infusion-related reaction (209 subjects, 16.1%) 
• 
Nausea (108 subjects, 8.3%) 
• 
Chills (102 subjects, 7.8%) 
Diarrhea (79 subjects, 6.1%) 
• 
Pyrexia (72 subjects, 5.5%).  
 
Grade ≥3 treatment-related TEAEs were observed in 124 subjects (9.5%) in the pooled 
expansion cohort. The most frequently reported Grade ≥3 treatment-related TEAEs were: 
 
• 
Gamma-glutamyl transferase increased (GGT) (9 subjects; 0.7%) 
• 
Infusion-related reaction (9 subjects; 0.7%).  
 
Infusion-related reactions including drug hypersensitivity reactions and immune-mediated 
adverse reactions have been identified as expected adverse drug reactions of Avelumab. The 
safety profile of Avelumab is consistent with findings reported for other anti-PD-1 or anti-PD-L1 
antibodies. 
 

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In conclusion, preliminary data from EMR 100070-001 showed that Avelumab at doses up to 
20mg/kg IV every 2 weeks was well tolerated, and the dose of 10 mg/kg IV every 2 weeks was 
considered to have an acceptable safety profile for further investigation in clinical studies. 
 
Conclusion: 
 
Based on the PK results and the receptor occupancy data, sufficient trough concentrations 
appear to be achieved for full TO in the blood in the majority of subjects receiving the 10 mg/kg 
dose. Within the dose range of 1 mg/kg to 20 mg/kg, Avelumab was well tolerated and is deemed 
to have an acceptable safety profile. 
 
Based on the above analyses, a dose of 10 mg/kg IV once every 2 weeks was considered to 
have a favorable risk benefit profile and thus represents an appropriate dose for further 
investigation in registration studies of Avelumab. 
1.5 Research Risks & Benefits 
1.5.1 Risk of Avelumab administration  
Most of the observed adverse events (AEs) for Avelumab were either in line with those expected 
in subjects with progressive advanced solid tumors or with class effects of mAb blocking the PD-
1/PD-L1 axis. Infusion-related reactions including drug hypersensitivity reactions and immune-
mediated adverse reactions have been identified as important risks for Avelumab. For details 
regarding the risks and clinical safety profile of Avelumab, see Section 1.2.8 and the Dose 
Rationale, Section 1.4. 
 
To minimize risk to the subject, vital signs, symptom-directed physical exams and safety labs will 
be performed at frequent intervals throughout the study and as indicated in the Schedule of 
Events (Attachment 1). Pre-medication will be given prior to every Avelumab infusion, and risk 
mitigation measures for infusion-related reactions will be implemented in this study consistent 
with all ongoing clinical studies with Avelumab. In addition, subjects will be asked to report any 
potential adverse events and concomitant medications continually throughout the study as 
indicated in the Schedule of Events, and complete physical exams performed prior to the initiation 
of every cycle. Furthermore, investigators will be educated on expected immune-related 
adverse events (irAE) as defined in Section 5.2.3.3 as well as adverse events of special 
interest (AESIs) as defined in Section 3.4.  A table is included that describes specific irAEs and 
provides supportive care, dose modification and discontinuation guidelines for Avelumab-related 
adverse events (Attachment 4). 
1.5.2 Risk with Radiation Therapy (RT) 
Salvage re-irradiation has long been offered as a treatment modality for recurrent GBM patients 
and has been established to be generally safe and well tolerated (see Section 1.1.4).  However, 
the risk of radiation necrosis and other adverse events listed below are increased in the setting of 
re-irradiation for glioma. 
 
Expected acute radiation therapy adverse events include skin reaction, including dryness, 
redness, itching (pruritis), tanning, soreness and hair loss, fatigue, nausea, vomiting, dry mouth, 
altered taste, decrease in blood counts, short-term hearing impairment due to reactions in the ear 
canals and on the ear, serous otitis media (fluid in the middle ear) as well as temporary 
aggravation of brain tumor symptoms such as headaches, seizures, and weakness.  
 
Expected early delayed radiation therapy adverse events (occurring 1-3 months after 
radiotherapy treatment) include fatigue, lethargy and transient worsening of existing neurological 
deficits.  

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Expected late delayed radiation therapy adverse events (occurring 3 months or more after 
radiation therapy treatment) include radiation necrosis (severe local damage to normal brain 
tissue), which may result in permanent neurocognitive deficits (difficulties with short term 
memory, calculations, language and more severe neurocognitive deficits) or motor dysfunction, 
leukoencephalopathy, permanent hearing impairment, radiation injury to the visual structures 
including the optic nerve and chiasm, which can result in partial or complete blindness, cataracts 
endocrine dysfunction and radiation-induced neoplasms. Radiation necrosis can mimic recurrent 
brain tumor and may require surgery for diagnosis and treatment. 
 
To minimize risk to the subject, modern RT techniques will be used including fractionated 
stereotactic radiotherapy, protons, and IMRT, which allow for highly conformal treatment to a 
considerably more precise target volume. These technologies have the potential to significantly 
reduce the toxicity associated with re-irradiation.66  Fractionated and hypofractionated RT (HFRT) 
have well-established safety and adverse event profiles and is generally well tolerated in 
recurrent GBM patients, with uncommon occurrences of late CNS toxicity and radiation necrosis 
(see Section 1.1.4).  
 
1.5.3 Potential Overlapping Toxicities with Avelumab and Re-Irradiation 
 
There is a theoretical risk that immunotherapy may potentiate the effects of central nervous 
system radiation necrosis given that radiation-related central nervous system necrosis is partially 
immune-mediated.67-69 Thus, there is potential for increased frequency of cerebral radiation 
necrosis and severe neurotoxicity from cerebral radiation necrosis. This potential for overlapping 
toxicity may also result in an increased risk of surgery for diagnosis and treatment of radiation 
necrosis.  
 
However, a recent phase I study has demonstrated that HFRT can be safely combined with anti-
PD-1 antibody therapy in recurrent high-grade glioma patients62 and a retrospective study has 
reported that anti-PD-1 antibody therapy can be safely combined with various hypofractionated 
radiation prescriptions in melanoma brain metastasis patients.63   
 
Therefore, we will conduct a Safety Lead-in (see Section 1.1.5 for rationale) that will include the 
first 6 subjects to further define the safety and determine the RP2D of Avelumab when combined 
with HFRT.  The dose of Avelumab administered during the safety lead-in will initiate with the 
established RP2D of Avelumab when administered as monotherapy and incorporates a de-
escalation of Avelumab dosing following 3+3 phase I guidelines if unexpected DLT is observed in 
the first 6 subjects. 
1.5.4 Other Risks of Study Participation 
Beyond the risk of study therapy exposure, subjects will not be exposed to additional risk beyond 
the risks associated with standard of care safety procedures for recurrent GBM therapy. The 
study procedures including subject visits, vital signs, phlebotomy approximately every 2 weeks, 
and imaging/response assessments approximately every 2 months, are equivalent to the 
procedures that would be performed for standard therapy for recurrent GBM.  An alternative 
course of management would be no interventional therapy and palliative care only.  Compared to 
palliative care, the risks associated with study participation outside of study therapy exposure 
include the risk of phlebotomy, imaging response assessments including cranial MRI and CT, and 
visits with practitioners. Risks associated with phlebotomy include weakness, redness, pain, 
bruising, bleeding, or infection at the needle site.  To minimize risk, patients will be counseled on 
study procedures and associated risks throughout the duration of the study.   
 

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Risk of harm from genetic testing may be a possibility should the principal investigator identify 
important findings in the future research and the subject opt into receiving these results. Genetic 
testing can generate information about a subjects’ personal health risks and can cause or 
increase anxiety, damage family relationships, and/or compromise insurability, employability and 
can even lead to discrimination. Results will only be disclosed by a qualified genetic counselor 
under the circumstance that the PI believes they are important for the subject’s health, and 
results will not be shared with employers, insurers, or placed in the subject’s medical record, 
thereby greatly reducing the possibility of psychological or social risks that could arise from 
knowledge of this genetic information, such as risk for employability or insurability or the risk of 
discrimination. 
 
1.5.5 Potential benefits 
The potential benefits to subjects with study participation are improved tumor control and 
improved overall survival with study participation.  Currently there is no effective therapy for 
secondary, recurrent IDH mutant glioblastoma that has transformed after chemotherapy including 
temozolomide and PCV. No therapy has been proven to improve survival in this setting in a 
randomized, prospective trial. 
2 Study Objectives 
This is a single arm, open-label phase II study with a 6 patient safety lead-in cohort with the primary 
objective of determining the safety and toxicities of, and recommended phase 2 dose (RP2D) of 
Avelumab when administered with HFRT in adults with IDH mutant gliomas that have transformed to 
GBM after temozolomide or PCV chemotherapy. An additional primary objective will be to estimate the 
PFS6 of the study therapy (Avelumab + HFSRT) in a two stage phase II trial design.  Secondary 
objectives will be to estimate additional measures of efficacy, including 12-month OS, median PFS, 
radiographic response rate, and median duration of response, as well as explore the association of 
biomarkers with PFS6, including hypermutation phenotype, proportion of predicted mutation-associated 
neoantigens, tumor PD-L1 expression, and circulating baseline and changes in Treg and MDSC levels.  
3 Study Design 
3.1 General Design 
3.1.1 Study Schema 
 

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Timeline of Selected Important Events 
 
 
 
 
3.1.2 General Study Design 
This is a multicenter, single arm, open label, phase II trial of Avelumab and radiation in adult 
patients with transformed IDH mutant GBM with the primary objective of estimating PFS6.   
 
The study will start with a Safety Lead-In (Section 5.2.1), which will be conducted to further 
define the safety and determine the recommended phase II dose (RP2D) of Avelumab in a 
subsequent expansion cohort when combined with HFRT. The Safety Lead-In also incorporates a 
de-escalation of Avelumab dosing if unexpected dose-limiting toxicity is observed in the first 6 
subjects and follows a 3+3 phase I design. The first 6 subjects will be considered as a Safety 
Lead-In and will be observed for dose-limiting toxicities (DLTs) for an evaluation period of 28 

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days.  The dose of Avelumab administered during the Safety Lead-In will not exceed the 
established RP2D of Avelumab when administered as monotherapy. 
 
The Phase II trial (Section 5.2.2) is a two-stage design study at the Avelumab dose determined 
to be safe in combination with HFRT (RP2D) in the Safety Lead-in. The phase II trial will enroll a 
total of 18 subjects in stage 1. In interim evaluation for efficacy will be conducted at the end of 
stage 1. If the efficacy measures are met, 25 additional subjects will be enrolled in stage 2 for a 
total planned enrollment in the phase II trial of 43 patients. Monitoring of toxicity will be carefully 
assessed during the phase II trial (see Primary Safety Endpoints, Section 3.4).  For study 
purposes, the occurrence of toxicity attributable to Avelumab that requires discontinuation of 
Avelumab therapy as defined in Section 5.2.3.2 is defined as unacceptable. Dose limiting toxicity 
rates of 40% or less are considered acceptable. Interim analyses of safety will be conducted at 10 
patients and again at 18 patients as described in the Primary Safety Endpoints (Section 3.4).  
 
After screening procedures and registration, subjects will be treated with one dose of Avelumab 
(10 mg/kg IV) followed by hypofractionated radiotherapy (HFRT, 5 fractions of 5 Gy each fraction 
on consecutive days) that initiates 7 days after the first dose of Avelumab. Avelumab will continue 
to be given once every 2 weeks after the first dose. One treatment cycle is defined as 28 days, 
corresponding to 2 doses of Avelumab. Subjects will be evaluated every 8 weeks with 
radiographic imaging to assess response to treatment. The Immunotherapy Response 
Assessment for Neuro-Oncology (iRANO) criteria (Attachment 3), which is based on the 
immune-related response criteria and the RANO criteria for brain tumor response assessment, 
will be used as the primary efficacy endpoint of PFS6.70. Adverse events will be monitored 
throughout the trial and graded in severity according to the guidelines outlined in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.   
 
Avelumab administration will continue for 2 years or until progression of disease, unacceptable 
adverse event(s), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdrawal of consent, pregnancy of the 
subject, noncompliance with trial treatment or procedure requirements.  Expected duration of 
subject participation is 4 months, which is the median progression-free survival for standard 
therapy in recurrent GBM.   
 
End of treatment assessments will be performed within 7 days after last drug administration or 
within 7 days after decision to end treatment.  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring and 90 days for serious adverse event 
reporting. All subjects will be followed until resolution or stabilization of any serious or reportable 
adverse events occurring during treatment or starting within 30 days of last study drug. 
Assessments may continue for ongoing reportable adverse events. All subjects will be followed 
by telephone contact every 3 months or medical record review for overall survival until death. 
 
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Events (Attachment 1). 
3.2 Primary Study Endpoints 
1. Determine the safety and tolerability and RP2D of Avelumab when administered with HFRT 
in adults with IDH mutant gliomas that have transformed to GBM after temozolomide or 
PCV chemotherapy. 
A Safety Lead-In will be conducted that incorporates a de-escalation of Avelumab dosing if 
unexpected dose-limiting toxicity (DLT, Section 5.2.1.2) is observed in the first 6 subjects and 
follows a 3+3 phase I design for dose de-escalation, if necessary (see Section 5.2 for details). 
The first 6 patients will be considered as safety lead-in and observed for an evaluation period of 
28 days. Patients who experience DLT will be discontinued from study therapy and will enter the 
post-study follow-up phase of the study. To be evaluable for a DLT, an individual subject must 

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have received at least the first administration of Avelumab, complete HFRT per protocol and be 
monitored for at least 28 days following the first Avelumab administration. 
The safety analysis will include all subjects who experience toxicities as defined by CTCAE 4.03 
criteria. Safety will be assessed by quantifying the toxicities and grades experienced by subjects 
who have received Avelumab with HFRT, including serious adverse events (SAEs, Section 8.1), 
immune-related adverse events (irAEs, Section 5.2.3.3), and adverse events of special interest 
(AESIs, Section 3.4). The frequency, time to onset, and severity of toxicities, as well as the 
success of standard medical management and dosing interruptions/delays, will be analyzed to 
determine if a given toxicity should be considered a DLT for dose de-escalation purposes. 
Adverse events that meet DLT criteria but occur outside the DLT window will be classified as 
unacceptable AEs and study treatment will be discontinued. 
2. Estimate the PFS6 of Avelumab + HFRT in adults with IDH mutant gliomas that have 
transformed to GBM after temozolomide or PCV chemotherapy 
Once the RP2D has been determined, the phase II portion of the study will be conducted. The 
phase II trial is a two-stage design, single arm trial to estimate the 6-month progression-free 
survival PFS6 with Avelumab in combination with HFRT in adults with IDH mutant glioma that has 
transformed to GBM (Grade IV) after prior treatment with temozolomide or PCV (see Statistical 
Methods, Section 7.2 for details).  PFS6 is a standard outcome measure for recurrent 
glioblastoma clinical trials.71  The iRANO criteria (Attachment 3), which is based on the immune-
related response criteria and the RANO criteria for brain tumor response assessment, will be 
used to assess the primary efficacy endpoint of PFS6.  All subjects that receive at least 1 dose of 
Avelumab and/or radiation will be included in the primary analysis. 
3.3 Secondary Study Endpoints 
• 
Assess the safety and tolerability of Avelumab + HFRT in adults with IDH mutant gliomas 
that have transformed to GBM after temozolomide or PCV chemotherapy. 
An important secondary objective of this study is to characterize the safety, toxicities and 
tolerability of Avelumab when administered with HFRT among subjects with transformed IDH 
mutant GBM beyond the Safety Lead-In. A safety analysis of the phase II portion of the trial will 
include all subjects who experience toxicities as defined by CTCAE 4.03 criteria. Safety will be 
assessed by quantifying the toxicities and grades experienced by subjects who have received 
Avelumab with HFRT, including serious adverse events (SAEs), immune-related adverse events 
(irAEs) and AESIs. 
 
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.03. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to all 
AEs, SAEs, and fatal AEs. Furthermore, irAEs and AESIs will be collected and designated as 
adverse events as described in Section 3.4 and Section 5.2.3.3. For statistical details of the 
Primary Safety Endpoint for the phase II trial, see Section 3.4. 
• 
Estimate the 12-month OS, median PFS, Response Rate, and median duration of response. 
To further define efficacy of Avelumab + HFRT in this study population, secondary measures of 
efficacy will be assessed, including 12-month overall survival (OS), median progression-free 
survival (PFS), the radiographic response rate and median duration of response. The subjects 
treated at the RP2D in the Safety Lead-In will be included as a separate cohort for the evaluation 
of outcomes in the phase II study. See Statistical Methods, Section 7.2, for details of these 
secondary study endpoints. 

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• 
Association of PFS6 with: hypermutation phenotype; proportion of predicted mutation-
associated neoantigens among all somatic mutations; tumor PD-L1 expression; baseline 
and change in regulatory T cell (Treg) and myeloid-derived suppressor cell (MDSC) levels.  
For complete details of laboratory correlative secondary endpoints, including background and 
rationale, handling/shipping of research specimens and description of the methods, see 
Attachment 7 and the Lab Manual. 
3.4 Primary Safety Endpoints 
For the overall endpoints of the Safety Lead-In portion of the study, see Section 3.2.1. Safety summaries 
will be reported for both the Safety Lead-in and the phase II trial.  All subjects who received at least one 
dose of Avelumab and/or radiation will be used for the analysis of safety data in this study. Safety and 
tolerability will be assessed by clinical review of all relevant parameters including adverse experiences 
(AEs), laboratory tests, and vital signs.  
 
For the phase II portion of the study, we consider a rate of toxicity of 40% or greater (defined as CTCAE 
grade 3, grade 4, or intolerable grade 2 toxicity that is possibly, probably, or definitely related to study 
therapy) to be unacceptable. We will conduct an interim assessment for safety after 10 patients are 
treated for at least 2 cycles (56 days) and again after 18 patients are treated for at least 2 cycles (56 
days). If there are 7 or fewer unacceptable toxicities among the first 10 patients, the trial will continue and 
not be stopped for safety. After safety analysis of 18 patients, the trial will continue if there are 11 or fewer 
patients with an unacceptable toxicity. These analyses are not adjusted for multiple assessments and at 
each analysis, there is a 5% alpha level and 80% power. At the conclusion of the trial, with 43 patients, 
the trial would be considered to have an unacceptably high toxicity rate if 24 or more patients experienced 
the specified toxicities. 
 
Due to a possible increased incidence of CNS toxicity from delayed radiation necrosis or radiation injury 
occurring during the first 6 months post RT, a special interim analysis will be performed. After the first 20 
subjects treated at the RP2D, including subjects in the Safety Lead-In portion of the trial, have a minimum 
24 week overall survival follow-up time from the end of RT, an interim safety analysis for delayed 
treatment-induced neurotoxicity will be performed. If the incidence of CTCAE grade 3 CNS (neurologic) 
toxicity deemed possibly, probably, or definitely related to treatment is 30% or higher in this group, the 
trial will be halted due to lack of safety. 
 
Additionally, for safety summary purposes, specific immune related adverse experiences (irAEs, as 
defined Section 5.2.3.3) and adverse events of special interest (AESI, as defined below) will be 
collected and summarized in separate tables from other AEs by toxicity grade and will include the counts, 
percentage, and 95% CI.  Any AE of unknown etiology associated with Avelumab exposure will be 
evaluated to determine if it is of a potentially immunologic etiology. 
 
Adverse events of special interest (AESI) in this study will be defined as: 
 
• 
Any AE that meets Dose-Limiting Toxicity (DLT) criteria (see Section 5.2.1.2) 
• 
Grade 2 or greater infusion-related reactions (See Section 5.2.3.5) 
• 
Grade 2 or greater allergic/hypersensitivity reactions (see Section 5.2.3.5) 
• 
Grade 3 or greater symptoms suspected to be attributable to brain edema (see Section 5.2.1.2 
for Rules for Brain Edema). 
• 
Grade 3 or greater immune-related toxicities (irAEs) (see Section 5.2.3.3) 
 
All AESIs must be reported to the study sponsor within 24 hours of awareness of the event per Section 
8.3.1. AESIs should be reported to the local institution's DSMC and IRB per local institution guidelines.  If 
the AESI is not a DLT or SAE, there is no need to report to the DSMC or IRB within 24 hours unless 
specified by the local institution's DSMC or IRB. 
 

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Adverse events (specific terms as well as system organ class terms) and predefined limits of change in 
laboratory, and vital sign parameters will be summarized with descriptive statistics (counts, percentage, 
mean, standard deviation, etc.). Continuous measures such as changes from baseline in laboratory, and 
vital signs parameters will be summarized using descriptive statistics (mean, standard deviation, etc.) for 
baseline, on-treatment, and change from baseline values. 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. 
Male or female subjects aged ≥18 years. 
2. 
Documentation of IDH1 or IDH2 mutation in any tumor specimen. 
3. 
Pathologic evidence (either diagnostic pathology slides or pathology report) of a diagnosis of 
WHO grade II or III glioma prior to treatment with temozolomide or PCV chemotherapy. 
4. 
Histopathological evidence of glioblastoma (WHO grade IV) on a progressive tumor specimen after 
treatment with temozolomide or PCV chemotherapy. The diagnosis of glioblastoma must be 
confirmed on central review by a study-designated neuropathologist at NYULMC at screening. 
Exceptions to this eligibility include the following: 
a. Any progressive glioma with IDH1 or IDH2 mutation, regardless of WHO grade, 
histopathological diagnosis, or prior therapy, will be eligible if the progressive tumor 
specimen is found to have one of the genetic alterations below: 
1. ≥20 somatic mutations per Mb by whole-exome sequencing  
2. High mutation burden or microsatellite instability (MSI) identified by Foundation 
Medicine panel next-generation sequencing (FoundationOne®, FoundationOne CDx™). 
Foundation Medicine's threshold for high mutation burden (HMB) in their panel NGS 
assays is ≥20 somatic mutations per Mb. Foundation Medicine's panel NGS assay has 
been validated by whole-exome and whole-genome sequencing to correlate tightly with 
tumor mutation burden (R2 = 0.94).96 
3. Mutation in a mismatch repair gene or other genes known to be associated with 
hypermutator phenotypes or microsatellite instability, including but not limited to MSH2, 
MSH6, MLH1, POLE, PMS2, POLD as determined by validated methods. 
4. Microsatellite instability as identified by polymerase chain reaction (PCR) or other 
validated methods. 
b. Progressive oligodendroglioma (with 1p/19q codeletion) that has hallmark histopathological 
features of glioblastoma (i.e. necrosis, pseudopalisading necrosis, or microvascular 
proliferation) is eligible as IDH1/2 mutant, 1p/19q codeleted oligodendrogliomas that have 
progressed after chemotherapy have been shown to develop hypermutation phenotype.32 
5. 
Availability of a paraffin-embedded or frozen tumor-tissue block with a minimum of 1 cm2 of tumor 
surface area from a tissue specimen that demonstrates pathological transformation to glioblastoma 
(WHO grade IV) or a progressive specimen that harbors one of the genetic alterations specified in 
Inclusion Criteria 4a. 
a. If a tumor block cannot be submitted, then 20 unstained slides (preferably 10 slides from 
two different tumor blocks from the same surgery) from the tumor specimen must be 
submitted. 
6. 
Patients must have had treatment with temozolomide, lomustine (CCNU) or PCV [procarbazine, 
lomustine (CCNU), vincristine] chemotherapy prior to histopathologic transformation to 
glioblastoma or prior to identification of one of the genetic alterations specified in Inclusion 
Criteria 4a. Notes or records from the treating oncologist are required for documentation of 
treatment history. Prior treatment with at least one of the following chemotherapy schedules is 
required to be eligible: 
a. At least one 6 week course of continuous daily temozolomide 

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b. At least six 28-day cycles given in one of the following schedules: 
1. Daily for 5 days of a 28-day cycle 
2. Daily for 21 days of a 28-day cycle 
3. Daily for 14 days of a 28-day cycle 
4. Alternating 7 days on/7 days per 28-day cycle 
5. Continuous daily dosing of a 28-day cycle. 
c. Other schedules of temozolomide may be considered after discussion with the overall 
Principal Investigator. 
d. At least 3 cycles of PCV or lomustine (CCNU) chemotherapy. 
7. 
Patients who received anti-tumor therapy after histopathologic transformation to glioblastoma must 
have shown unequivocal radiographic evidence of tumor progression by contrast-enhanced MRI 
scan (or CT scan if MRI is contraindicated). 
8. 
Patients must have had prior CNS radiotherapy for their glioma, including standard doses for low-
grade or high-grade glioma as well as non-standard dose and fractionation, including 
hypofractionated regimens, stereotactic radiosurgery, etc. 
9. 
Patients can have had any number of prior therapies, including but not limited to molecularly 
targeted therapies and anti-angiogenic therapies, however they must have had prior 
chemotherapy with either temozolomide or lomustine as per Eligibility Criteria 6. 
10. Karnofsky performance status (Attachment 2) of ≥60. 
11. Interval of at least 6 months from the completion of any prior radiotherapy and registration. If 
patients have not passed an interval of at least 6 months, they may still be eligible if they meet 
one or more of the following criteria: 
a. New areas of tumor outside the original radiotherapy fields as determined by the 
investigator, or 
b. Histologic confirmation of tumor through biopsy or resection, or 
c. Nuclear medicine imaging, MR spectroscopy, or MR perfusion imaging consistent with 
true progressive disease, rather than pseudoprogression or radiation necrosis obtained 
within 28 days of registration AND an interval of at least 90 days between completion of 
radiotherapy and registration. 
12.  The following time periods must have elapsed prior to start of study treatment, the following time 
periods must have elapsed:  
a. 5 half-lives from any investigational agent 
b. 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from 
nitrosoureas) 
c. 6 weeks from antibodies 
d. Prior treatment with other immune modulating agents within fewer than 4 weeks prior to 
the first dose of Avelumab. 
1. Examples of immune modulating agents include blockers of CTLA-4, 4-1BB 
(CD137), OX-40, therapeutic vaccines, or cytokine treatments. 
e. 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies. 
13. An interval of at least 2 weeks (to start of study agent) between prior surgical resection or one 
week for stereotactic biopsy. 
14. Adequate hematologic, hepatic, and renal function defined by absolute neutrophil count ≥1.5 x 
109/L, hemoglobin >9 g/dL, platelet count ≥ 100 x 109/L (may have been transfused), aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN), 
total bilirubin ≤1.5 x ULN, and estimated creatinine clearance (CrCl) ≥ 30 mL/min according to the 
Cockcroft-Gault formula or local institutional standard method. 
15. Women of child-bearing potential (WOCBP) and men able to father a child must agree to use 
highly effective contraception while on study drug and for 30 days after the last dose of 

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Avelumab. WOCBP must have a negative pregnancy test within 28 days of initiation of dosing. 
Highly effective contraceptive measures include: stable use of oral contraceptives such as 
combined estrogen and progestogen and progestogen only hormonal contraception or other 
prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; 
intrauterine device [IUD]; intrauterine hormone-releasing system (IUS); bilateral tubal ligation; 
vasectomy and sexual abstinence. 
a. Contraception is not required for men with documented vasectomy. 
b. Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.  
c. Pregnancy testing and contraception are not required for women with documented 
hysterectomy or tubal ligation. 
16. Willing to and capable of providing written informed consent prior to any study related 
procedures. 
17. Ability and willingness to comply with all study requirements, including scheduled visits, treatment 
plans, laboratory tests, and other study-related procedures. 
4.2 Exclusion Criteria 
1. 
Investigational drug use within 28 days of the first dose of Avelumab. 
2. 
Planned participation in another study of an investigational agent or investigational device or use 
of a therapeutic device intended for therapy of glioma. 
3. 
Prior therapy with an agent that blocks the PD-1/PD-L1 pathway. 
4. 
Primary brainstem or spinal cord tumor. 
5. 
Diffuse leptomeningeal disease at recurrence 
6. 
Recurrent infratentorial tumor 
7. 
Prior re-irradiation or stereotactic radiosurgery for recurrent disease at the same tumor location 
intended for HFRT in this study. 
8. 
Maximal tumor diameter >4 cm 
9. 
Patients with evidence of significant intracranial mass effect that requires >4 mg of 
dexamethasone or bioequivalent per day for 5 consecutive days for management of symptoms at 
any time within 14 days of registration. 
a. Subjects on a standard high-dose steroid taper after craniotomy may receive a higher 
dose of corticosteroids within 14 days of registration, however must be at a dose ≤4 mg 
of dexamethasone or bioequivalent per day within 5 days prior to registration. 
b. Administration of steroids through a route known to result in a minimal systemic exposure 
[i.e., intranasal, intraocular, inhaled, topical, or local injection (e.g., intra-articular 
injection) corticosteroids (<5% of body surface area)] are permitted.  
c. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids 
are at doses ≤ 10 mg prednisone or bioequivalent per day. 
d. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) 
are allowed. 
10. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. 
The following are not exclusions:  
a. Patients with diabetes type I, vitiligo, hypo- or hyperthyroid diseases, or psoriasis not 
requiring systemic immunosuppressive treatment are eligible. 
11. Prior organ transplantation, including allogeneic stem cell transplantation. 
12. Known history of, or any evidence of active, non-infectious pneumonitis within the last 5 years. 
13. Known prior, severe hypersensitivity (NCI-CTCAE v4.03 Grade 3 or 4) to investigational product 
or any component in its formulations including known severe hypersensitivity reactions to 
monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more 

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features of partially controlled asthma). 
14. Active infection requiring systemic therapy.  
15. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome. 
16. Positive test for Hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus (HCV antibody) at 
screening indicating acute or chronic infection. 
17. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except 
for administration of inactivated vaccines. 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. 
18. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 
months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable 
angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious 
cardiac arrhythmia requiring medication. 
19. Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however, alopecia and 
sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on 
investigator’s judgment, are acceptable. 
20. Patients with another active cancer [excluding basal cell carcinoma, cervical carcinoma in situ or 
melanoma in situ]. Prior history of other cancer is allowed, as long as there was no active disease 
within the prior 2 years. 
21. Pregnant or breastfeeding (negative serum or urine pregnancy test required for women of 
childbearing potential), or unable to maintain use of contraception while on study and for 30 days 
after the last dose of Avelumab. 
22. Known alcohol or drug abuse 
23. All other unstable, severe, or chronic medical conditions including immune colitis, inflammatory 
bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent 
(within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may 
increase the risk associated with study participation or study treatment administration or may 
interfere with the interpretation of study results and, in the judgment of the investigator, would 
make the patient inappropriate for entry into this study. 
24. Any condition that would prohibit the understanding or rendering of informed consent. 
4.3 Subject Recruitment and Screening 
All efforts will be made to actively recruit and retain women and members of minority groups and their 
subpopulations in this study, with the objective of accruing a study population that resembles the age, 
gender, ethnic and racial composition of the adult U.S. population as closely as possible. The inclusion 
and exclusion criteria in this study should not have a negative effect on the enrollment of these 
populations. If any differences are observed in the outcomes of these populations, these results will be 
reported. 
 
Patients will be recruited for the study from investigator or sub-investigator clinical practices. Screening 
requirements and diagnostic testing necessary to meet all inclusion and exclusion criteria (Section 4.1 
and Section 4.2) are listed in detail in Section 6.1.  Identification of prospective subjects will be 
conducted by reviewing the medical records of patients in the investigator or sub-investigator's clinical 
practice and the investigator and sub-investigators will use all efforts to limit its use of protected health 
information. For study requirements to maintain subject confidentiality and management of study 
information according to the requirements of the Health Insurance Portability and Accountability Act of 
1996 (HIPAA), refer to Section 9.1 and Section 9.2. 
 
Informed consent will take place in the investigator or sub-investigator's clinical practice per institutional 
guidelines when a patient is deemed potentially eligible for participation by the study investigator or sub-
investigator. Patients will be asked to give medical information about themselves specific to the inclusion 

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and exclusion criteria outlined in the protocol.  Only study investigators will have access to this 
information.  Information collected will include Participant Demographics (address, zip code, sex, race, 
ethnicity, initials, date of birth), Parameters for eligibility, Parameters for exclusion, and Parameters for 
stratifications. 
4.3.1 
Informed Consent 
Consent will be obtained only by a participating investigator who has completed requisite training 
for human subject research and has been instructed by the Principal Investigator about the 
research study and consent process. The participating investigator must assess the subject's 
capacity to provide informed consent to ensure subjects who lack capacity to provide informed 
consent are not enrolled. The assessment should include open-ended questions (i.e., not yes or 
no questions) regarding the purpose and involvement of the research. The investigator evaluating 
patient capacity must be an M.D. with experience in evaluating patient capacity. Investigators will 
review the informed consent form with patients and address any questions or concerns prior to 
obtaining written informed consent for participation and HIPAA authorization. 
 
Patients who are evaluated and/or treated by physicians in the oncology program will be given a 
consent form describing participation in the study. Patients will be given adequate time to read 
the consent form. They will be given time to ask questions about the study in private exam rooms. 
Questions will be answered by a participating physician, nurse practitioner, or research nurse all 
of whom have completed requisite training for human subject research. Investigators will review 
the informed consent form with patients and address any questions or concerns prior to obtaining 
written informed consent for participation. Investigators will stress that participation in the study is 
completely voluntary and will not affect the care patients receive or result in any loss of benefits to 
which patients are otherwise entitled. 
 
For non-English speaking patients, institutional translation services will be utilized. For these 
patients, the consent letter and all other information will be administered orally and a witness, not 
related to the research project, will be present while the oral presentation is given. A short form 
will be utilized for the subject to sign in his/her name and the translator and/or witness must sign 
the short form. The translator will also sign the main consent form. 
 
For patients who cannot read, a witness, not related to the research study will be present. The 
consent will be read to the patient. The patient will also be allowed to ask any questions s/he may 
have. The investigator will ask the patient questions to ensure s/he understands the study. If the 
investigator determines the subject understands the study, the patient will mark an X where 
his/her name would go and the witness will sign the consent form. 
4.3.2 
Documentation of Consent 
The Principal Investigator or IRB approved sub-investigator will be responsible for documentation 
in the medical record that consent has been obtained from all participants. A signed copy of the 
consent form will be given to each participant. Original consent forms will be stored in the 
subject’s medical chart. 
4.3.3 
Multi-Site Surveillance 
As the lead investigator in a multi-site trial, the Overall Principal Investigator is responsible for 
organizing and conducting monthly teleconferences with all participating sites.  The PI will also be 
responsible for including data from all of the participating sites within the overall trial’s six month 
Data and Safety Monitoring report to the DSMC to include minutes from monthly PI 
teleconferences.  Each participating site will be responsible for submitting the results and 
recommendations from the DSMC’s six month review to their IRB of record at the time of 
continuing review. 

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4.3.4 
Patient Informed Consent at Additional Sites 
The Principal Investigator (PI) at each participating site will identify the physician members of the 
study team who will be obtaining consent and signing the consent form for therapeutic protocols. 
It is NYULMC policy that Nurses and Fellows cannot obtain consent to greater than minimal risk 
trials, unless Fellows are listed as co-investigators.  
 
The Investigator must ensure that each participant is fully informed about the nature and 
objectives of the study and possible risks associated with participation. All participants must be 
provided a consent form describing this study and providing sufficient information for participants 
to make an informed decision about their participation in this study. The formal consent of a 
participant, using the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and dated by the 
participant and by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent document must be 
retained in the medical record or research file. 
 
All parties will ensure protection of participant personal data and will not include participant 
names on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.  In case of data transfer, NYULMC Perlmutter Cancer Center (PCC) will 
maintain high standards of confidentiality and protection of participant personal data. 
 
The informed consent form must be in compliance with ICH/GCP, local regulatory requirements, 
and legal requirements. 
 
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB and NYULMC before use. 
4.4 Registration Procedures 
4.4.1 General Guidelines 
Each patient must sign and date an informed consent form before undergoing any study specific 
procedure unless a procedure is being performed as part of the patient’s standard of care. 
 
Enrollment in the study requires that all inclusion and exclusion criteria have been met.  
Enrollment occurs upon confirmation of registration from the NYULMC PCC Clinical Trials Office 
(CTO).  The following materials must be submitted to the Research Coordinator for registration: 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated informed consent checklist 
3. Complete signed and dated eligibility checklist 
4. All supporting documentation verifying each criterion has been met 
 
Registration will occur within 24 hours of research coordinators’ receipt of all the above 
documents.  A written confirmation of enrollment including a unique study identification number 
assigned by the research coordinator will be distributed to the study team upon registration. 
 
Pretreatment evaluation will therefore be dictated by standard clinical practice.  Eligible patients 
will be entered into the study by the study coordinator. 
 
All patients will be required to sign a written informed consent prior to being registered on this 
study.  Any patient not registered to the study before treatment begins will be considered 
ineligible and registration will be denied.  Every effort will be made to answer questions raised by 

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patients and their families or advocates regarding the protocol and alternative therapies prior to 
asking a patient to sign the consent form. 
 
Once eligibility is verified, a unique patient study number will be issued within 24 hours of 
receiving all required registration material.  The patient will not be identified by name.  This is the 
point, at which, the patient is considered on the study.  Subjects must not start any protocol 
procedures prior to registration 
 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator. 
4.4.2 Patient Registration at Other Participating Institutions 
 
The Principal Investigator (PI) at each participating site will identify the physician members of the 
study team who will be obtaining consent and signing the consent form for therapeutic protocols. 
It is NYULMC policy that Nurses and Fellows cannot obtain consent to greater than minimal risk 
trials.  
 
Enrollment at additional sites can occur once each site’s IRB has approved this protocol, a copy 
of each site’s IRB approval, Citi training certificates, Medical Licenses and signed CVs are 
provided to NYULMC Perlmutter Cancer Center Clinical Trials Office.  Once, all required 
documents are provided to NYULMC PCC Clinical Trials Office an activation notification will be 
sent to the PI and research coordinator at that site.   
 
Central registration for this study will take place at NYULMC PCC. 
 
Each patient must sign and date an informed consent form before undergoing any study specific 
procedure unless a procedure is being performed as part of the patient’s standard of care.  Once 
a patient has signed consent, each site must notify the NYULMC PCC Research Coordinator and 
forward a copy of the signed consent to NYULMC PCC Clinical Trials Office within 24 hours. 
 
Enrollment in the study requires that all inclusion and exclusion criteria have been met.  
Enrollment occurs upon confirmation of registration from the NYULMC PCC Clinical Trials Office.  
The following materials must be submitted to the Research Coordinator at NYULMC via email: 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated informed consent checklist 
3. Complete signed and dated eligibility checklist 
4. All supporting documentation verifying each criterion has been met 
 
Registration will occur within 24 hours of research coordinators receipt of all of the above 
documents.  Once eligibility is verified, a unique subject study number will be issued within 24 
hours of receiving all required registration material.  This number is unique to the participant and 
must be written on all data and correspondence for the participant.  The NYULMC PCC Clinical 
Trials Office will return a signed eligibility confirmation worksheet with the subject’s unique study 
number.  The subject will not be identified by name.  This is the point, at which, the patient is 
considered on the study. Protocol treatment should begin within 5 days; issues that would cause 
treatment delays should be discussed with the overall PI, Sylvia Kurz, MD, PhD.   Subjects must 
not start any protocol procedures prior to registration.  Pretreatment evaluation will therefore be 
dictated by standard clinical practice. 
 
Except in very unusual circumstances, each participating institution will order the study agent 
directly from the supplier. 
 

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Each site is responsible for reporting all unexpected problems involving risks to participants or 
others to NYULMC PCC Clinical Trials Office and to their IRB as per site institutional policy. See 
Section 8.4 for detailed instructions on reporting requirements. 
 
 
4.5 Early Withdrawal of Subjects 
4.5.1 When and How to Withdraw Subjects 
A subject has the right to voluntarily discontinue study treatment or withdraw from the study at any time, 
for any reason, and without repercussion. The investigator and sponsor have the right to discontinue a 
patient from study treatment or withdraw a patient from the study at any time. 
 
Reasons for subject withdrawal from the study may include, but are not limited to: 
• 
Subject withdrawal of consent at any time 
• 
Disease progression 
• 
Intolerable toxicity 
• 
Any medical condition that the investigator or sponsor determines may jeopardize the patient’s 
safety if he or she continues in the study or continues treatment with study drug. 
• 
The investigator or sponsor determines it is in the best interest of the patient 
• 
Failure of subject to adhere to protocol requirements (e.g., not complying with protocol required 
visits, assessments, and dosing instructions)  
• 
Pregnancy  
• 
Meeting of another study withdrawal criterion 
• 
Study termination by Sponsor 
Every effort should be made to obtain information on patients who withdraw from the study, including the 
reason for taking a participant off study. The date the participant was removed, must be documented. An 
excessive rate of withdrawals would render the study uninterpretable; therefore, unnecessary withdrawal 
of patients should be avoided. 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
For End of Treatment required assessments see Section 6 (Study Procedures), and Schedule of 
Events (Attachment 1).  After the end of treatment, each subject will be followed for 30 days for adverse 
event monitoring and 90 days for serious adverse event reporting. Assessments may continue for 
ongoing reportable adverse events. A visit is to be performed at 30 days (±7 days) after the last study 
drug is given. Participants removed from protocol therapy for unacceptable adverse events will be 
following until resolution or stabilization of the adverse event. 
 
Subjects who discontinue for reasons other than progressive disease will have post-treatment follow-up 
for survival. After coming off study, each subject will be contacted every 3 months by telephone or 
medical record review to assess survival status until they meet criteria for removal from study as detailed 
below. 
 
• 
Withdrawal of permission to record at least survival data 
• 
Lost to follow-up 
• 
Death 

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If a subject withdraws permission to record at least survival data after coming off treatment, this must be 
documented along with the date the subject withdraws permission.  Subjects will be considered lost to 
follow up if no medical records are available to be reviewed and two phone calls each to the subject and 
then the subject's next-of-kin (if the subject does not respond) are not returned over two consecutive 3 
month periods. 
5 Study Drug  
5.1 Description 
Avelumab (company code: MSB0010718C) is a fully human antibody (calculated molecular weight of 
143,832 Dalton) of the immunoglobulin G (IgG) 1 isotype that specifically targets and blocks PD-L1, the 
ligand for PD-1 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. 
 
Avelumab drug product is a sterile, clear, and colorless concentrate for solution intended for intravenous 
(IV) infusion. The drug is presented at a concentration of 20 mg/mL in single-use glass vial containing 200 
mg of Avelumab.  
 
Avelumab drug product must be stored at 2°C to 8°C until use, and it must not be frozen. Rough shaking 
of avelumab product must be avoided. Avelumab drug product must be diluted with 0.9% saline solution; 
alternatively a 0.45% saline solution can be used if needed. It is recommended that the diluted avelumab 
solution is used immediately.  Avelumab is administered as a 1-hour (-10/+20 minutes) IV infusion.  
 
The Pharmacy Manual will be provided and contains specific instructions for Avelumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
5.2 Treatment Regimen 
This is a multicenter, open-label, single-arm phase II trial of Avelumab in combination with 
hypofractionated radiation (HFRT) in adults with transformed IDH mutant GBM (for Subject Selection 
Criteria see Section 4; for Study Schema, see Section 3.1.1; for Schedule of Events, see Attachment 
1; for details on Radiation Treatment, see Attachment 6).   
 
An initial Safety Lead-In of 6 subjects will be conducted to define the safety and RP2D of Avelumab in 
combination with HFRT as detailed below in Section 5.2.1. The dose of Avelumab administered during 
the safety lead-in will initiate at the established phase II dose of Avelumab when administered as 
monotherapy (Dose Level 0). The safety lead-in also incorporates a de-escalation of Avelumab dosing if 
unexpected dose-limiting toxicity is observed in the first 6 subjects and follows a 3+3 phase I design as 
described below (Section 5.2.1). In the unlikely event that the Safety Lead-In phase of this study is 
unable to define an adequately safe dose of Avelumab administered with HFRT, the study will be 
stopped. 
 
The RP2D of Avelumab administered with HFRT will be incorporated into the Phase II portion of this 
study.  
 
Avelumab will be administered in an outpatient setting as an intravenous (IV) infusion; however, inpatient 
administration is permitted. Avelumab will be provided to patients enrolled on this study by EMD 
Serono/Merck KGaA.  
 
Pre-medication for Avelumab:  Subjects will receive Avelumab by IV infusion once every 2 weeks.  
Premedication with an antihistamine and with paracetamol (acetaminophen) (for example, 25-50 
mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or oral equivalent) 
approximately 30 to 60 minutes prior to each dose of Avelumab is mandatory prior to the first 4 
infusions.  Premedication should be administered for subsequent avelumab infusions based upon 

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clinical judgment and presence/severity of prior infusion reactions. This regimen may be modified 
based on local treatment standards and guidelines as appropriate provided it does not include 
systemic corticosteroids. 
 
Infusion: Avelumab is administered as a 1-hour (-10/+20 minutes) IV infusion. Each patient’s 
dose will depend on individual body weight. The dose of Avelumab must be adjusted each dose 
for changes in body weight of ≥10%. Dose adjustments for changes in body weight of <10% will 
be at the discretion of the investigator. Following all avelumab infusions, subjects must be 
observed for 30 minutes post‑infusion for potential infusion-related reactions. The Pharmacy 
Manual contains specific instructions for Avelumab dose calculation, reconstitution, preparation 
of the infusion fluid, and administration.  
 
Setting: Avelumab should be administered in a setting that allows for immediate access to an 
environment that can immediately administer therapy for anaphylaxis, such as the ability to 
implement immediate resuscitation measures.  Steroids (dexamethasone 10 mg), epinephrine 
(1:1,000 dilution), allergy medications (IV antihistamines), bronchodilators, or equivalents, and 
oxygen should be available for immediate access. 
 
Planned Avelumab regimens to be assigned may include: 
 
• 
1 mg/kg IV infusion every 14 days for 2 years 
• 
3 mg/kg IV infusion every 14 days for 2 years 
• 
10 mg/kg IV infusion every 14 days for 2 years 
 
After screening procedures and registration, all subjects will be treated with one dose of Avelumab IV at 
the assigned dose level. Study treatment should begin as close as possible to the date on which the 
participant is registered.  One treatment cycle is defined as 28 days, corresponding to 2 doses of 
Avelumab. Avelumab will be administered every 14 days after the first Avelumab dose up to 3 days 
before or after the scheduled Day (±3) of each drug administration due to administrative reasons (i.e., 
Days 1±3 and 15±3 of a 28-day cycle). 
 
All subjects will receive hypofractionated radiation (HFRT) to a total dose of 25 Gy given as 5 Gy per 
fraction over 5 consecutive fractions (for details on Radiation Therapy administration see Attachment 6). 
HFRT must begin 1 week after the first dose of Avelumab (i.e., Day 8 of Cycle 1). HFRT should preferably 
be given on consecutive days (i.e., Day 8 to Day 12).  
 
Every attempt must be made to obtain the original radiotherapy treatment plan in order to guide re-
irradiation treatment planning 
 
All subjects will be evaluated every 8 weeks with radiographic imaging to assess response to treatment. 
The Immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria (Attachment 3), 
which is based on the immune-related response criteria and the RANO criteria for brain tumor response 
assessment, will be used as the primary efficacy endpoint of PFS6.70. Adverse events will be monitored 
throughout the trial and graded in severity according to the guidelines outlined in the NCI-CTCAE version 
4.03. 
 
Avelumab administration will continue for all subjects for 2 years or until the subject discontinues study 
therapy as per Subject Withdrawal guidelines, whichever comes first (Section 4.5). Subjects who are 
discontinued from study therapy will enter the post-study follow-up phase of the study as per Section 
4.5.2. 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of trial treatments in accordance with 
the protocol and any applicable laws and regulations. 

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5.2.1 Safety Lead-In 
The study will initiate with a Safety Lead-In of 6 subjects.  The first dose of study agent 
(Avelumab) will be administered after all procedures / assessments have been completed as 
detailed on the Schedule of Events (Attachment 1). Avelumab will initially be administered at 10 
mg/kg (IV) every 2 weeks (Dose Level 0, see Table 1 below), which is the RP2D established for 
monotherapy administration (see section 1.4, Dose Rationale).  
 
Beginning 7 days after the first dose of Avelumab (i.e. Day 8), all subjects will be administered 
HFRT to a total of 25 Gy, given in 5 fractions of 5 Gy on consecutive days (i.e., Day 8 to Day 12). 
Avelumab will continue to be given once every 2 weeks after the first Avelumab dose.  
 
Once the initial 6 subjects are enrolled in the Safety Lead-In, enrollment will stop and subjects will 
be observed for 28 days for dose-limiting toxicities (DLTs, see DLT definitions, Section 5.2.1.2).  
At the end of the DLT period of 28 days, a Safety Monitoring Team consisting of the overall PI 
(Sylvia Kurz, MD, PhD), the Deputy Director of the Perlmutter Cancer Center who is not an 
investigator on the study, and the study biostatistician will review the safety data at a Safety 
Lead-In Dose Review meeting. This meeting will be led by the overall PI and at a minimum will be 
attended by the Safety Monitoring Team, the NYULMC Data Safety Monitoring Committee 
(DSMC), and a designated representative from each study site; other individuals, including sub-
investigators, may be included. Continuation of enrollment will occur once all of the initial 6 
subjects have completed the Day 28 safety assessments and the final dosing decision is made by 
the Safety Monitoring Team.  However, screening for the next dose cohort may begin prior to 
confirmation that the current dose is safe.  
 
The Safety Lead-In incorporates a de-escalation of Avelumab dosing if unexpected DLT is 
observed in the first 6 subjects. The Safety Monitoring Team and NYULMC DSMC will review the 
safety data at the end of the DLT period for the first 6 subjects and determine whether the study 
should proceed to phase II at Dose Level 0 or enter the dose de-escalation phase, which will 
follow a 3+3 phase I design. In the dose de-escalation phase, subjects will be enrolled and 
observed in groups of 3 for DLTs for an evaluation period of 28 days (see Dose De-Escalation 
Rules, Section 5.2.1.1, and Study Schema, Section 3.1.1).  After 3 subjects are enrolled in 
each cohort, enrollment will stop and subjects will be observed for 28 days for DLTs.  At the end 
of the DLT period, the Safety Monitoring Team and NYULMC DSMC will review the safety data at 
a Safety Lead-In Dose Review meeting that will include at least a representative from each site; 
sub-investigators may be included. Continuation of enrollment will occur once all 3 of the subjects 
have completed the Day 28 safety assessments and the final dosing decision is made by the 
Safety Monitoring Team.  However, screening for the next dose cohort may begin prior to 
confirmation that the current dose is safe. 
 
DLT will be determined by toxicities related to Avelumab during or beginning over the first 28 
days of treatment as defined below in Section 5.2.1.2 (Definition of DLT in for the Safety 
Lead-In). Subjects who experience DLT will be discontinued from study therapy and will enter the 
post-study follow-up phase of the study. Adverse events that meet DLT criteria but occur outside 
the DLT window will be classified as unacceptable AEs and study treatment will be discontinued. 
 
Subjects are evaluable for DLTs if they have received at least one dose of Avelumab, have 
completed HFRT per protocol and have completed safety assessments over the entire DLT 
evaluation period (days 1 through 28). Any subject who discontinues treatment or withdraws from 
the study prior to completing the DLT evaluation period for any reason other than the occurrence 
of a protocol-defined DLT or other AE leading to study treatment discontinuation will be replaced 
(see also Section 7.3.1). Each replacement patient will be assigned a unique patient number, 
and will be treated at the same dose level as the replaced, prematurely withdrawn patient. Any 
patient who discontinues after the DLT observation period will not be replaced. 
 

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Subjects who do not experience a DLT during the DLT period (28 days) and remain on study after 
the DLT period will continue Avelumab administration every 2 weeks for up to 2 years or until the 
subject discontinues study therapy as per Subject Withdrawal guidelines (Section 4.5). Subjects 
in the Safety Lead-In who are discontinued from study therapy may be considered for treatment 
resumption after resolution or stabilization of the condition if resuming treatment is thought to be 
in the best interest of the patient, however treatment may resume only after discussion with the 
Safety Monitoring Team, NYULMC DSMC and overall PI (see Section 5.2.6.2). Otherwise, all 
subjects who discontinue study therapy will enter the post-study follow-up phase of the study as 
per Section 4.4.2.    
5.2.1.1 Dose De-Escalation Rules 
• 
If at Dose Level 0, ≤1 of the first 6 subjects develop DLT, the study will continue to phase II 
at Dose Level 0, which will be considered the RP2D. 
• 
If at Dose Level 0, >1 of the first 6 subjects develop DLT, cohort enrollment will be stopped 
immediately, and re-started from the beginning with 3+3 patients enrolled at Dose Level -1. 
• 
If at Dose Level -1, ≤1 of the first 3 subjects develop DLT, 3 more subjects will be enrolled to 
Dose Level -1. 
• 
If at Dose Level -1, ≤1 of the first 6 subjects develop DLT, the study will continue to phase II 
at Dose Level -1, which will be considered the RP2D. 
• 
If at Dose Level -1, >1 of the first 3 subjects develop DLT, cohort enrollment will be stopped 
immediately, and re-started from the beginning with 3+3 patients enrolled at Dose Level -2. 
• 
If at Dose Level -1, >1 of 6 subjects develop DLT, cohort enrollment will be stopped 
immediately, and re-started from the beginning with 3+3 patients enrolled at Dose Level -2. 
• 
If at Dose Level -2, ≤1 of the first 3 subjects develop DLT, 3 more subjects will be enrolled to 
Dose Level -2. 
• 
If at Dose Level -2, >1 of the first 3 subjects develop DLT, the Safety Lead-In will be 
discontinued. In this case, the phase II portion of this study will not be conducted. 
• 
If at Dose Level -2, ≤1 of the first 6 subjects develop DLT, the study will continue to phase II 
at Dose Level -2, which will be considered the RP2D. 
• 
If at Dose level -2, >1 of the first 6 subjects develops DLT, the Safety Lead-In will be 
discontinued. In this case, the phase II portion of this study will not be conducted. 
Table 1: Dose levels and doses to be evaluated in Safety Lead-In and for dose reductions 
 
Dose Level 
Avelumab Dose 
(mg/kg) 
Zero (0) 
10 mg/kg 
Minus one (-1) 
3 mg/kg 
Minus two (-2) 
1 mg/kg 
 
5.2.1.2 Definition of Dose-Limiting Toxicity (DLT) for the Safety Lead-In 
A DLT is defined as any grade ≥3 adverse event (AE) that is at least possibly, probably or 
definitely related to Avelumab or HFRT during the DLT period with the exceptions noted below.  

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For guidance on assessing the relationship of AEs to Avelumab, HFRT, or study procedures, see 
Attachment 5. The sponsor may request information to justify the causality assessment of DLTs, 
as needed. 
 
The DLT period is considered the first 28 days of study therapy, and will include labs and other 
evaluations taken at C1D28 (end of the first 28 days). The frequency, time to onset, and severity 
of toxicities, as well as the success of standard medical management and dosing 
interruptions/delays, will be analyzed to determine if a given toxicity should be considered a DLT 
for dose decision purposes. The final decision of whether or not the AE meets the DLT definition 
will be based on a careful review of all relevant data by the Safety Monitoring Team. The 
investigator may also be consulted. 
 
In addition to the above, the following DLT exceptions will apply: 
 
A DLT will be defined as any of the following: 
• Grade ≥2 uveitis (considered as a potential immune-related adverse event [irAEs – see 
definition in Section 5.2.3.3])  
• Any Grade 4 AE except for single laboratory values out of normal range that are unlikely 
related to study treatment as described below in the DLT exceptions. 
The following exceptions will NOT be classified as DLT: 
• Grade 4 single laboratory values out of normal range that are unlikely related to study 
treatment as assessed by the Investigator, do not have any clinical correlate, and 
resolve within 7 days with adequate medical management 
• Grade 3 immune-related adverse events (irAEs – see definition in Section 5.2.3.3 and 
Attachment 4) other than uveitis that downgrade to Grade ≤2 within 14 days after 
onset of the event with maximal supportive care, including systemic corticosteroids. 
• Grade 3 asymptomatic endocrinopathy, managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy. 
• Grade ≤3 symptoms attributable to brain edema, per details in the Rules for Brain 
Edema below. 
• Any pre-existing lab abnormality that deteriorates to Grade 3 or 4 that is considered 
unlikely related to study treatment as assessed by the Investigator, do not have any 
clinical correlate, and resolves within 7 days with adequate medical management. 
• Transient (≤6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management 
• Transient (≤24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that 
resolves to Grade ≤1. 
• Change in KPS to <60 that resolves to ≥60 within 14 days 
While rules for adjudicating DLTs are specified above, an AE of Grade <3 (except if listed as 
exempt above), may also be defined as a DLT after a consultation with the overall study Principal 
Investigator, based on the emerging safety profile of Avelumab. In the absence of clinical 
abnormality, repeat laboratory testing will be conducted to confirm significant laboratory findings 
prior to designation as a DLT.   
 

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irAEs are defined as AEs of immune nature (i.e., inflammatory) in the absence of a clear 
alternative etiology (see Section 5.2.3.3 and Attachment 4 for Definitions and guidelines for 
management of irAEs).  
 
Note: See Section 8.1, Adverse Event Definitions, for expected AEs related to Avelumab. 
 
Note, any AE that meets DLT criteria will be considered an AESI and must be reported to the 
study sponsor (overall PI) within 24 hours of awareness of the event per Section 8.3.1. The study 
sponsor or designee will then notify the NYULMC PCC DSMC and IRB within 24 hours of 
awareness of the event. 
 
Rules for Brain Edema: Development of edema in the brain is common following fractionated 
brain radiation therapy and may be asymptomatic (solely a radiographic finding) or associated 
with mild, moderate or severe symptoms. Therefore, brain edema will be considered an expected 
event related to study therapy (HFRT) and will not be considered a DLT unless brain edema 
meets CTCAE 4.03 criteria for "Edema cerebral" which only has a severity of Grade 4.  
 
Note: Grade 4 "Edema cerebral" should only be used if the event meets CTCAE v4.03 
criteria (i.e., Life-threatening consequences; urgent intervention indicated).  Grade 4 
Edema cerebral is considered a DLT and is defined by any of the following criteria: 
• 
Any neurosurgical procedure is required to manage brain edema 
• 
Requires an osmotic diuretic for management of symptomatic brain edema 
• 
Requires >8 mg per day of dexamethasone or bioequivalent for more than 7 
consecutive days to manage symptoms of brain edema 
• 
Brain edema is deemed life-threatening per judgment of the treating 
investigator 
Subjects who experience Edema cerebral Grade 4 will discontinue Avelumab 
immediately and will enter the post-study follow-up phase of the study.  The overall PI 
may request additional information on events classified as Grade 4 cerebral edema.  
 
For study purposes, the AEs deemed attributable to brain edema that do not meet 
Edema cerebral Grade 4 per CTCAE v4.03 should be described by the symptom (e.g. 
headache, nausea, focal neurological deficit) and graded for severity accordingly.  If 
appropriate, the investigator should use the term "Central nervous system necrosis" 
per CTCAE 4.03 criteria if the investigator deems the radiographic findings are consistent 
with central nervous system radiation necrosis without symptomatic Grade 4 severity. 
Grade ≤3 AEs that are attributable brain edema or central nervous system necrosis will 
not be classified as DLT if: 
 
• 
The grade 3 AE downgrades to Grade ≤2 within 7 days, or to Grade ≤1 or 
baseline within 14 days after onset of the event with maximal supportive 
care, including bevacizumab (see bevacizumab guidelines below) and/or 
systemic corticosteroid administration (no more than 7 consecutive days of 
dexamethasone dosed at >8 mg per day or bioequivalent). 
• 
The grade 2 AE improves to grade ≤1 or baseline within 14 days after onset 
of the event with maximal supportive care, including bevacizumab and/or 
systemic corticosteroid administration (no more than 7 consecutive days of 
dexamethasone dosed at >8 mg per day or bioequivalent). 
Note: For subjects who are suspected to have study treatment-related symptomatic 
intracranial or brain edema at any time during the study, Avelumab dosing should be 

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immediately interrupted. VEGF inhibition is preferred over corticosteroids for 
management of suspected intracranial or brain edema, radiation necrosis, or intracranial 
hypertension, due to the risk that corticosteroids may suppress immune response against 
the tumor. Bevacizumab was granted accelerated approved by the US FDA for use as 
monotherapy in progressive GBM based on two historically-controlled, single-arm or non-
comparative phase II trials however the addition of bevacizumab to standard of care in 
newly diagnosed GBM or to lomustine in recurrent GBM failed to show a benefit in overall 
survival in multi-institutional, randomized phase III trials.77,94,95  Therefore, the addition of 
bevacizumab should not alter the survival outcomes of the study regimen. In addition, 
bevacizumab has been reported to be safe in combination with anti-PD-1/PD-L1 pathway 
inhibitors and re-irradiation to 30 Gy in a phase I trial of recurrent GBM patients,62 and the 
combination of bevacizumab with anti-PD-1/PD-L1 pathway inhibitors is being 
investigated in a number of clinical trials, including for gliomas. 
 
The VEGF inhibition strategy will be bevacizumab (at a maximal dose of 10 mg/kg IV) 
every 2 weeks, for a minimum of 2 doses.  If VEGF inhibition does not resolve the 
symptoms to grade ≤ 1 or baseline, the investigator may institute systemic 
corticosteroids, in addition to or as a replacement for bevacizumab, at the lowest dose 
that is appropriate for symptom management.  
 
If the symptoms improve to grade ≤ 1 or baseline by 2 weeks after the last dose of 
Avelumab, the subject may stop bevacizumab and continue Avelumab on study.  If 
symptoms do not improve to grade ≤ 1 or baseline by 2 weeks after the last dose of 
Avelumab, the subject must permanently discontinue study treatment. If a subject 
requires a neurosurgical procedure or mannitol to manage grade ≥3 symptom attributable 
to intracranial or brain edema, the AE will be considered a DLT and the subject must 
permanently discontinue study treatment. 
 
Note: Any AE of grade 3 or greater that is suspected to be attributable to brain edema will 
be considered an AESI and must be reported to the study sponsor (overall PI) within 24 
hours of awareness of the event per Section 8.3.1. The study sponsor or designee will 
then notify the NYU DSMC and IRB within 24 hours of awareness of the event. 
 
Note: Immune cell infiltration may be associated with increasing enhancement and 
edema on brain MRI or CT (i.e. pseudoprogression) and may mimic therapy-related 
central nervous system radiation necrosis or disease progression. Due to the well-
described difficulty in differentiating between immune-mediated pseudoprogression and 
true tumor progression using standard imaging techniques,72 particularly in brain 
tumors,70 special attention must be made to events that are suspected to be attributed to 
possible brain edema and central nervous system necrosis.  
 
For guidelines on managing radiographic findings, refer to Section 6.7, Efficacy 
Procedures and Attachment 3, iRANO criteria. A symptom or AE is initially suspected 
to be due to pseudoprogression or central nervous system necrosis may be later 
considered to be due to disease progression after review of additional imaging, biopsies 
and consultations with the treating investigators by the Safety Monitoring Team. These 
events may be reviewed for dosing decisions during the Safety Lead-In and toxicity 
monitoring during the phase II trial. 
5.2.2 Phase II Trial 
Following determination of the RP2D for Avelumab when combined with HFRT in the Safety 
Lead-In, subjects meeting eligibility criteria will receive Avelumab administered intravenously at 
the RP2D. A total of 43 patients are anticipated to be treated in the Phase II trial. The Phase II 
trial is a two stage design phase II trial with a planned interim analysis for futility and planned 
interim analyses for safety (see Section 7.2.2 for Statistical Methods). 

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The first dose of study agent (Avelumab) will be administered after all procedures / assessments 
have been completed as detailed on the Schedule of Events (Attachment 1). Avelumab will be 
administered IV at the RP2D established for administration with HFRT in the Safety Lead-In.  
 
Beginning 7 days after the first dose of Avelumab (i.e. Day 8), all subjects will be administered 
HFRT to a total of 25 Gy, given in 5 fractions of 5 Gy on consecutive days (i.e., Day 8 to Day 12). 
 
After the first dose, Avelumab administration will continue every 2 weeks. Avelumab 
administration will continue for up to 2 years or until the subject discontinues study therapy as per 
Subject Withdrawal guidelines (Section 4.5). Subjects who are discontinued from study therapy 
will enter the post-study follow-up phase of the study as per Section 4.5.2. 
5.2.3 Dose Modification and Study Treatment Discontinuation Rules 
5.2.3.1 Avelumab Dose Modification 
Once the RP2D is established in the Safety Lead-In portion of the study, no dose reductions of 
Avelumab will be allowed. During the Safety Lead-in portion of the study, dose reductions for 
an individual subject will not be allowed. 
5.2.3.2 Avelumab Hold or Discontinuation 
Safety Lead-In: All subjects who experience protocol-defined DLTs (either during or outside the 
DLT observation period) during the Safety Lead-In will be required to discontinue treatment with 
Avelumab. In addition, treatment hold and discontinuation guidelines are provided below. 
For all subjects: 
 
Note: For additional information regarding AEs with a potential immune etiology (irAEs), see 
Section 5.2.3.3, Table 3 and Attachment 4.  
 
Attachment 4 includes guidelines on the management of specific treatment-related AEs 
and when to delay and/or discontinue Avelumab. These guidelines are intended to be 
applied when the investigator determines the events to be treatment-related. 
 
Note: Infusion-related reactions, hypersensitivity reactions (Grades 1 to 4), should be handled 
according to guidelines in Section 5.2.3.5. 
 
Note: See Section 8.1, Adverse Event Definitions, for expected AEs related to Avelumab. 
Brain edema is an expected AE related to HFRT. 
 
No Avelumab dose reductions are permitted.  
 
If Avelumab is temporarily withheld, the cycle count should be interrupted. Subjects who 
experience an adverse event that requires a treatment delay should be monitored with 
appropriate laboratory testing or other clinical evaluation at least weekly until resolution.  
 
If Avelumab is discontinued (either permanently or temporarily) for an AE, the subject will 
generally discontinue the combination therapy treatment (HFRT) as well. If, however, a subject 
experiences an AE that in the opinion of the investigator is SOLELY related to HFRT, 
Avelumab may be continued and HFRT may be discontinued as per Section 5.2.3.4. 
Conversely, if a subject experiences an AE that in the opinion of the investigator is SOLELY 
related to Avelumab, then HFRT may be continued while Avelumab may be discontinued as 
per Section 5.2.3.2. 
 

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Table 2: Guidelines for Avelumab Hold and/or Discontinuations for Symptoms Related to Brain 
Edema or Central Nervous System Necrosis 
 
Grade 
Hold Avelumab? 
Restarting 
Criteria 
Discontinuation Criteria 
1 
No 
N/A 
N/A 
2 
Consider withholding for 
persistent symptoms  
Consider bevacizumab if 
symptoms persist1 
Toxicity 
resolves to 
Grade 0–1 or 
baseline  
Toxicity does not resolve to Grade 0–1 or baseline within 
14 days of last infusion or requires >8 mg/day of 
dexamethasone or bioequivalent for >7 consecutive days 
to treat symptoms 
3 
Yes 
Initiate bevacizumab in 
addition to appropriate 
symptomatic treatment 1 
Toxicity 
resolves to 
Grade 0–1 or 
baseline  
Toxicity does not resolve to Grade ≤2 within 7 days, or to 
Grade ≤1 or baseline within 14 days of last infusion, or 
requires >8 mg/day of dexamethasone or bioequivalent for 
>7 consecutive days to treat symptoms 
4 2 
Yes 
N/A 
Patient must be discontinued 
Note: Per CTCAE v4.03, the AE "Edema cerebral" only has Grade 4 severity. The AE "Edema cerebral" should be 
used only if the symptom severity meets the CTCAE v4.03 criteria (i.e., "Life-threatening consequences; 
urgent intervention indicated"). See Rules for Brain Edema, Section 5.2.1.2) 
1 For subjects who develop symptoms of Grade ≤3 attributable to brain edema or central nervous system 
necrosis, maximal supportive care and symptomatic treatment, including bevacizumab and/or systemic 
corticosteroids, should be administered as clinically appropriate. Bevacizumab is preferred over 
corticosteroids for management of suspected intracranial or brain edema, radiation necrosis, or intracranial 
hypertension, due to the risk that corticosteroids may suppress immune response against the tumor. 
Bevacizumab should be given at a maximal dose of 10 mg/kg IV every 2 weeks, for a minimum of 2 doses.  If 
bevacizumab does not resolve the symptoms to grade ≤ 1 or baseline, the investigator may institute systemic 
corticosteroids, in addition to or as a replacement for bevacizumab, at the lowest dose that is appropriate for 
symptom management in order to avoid significant immunosuppression. Corticosteroid taper should be 
considered once symptoms improve to Grade 1 or less and tapered over at least 4 weeks if doses >4 mg/day of 
dexamethasone or bioequivalent are administered for >7 days. See Rules for Brain Edema in Section 5.2.1.2 
for guidance of AE classification and management. 
2 Subjects who experience Edema cerebral, Grade 4 per CTCAE v4.03 criteria, must discontinue Avelumab. For 
study criteria that qualify for Grade 4 Edema cerebral see Rules for Brain Edema in Section 5.2.1.2. 
5.2.3.3 Immune-related adverse events (irAEs) 
Special attention should be paid to AEs that may be suggestive of a potential immune-mediated 
pathophysiology (irAEs), defined as AEs of unknown etiology associated with drug exposure 
and consistent with an immune phenomenon. Since inhibition of PD-L1 stimulates the immune 
system, irAEs may occur.  Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE 
v4.03 Grade). 
 
An irAE can occur shortly after the first dose or several months after the last dose of treatment. 
All AEs of unknown etiology associated with drug exposure should be evaluated to determine 
possible immune etiology. If an irAE is suspected, efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin or other etiologic causes prior to labeling an adverse event as an 
irAE. Subjects who develop a Grade 2 or higher irAE should be discussed immediately with the 
overall Principal Investigator. 
 
General recommendations for symptomatic management of irAEs include the following: 

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• Grade 1 to 2:  Treat symptomatically or with moderate dose corticosteroids, more 
frequent monitoring 
• Grade 1 to 2 (persistent): Manage similar to high grade AE (Grade 3 to 4) 
• Grade 3 to 4:  Treat with high dose corticosteroids 
Treatment of gastrointestinal, dermatological, pulmonary, hepatic and endocrine irAEs should 
follow guidelines set forth in Attachment 4 (Recommended Dose Modification or 
Discontinuation and Supportive Care Guidelines for Specific Drug-Related Adverse 
Events). 
 
Note: Any irAE of grade 3 or greater will be considered an AESI and must be reported to the 
study sponsor within 24 hours of awareness of the event per Section 8.3.1. AESIs should be 
reported to the local institution's DSMC and IRB per local institution guidelines.  If the AESI is 
not a DLT or SAE, there is no need to report to the DSMC or IRB within 24 hours unless 
specified by the local institution's DSMC or IRB. 
 
Table 3 includes general guidelines for managing irAEs. Attachment 4 includes 
recommendations on the management of specific treatment-related irAEs and when to delay 
and/or discontinue Avelumab. These guidelines are intended to be applied when the 
investigator determines the events to be treatment-related. 
Table 3: General Treatment Hold Guidelines for Immune-Related Adverse Events (irAEs) 
Severity 
Withhold/ 
Discontinue Avelumab?  
Supportive Care  
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold Avelumab at the 
treating investigator's discretion 
Consider systemic corticosteroids in 
addition to appropriate symptomatic 
treatment 
Grade 3 
Withhold Avelumab 
Discontinue if unable to reduce 
corticosteroid dose to <10 mg per 
day prednisone or bioequivalent 
within 4 weeks of toxicity 
Systemic corticosteroids are indicated in 
addition to appropriate symptomatic 
treatment. May utilize 0.5 to 1.0 mg/kg/day 
methylprednisolone or bioequivalent. 
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks. 
Grade 4* 
Discontinue Avelumab 
Discontinue Avelumab 
Note: These recommendations should be seen as guidelines, and the treating physician should exercise clinical 
judgment based on the symptoms and condition of the individual patient. 
Note: For guidelines regarding specific AEs with a potential immune etiology (irAEs), reference Attachment 4. 
For any AE that is of a type known to be potentially immune-related (e.g., rash, colitis, transaminitis, 
endocrine), but is deemed not to be an irAE by the investigator, the overall PI may request additional 
information. 
Note: During the Safety Lead-In, depending on the nature of AE, for subjects who develop Grade 2 irAE, 
Avelumab will be held if symptoms do not improve to grade ≤1 with appropriate supportive care and 
symptomatic treatment within 14 days after onset of the event and will be considered DLT. See Section 
5.2.1.2 for DLT definitions. 

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Note: During the Safety Lead-In, for subjects who develop Grade 3 irAE, Avelumab will be held and will be 
considered at DLT if symptoms do not improve to grade ≤2 within 14 days after onset of the event with 
appropriate supportive care and symptomatic treatment. See Section 5.2.1.2 and Attachment 4. 
* For Grade 4 amylase and lipase elevations, follow guidelines for Grade 3 irAE. Avelumab only requires 
permanent discontinuation for Grade 4 amylase and lipase elevations if the corticosteroid dose cannot be 
reduced to <10 mg day prednisone or bioequivalent within 4 weeks of toxicity. 
5.2.3.4 Hold of Hypofractionated Radiation Therapy (HFRT) 
Radiation therapy will be held for Grade 3 or higher radiation therapy-related, nonhematologic 
toxicity. Radiation therapy will resume at the discretion of the investigator at full dose when 
toxicity returns to Grade 1 or 0.  
 
In addition, though development of symptomatic brain edema during the actual period of 
radiation treatment is unlikely, radiation therapy for any patient experiencing grade 3 or higher 
symptoms related to brain edema prior to completing radiation treatment should be put on hold 
until symptoms resolve and the case is clinically evaluated. See Table 2 in Section 5.2.3.2 and 
Rules for Brain Edema in Section 5.2.1.2 for detailed instructions regarding management of 
radiation therapy-related brain edema. 
5.2.3.5 Management of Infusion/Allergic/Hypersensitivity Reactions 
Acute infusion reactions are defined as any AE that occurs during the infusion or within 2 hours 
after the infusion is completed. Emergency equipment and medication for the treatment of 
these potential adverse effects (e.g., antihistamines, bronchodilators, IV saline, corticosteroids, 
acetaminophen, and/or epinephrine) must be available for immediate use. Infusion reactions 
must be reported as AEs (Section 8) and graded according to the NCI-CTCAE version 4.03 
grading scale (Section 8). 
 
Signs/symptoms may include:  
Fever 
Chills  
Rigors 
Diaphoresis (sweating) 
Headache 
 
Table 4 - Modification of Avelumab Infusion for Symptoms of Infusion-Related Reactions 
 
NCI-CTCAE Grade 
Treatment Modification for Study Drug 
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. 
Grade 2 – moderate 
Therapy or infusion interruption indicated 
but responds promptly to symptomatic 
treatment (for example, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for  24 h. 
Temporarily discontinue 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 
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. 

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indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
- If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it 
must remain decreased for the next scheduled infusion.  If no infusion reaction is observed in the next 
scheduled infusion, the infusion rate may be returned to baseline at the subsequent infusions based 
on investigator’s medical judgment. 
- If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. 
IV = intravenous; 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 study treatment.  If a subject experiences a 
Grade 3 or 4 infusion-related reaction at any time, the subject must discontinue study drug. 
 
Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. Subjects should be instructed to report any delayed reactions to the 
Investigator immediately. 
 
For prophylaxis of flu-like symptoms, 25 mg of indomethacin or comparable nonsteroidal anti-
inflammatory drug (NSAID) dose (for example, ibuprofen 600 mg, naproxen sodium 500 mg) 
may be administered 2 hours before and 8 hours after the start of each dose of avelumab IV 
infusion.  Alternative treatments for fever (for example, paracetamol) may be given to subjects 
at the discretion of the Investigator. 
 
Note: Grade 2 or greater infusion-related reactions or Grade 2 or greater allergic/ 
hypersensitivity reactions will be considered an AESI and must be reported to the study 
sponsor within 24 hours of awareness of the event per Section 8.3.1. AESIs should be 
reported to the local institution's DSMC and IRB per local institution guidelines.  If the AESI is 
not a DLT or SAE, there is no need to report to the DSMC or IRB within 24 hours unless 
specified by the local institution's DSMC or IRB. 
 
Interruption of the Infusion 
 
The infusion should be interrupted if any of the following AEs are observed: 
• 
cough 
• 
rigors/chills 
• 
rash, pruritus (itching) 
• 
urticaria (hives, welts, wheals) 
• 
diaphoresis (sweating) 
• 
hypotension 
• 
dyspnea (shortness of breath) 
• 
vomiting 
• 
flushing 
 
If investigators feel there is a medical need for treatment or discontinuation of the infusion 
other than described above, they should use clinical judgment to provide the appropriate 
response according to typical clinical practice. 
 
Termination of the Infusion 
 

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The infusion should be terminated and NOT restarted if any of the following AEs occur: 
 
• 
anaphylaxis laryngeal/pharyngeal edema severe bronchospasm 
• 
chest pain 
• 
seizure 
• 
severe hypotension 
5.2.3.6 Note on continuation of therapy pending confirmation of radiographic disease progression 
Immunotherapy response criteria in neuro-oncology (iRANO) criteria (Attachment 3), which is 
used in this study for efficacy evaluation, recommends confirmation of disease progression on 
follow-up imaging 3 months after initial radiographic progression if there is no new or 
substantially worsened neurological deficits that are not due to comorbid events or concurrent 
medication, and it is 6 months or less from starting immunotherapy. A decision of whether a 
patient should continue immunotherapy pending confirmation of radiographic disease 
progression should be established based on perceived benefits and risks. Continuation of 
immunotherapy may be considered pending follow-up imaging as long as subjects are deriving 
apparent clinical benefit with minimal and acceptable toxic effects.  See Attachment 3 and 
Section 6.7, Efficacy Procedures, for further details. 
5.2.3.7 Permanent Discontinuation of Study Treatment 
In the event of an infusion reaction of Grade ≥3 severity during or directly following Avelumab 
infusion, dosing should be stopped and the patient must permanently discontinue Avelumab 
treatment. 
 
Study treatment will be permanently stopped in the event of evidence of pregnancy. 
 
In addition, study treatment for any subject may be discontinued for other safety reasons or 
compliance issues at the discretion of the investigator, overall PI or sponsor. A subject may 
choose to discontinue study treatment or study participation at any time for any reason. 
 
A subject who permanently discontinues Avelumab treatment may continue follow-up in the 
study without additional treatment until progression of disease or closure of the study (Section 
4.5). A patient who permanently discontinues study treatment and who does not withdraw from 
study participation will be asked to return to the clinic for all remaining study visits per the visit 
schedule (Attachment 1) or continue in the follow-up phase of the study until progression of 
disease or closure of the study (Section 4.5.2). 
5.3 Preparation and Administration of Study Drug 
 
Avelumab will be prepared in the site investigational pharmacy. Preparation of the diluted Avelumab for 
administration must be accomplished by adequate trained personnel to guarantee the sterility of the 
product to be injected. Only clinical site personnel who are appropriately trained on the procedure 
detailed in this document may perform the preparation and administration procedures specified in this 
manual. Clinical site personnel involved in these procedures must comply with all applicable regulations 
and standards. The administration must be performed by adequately trained personnel. Prior to dosing 
the subject, adhere to normal standard of care and aseptic techniques.  Utilize local site procedures as 
appropriate.  See Section 1.2.4 for specific Avelumab handling instructions and refer to the Pharmacy 
Manual for complete instructions for Avelumab dose calculation, reconstitution, preparation of the 
infusion fluid, and administration. 
 
General Preparation Instructions: 
 

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To prepare the dilutions, subsequent preparation steps must be accomplished by adequate 
trained personnel under a laminar flow box using aseptic techniques.   
 
Avelumab drug product must be diluted with 0.9% saline solution (sodium chloride injection) 
supplied in an infusion bag; alternatively a 0.45% saline solution can be used only if the first 
option is not applicable. The verified Avelumab concentration range in the infusion solution is 
0.016 mg/mL to 8 mg/mL.  
 
• 
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room 
temperature.  
• 
Use a disposable syringe equipped with a needle of suitable size to remove a volume of 
sodium chloride solution to be replaced by Avelumab from the infusion bag and discard the 
removed solution.  
• 
Use a new disposable syringe equipped with a needle of suitable size to inject a volume of 
avelumab drug product identical to the discarded volume of sodium chloride solution into the 
infusion bag.  
• 
Gently invert the mixture 10 times. Infusion bags must not be shaken, in order to avoid 
foaming or excessive shearing of the protein solution.  
• 
The preparation must be carefully inspected as it should result in a homogeneous looking 
clear solution, free of visible particles. 
 
No other drugs should be added to the solution for infusion containing Avelumab.  
 
Prepared solution for dosing should be kept at room temperature and used immediately after 
preparation. 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. 
 
General Administration Instructions: 
 
The administration must be performed by adequately trained personnel.  Prior to dosing the subject, 
adhere to normal standard of care and aseptic techniques.   
 
• 
The prepared Avelumab dosing solution for infusion is connected to the infusion set equipped 
with a 0.2 micron PES (or PSU but only if PES membrane is not available) in-line filter and an 
appropriate gauge standard venous catheter for the subject. Alternatively, a permanent venous 
catheter or implantable port may be used. Prior to infusion, prime the assembly with the dosing 
solution. 
 
• 
Set the infusion pump to deliver the entire infusion volume over 1 hour (-10/+20 minutes).   A 
constant infusion rate is achieved by using a microprocessor-controlled infusion pump. 
 
• 
Immediately following the infusion of Avelumab, it is recommended (but not mandatory) to 
conduct a normal saline flush using the same tubing and 25-100 mL normal saline infused at the 
same rate to clear the infusion set of residual drug. 
 
Special Precautions for Avelumab administration: 
 
Setting: Avelumab should be administered in a setting that allows for immediate access to an intensive 
care unit or equivalent environment and administration of therapy for anaphylaxis, such as the ability to 
implement immediate resuscitation measures.  Steroids (dexamethasone 10 mg), epinephrine (1:1,000 

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dilution), allergy medications (IV antihistamines), bronchodilators, or equivalents, and oxygen should be 
available for immediate access. 
 
Observation period:  Following all avelumab infusions, patients must be observed for 30 minutes 
post‑infusion for potential infusion‑related reactions. 
 
Detailed information on infusion bags and medical devices to be used for the preparation of the dilutions 
and subsequent administration are provided in the Pharmacy Manual. For detailed information on the 
assigned dose levels and the concrete volumes to be replaced to prepare the target doses, please refer 
to the Pharmacy Manual. 
5.4 Subject Compliance Monitoring 
Avelumab and radiation treatments will be administered at the study site and recorded on the case report 
form (CRF) and captured in Velos. All dosing records for each patient will be kept by the site. Patients will 
be administered IV Avelumab in a clinic or hospital setting under supervision of appropriate study 
personnel. Radiation therapy will be administered at the study site.  
 
Subjects who are significantly non-compliant (e.g., not complying with protocol required visits, 
assessments, and dosing instructions) may be withdrawn from the study by the investigator and/or 
sponsor.  The investigator and/or sponsor have the right to discontinue a subject from study treatment or 
withdraw a patient from the study at any time. 
 
All drug compliance records must be kept current and must be made available for inspection by the 
sponsor and regulatory agency inspectors.   
5.5 Prior and Concomitant Therapy 
Avelumab, as a mAb, is not expected to have a direct drug-drug interaction (DDI) effect on other small 
molecule drugs. In addition, like other immune checkpoint inhibitors in the class, Avelumab is not 
considered to be a cytokine modulator, which was confirmed by cytokine data collected from EMR 
1000700-001 (see Investigator's Brochure). In summary, Avelumab is not expected to have DDI with 
other drugs because it is primarily metabolized through catabolic pathways and is not expected to affect 
the expression of CYP450 enzymes. 
5.5.1 Concomitant Medications 
Any treatment administered from the time of informed consent until 30 days after the last study 
treatment will be considered concomitant treatment. This includes medications and other 
therapies for which administration started before the study and will continue during the study, as 
well as any therapies started in the 5 month follow-up period to treat a study-drug–related AE.  
 
All concomitant treatments must be recorded in the study CRF with the generic name, dose, dose 
unit, frequency, indication, and start/stop date, as appropriate. 
5.5.2 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  
 
Physiologic replacement doses of systemic corticosteroids are permitted after consultation with 
the overall PI or designee, even if >10 mg/day prednisone equivalents. Standard doses of 
hydrocortisone for maintenance therapy are 10–20 mg/m2/day divided 2–4 times per day. For a 
subject with a body surface area (BSA) of 1.73 m2, this translates to a total dose of 34.6 mg of 

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hydrocortisone per day. The equivalent dose of dexamethasone is 1.2 mg per day. Some 
subjects may additionally receive mineralocorticoid-replacement maintenance therapy with 
fludrocortisone. The maintenance dose of fludrocortisone for this indication is 0.05–0.1 mg/day.  
 
Intranasal, inhaled or topical corticosteroids (<5% of body surface area) for the treatment of 
mild/moderate asthma, allergies or dermatitis are permitted. Antihistamines and other non-
steroidal anti-allergy medications are also permitted. A brief course of corticosteroids for 
prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., 
delayed-type hypersensitivity reaction caused by contact allergen) is permitted. 
 
During the study, bevacizumab is permitted and preferred over corticosteroids for management of 
symptoms related to intracranial/brain edema or central nervous system radiation necrosis. See 
Rules for Brain Edema in Section 5.2.1.2 for guidelines on management of symptoms related to 
intracranial/brain edema, bevacizumab administration, and corticosteroid use in this setting. 
5.5.3 Prohibited Medications 
Medications or vaccinations specifically prohibited in the Exclusion Criteria (Section 4.2) are not 
allowed during the ongoing trial except as outlined below. While participating in this study, a 
patient may not receive any standard or investigational agent or device for treatment of a tumor 
other than Avelumab in combination with radiation therapy per the study’s specified dosing 
regimens.  
 
It is recommended that patients do not receive systemic corticosteroids such as hydrocortisone, 
prednisone, prednisolone (Solu-Medrol®) or dexamethasone (Decadron®) at any time throughout 
the study except in the cases of physiologic replacement, supportive post-operative management, 
a life-threatening emergency, to treat an irAE or suspected irAE, or to treat symptomatic brain 
edema or radiation necrosis. For guidance on systemic corticosteroid administration for 
symptomatic brain edema or radiation necrosis, See Rules for Brain Edema in Section 5.2.1.2 
and Table 2 in Section 5.2.3.2. 
 
If there is a clinical indication for one of these or other medications or vaccinations specifically 
prohibited during the trial, discontinuation from trial therapy or vaccination may be required. The 
treating investigator should discuss any questions regarding this with the overall study PI or his 
designee.  The final decision on any supportive therapy or vaccination rests with the treating 
investigator. However, the decision to continue the subject on trial therapy requires the mutual 
agreement of the Investigator, overall study PI or his designee, and the subject. 
5.6 Packaging 
Avelumab study agent will be packaged in a carton box labeled and tamper sealed containing a PET tray 
and 8 labeled vials. Each single-use 10 mL vial contains 200 mg of Avelumab (20 mg/mL). 
  
Study drug boxes consist of: 
Inserts for folding box (PET tray) 
Tamper Seal 
  
Label Example: 
Phase                                  Label description 
II                                           Vial & Box Single Panel Labels 
  
Master Label text in English according to US regulations 
  
US Vial Master Label Text: 
1.      EMD Serono/Merck assigned protocol number 

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2.      MSB0010718C (drug name) 
3.      200 mg (dose strength) 
4.      10 mL per vial 
5.      20 mg/mL 
6.      XXXXXXX (Medication no.) 
7.      Sponsor information 
8.      XXXXXXX (Lot no.) 
  
Concentrate for solution for intravenous infusion 
Caution:  New Drug!  Limited by Federal (or United States) law to investigational use 
Supplied by Merck KGaA, Darmstadt, Germany 
  
US Box Master Label Text: 
1.      EMD Serono/Merck assigned protocol number 
2.      MSB0010718C (drug name) 
3.      200 mg (dose strength) 
4.      10 mL per vial 
5.      20 mg/mL 
6.      8 (Quantity of vials) 
7.      36-46 ͦ / 2-8 ͦ (Storage Conditions  ͦF/  ͦC 
8.      Space for Subject Number to be written in by site 
9.      Space for Investigator to be written in by site 
10.    Sponsor 
11.    XXXXXX (Medication no.) 
12.    XXXXXX (Lot no.) 
  
Concentrate for solution for intravenous infusion 
Use according to handling instruction 
For clinical trial use only! 
Keep out of reach of children 
Store all items in original outer packaging, remove only prior to administration 
Do no freeze 
Do not shake 
Protect from light 
Caution:  New Drug!  Limited by Federal (or United States) law to investigational use 
Supplied by Merck KGaA, Darmstadt, Germany 
5.7 Receiving, Storage, Dispensing and Return 
5.7.1 Receipt of Drug Supplies 
EMD Serono/Merck KGaA will package and distribute the study drug to sites via their distribution vendor - 
Fisher Clinical Services. The study drug will be shipped in transport cool containers (2oC to 8oC) that are 
monitored with temperature control devices. The study drug will be shipped to the investigational 
pharmacy at each site. 
 
Upon receipt of the study treatment supplies, an inventory must be performed and a drug receipt log filled 
out and signed by the person accepting the shipment.  It is important that the designated study staff 
counts and verifies that the shipment contains all the items noted in the shipment inventory.  Any 
damaged or unusable study drug in a given shipment will be documented in the study files.  The 
investigator must notify study sponsor of any damaged or unusable study treatments that were supplied 
to the investigator’s site. 
5.7.2 Storage 

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See Section 1.2.3 for Instructions for storage and Section 1.2.4 for special instructions for handling. 
5.7.3 Dispensing of Study Drug 
The NYU Investigational pharmacist or their designee pharmacist or other qualified individual will be 
identified at each site to prepare Avelumab for administration. Refer to Section 5.3 for Avelumab 
administration instructions. 
 
All drug accountability records must be kept current. The investigator must be able to account for all 
opened and unopened study drug. These records should contain the dates, quantity, and study 
medication dispensed to each patient, returned from each patient (if applicable), and disposed of at the 
site or returned to the sponsor or designee. All accountability records must be made available for 
inspection by the sponsor and regulatory agency inspectors; photocopies must be provided to the 
sponsor at the conclusion of the study. 
5.7.4 Return or Destruction of Study Drug 
 
Retention of Drug Product Vials: 
All opened vials (full, partially full, and empty) may be destroyed at the site by the appropriate site 
personnel (e.g., pharmacist, study nurse/coordinator) following local environmental requirements and 
institutional policies.  All destruction must be fully documented at the time of destruction on the 
investigational product accountability log, or equivalent document at the time of destruction. 
 
If opened vials are not destroyed immediately following drug preparation, opened vials must be stored in 
sealed, clear plastic bags until destruction.   
 
All unopened vials must be destroyed at the end of the treatment period unless EMD 
Serono/Merck KGaA provides separate instructions for return. 
 
Retention of supplies: 
Normal saline solution may be disposed of according to local site procedures.  Other items used in the 
dose preparation and administration should be disposed of according to local site procedures.   
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and 
drug remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of 
unused study drug. All unused and/or partially used investigational product will be destroyed at the site 
per institutional policy. It is the Investigator’s 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. Drug destroyed on site will be documented in the study files. 
6 Study Procedures 
6.1 Screening Procedures 
After providing informed consent, patients will undergo screening for eligibility to participate in the study. 
Screening will start within 21 days prior to initiation of study treatment (first dose of Avelumab). Refer also 
to the Schedule of Events (Attachment 1) for complete details of study procedures. 
 
The following procedures will be performed at Screening for the purpose of determining study eligibility 
or characterizing the baseline population: 
 
• 
Documentation of an IDH1 or IDH2 mutation on any tumor specimen must be confirmed 

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• 
Diagnosis (pathology report is sufficient) of WHO grade II or III glioma prior to therapy with 
temozolomide or PCV must be confirmed.  
• 
The tumor specimen that has progressed after treatment with temozolomide, lomustine, or PCV (per 
Section 4.1, Inclusion Criteria 6) must have histopathologic diagnosis of transformation to 
glioblastoma (WHO Grade IV). Central review of the glioblastoma diagnosis in the progressive tumor 
specimen is required prior to registration. 
At least one (1) H&E slide that demonstrates the diagnosis of glioblastoma, WHO grade IV, and 
that is representative of the required archival tissue to be submitted is sufficient for central review. 
A recut slide is acceptable if the original clinical diagnostic slides cannot be sent. For the central 
review confirmation, there is no minimal tumor content required as long as the slide demonstrates 
characteristics satisfying WHO criteria for glioblastoma (grade IV). 
 
The diagnostic pathology slide(s) from the glioblastoma (WHO Grade IV) tumor specimen must 
be submitted to NYULMC at screening for central review confirmation prior to registration. 
 
 
 
 
Send diagnostic pathology slides for central review to: 
 
Matija Snuderl, MD 
Department of Pathology, NYU Langone Medical Center 
560 First Avenue 
Tisch Hospital HW 451 
New York, NY 10016 
Phone: 646-501-5281 
Fax: 212-263-7916 
Pager: 917-205-5543  
Matija.Snuderl@nyumc.org 
 
Exception Note: Any progressive glioma with IDH1 or IDH2 mutation, regardless of WHO grade, 
histopathological diagnosis, or prior therapy, will be eligible if the progressive tumor specimen is 
found to have one of the genetic alterations associated with hypermutation phenotype per 
Section 4.1, Inclusion Criteria 4a. A molecular pathology report indicating an eligible genetic 
alteration is sufficient documentation for an eligible genetic alteration and central histopathologic 
review is not needed for this exception.   
 
• 
Collection of archived tumor material for research: The subject will be asked to arrange to provide 
archival tumor tissue from a surgical resection that demonstrates histopathological evidence of 
glioblastoma (GBM, WHO grade IV) or a genetic alteration as specified in the Eligibility Criteria 
(Section 4.1). 
• 
Brain MRI (or CT if MRI is contraindicated): Contrast-enhanced brain MRI or CT must be performed 
within 14 days prior to the first dose of study treatment (Avelumab infusion)  
• 
Medical history: The subject must be eligible by all of the Subject Selection Criteria per Section 4. 
Concomitant therapeutics will be reviewed for allowed or prohibited medications. Of note: 
o 
Subjects must have documentation (treating oncologist note or treatment summary) of 
treatment with temozolomide, CCNU or PCV chemotherapy for their glioma prior to the 
transformation to GBM as specified in the Eligibility Criteria (Section 4.1). 
o 
Subjects who received anti-tumor therapy after histopathologic transformation to glioblastoma 
must have shown unequivocal radiographic evidence of tumor progression by contrast-
enhanced MRI scan (or CT scan if MRI is contraindicated). 

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• 
Chest x-ray: Chest x-ray is required at screening if not performed within 60 days prior to initiation of 
study treatment. 
o 
Note: Baseline chest x-ray is required as this may assist in subsequent clinical assessments 
that may occur during the study. For example, in a circumstance in which a patient presents 
to a provider with signs and symptoms that may be related to a pulmonary process, standard 
clinical practice often is to obtain a chest x-ray. In order to interpret a chest x-ray in this 
situation, it is clinically helpful to have a recent baseline chest x-ray on file. Hence, a baseline 
chest x-ray is required if not performed in the prior 60 days. In the absence of a baseline 
chest x-ray, the most recent chest imaging would be a CT scan of the chest, which could lead 
to the clinical decision to obtain another CT scan of the chest in clinical circumstances in 
which a chest x-ray would have been sufficient. 
• 
12-Lead ECG: A standard 12-lead ECG will be required only at screening. The ECG strips or reports 
will be retained with the source. The ECG will be reviewed by the investigator (paper or electronic 
tracing) and will be available for comparison with subsequent ECGs by the investigator if needed. Any 
ECG finding performed during the study period after screening that is judged by the investigator as a 
clinically significant change (worsening) compared to the baseline value will be considered an AE, 
recorded, and monitored. The following will be recorded on the CRF:  
o 
PR Interval (msec) 
o 
QRS Interval (msec) 
o 
QT Interval (msec) 
o 
Heart Rate (BPM; recorded from the ventricular rate). 
• 
Physical exam and laboratories:  Subjects will have the following vital signs, physical exam and 
laboratory procedures evaluated for eligibility if not already performed within 21 days prior to initiation 
of study treatment (first dose of Avelumab). For complete details see the Schedule of Events 
(Attachment 1). 
o 
Complete physical exam, including neurological exam, and KPS assessment 
o 
Vital signs: height (height is only required at screening), weight, temperature, resting blood 
pressure, pulse and respiration rate. 
o 
Serum chemistry: sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphorous, glucose, albumin, creatinine, blood urea nitrogen (BUN), uric acid, ALT, AST, 
total bilirubin, direct and/or indirect bilirubin, alkaline phosphatase (ALP), and lactate 
dehydrogenase (LDH) 
o 
Hematology: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), 
hemoglobin, hematocrit, and platelet count 
o 
Urinalysis: glucose, blood, pH, specific gravity, ketones, and urine protein 
o 
Coagulation test (required at screening only): PT/INR, PT, PTT 
o 
Thyroid stimulating hormone (TSH), free T4 
o 
Hepatitis B virus surface antibody, hepatitis B virus surface antigen, hepatitis B virus core 
antibody, and hepatitis C virus antibody 
o 
Pregnancy test (Urine or serum β-HCG) for women of child-bearing potential 
6.2 Cycle 1, Day 1 (C1D1) 
 
After screening and registration, all patients will have the C1D1 Safety Procedures detailed below within 3 
days of treatment initiation (first dose of Avelumab).  Evaluations performed at screening that fall within 3 
days of treatment initiation will not need to be repeated.  
 
o 
Adverse event assessment 

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o 
Complete physical exam, including neurological exam, and KPS assessment 
o 
Vital signs: When scheduled at the same visit as other procedures, vital signs should be 
measured prior to clinical laboratory assessments or research blood sample collection. 
 
Weight (can be taken within 3 days of scheduled Avelumab administration) 
 
For C1D1, the following vital signs will be collected prior to treatment, at the end of 
the infusion, and 30 minutes post-infusion (all infusion VS timepoints ±10 minutes): 
• 
Temperature, resting blood pressure, pulse and respiration rate. 
• 
Note: following all Avelumab infusions, subjects must be observed for 30 
minutes post‑infusion for potential infusion-related reactions. 
o 
Serum chemistry: sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphorous, glucose, albumin, creatinine, blood urea nitrogen (BUN), uric acid, ALT, AST, 
total bilirubin, direct and/or indirect bilirubin, alkaline phosphatase (ALP), and lactate 
dehydrogenase (LDH) 
o 
Hematology: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), 
hemoglobin, hematocrit, and platelet count 
o 
Thyroid stimulating hormone (TSH), free T4 
o 
Pregnancy test (urine or serum β-HCG) for women of child-bearing potential 
o 
Research blood samples. All subjects will have the below research blood samples collected. 
Note: Research blood samples will be taken at only 2 timepoints: C1D1 (pre-dose) and 
C2D1. For details on Background and Rationale of research studies, see Attachment 7. For 
details on specimen collection, processing, handling and shipping, refer to Section 6.8 and 
the study Lab Manual. 
 
NYULMC subjects: 40 mL (four 10 mL purple top EDTA tubes) of whole blood will be 
drawn and immediately sent to the below sites: 
• 
One (1) 10 mL tube will be sent to the Center for Biospecimen Research and 
Development (CBRD) at NYULMC for acquisition of whole blood, buffy coat, and 
plasma samples. 
• 
Three (3) 10 mL tubes will be sent to the Immune Monitoring Core (IMC) at 
NYULMC and immediately processed for isolation of PBMCs. 
 
Subjects at other sites:  40 mL of whole blood will be collected in two types of tubes 
provided by NYULMC. All tubes will be shipped overnight to the CBRD at NYULMC 
per instructions in the Lab Manual. 
• 
10 mL will be drawn into one Streck Cell-Free DNA BCT® collection tube. 
• 
30 mL total will be drawn into three 10 mL purple top EDTA tubes and 
immediately sent to NYULMC.  
Avelumab will be administered IV at the specified dose level in the Safety Lead-In or the RP2D for the 
phase II trial (for details see Treatment Regimen, Section 5.2). The day of the first Avelumab infusion 
will be designated as Cycle 1, Day 1. Each patient’s dose will depend on individual body weight.  
6.3 Cycle 1, Day 8 (C1D8) 
Seven days after the first Avelumab infusion (i.e. Cycle 1, Day 8), the subject will initiate HFRT.  HFRT 
must be provided at the study site. Technical details for radiation therapy are provided in Attachment 6.  
   

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• 
Prior to initiating radiation therapy on C1D8, adverse event assessment, a symptom-directed 
physical exam and limited vital signs (temperature, resting blood pressure, pulse, and respiration 
rate) must be performed.  
 
• 
All subjects will receive hypofractionated radiation (HFRT) to a total dose of 25 Gy given as 5 Gy 
per fraction over 5 consecutive fractions. HFRT must begin 1 week after the first dose of 
Avelumab (i.e., Day 8 of Cycle 1). HFRT should preferably be given on consecutive days (i.e., 
Day 8 to Day 12). 
6.4 Cycle 1, Day 15 (C1D15) and all subsequent mid-cycle (i.e., Day 15) visits 
The subject will have the C1D15 Safety Procedures detailed below performed prior to initiating study 
treatment. Required assessments and study drug (Avelumab) administration windows include ±3 days of 
scheduled visit.  
o 
Adverse event assessment 
o 
Symptom-directed physical exam as clinically indicated by the investigator or qualified 
designee at all mid-cycle visits (i.e. Day 15) 
o 
Vital signs: When scheduled at the same visit as other procedures, vital signs should be 
measured prior to clinical laboratory assessments or research blood sample collection. 
 
Weight (can be taken within 3 days of scheduled Avelumab administration) 
 
Vital signs on treatment days subsequent to C1D1 will be assessed and documented 
prior to the infusion and then approximately 30 minutes after the completion of the 
infusion (all infusion VS timepoints ±10 minutes): 
• 
Temperature, resting blood pressure, pulse and respiration rate. 
• 
Note: following all Avelumab infusions, subjects must be observed for 30 
minutes post‑infusion for potential infusion-related reactions. 
o 
Serum chemistry: sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphorous, glucose, albumin, creatinine, blood urea nitrogen (BUN), uric acid, ALT, AST, 
total bilirubin, direct and/or indirect bilirubin, alkaline phosphatase (ALP), and lactate 
dehydrogenase (LDH) 
o 
Hematology: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), 
hemoglobin, hematocrit, and platelet count 
o 
Urinalysis: glucose, blood, pH, specific gravity, ketones, and urine protein 
Avelumab will be administered in an outpatient setting as an IV infusion (see Treatment Regimen, 
Section 5.2). Each patient’s dose will depend on individual body weight. The dose of Avelumab must be 
adjusted each cycle for changes in body weight of ≥10%. Dose adjustments for changes in body weight of 
<10% will be at the discretion of the investigator. 
6.5 Cycle 2, Day 1 (C2D1) and all subsequent Day 1 cycle visits (i.e., C3D1, 
C4D1) 
The subject will have the C2D1 Safety Procedures detailed below performed prior to initiating study 
treatment. Required assessments and study drug (Avelumab) administration windows include ±3 days of 
scheduled visit.  
o 
Adverse event assessment 
o 
Complete physical exam, including neurological exam, and KPS assessment 

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o 
Vital signs: When scheduled at the same visit as other procedures, vital signs should be 
measured prior to clinical laboratory assessments or research blood sample collection. 
 
Weight (can be taken within 3 days of scheduled Avelumab administration) 
 
Vital signs on treatment days subsequent to C1D1 will be assessed and documented 
prior to the infusion and then approximately 30 minutes after the completion of the 
infusion (all infusion VS timepoints ±10 minutes): 
• 
Temperature, resting blood pressure, pulse and respiration rate. 
• 
Note: following all Avelumab infusions, subjects must be observed for 30 
minutes post‑infusion for potential infusion-related reactions. 
o 
Serum chemistry: sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphorous, glucose, albumin, creatinine, blood urea nitrogen (BUN), uric acid, ALT, AST, 
total bilirubin, direct and/or indirect bilirubin, alkaline phosphatase (ALP), and lactate 
dehydrogenase (LDH) 
o 
Hematology: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), 
hemoglobin, hematocrit, and platelet count 
o 
Urinalysis: glucose, blood, pH, specific gravity, ketones, and urine protein 
o 
Pregnancy test (urine or serum β-HCG) for women of child-bearing potential  
o 
Research Blood Samples (C2D1 only, not required at subsequent visits): Note: Research 
blood samples will be taken at only 2 timepoints: C1D1 (pre-dose) and C2D1. All subjects 
will have the below research blood samples collected. For details on specimen collection, 
processing, handling and shipping, refer to Section 6.8, Attachment 7 and the study Lab 
Manual.  
 
NYULMC subjects: 40 mL (four 10 mL purple top EDTA tubes) of whole blood will be 
drawn and immediately sent to the below sites: 
• 
One (1) 10 mL tube will be sent to the CBRD at NYULMC for acquisition of whole 
blood, buffy coat, and plasma samples. 
• 
Three (3) 10 mL tubes will be sent to the IMC at NYULMC and immediately 
processed for isolation of PBMCs. 
• 
Subjects at other sites:  40 mL of whole blood will be collected in two types of tubes 
provided by NYULMC. All tubes will be shipped overnight to the CBRD at NYULMC 
per instructions in the Lab Manual. 
• 
10 mL will be drawn into one Streck Cell-Free DNA BCT® collection tube 
• 
30 mL total will be drawn into three 10 mL purple top EDTA tubes and 
immediately sent to NYULMC.  
Avelumab will be administered in an outpatient setting as an IV infusion (see Treatment Regimen, 
Section 5.2). Each patient’s dose will depend on individual body weight. The dose of Avelumab must be 
adjusted each cycle for changes in body weight of ≥10%. Dose adjustments for changes in body weight of 
<10% will be at the discretion of the investigator. 
6.6 Cycle 3, Day 1 (C3D1) and then every 8 weeks thereafter  
 
At C3D1, all required procedures listed in the visit for Cycle 2, Day 1+ (Section 6.5) will be required 
except research blood samples.  In addition: 
 

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• 
Efficacy assessment consisting of a contrast-enhanced brain MRI or CT will be performed prior to 
C3D1. Efficacy assessments will then be performed every 8 weeks thereafter. MRIs or CTs can 
be performed within 7 days (-7 days) of scheduled visit. On-study imaging should follow calendar 
days (every 8 weeks) and should not be adjusted for delays in cycle starts.  
 
o 
Local reading (investigator assessment) will be used to determine eligibility and for 
participant management. Response Assessments will be performed on every brain 
imaging assessment performed on protocol per iRANO criteria (see Section 6.7, 
Efficacy Procedures, and iRANO criteria in Attachment 3). 
 
• 
Thyroid stimulating hormone (TSH), free T4 
6.7 End of Treatment Procedures 
Avelumab administration will continue for 2 years or until progression of disease, unacceptable adverse 
event(s), subject withdrawal of consent, or other event that meets criteria for subject withdrawal or 
treatment discontinuation as per guidelines outlined in Section 4.5 and Section 5.2.3. 
 
End of treatment assessments below will be performed within 7 days after last drug administration or 
within 7 days after decision to end treatment.   
 
o 
Adverse event assessment 
o 
Complete physical exam, including neurological exam, and KPS assessment 
o 
Vital signs: weight, temperature, resting blood pressure, pulse and respiration rate. 
o 
Serum chemistry: sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphorous, glucose, albumin, creatinine, blood urea nitrogen (BUN), uric acid, ALT, AST, 
total bilirubin, direct and/or indirect bilirubin, alkaline phosphatase (ALP), and lactate 
dehydrogenase (LDH) 
o 
Hematology: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), 
hemoglobin, hematocrit, and platelet count 
o 
Urinalysis: glucose, blood, pH, specific gravity, ketones, and urine protein 
o Thyroid stimulating hormone (TSH), free T4 
o Pregnancy test (urine or serum β-HCG) for women of child-bearing potential 
6.8 Post Treatment Procedures 
 
Follow up post-treatment:  All participants will be followed until resolution or stabilization of any serious or 
reportable adverse events occurring during treatment or starting within 30 days of last study drug. After 
the end of treatment, each subject will be followed for 30 days for adverse event monitoring and 90 days 
for serious adverse event reporting. Assessments may continue for ongoing reportable adverse events. 
Participants removed from protocol therapy for unacceptable adverse events will be following until 
resolution or stabilization of the adverse event. 
 
30-day post-drug visit: A site visit is to be performed at 30 days (±7 days) after the last study drug is 
given, unless the subject is unable to travel due to deteriorating medical condition, due to the potential 
risk for delayed immune-related toxicities. The visit will include the safety procedures detailed below:  
 
o 
Adverse event assessment. 
o 
Symptom-directed physical exam and KPS assessment. 
o 
Vital signs: weight, temperature, resting blood pressure, pulse and respiration rate. 

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o 
Serum chemistry: sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphorous, glucose, albumin, creatinine, blood urea nitrogen (BUN), uric acid, ALT, AST, 
total bilirubin, direct and/or indirect bilirubin, alkaline phosphatase (ALP), and lactate 
dehydrogenase (LDH). 
o 
Hematology: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), 
hemoglobin, hematocrit, and platelet count. 
 
90-day post-drug safety follow-up: An extended safety follow-up is to be performed at 90 days (±14 days) 
after the last study drug is given. This may be performed via documented phone conversation with a 
study nurse or clinician or physician.  
 
Extended follow-up post-treatment: Subjects should be contacted every 3 months (±14 days) for survival 
status and initiation of any new anti-cancer treatments until death, withdrawal of permission to record at 
least survival data, or subject is lost to follow-up. Contact may include clinic visit, telephone contact, e-
mail, mail or medical record review. The date of death, initiation of any new anti-cancer treatments and 
date of last contact should be documented. 
 
If a subject withdraws permission to record at least survival data after coming off treatment, this must be 
documented along with the date the subject withdraws permission.  Subjects will be considered lost to 
follow up if no medical records are available to be reviewed and two phone calls each to the subject and 
then the subject's next-of-kin (if the subject does not respond) are not returned over two consecutive 3 
month periods. 
6.9 Efficacy Procedures 
Tumor response will be assessed every 8 weeks (see Section 6.6) using iRANO criteria70 as outlined. 
Clinicians may repeat response assessment more frequently as clinically indicated. 
 
Refer to Attachment 3 for details on iRANO criteria, guidelines for assessing radiologic findings, and 
treatment algorithm for the assessment of progressive imaging findings in patients with neuro-oncological 
malignancies undergoing immunotherapy.  
 
Evaluable for objective response. Only those participants who have measurable disease present at 
baseline (obtained within 14 days of cycle 1, day 1) scan and have received at least one dose of therapy 
will be considered evaluable for response. These participants will have their response classified 
according to the definitions stated in Attachment 3. (Note: Participants who exhibit objective disease 
progression or die prior to the end of cycle 1 will also be considered evaluable.) 
 
Note on continuation of therapy pending confirmation of radiographic disease progression: iRANO 
recommends confirmation of disease progression on follow-up imaging 3 months after initial 
radiographic progression if there is no new or substantially worsened neurological deficits that are not 
due to comorbid events or concurrent medication, and it is 6 months or less from starting immunotherapy 
(see Attachment 3 for iRANO criteria details). A decision of whether a patient should continue 
immunotherapy pending confirmation of radiographic disease progression should be established based 
on perceived benefits and risks. Continuation of immunotherapy may be considered pending follow-up 
imaging as long as subjects are deriving apparent clinical benefit with minimal and acceptable toxic 
effects.  
 
By contrast, investigators may consider interrupting immunotherapy for subjects who need a substantial 
increase in corticosteroids (i.e., >4 mg of dexamethasone or equivalent per day) for evolving symptoms 
associated with brain edema or who have more than mild treatment-related toxic effects such as at least 
grade 2 irAEs. These guidelines are included to limit the likelihood of progressive immunotherapy-induced 
inflammatory changes leading to substantial deficits in otherwise stable or symptom-free patients. In such 
subjects, an interruption of immunotherapy dosing might be considered pending follow-up imaging.  
 

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Furthermore, investigators may discontinue or interrupt immunotherapy at any time if this option seems to 
be in the best medical interest of the subjects. As a general guidance, resumption of immunotherapy 
might be taken into account when systemic dexamethasone is decreased to 4 mg/day or less and the 
contrast-enhancing tumor burden is classified as stable disease, partial response, or complete response 
on a follow-up scan, or when relevant treatment-related toxic effects have resolved to grade 1 or less or 
pre-treatment baseline. 
6.10 Research Specimen Procedures 
See Attachment 7 for Background and Rationale of Research Correlative Studies. Refer to the study 
procedures above in Section 6.1 and Section 6.5 for research blood sample collection.  Also, refer to the 
study Lab Manual for specific processing and handling procedures for research blood specimens. 
 
Note: This study involves collection of required archival tumor tissue and blood specimens for research as 
well as collection of an optional tumor specimen if a biopsy is required during or after protocol therapy.  
All patients will be given the option to have leftover research specimens after study completion and 
completion of protocol-defined research studies banked for future research at the time of informed 
consent. See Section 9.1.1 for details on leftover research samples. 
6.10.1 Archival Tumor Specimen 
Archival tumor tissue from a previous surgical resection that demonstrates histopathological evidence of 
transformation to glioblastoma (GBM, WHO grade IV) or genetic alteration as specified in the Eligibility 
Criteria (Section 4.1) must be submitted.   
 
A paraffin-embedded or frozen tumor-tissue block with a minimum of 1 cm2 surface area of viable tumor is 
required.  The tumor block should contain at least 20% viable tumor, i.e., a representative H&E slide 
should show that at least 20% of the specimen contains viable tumor.   
 
If a tumor block cannot be submitted, then twenty (20) unstained 5-micron slides (preferably 10 slides 
from two different tumor blocks from the same surgery) from the tumor specimen must be submitted. 
 
Note, an archival tumor specimen from the prior lower-grade glioma tumor is not required. 
 
Send archival tumor specimens for research to: 
 
Matija Snuderl, MD 
Department of Pathology, NYU Langone Medical Center 
560 First Avenue 
Tisch Hospital HW 451 
New York, NY 10016 
Phone: 646-501-5281 
Fax: 212-263-7916 
Pager: 917-205-5543  
Matija.Snuderl@nyumc.org 
6.10.2 Research Blood Samples 
Research blood samples will be taken at only 2 timepoints: C1D1 (up to 3 days prior to C1D1) and at the 
C2D1 visit.  
 
Refer to the Lab Manual for specific processing and handling procedures for research blood specimens. 
All subjects will have the below research blood samples collected. For details on specimen collection, 
processing, handling and shipping, refer to Section 6.8 (Study Procedures), Attachment 7 (Background 
and Rationale) and the study Lab Manual. 

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Whole blood for research will be collected from all subjects as described below: 
• 
NYULMC subjects: 40 mL (four 10 mL purple top EDTA tubes) of whole blood will be drawn 
and immediately sent to the below sites: 
 
One (1) 10 mL tube will be sent to the CBRD at NYULMC for acquisition of whole blood, 
buffy coat, and plasma samples. 
 
 
Three (3) 10 mL tubes will be sent to the IMC at NYULMC and immediately processed 
for isolation of PBMCs. 
• 
Subjects at other sites:  40 mL of whole blood will be collected in two types of tubes 
provided by NYULMC. All tubes will be shipped overnight to the CBRD at NYULMC per 
instructions in the Lab Manual. *Subsites should NOT schedule research blood draws 
on Fridays as the NYU CBRD will not be able to receive specimens on weekends. 
• 10 mL will be drawn into one Streck Cell-Free DNA BCT® collection tube 
• Three (3) 10 mL purple top EDTA tubes of whole blood will be drawn and immediately 
shipped to NYULMC and then immediately processed for isolation of PBMCs. 
6.10.3 Optional Tumor Biopsy for Research 
If subjects undergo tumor resections or biopsies during the study period after treatment initiation, or after 
progression on HFRT + Avelumab, a tumor specimen will be collected for research purposes. For details 
see Attachment 7.  A section of frozen tumor or a FFPE block (surface area of 1 cm2 containing at least 
20% viable tumor, as described above in Section 6.8.2) from the tumor surgery is preferred.  If a frozen 
tumor specimen or a tumor block cannot be provided, then 20 unstained 5-micron slides (preferably 10 
slides from two different tumor blocks from the same surgery) from the tumor block should be sent.  
 
Send optional tumor samples to: 
 
Matija Snuderl, MD 
Department of Pathology, NYU Langone Medical Center 
560 First Avenue 
Tisch Hospital HW 451 
New York, NY 10016 
Phone: 646-501-5281 
Fax: 212-263-7916 
Pager: 917-205-5543  
Matija.Snuderl@nyumc.org 
7 Statistical Plan 
7.1 Sample Size Determination 
7.1.1 Background for Statistical Plan:  
Secondary GBM outcomes: Although patients with IDH mutant gliomas survive relatively longer 
than those with IDH wildtype gliomas from the time of initial diagnosis, nearly all IDH mutant 
gliomas eventually become lethal, with most transforming to "secondary GBM". Outcomes for 
patients with secondary GBM (transformed IDH mutant gliomas), including PFS and OS, have 
been shown to be equivalent to patients with recurrent "de novo GBM", the vast majority of which 
are IDH wildtype.7,8  The median OS from the time of recurrence or transformation is equivalently 

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dismal, ranging from 7-9 months.  Therefore, efficacy endpoints for IDH wildtype GBM therapeutic 
clinical trials can be considered equivalent for the IDH mutant secondary GBM population.  
 
PFS6 reference measures: Previous meta-analyses have demonstrated that PFS6 is an 
adequate indicator of antitumor benefit for salvage GBM clinical trials and is the standard 
benchmark used in GBM chemotherapy trials.71,73,74  Published reference outcomes in recurrent 
GBM report a PFS6 of 9-15%.71,73,74 Temozolomide, the only chemotherapy that has 
demonstrated improved survival in any prospective, randomized phase III trial in GBM,75 
produced a PFS6 of 21% when tested in recurrent GBM patients.76 More recently, a number of 
recently reported randomized, prospective trials in recurrent GBM used conventional cytotoxic 
chemotherapies such as lomustine and carboplatin for the control arm and have reported 
remarkably similar estimated PFS6 rates in the chemotherapy control arms, ranging between 
15%-25%.77-81  Otherwise, bevacizumab, which was granted accelerated approved by the US 
FDA for use as monotherapy in progressive GBM in 2009 based on two historically-controlled, 
single-arm or non-comparative phase II trials,82,83 has been reported to have relatively higher 
estimated PFS6 rates of 29% and 42.6%. However, despite improved PFS6 rates observed in 
phase II trials, the addition of bevacizumab to lomustine failed to show a benefit in overall or 
neurologic progression-free survival compared to lomustine alone in a multi-institutional, 
randomized phase III trial of recurrent GBM.77  Therefore, based on the aggregate results of the 
above studies, the reference benchmark for our study will be PFS6 of 40%. 
 
Overall Survival (OS) reference measures:  In recent randomized, controlled trials of recurrent 
GBM, all of which have failed to demonstrate differences between arms, the median OS of 
experimental and control arms from the time of recurrence across all of these studies have been 
remarkably similar and have ranged between 6-10 months, with most arms in these studies 
reporting a median OS of approximately 9 months. 77-81  These data indicate the chemotherapies 
in these studies have similar minimal efficacy in recurrent GBM.   
 
With regards to salvage radiotherapy in recurrent GBM, a wide range of outcomes have been 
reported from numerous retrospective and phase II trials, likely due to small sample sizes, 
significant selection bias and differences in dose prescriptions and schedules.  Notably, however, 
reported OS rates from the time of salvage re-irradiation are highly similar to recent randomized 
trials using salvage chemotherapy, with one analysis of >300 recurrent GBM patients reporting 
PFS6 rates between 28% to 39% and a median 1-year overall survival rate of 26%.61,66,84-87  
Median OS rates reported in re-irradiation studies with larger numbers of patients are also similar 
to salvage chemotherapy studies, ranging between 7-11 months.66,84-87 Based on these and other 
studies, the RTOG 1205 randomized trial of re-irradiation with bevacizumab versus bevacizumab 
alone uses 9 month OS as the ineffective measure.  Based on the aggregate data above, we 
chose as a reference measure a 1-year median OS rate of 25%. 
7.1.2 Safety Lead-In sample size determination 
Based on the design of the Safety Lead-In and Dose De-Escalation Rules (Refer to Section 5.2.1 
and Section 5.2.1.1), the minimum number of patients in the Safety Lead-In will be 6 subjects if 
the initial dose level (Dose Level 0) is found to be safe and considered the RP2D (Section 7.1.3).  
 
If the Safety Lead-In enters into the Dose De-Escalation phase (Section 5.2.1.1), then the 
minimum number of total subjects in the entire study will be 12 if a RP2D cannot be determined.  
The maximum number of subjects in the Safety Lead-In based on the dose de-escalation design 
will be 18, with 6 subjects at each Dose Level (Section 5.2.1.1, Table 1).  If a RP2D is 
determined after 18 subjects, a total maximal sample size in the entire study of 61 subjects 
including both the Safety Lead-In and Phase II portions of the study. 
7.1.3 Phase II trial sample size determination 
 

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Forty-three patients (43) patients will be enrolled and treated in the phase II portion of this trial. All 
patients who receive one or more doses will be included in the estimate of PFS6. Patients who do 
not remain on treatment through the 6 cycles will be considered as failures in the primary 
analysis. With an optimum 2 stage Simon Phase II design, we can test the null hypothesis that 
PFS6 ≤0.40 versus the alternative that PFS6 ≥0.60 with alpha = 0.05 (actual alpha =0.047) and 
power of 80% (actual is 82.7%) with a total of 43 patients. If there are 7 or fewer progression free 
survivors at 6 months among 18 patients, the study will conclude at the end of stage 1; if there 
are 8 or more patients surviving for 6 months, the trial will continue for up to 43 patients. If there 
are 23 or more patients alive without progression by 6 months in the total of 43 patients, the 
therapy will be considered interesting for further study. Calculations from PASS, NCSS 2014 J. 
Hintze, Kaysville, UT.   
7.2 Statistical Methods 
7.2.1 Safety Lead-In 
 
The Safety Lead-In portion of the study is based on a 3 + 3 design with 3 to 6 patients assigned 
per dose level. The exact number of patients enrolled in the study will depend on the number of 
protocol-defined DLTs observed and the need to expand currently defined dose levels, or open 
additional cohorts at lower dose levels as described in Section 5.2.1 (Safety Lead-In Design) 
and Section 7.1.2 (Sample Size Determination).  
 
The subjects treated at the RP2D in the Safety Lead-In will be included as a separate cohort for 
the evaluation of outcomes in the phase II study. Data for the Safety Lead-In will be summarized 
using descriptive statistics. In general, data will be summarized by dose levels. See below in 
Section 7.3.1 for Safety Lead-In population for Analysis. 
7.2.2 Phase II trial  
 
See Section 7.1.3 for sample size determination. Six months will be defined as six 28-day cycles. 
Patients will be evaluated for radiographic responses by conventional contrast enhanced MRI 
every 8 weeks. Radiographic response assessments will be determined using recently developed 
iRANO criteria for GBM. All subjects who initiate therapy (receive at least one dose of Avelumab 
and/or radiotherapy) will be evaluated for radiographic response and safety. PFS6 and 
radiographic response rates will be estimated with exact 95% confidence intervals. 
 
PFS, defined as the time between treatment initiation and first occurrence of disease progression 
or death, will be censored at last follow-up if the patient remained alive without disease 
progression. OS will be determined from the time of treatment initiation until the time of death, 
with OS being censored at last follow-up if the patient remained alive. The Kaplan–Meier curves 
will be used to summarize PFS and OS and to estimate the medians and 6-month OS and PFS 
(PFS6). 
 
For toxicity monitoring statistical methods, see the Primary Safety Endpoints in Section 3.4. 
7.3 Subject Population(s) for Analysis 
7.3.1 Safety Lead-In Population 
Subjects are evaluable for DLTs if: 1) they experience a DLT at any time during the DLT 
evaluation period; or 2) in the absence of DLT have received at least one dose of Avelumab and 
at completed HFRT per protocol and have completed respective safety assessments without 
major violations over the entire DLT evaluation period. Patients who are not fully evaluable for 
DLTs during the DLT evaluation period of 28 days following Day 1 will be replaced. 

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7.3.2 Phase II Trial Efficacy Analysis Population 
All subjects that receive at least 1 dose of Avelumab will be included in the primary analysis for 
the phase II study. The subjects treated at the RP2D in the Safety Lead-In will be included as a 
separate cohort for the evaluation of outcomes in the phase II study. 
7.3.3 Safety Analysis Populations 
All subjects who received at least one dose of Avelumab will be used for the analysis of safety 
data in this study.  Safety summaries will be reported for both the Safety Lead-In and the phase II 
trial. 
 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required. 
 
Details on the approach to handling missing data for safety analyses are provided in Section 3.4 
(Primary Safety Endpoints). 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs in-patient hospital stay (In-patient hospitalization is defined as admission to a 
hospital or an emergency room for longer than 24 hours. Prolongation of existing hospitalization is 
defined as a hospital stay that is longer than was originally anticipated for the event, or is 
prolonged due to the development of a new AE as determined by the investigator or treating 
physician. Hospitalization or prolongation of existing hospitalization due to the progression of 
underlying malignancy will not be considered an SAE, if it is clearly consistent with the typical 
progression pattern of the underlying cancer. 

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• results in persistent or significant disability or incapacity (substantial disruption of one’s ability to 
conduct normal life functions) 
• a congenital anomaly or birth defect 
• an important medical event - Important medical events are those that may not be immediately life 
threatening, but are clearly of major clinical significance.   They may jeopardize the subject, and 
may require intervention to prevent one of the other serious outcomes noted above.  For example, 
drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered serious.  
 
An AE also includes any worsening (i.e., any clinically significant change in frequency and/or intensity) of 
a pre-existing condition that is temporally associated with the use of the study drug. 
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Expected Adverse Events for Avelumab 
For the purpose of regulatory reporting requirements during clinical development, the following AEs will 
be considered as expected and meet the threshold of causal association (based on comprehensive 
medical evaluation considering the mechanism of action and temporal relationship after excluding other 
possible etiologies) defined by EMD Serono based on safety data from completed and ongoing clinical 
studies: 
 
• 
Infusion-related reactions including drug 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, pruritus, rash generalized, rash maculo-papular, 
erythema, pemphigoid, other immune-mediated reactions including myocarditis, adrenal 
insufficiency, uveitis, iritis, myositis. 
 
Note: Development of edema in the brain is common following fractionated brain radiation therapy and 
may be asymptomatic (solely a radiographic finding) or associated with mild, moderate or severe 
symptoms. Therefore, brain edema will be considered an expected event related to study therapy 
(HFRT). 
 
Progression of underlying malignancy  
Progression of underlying malignancy will not be considered an AE if it is clearly consistent with the 
typical progression pattern of the underlying cancer (including time course, affected organs, etc.). 
Hospitalization or death due solely to manifestations consistent with typical progression of underlying 
malignancy will not be considered a SAE. Clinical symptoms of progression may be reported as AEs if the 
symptom cannot be determined as exclusively due to the progression of the underlying malignancy, or 
does not fit the expected pattern of progression for the disease under study. 
 
If there is any uncertainty about an AE being due only to progression of the underlying malignancy, it 
should be reported as an AE or SAE as outlined in Section 8.4. 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 

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General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an 
adverse event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study.  
The sponsor should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. more frequent follow-up 
assessments, further diagnostic investigation, etc. 
• The abnormality leads to a change in dosing (outside of protocol-stipulated dose adjustments) 
• The abnormality leads to discontinuation from the study, significant additional concomitant 
medication, or other therapy 
 
Contact the sponsor in the event the investigator feels that an abnormal test finding should be reported as 
an AE, although it does not meet any of the above criteria. 
 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. 
Any abnormal test result that is determined to be an error does not require reporting as an AE. 
 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined in 
Section 8.2.1. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any 
condition responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 

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8.2 Evaluation of Severity and Causality 
8.2.1 Evaluation of Severity 
The severity of AEs (including test findings classified as AEs) will be graded using the current version of 
the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading 
system. Adverse events not listed in the NCI-CTCAE, will be graded according to the following scale: 
 
1 (Mild): 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 
2 (Moderate): 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*. 
 
3 (Severe): 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
 
4 (Life-threatening): 
Life-threatening consequences; urgent intervention indicated. 
 
5 (Death): 
Death related to AE. 
 
* Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
8.2.2 Evaluation of Causality 
 
Relationship of AEs to Study Drug: 
The relationship of AEs to study drug will be assessed by the investigator, and will be a clinical decision 
based on all available information. The following question will be addressed: 
 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
 
The possible answers are: 
 
Not Related: 
There is no reasonable possibility that the event may have been caused by the study 
drug 
 
Related: 
There is a reasonable possibility that the event may have been caused by the study drug. 
 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
 
Attachment 5 lists factors to consider in assessing the relationship of AEs to Avelumab or infusion 
procedures, radiation therapy, combination treatment, study procedures, or background treatment. 
8.3 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 

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All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately. 
8.4 Reporting of Serious Adverse Events and Unanticipated Problems 
 
The investigator (or designee) will seek information on AEs at each patient contact, and record all AEs 
that occur from the time the informed consent is signed until 30 days after the end of study treatment. 
CTCAE version 4.03 terms should be used.  
 
All AEs after initiation of study treatment and until 30 days after the last study treatment, regardless of 
relationship to study treatment, will be reported. Additionally, any SAE or other AE of concern that the 
investigator believes may be related to study treatment and that occurs later than 30 days after last study 
treatment should be reported. Information for any nonserious AE that starts during the treatment period or 
within 30 days after last treatment will be collected from the time of the event until resolution of the event, 
or until the patient’s last study visit, whichever comes first. Serious adverse event information will be 
collected until the event is considered chronic and/or stable. 
 
Study treatment includes Avelumab and radiation therapy. 
 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats 
and requirements of the various entities to which they are responsible, but at a minimum those events 
that must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 8.1).   
 
Serious adverse event reporting will begin in conjunction with the date of informed consent. Any SAEs 
occurring prior to study drug administration that the investigator believes may have been caused by a 
protocol procedure must be reported immediately to the Sponsor or its designee and recorded on the 
case report form. 
 
All fatal or life-threatening adverse events must be immediately reported to the Sponsor by telephone or 
e-mail. Within 24 hours of the event, the Serious Adverse Event (SAE) Form supplied by NYULMC must 
be faxed to the Sponsor, who must then inform the NYULMC IRB, PCC CTO, and DSMC within 24 hours 
of the event whether full information regarding the event is known or not. Additional follow-up by the 
investigator will be required if complete information is not known. De-identified source documentation of 
all examinations, diagnostic procedures, etc. which were completed with respect to the event should be 
included with the SAE form. Care should be taken to ensure that the patient’s identity is protected and the 
patient’s identifiers (as assigned at the time of study enrollment) are properly mentioned on any copy of 
source document provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
 
In case of accidental or intentional overdose of study drug (Avelumab), even if asymptomatic or not 
fulfilling a seriousness criterion, the overdose is to be reported to the Sponsor immediately (within 1 
working day) using the AE and SAE forms supplied by NYULMC. Overdose of study drug will be defined 
as at least 2 times the intended dose of study drug within the intended therapeutic window. 
 
All serious adverse events (SAEs) will be evaluated by the DSMC If meeting the requirements for 
expedited reporting, the Sponsor will report the adverse event to all regulatory authorities with jurisdiction 
over ongoing trials with the study drug and to all other investigators involved in clinical trials with the study 
drug. The investigator is responsible for reporting all SAEs to the appropriate IRB, DSMC, and FDA. 

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For Narrative Reports of Safety Events 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of 
the initial report includes: 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study treatment 
8.4.1 Investigator reporting: notifying the study sponsor, NYULMC IRB, Perlmutter 
Cancer Center Clinical Trials Office, and EMD Serono/Merck KGaA 
 
The following describes events that must be reported to the study sponsor in an expedited fashion. 
 
Initial Report: within 24 hours of awareness of the event: 
The following events must be reported to the study sponsor by telephone within 24 hours of awareness of 
the event:  
• 
Unanticipated problems related to study participation,  
• 
Serious adverse events, regardless of whether they are unexpected.  
• 
Symptomatic Overdose of Study Drug, Accidental or intentional overdose of at least 2 times the 
intended dose of study drug within the intended therapeutic window, if associated with an AE. 
• 
Pregnancy: Although pregnancy is not considered an AE, it is the responsibility of the investigator 
to report to the sponsor (or designee), by telephone within 24 hours of identification, any 
pregnancy occurring in a female patient or female partner of a male patient, during the study or 
within 90 days of the last dose of study drug. Any complication of pregnancy affecting a female 
study patient or female partner of a male study patient, and/or fetus and/or newborn must be 
reported as an SAE. All pregnancy outcomes will be followed. 
• 
Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse event) 
• 
Occupational exposure (even if not associated with an adverse event) 
• 
Potential drug-induced liver injury (Hy’s Law cases): These events are considered important 
medical events and should be reported as SAEs. 
• 
Adverse Events of Special Interest (AESI) 
An AE of special interest (AESI) may or may not be a DLT or SAE.  AESIs must be reported 
within 24 hours of awareness of the event to the Sponsor/Overall PI and the local institution's 
DSMC and IRB per institutional guidelines. If the AESI is not an SAE or DLT, there is no 
need to report within 24 hours to the local institution's DSMC or IRB unless specified 
specifically by the local institution's guidelines.  AEs of special interest for this study include: 
o 
Any AE that meets DLT criteria (see Section 5.2.1.2) 
o 
Grade 2 or greater infusion-related reactions (See Section 5.2.3.5) 
o 
Grade 2 or greater allergic/hypersensitivity reactions (see Section 5.2.3.5) 
o 
Grade 3 or greater symptoms suspected to be attributable to brain edema (see Section 
5.2.1.2 for Rules for Brain Edema). 
o 
Grade 3 or greater immune-related toxicities (irAE) (see Section 5.2.3.3) 

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In the event the investigator is informed of an SAE that occurs after 30 days after the last dose of study 
treatment, only those SAEs or other AEs of concern deemed by the investigator to be related to study 
treatment will be reported to the sponsor. The investigator should make every effort to obtain follow-up 
information on the outcome of a treatment-related SAE until the event is considered chronic and/or stable. 
Additionally, an FDA Form 3500A (MEDWATCH Form) must be completed by the investigator and faxed 
to the study sponsor within 24 hours.  The investigator shall maintain a copy of the MEDWATCH Form on 
file at the study site or can be obtained from the FDA website: 
http://www.fda.gov/safety/medwatch/howtoreport/downloadforms/default.htm.  
Contact information for submission of reportable events to the Sponsor (NYULMC): 
   
NYUPCCsafetyreports@nyumc.org 
 
AND 
 
Sylvia Kurz, MD, PhD 
Laura and Isaac Perlmutter Cancer Center 
NYU Langone Medical Center 
240 East 38th Street, 19th Floor 
New York, NY 10016 
Phone:  212-731-6267 
Fax:  646-754-9696 
Email:  Sylvia.Kurz@nyulangone.org 
 
 
Follow-up report: within 48 hours of awareness of the event: 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated device event or the unanticipated 
problem in the form of a written narrative.  This should include a copy of the completed Unanticipated 
Problem form, and any other diagnostic information that will assist the understanding of the event.  
Significant new information on ongoing unanticipated adverse device effects shall be provided promptly to 
the study sponsor. 
 
New information available after 48 hours of initial event: within 24 hours of awareness of new 
information 
If new information about a previously reported event becomes available 48 hours after the initial 
awareness of the event, this new Information should be reported within 24 hours of awareness of the new 
information. Any new follow-up information that is received or that the investigator is newly made aware of 
after the initial 48 hour reporting period should be reported within 24 hours from the time of awareness of 
the new information. 
 
Other Reportable events: 
• 
Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval 
before they are initiated. Any protocol deviations initiated without Sponsor and the investigator’s 
IRB approval that may affect the scientific soundness of the study, or affect the rights, safety, or 
welfare of study subjects, must be reported to the Sponsor and to the investigator’s IRB as soon 
as a possible, but no later than 5 working days of the protocol deviation. 
• 
Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s reviewing 
IRB as soon as a possible, but no later than 5 working days of the IRB notification of withdrawal 
of approval. 
8.4.2 Investigator reporting: notifying the IRB 
 

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Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to subjects or others. The IRB requirements reflect the current guidance documents released 
by the Office of Human Research Protection (OHRP), and the Food and Drug Administration (FDA) and 
are respectively entitled “Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks 
to Subjects or Others and Adverse Events” and “Guidance for Clinical Investigators, Sponsors, and IRBs:  
Adverse Event Reporting-Improving Human Subject Protection.”   The following describes the NYULMC 
IRB reporting requirements, though Investigators at participating sites are responsible for meeting the 
specific requirements of their IRB of record. The NYU IRB address is: 
 
NYULMC IRB 
1 Park Avenue, 6th Floor 
New York, NY 10016 
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 working 
days from the time the investigator becomes aware of the event: 
• 
Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information, such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be 
caused by the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations 
from the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• New Information indicating a change to the risks or potential benefits of the research, in 
terms of severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a 
more severe or frequent side effect; Other research finds arm of study has no therapeutic value; 
FDA labeling change or withdrawal from market) 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable Event Form” or 
as a written report of the event (including a description of the event with information regarding its 
fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or other 
study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 

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8.4.3 Sponsor reporting: Notifying the FDA 
 
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  These 
written notifications of adverse events are referred to as IND safety reports. The following describes the 
safety reporting requirements by timeline for reporting and associated type of event: 
 
• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, teratogenicity, 
or carcinogenicity. 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A (MEDWATCH Form, obtained from the FDA 
website: http://www.fda.gov/safety/medwatch/howtoreport/downloadforms/default.htm), or in a narrative 
format. If supplied as in a narrative format, the minimum information to be supplied is noted above at the 
beginning of section 8.3. The contact information for submitting IND safety reports is noted below: 
 
Email:  NYUPCCsafety@nyumc.org 
Tel:  212-263-4427 
8.4.4 Sponsor Reporting: Notifying EMD Serono 
 
The following reportable events must be submitted to the Sponsor (NYULMC) within 24 hours (or 
immediately for death or life-threatening events) using the applicable safety report form provided. The 
Sponsor/Overall PI will assume responsibility for submitting the reportable event(s) to EMD Serono within 
2 business days or 3 calendar days (whichever comes first), as well as ensuring that any local reporting 
requirements are completed in parallel. 
 
• 
Serious Adverse Events 
• 
Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse event) 
• 
Occupational exposure (even if not associated with an adverse event) 
• 
Potential drug-induced liver injury (Hy’s Law cases):  These events are considered important 
medical events and should be reported as SAEs. 
 
Contact information for submission of reportable events to Sponsor/Overall Principal Investigator: 
 

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NYUPCCsafetyreports@nyumc.org 
 
AND 
 
Sylvia Kurz, MD, PhD 
Laura and Isaac Perlmutter Cancer Center 
NYU Langone Medical Center 
240 East 38th Street, 19th Floor 
New York, NY 10016 
Phone:  212-731-6267 
Fax:  646-754-9696 
Email:  Sylvia.Kurz@nyulangone.org 
Specifying: 
• 
PROTOCOL Number and/or Title 
• 
EMD Serono assigned Study Number 
• 
SUBJECT Number 
• 
SITE Number/PI Name 
• 
SAE/ONSET DATE 
 
8.4.5 Sponsor reporting: Notifying participating investigators 
 
It is the responsibility of the study sponsor to notify all participating investigators of any adverse event that 
meets the FDA 15-day reporting requirement criteria as note above in Section 8.4.3.  The same materials 
and timeline used to report to the FDA are used for notifying participating investigators. 
8.5 Stopping Rules  
 
For the Safety Lead-In, see Section 5.2.1, Safety Lead-In Treatment Regimen, for detailed rules for 
continuing enrollment, dose decisions, and study discontinuation. In summary, once each cohort has filled 
enrollment, enrollment will stop and subjects will be observed for 28 days for dose-limiting toxicities 
(DLTs). At the end of each DLT period, the Safety Monitoring Team will review the safety data at a Safety 
Lead-In Dose Review meeting that will include at least a representative from each site; sub-investigators 
may be included. Continuation of enrollment will occur once all of the subjects have completed the Day 
28 safety assessments of that particular cohort and the final dosing decisions, including whether the study 
should be discontinued or proceed to phase II, will be made by the Safety Monitoring Team. 
 
For the Phase II trial, stopping rules for unexpected toxicity are outlined in see Section 3.4, Primary 
Safety Endpoints, and stopping rules for futility at the end of stage 1 of the phase II trial are outlined in 
Section 7.2.2, Statistical Methods.  
8.6 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see 
Section 10 Auditing, Monitoring and Inspecting).  Adverse events are evaluated monthly by the 
principal investigator in conjunction with the research team.  The Data Safety and Monitoring Committee 
(DSMC) will review the study twice a year.  Medical monitoring will include a regular assessment of the 
number and type of serious adverse events. 
8.6.1 Data and Safety Monitoring Committee 

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This investigator-initiated study will be monitored by the Data Safety Monitoring Committee (DSMC) of the 
New York University (NYU) Perlmutter Cancer Center (PCC). The DSMC operates based on the 2011 
National Cancer Institute approved Charter.  It is an existing and multidisciplinary committee (consisting of 
clinical investigators/oncologists, biostatisticians, nurses, and research administration staff 
knowledgeable of research methodology and design and in proper conduct of clinical trials) that is 
responsible for monitoring safety, conduct and compliance in accordance with protocol data monitoring 
plans for clinical trials conducted in the NYULMC Perlmutter Cancer Center that are not monitored by 
another institution or agency. The DSMC reports to the Director of the NYULMC PCC.  Per the NYU PCC 
Institutional Data Safety and Monitoring Plan, this phase 2 trial will be monitored by DSMC twice annually 
(from the date the first patient is enrolled), at dose escalation point and subsequent cohort activation, and 
at the completion of the study prior to study closure. This review includes accrual data, subject 
demographics and adverse events.  Accrual to the next dose within a cohort will be held until real-time 
review of the toxicity from the prior cohort has occurred to assure no defined DLTs have occurred prior to 
proceeding to the next level or expanding the current cohort.   Principal Investigators are required to 
attend the review of their studies. Additional reviews can be scheduled based on SAE reports, 
investigator identified issues, external information, etc. The DSMC will review safety data every 6-8 
weeks. 
 
Other external sites will be monitored and informed of other adverse events by the medical monitor within 
7 days of toxicities and within 3 business days of SAE.  Scheduled conference calls will be conducted 
after 3 patients are enrolled and at each dose escalation point.  Additional conference calls will be 
scheduled as indicated based on the recommendations from the medical monitor, the Overall PI of this 
study. 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
The study team will maintain clinical and laboratory data in a designed manner to ensure patient 
confidentiality.  All study personnel have passed human subject protection courses.  If applicable, tissue 
samples sent to collaborators outside of NYULMC will only be labeled with an assigned protocol-subject 
identification number without patient identifiers.  Systems used for electronic data capture are compliant 
with HIPAA and applicable local regulatory agency guidelines.  All documents are kept in strictly 
confidential files and are only made accessible for specific study personnel, CTO quality assurance 
specialists, and authorized representatives of regulatory agencies as described in the informed consent 
document.  
9.1.1 Leftover Research Samples (Tissue and Blood) 
At the time of informed consent to participate in this trial, patients will have the option to allow all research 
samples (archival tumor sample, research blood samples, and optional tumor biopsy sample) remaining 
after completion of the study and protocol-specified correlative biomarker research to be banked for future 
research studies. Future studies may include, but are not limited to, genetic, epigenetic, and molecular 
studies with the overall goal of correlating any scientific findings with the patients’ outcome to protocol 
therapy.  Leftover samples will be stored in a repository in the NYULMC Center for Biospecimen 
Research and Development (CBRD) and labeled with an assigned protocol-patient identification number 
without subject identifiers. The assigned protocol-patient identification numbers will be stored in a central 
database on a password-protected NYULMC server. This central database will contain the key to 
decoding assigned protocol-patient identification numbers used for sample labeling and patient’s 
identifiable medical information (PHI). Only the Overall PI will have the linking key to the subject 
identifiers. 
 
For each leftover research sample, key clinical information including, but not limited to, gender, age at 
diagnosis, tumor location, prior treatment and histology will be abstracted from the medical record and 
recorded with the assigned protocol-patient identification number on a separate database from the central 

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database containing the identifiable PHI. This de-identified database will also be on a password-protected 
NYULMC server and will be administered by the overall PI. Only the Overall PI and IRB-approved study 
investigators with permission from the Overall PI will have access to this de-identified database.  
 
The de-identified samples and data may be made available to researchers at NYULMC (NYU Langone 
Medical Center), NYU SoM (NYU School of Medicine), and other NYULMC affiliates, as well as 
researchers outside of NYU. De-identified samples may be shared with for-profit companies that are 
working with NYULMC, NYU SoM or other NYULMC affiliate researchers on a specific IRB-approved 
research project. De-identified specimens may also be made available to other researchers through 
research organizations whose mission focuses on the acquisition, authentication, production, 
preservation, development and/or distribution of data and materials for research in the life sciences, such 
as The Cancer Genome Atlas, a collaboration between the National Cancer Institute (NCI) and the 
National Human Genome Research Institute (NHGRI). 
 
Patients not agreeing to allow their leftover samples/data to be stored for future use will be able to fully 
participate in the study with no restrictions. The central database and de-identified database maintained 
for at least 5 years after termination of the study.  
 
If a result from a genetic test on mandatory or leftover research samples is deemed by the Study 
Sponsor/Overall PI to be important to report to the subject, the Subject may elect at the time of informed 
consent to receive results of genetic tests. If results are shared with the subject, the genetic test result will 
be validated with a repeat genetic test prior to sharing the information with the subject. The subject must 
consent to have a consultation with a genetic counselor at the participating institution at the time results 
are released.  The costs associated with the genetic counselor involved with the disclosure of these 
potentially clinically important results may be billed to the subject's insurance company or other third 
parties, if appropriate, and the subject may also be responsible for some of them. The funding sponsor 
(EMD Serono, Inc.) will not pay for costs for the genetic counselor involved with the disclosure of these 
potentially clinically important results. 
 
Subjects can withdraw their samples/data from future use at any time. The subject may contact the Study 
Sponsor/Overall PI or designee to express his or her wish to withdraw leftover samples from storage. 
 
9.2 Confidentiality and HIPAA 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
9.3 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, microfilm or magnetic media, x-

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rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
9.4 Data and Source Documentation 
Velos, an electronic database capture system will be created to record the data for this trial.  Research 
coordinators will input clinical trial data into the database.  This database is password protected and only 
the PI, assigned research coordinator, and CTO quality assurance specialists will have access to the 
database.  Velos is the primary data collection instrument for the study.  All data requested in Velos must 
be reported.  All missing data must be explained.  The quality assurance specialists will monitor this trial 
every 6-8 weeks for data entry accuracy. 
9.5 Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents should be retained for a longer 
period if required by an agreement with the sponsor.  In such an instance, it is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be retained.  
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan detailed below.  The investigator will 
allocate adequate time for such monitoring activities.  The Investigator will also ensure that the monitor or 
other compliance or quality assurance reviewer is given access to all the above noted study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate 
space to conduct the monitoring visit. A risk-based, data-driven monitoring approach will be used to verify 
data for this trial which will also include a centralized review of data for quality, trends, consistency and 
general safety review.  A quality assurance specialist will make regularly scheduled trips to the 
investigational site to review the progress of the trial, study data and site processes.  At each visit, the 
monitor will review various aspects of the trial including, but not limited to:  screening and enrollment logs; 
compliance with the protocol and study manual and with the principles of Good Clinical Practice; 
completion of case report forms; source data verification; study drug accountability and storage; facilities 
and staff. 
 
During scheduled monitoring visits, the investigator and the investigational site staff must be available to 
meet with the quality assurance specialist in order to discuss the progress of the trial, make necessary 
corrections to case report form entries, respond to data clarification requests and respond to any other 
trial-related inquiries of the monitor. In addition to on-site monitoring visits, the Sponsor and/or 
representatives will also be routinely reviewing data. Any queries identified through this review will be 
managed within the systems established for query resolution and tracking. Inquiries related to study 
conduct, which require further information or action will be discussed within the study team for appropriate 
and documented escalation plans. It is expected that response to data clarification requests and other 
trial-related inquiries will occur throughout the course of the study through regular communication with the 
site monitor, the Sponsor or representatives, and review/entry of data into the electronic study database. 
 
At any time during the course of the study, representatives of the FDA and/or local regulatory agencies 
may review the conduct or results of the study at the investigational site. The investigator must promptly 
inform EMD Serono/Merck KGaA of any audit requests by health authorities, and will provide EMD 
Serono/Merck KGaA Pharmaceuticals with the results of any such audits and with copies of any 
regulatory documents related to such audits. 

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In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use personal 
identifiable health information may be required from each patient before commencement of research 
activities. This authorization document must clearly specify what parties will have access to a patient’s 
personal health information, for what purpose and for what duration. 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), 
and has adequate space to conduct the monitoring visit. 
 
At the NYU Perlmutter Cancer Center, all investigator-initiated protocols are subject to a standardized 
data and safety monitoring, which includes scientific peer review, IRB review and DSMC review as well as 
internal auditing.  
 
The review of AEs and trial conduct for this trial occurs at several levels: 
 
(1) Principal Investigator: Adverse events are evaluated monthly by the principal investigator in 
conjunction with the research nurses, data manager and research team.  
 
(2) DSMC, twice annually 
 
(3) Institutional Review Board (IRB): An annual report to the IRB is submitted by the trial PI for 
continuation of the protocol. It includes a summary of all AEs, total enrollment with demographics, 
protocol violations, and current status of subjects as well as available research data. 
 
(4) In addition, the quality assurance unit will monitor this trial every 6-8 weeks, to verify 
adherence to the protocol; the completeness, accuracy and consistency of the data; and 
adherence to ICH Good Clinical Practice guidelines. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
 
This study is to be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice (GCP), and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional Review Board 
(IRB) in agreement with local legal prescriptions, for formal approval of the study conduct.  The decision 
of the IRB concerning the conduct of the study will be made in writing to the investigator and a copy of 
this decision will be provided to the sponsor before commencement of this study.  The investigator should 
provide a list of IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. This consent 
form will be submitted with the protocol for review and approval by the IRB for the study.  The formal 

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consent of a subject, using the IRB-approved consent form, must be obtained before that subject 
undergoes any study procedure.  The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent.  
 
12 Study Finances 
12.1 Funding Source 
Funding for conducting the trial will be provided by EMD Serono/Merck KGaA. The investigational agent 
(Avelumab) will be provided to patients enrolled on this study by EMD Serono/Merck KGaA. 
12.2 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 by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved by the study sponsor prior to participation in this study.  All NYULMC 
investigators will follow the applicable University conflict of interest policies. 
12.3 Subject Stipends or Payments 
No patient or subject will receive payments or stipends for participation in this research study.  EMD 
Serono/Merck KGaA may provide coverage for tests and/or procedures that are a part of the research 
study, if it is not covered by the subject’s insurance. 
13 Publication Plan 
NYULMC fulfills its commitment to publicly disclose the results of studies.   
 
The overall Principal Investigator, Sylvia Kurz, M.D., Ph.D., holds the primary responsibility for publication 
of the study results. The co-investigators of this study must first obtain approval from Dr. Kurz, the primary 
responsible party for publication, before any information collected in this trial can be used or passed on to 
a third party. Neither the complete nor any part of the results of the study carried out under this protocol, 
nor any of the information provided by the overall Principal Investigator for the purposes of performing the 
study, will be published or passed on to any third party without the consent of the study overall Principal 
Investigator.  Any investigator involved with this study is obligated to provide the overall Principal 
Investigator with complete test results and all data derived from the study. 
 
EMD Serono/Merck KGaA has no objection to publication by the study overall Principal Investigator of 
any information collected or generated by the study overall Principal Investigator, whether or not the 
results are favorable to the investigational drug.  However, to ensure against inadvertent disclosure of 
confidential information or unprotected inventions, Investigator will provide EMD Serono/Merck KGaA an 
opportunity to review any proposed publication or other type of disclosure before it is submitted or 
otherwise disclosed. 
14 References 
 
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87 Redmond, K. J. & Mehta, M. Stereotactic Radiosurgery for Glioblastoma. Cureus 7, e413 (2015). 
88 Wen, P. Y. et al. Updated response assessment criteria for high-grade gliomas: response 
assessment in neuro-oncology working group. J Clin Oncol 28, 1963-1972 (2010). 
89 Lundegaard, C. et al. NetMHC-3.0: accurate web accessible predictions of human, mouse and 
monkey MHC class I affinities for peptides of length 8-11. Nucleic Acids Res 36, W509-512 (2008). 
90 Lundegaard, C., Lund, O. & Nielsen, M. Accurate approximation method for prediction of class I MHC 
affinities for peptides of length 8, 10 and 11 using prediction tools trained on 9mers. Bioinformatics 
24, 1397-1398 (2008). 
91 Rempala, G. A. & Seweryn, M. Methods for diversity and overlap analysis in T-cell receptor 
populations. J Math Biol 67, 1339-1368 (2013). 
92 Fecci, P. E. et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains 
cellular immune defects in patients with malignant glioma. Cancer Res 66, 3294-3302 (2006). 
93 Gielen, P. R. et al. Increase in both CD14-positive and CD15-positive myeloid-derived suppressor cell 
subpopulations in the blood of patients with glioma but predominance of CD15-positive myeloid-
derived suppressor cells in glioma tissue. J Neuropathol Exp Neurol 74, 390-400 (2015). 
94 Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J 
Med 370, 699-708, doi:10.1056/NEJMoa1308573 (2014). 
95 Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. 
N Engl J Med 370, 709-722, doi:10.1056/NEJMoa1308345 (2014). 
96 Campbell, B. B. et al. Comprehensive Analysis of Hypermutation in Human Cancer. Cell 171, 1042-
1056.e10 (2017). 
15 Attachments 
 
Attachment 1: Schedule of Events 
Attachment 2: Karnofsky Performance Status Scale 
Attachment 3: iRANO Criteria 
Attachment 4: Recommended Dose Modification or Discontinuation and Supportive Care 
Guidelines for Specific Drug-Related Adverse Events 
Attachment 5: Factors to Consider in Assessing the Relationship of AEs to Avelumab or Infusion 
Procedure, Study Procedure, or Combination Treatment 
Attachment 6: Technical Specifications and Structural Considerations for Planning Radiotherapy 
Attachment 7: Research Correlative/Biomarker Studies: Background and Rationale 
 

Avelumab in transformed IDH mutant GBM 
 
Attachments - Page 1 
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15.1 Attachment 1: Schedule of Events  
STUDY DAY ► 
Day -21 
to -11 
C1 
D14 
C1 
D811 
C1 
D155 
C2 
D1 
C2 
D15 
D1 of 
C3+ 
End  
of Rx 26 
30-Day 
Post-
Drug 27 
90-Day 
Post-
Drug 28 
Study Team Procedures 
 
 
 
 
 
 
 
 
 
 
Informed Consent 2 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 3 
X 
 
 
 
 
 
 
 
 
 
Medical/Disease History 6 
X 
 
 
 
 
 
 
 
 
 
KPS Assessment 8 
X 
X 
 
 
X 
 
X 
X 
X 
 
Concomitant Medications 9 
X 
X 
 
 
X 
 
X 
X 
X 
 
Height and Weight 10 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Vital Signs 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete Physical Exam 12 
X 
X 
 
 
X 
 
X 
X 
 
 
Directed Physical Exam 13 
 
 
X 
X 
 
X 
 
 
X 
 
Adverse Events 25 
 
X 
X 
 
X 
 
X 
X 
X 
X 
Survival 
 
 
 
 
 
 
 
X 
X 
X 
Laboratory/Cardiology Assessments 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry 14 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Hematology 15 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Urinalysis 16 
X 
 
 
X 
X 
X 
X 
X 
 
 
Coagulation 17 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B and C 29 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test 18 
X 
X 
 
 
X 
 
X 
X 
 
 
TSH, free T4 19 
X 
X 
 
 
 
 
X 
(every 
other 
cycle) 
X19 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
 
 
Radiotherapy: 5 Gy x 5 fractions  
(25 Gy total) 20 
 
 
X11 
 
 
 
 
 
 
 
Avelumab IV 21 
 
X 
 
X 
X 
X 
X 
 
 
 
Imaging Assessments 
 
 
 
 
 
 
 
 
 
 
MRI Brain Scan 22 
X 
 
 
 
 
 
X 
 
 
 
Chest X-ray 30 
X 
 
 
 
 
 
 
 
 
 
Research Samples 
 
 
 
 
 
 
 
 
 
 
Archival tumor tissue 7 
X 
 
 
 
 
 
 
 
 
 
Research blood samples 23 
 
X 
 
 
X 
 
 
 
 
 
Tumor biopsy (optional) 24 
 
 
 
 
 
 
 
X 
 
 
EXPLANATION OF SUPERSCRIPTS: 
1. 
Screening will start within 21 days prior to initiation of study treatment (first dose of Avelumab). 
2. 
Informed Consent: Performed by MD attending only. Informed consent process to be fully document: e.g. 
prospective participant had sufficient time for deliberation, all questions were answered, treatment options 
provided by MD, full study reviewed including risks, and a copy of signed consent given to the participant. No 
study specific screening procedures may occur until after the informed consent process is complete. Informed 
consent may be obtained more than 21 days before the start of screening procedures. Assessments performed 
as part of standard of care that fall within the screening window but before informed consent is obtained may be 
used for screening, and need not be repeated for enrollment eligibility. 

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3. 
Inclusion/exclusion criteria: source documentation providing investigator’s confirmation that the participant had 
met all eligibility criteria must be available prior to registration. 
4. 
C1D1 assessments must be performed within 3 days prior to the first dose of Avelumab.  
5. 
If well tolerated and no tumor progression, clinic visits and laboratories will be conducted every 2 weeks with 
radiographic assessment performed every 8 weeks (approximately every 2 cycles). For all study visits 
subsequent to C1D8, required assessments must be performed within 3 days of each scheduled Visit Day. 
6. 
All patients must have histopathological documentation of a prior lower-grade (WHO grade II or III) glioma on a 
previous biopsy specimen and documentation of temozolomide or PCV chemotherapy prior to transformation to 
glioblastoma (WHO grade IV).  All patients must have histopathological diagnosis of glioblastoma, WHO grade 
IV, at progression from the prior grade II or III glioma. The diagnosis of glioblastoma must be confirmed by 
central review prior to registration.  An IDH1 or IDH2 mutation must be present in at least one tumor specimen. 
Subjects who received anti-tumor therapy after histopathologic transformation to glioblastoma must have shown 
unequivocal radiographic evidence of tumor progression by contrast-enhanced MRI scan (or CT scan if MRI is 
contraindicated). Medical history should also include review of all treatment history for GBM and any ongoing 
medical conditions and medical history pertaining to eligibility on study and involvement during study. 
7. 
After registration, all patients will be required to provide a tumor block with a minimum of 1 cm2 of tumor surface 
area from a previous tissue specimen that demonstrates pathological transformation to glioblastoma (WHO grade 
IV). If a tumor block cannot be submitted, then 20 unstained slides (preferably 10 slides from two different tumor 
blocks from the same surgery) from the tumor specimen must be submitted.  
8. 
Karnofsky Performance Status (KPS) assessment: See Attachment 2 for KPS scale. 
9. 
Concomitant medication recording will be ongoing throughout the course of the study. Record concomitant 
medications from within 21 days before starting study treatment up to the 30-Day Post Drug Visit. 
10. Height is required only at screening. Weight can be taken within 3 days of scheduled study drug administration. 
11. Vital signs include temperature, resting blood pressure, pulse, and respiration rate. When scheduled at the same 
visit as other procedures, vital signs should be measured prior to clinical laboratory assessments or research 
blood sample collection.  At C1D1, vital signs will be collected prior to treatment, at the end of the infusion, and 
30 minutes post-infusion. Vital signs on subsequent treatment days of cycle 1 and all subsequent cycles will be 
assessed and documented prior to the infusion and then approximately 30 minutes after the completion of the 
infusion (all infusion VS timepoints ±10 minutes). Following all Avelumab infusions, subjects must be observed 
for 30 minutes post‑infusion for potential infusion-related reactions. During Radiation Therapy, vital signs will 
only be recorded on the first day of radiation therapy (C1D8). 
12. Complete physical exam to be completed by the investigator or qualified designee at screening, C1D1 and start 
of all subsequent cycles. Complete physical exam includes skin, head, eyes, throat, neck, joints, lungs, heart, 
abdomen (including liver and spleen), lymph nodes, extremities, and neurological exam. The exam may be 
performed within 3 days prior to the day of each scheduled study visit. 
13. Symptom-direct physical exam to be completed as clinically indicated by the investigator or qualified designee on 
the first day of radiation therapy (C1D8) and at all mid-cycle visits (i.e. Day 15). 
14. Serum Chemistry includes: sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorous, 
glucose, albumin, creatinine, blood urea nitrogen (BUN), uric acid, ALT, AST, total bilirubin, direct and/or indirect 
bilirubin, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH). Samples may be collected within 3 
days prior to the scheduled day of each visit. 
15. Hematology includes: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), hemoglobin, 
hematocrit, and platelet count. Samples may be collected within 3 days prior to each scheduled study visit. 
16. Urinalysis: glucose, blood, pH, specific gravity, ketones, and urine protein. Samples may be collected within 3 
days prior to each scheduled study visit. 
17. Coagulation – PT/INR, PT, PTT required at screening only. 
18. Urine or serum β-HCG for women of child-bearing potential at screening and at Day 1 of every cycle. 
19. TSH (thyroid stimulating hormone) and free T4 (free thyroxine) at C1D1, every other cycle thereafter, and at end 
of treatment or 30 days post-treatment safety follow-up (if not performed in the previous 8 weeks). 
20. Hypofractionated radiation therapy (HFRT): Administered 5 Gy per fraction for 5 fractions over 5 consecutive 
days. Total HFRT dose will be 25 Gy. See Attachment 6 for technical details of HFRT. On the first day (C1D8) 
of HFRT, adverse event assessment, a symptom-directed physical exam and limited vital signs (temperature, 
resting blood pressure, pulse, and respiration rate) must be performed. 
21. Study drug (Avelumab) administration windows include ±3 days of scheduled visit. Avelumab will be 
administered in an outpatient setting as an IV infusion. Each patient’s dose will depend on individual body 

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weight. The dose of Avelumab must be adjusted each dose for changes in body weight of ≥10%. Dose 
adjustments for changes in body weight of <10% will be at the discretion of the investigator. 
22. Contrast-enhanced brain MRI for response assessment will be performed prior to C1D1, then prior to C3D1, and 
then every 8 weeks thereafter. Initial imaging should be performed within 14 days prior to first dose of study 
treatment (Avelumab). MRIs can be performed within 7 days (-7 days) of scheduled assessment. On-study 
imaging should follow calendar days (every 8 weeks) and should not be adjusted for delays in cycle starts.  A 
contrast-enhanced CT can be performed if MRI is contraindicated. Local reading (investigator assessment) will 
be used to determine eligibility and for participant management. Response Assessments will be performed on 
every brain imaging assessment performed on protocol per iRANO criteria (see Attachment 3).  
23. Research Blood Samples: For all patients, whole blood will be drawn at two timepoints: C1D1 (pre-dose) and at 
C2D1. For subjects at NYULMC, four purple top EDTA tubes (40 mL) will be drawn, one EDTA tube will be sent 
to the CBRD and three EDTA tubes will be sent immediately to the IMC. For subjects at other sites: *Subsites 
should NOT schedule research blood draws on Fridays as the NYU CBRD will not be able to receive 
specimens on weekends. 40 mL of blood will be drawn into two types of tubes: 10 mL will be drawn into one 
Cell-Free DNA BCT® collection tube and 30 mL will be drawn into three purple top EDTA (10 mL) tubes. Blood 
samples will be immediately shipped overnight to NYULMC per instructions in the Lab Manual. 
24. Optional tumor biopsy: If subjects undergo tumor resections or biopsies during the study period after treatment 
initiation, or after progression on HFRT + Avelumab, a tumor specimen will be collected for research purposes. 
For details see Section 6.8.3 and Attachment 7. 
25. Monitored throughout the study via safety assessments, observation, and participant reporting.  
26. End of treatment assessments to be performed within 7 days after the last drug administration or within 7 days 
after decision to end treatment. After the end of treatment, each subject will be followed for 30 days for adverse 
event monitoring and 90 days for serious adverse event reporting. Assessments may continue for ongoing 
reportable adverse events. After coming off study, patients will be contacted every 3 months to assess survival 
status. 
27. A site visit is to be performed at 30 days (±7 days) after the last study drug is given, unless the subject is unable 
to travel due to deteriorating medical condition, due to the potential risk for delayed immune-related toxicities. All 
participants will be followed until resolution or stabilization of any serious or reportable adverse events occurring 
during treatment or starting within 30 days of last study drug. 
28. Given the potential risk for delayed immune-related toxicities, safety follow-up must be performed up to 90 days 
(+/- 14 days) after the last dose of avelumab administration. The extended safety follow-up beyond 30 days after 
last study drug administration may be performed either via a site visit or via a telephone call with subsequent site 
visit requested in case any concerns noted during the telephone call. This may be performed via documented 
phone conversation with a study nurse or physician.  
29. Hepatitis B virus surface antibody, hepatitis B virus surface antigen, hepatitis B virus core antibody, and hepatitis 
C virus antibody at screening only. 
30. Chest x-ray is required at screening if not performed within 60 days prior to initiation of study treatment. 
 

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15.2 Attachment: 2 
 
Karnofsky Performance Status Scale 
 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
 
0 
Dead. 
 
 

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15.3 Attachment: 3 
 
iRANO (immunotherapy response assessment in neuro-oncology) 
Criteria 
Tumor response will be assessed every 8 weeks for patients treated on this study using modified iRANO 
criteria70,88 as outlined in the Study Procedures (Section 6).  
 
Anti-Tumor Effect Definitions 
 
Evaluable for objective response. Only those participants who have measurable disease present at 
baseline (obtained within 14 days of cycle 1, day 1) scan and have received at least one dose of therapy 
will be considered evaluable for response. These participants will have their response classified 
according to the definitions stated below. (Note: Participants who exhibit objective disease progression or 
die prior to the end of cycle 1 will also be considered evaluable.) 
 
Measurable disease. Bi-dimensionally, contrast-enhancing, measurable lesions with clearly defined 
margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices which are at 
least 5 mm apart with 0 mm skip. Measurement of tumor around a cyst or surgical cavity, if necessary, 
requires a minimum thickness of 3 mm. If there are too many measurable lesions to measure at each 
evaluation, the investigator must choose the largest two to be followed before a participant is entered on 
study. The remaining lesions will be considered non-measureable for the purpose of objective response 
determination. Unless progression is observed, objective response can only be determined when all 
measurable and non-measurable lesions are assessed. 
 
Non-measurable evaluable disease. Unidimensionally measurable lesions, masses with margins not 
clearly defined, lesions with maximal diameter < 1cm. 
 
Response/Progression Categories 
 
Complete response (CR). All of the following criteria must be met: 
 
1. Complete disappearance of all enhancing measurable and non-measurable disease sustained for 
at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan will be considered 
only stable disease. 
2. No new lesions*. 
3. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
4. Participants must be on no steroids or must not be on increased doses of steroids within 2 weeks 
of assessment relative to the dose taken at the time of the previous assessment 
5. Stable or improved non-enhancing (T2/FLAIR) lesions 
6. Stable or improved clinically, for clinical signs and symptoms present at baseline and recorded to 
be disease related 
 
Participants with non-measurable disease cannot have a complete response. The best response possible 
is stable disease. 
 
*See immunotherapy considerations below regarding new lesions 
 
Partial response (PR). All of the following criteria must be met: 
 

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1. Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. In 
the absence of a confirming scan 4 weeks later, this scan will be considered only stable disease. 
2. No progression of non-measurable disease. 
3. No new lesions.* 
4. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
5. Participants must be on no steroids or must not be on increased doses of steroids within 2 weeks 
of assessment relative to the dose taken at the time of the previous assessment 
6. Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. 
7. Stable or improved, for clinical signs and symptoms present at baseline and recorded to be 
disease related clinically. 
 
Participants with non-measurable disease cannot have a partial response. The best response possible is 
stable disease. 
 
*See immunotherapy considerations below regarding new lesions 
 
Progressive disease (PD). Any of the following criterion must be met: 
 
1. 25% increase in sum of the products of perpendicular diameters of enhancing lesions (over best 
response or baseline if no decrease) on stable or increasing doses of corticosteroids 
2. Patients who decrease corticosteroid use within 2 weeks of MRI assessment relative to the dose 
taken at the time of the previous assessment cannot be classified as having progressive disease 
and should be classified as non-evaluable. 
3. Any new enhancing measurable lesion* 
4. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. seizures, 
medication side effects, complications of therapy, cerebrovascular events, infection, etc.). The 
definition of clinical deterioration is left to the discretion of the investigator but it is recommended 
that a decline in the Karnofsky Performance Score (KPS) from 100 or 90 to 70 or less, a decline 
in KPS of at least 20 from 80 or less, or a decline in KPS from any baseline to 50 or less, for at 
least 7 days, be considered neurologic deterioration, unless attributable to co-morbid events or 
changes in corticosteroid dose. 
5. Failure to return for evaluation due to death or deteriorating condition 
 
*See immunotherapy considerations below regarding new lesions 
 
Stable disease (SD). All of the following criteria must be met: 
 
1. Does not qualify for CR, PR, or progression.  
2. All measurable and non-measurable sites must be assessed using the same techniques as 
baseline. 
3. Stable clinically. 
 
Unknown response status. Progressive disease has not been documented and one or more measurable 
or non-measurable lesions have not been assessed. 
 
Special Considerations for Immunotherapies. 
 
Appearance of new lesions is a criterion that defines progression of disease by RANO criteria. However, 
transient appearance of new enhancing lesions at either local or distant sites might occur in patients with 
neuro-oncological malignancies receiving immunotherapy. In such situations, careful radiological and 
clinical assessments are warranted. In some cases, new enhancing lesions might represent immune 
responses directed against infiltrative brain tumor cells. In addition, Immune-related response criteria 
guidelines for non-brain tumor cancers state that early increases in lesion size or new lesions do not 

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define progressive disease unless further progressive changes are confirmed upon follow-up imaging, 
provided that patients do not have a clinical decline.72  Therefore, confirmation to define progressive 
disease is an important, novel aspect of immune-related response criteria. Additionally, the converse 
argument, the need of follow-up imaging to confirm a radiographic response, has been an accepted 
component of most response assessment metrics including RANO. 
 
Confirmation of radiographic progression to define progressive disease in iRANO: 
 
• 
iRANO recommends confirmation of disease progression on follow-up imaging 3 months 
after initial radiographic progression if there is no new or substantially worsened 
neurological deficits that are not due to comorbid events or concurrent medication, and it is 6 
months or less from starting immunotherapy. 
• 
Imaging within the 3-month follow-up can be done as medically appropriate at the discretion 
of the treating clinician. 
• 
The appearance of new lesions 6 months or less from the initiation of immunotherapy alone 
does not define progressive disease. 
• 
If follow-up imaging confirms disease progression, the date of actual progression should be 
back-dated to the date of initial radiographic progression. 
 
Note on continuation of therapy pending confirmation of radiographic disease progression: iRANO 
recommends confirmation of disease progression on follow-up imaging 3 months after initial 
radiographic progression if there is no new or substantially worsened neurological deficits that are not 
due to comorbid events or concurrent medication, and it is 6 months or less from starting immunotherapy 
(see Attachment 3 for iRANO criteria details). A decision of whether a patient should continue 
immunotherapy pending confirmation of radiographic disease progression should be established based 
on perceived benefits and risks. Continuation of immunotherapy may be considered pending follow-up 
imaging as long as subjects are deriving apparent clinical benefit with minimal and acceptable toxic 
effects.  
 
By contrast, investigators may consider interrupting immunotherapy for subjects who need a substantial 
increase in corticosteroids (i.e., >4 mg of dexamethasone or equivalent per day) for evolving symptoms 
associated with brain edema or who have more than mild treatment-related toxic effects such as at least 
grade 2 irAEs. These guidelines are included to limit the likelihood of progressive immunotherapy-induced 
inflammatory changes leading to substantial deficits in otherwise stable or symptom-free patients. In such 
subjects, an interruption of immunotherapy dosing might be considered pending follow-up imaging.  
 
Furthermore, investigators may discontinue or interrupt immunotherapy at any time if this option seems to 
be in the best medical interest of the subjects. As a general guidance, resumption of immunotherapy 
might be taken into account when systemic dexamethasone is decreased to 4 mg/day or less and the 
contrast-enhancing tumor burden is classified as stable disease, partial response, or complete response 
on a follow-up scan, or when relevant treatment-related toxic effects have resolved to grade 1 or less or 
pre-treatment baseline. 
 
The iRANO Response Criteria to be used in this study are summarized in the Table below. 
 

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Summary of iRANO Response Criteria 
 
 
 
 
Note: iRANO recommends confirmation of disease progression on follow-up imaging 3 months after initial 
radiographic progression if there is no new or substantially worsened neurological deficits that are not due 
to comorbid events or concurrent medication, and it is 6 months or less from starting immunotherapy. If 
follow-up imaging confirms disease progression, the date of actual progression should be back-dated to 
the date of initial radiographic progression. The appearance of new lesions 6 months or less from the 
initiation of immunotherapy alone does not define progressive disease. FLAIR=fluid-attenuated inversion 
recovery. 
 
Note: Typographical error in the Progressive Disease definition, the correct criteria should be "increase" 
rather than "decrease". 
 

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iRANO treatment algorithm for the assessment of progressive imaging findings in 
patients with neuro-oncological malignancies undergoing immunotherapy 
 
 

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15.4 Attachment: 4 
 
Dose Modification or Discontinuation and Supportive Care Guidelines 
for Specific Drug-Related Adverse Events 
 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
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, 3 or 4.  
Grade 2  
Diarrhea: 4 to 6 stools per day 
over Baseline; IV fluids indicated 
< 24 hours; not interfering with 
ADL 
Colitis: abdominal pain; blood in 
stool  
 
Withhold avelumab 
therapy 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume avelumab therapy 
 
If persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools 
per day over Baseline; 
incontinence; IV fluids ≥ 24 h; 
interfering with ADL 
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs 
Grade 4: life-threatening, 
perforation 
Withhold avelumab for 
Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day 
prednisone IV or 
equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade ≤ 1, then taper over at 
least 1 month; resume avelumab therapy following 
steroids taper (for initial Grade 3).  
 
If worsens, persists > 3 to 5 days, or recurs after 
improvement: 
Add infliximab 5mg/kg (if no contraindication). Note: 
infliximab should not be used in cases of perforation 
or sepsis.  

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Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface 
area  
Continue avelumab 
therapy Symptomatic 
therapy (for example, 
antihistamines, topical 
steroids)  
If persists > 1 to 2 weeks or recurs:  
Withhold avelumab therapy  
Consider skin biopsy  
 
Consider 0.5-1.0 mg/kg/day prednisone or 
equivalent. Once improving, taper steroids over at 
least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume avelumab 
therapy following steroids taper. 
If worsens:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: Life threatening 
consequences  
Withhold avelumab for 
Grade 3. 
Permanently discontinue 
for Grade 4 or recurrent 
Grade 3.  
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume 
avelumab therapy following steroids taper (for initial 
Grade 3). 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider withholding 
avelumab therapy  
Monitor for symptoms 
every 2 to 3 days  
Consider Pulmonary and 
Infectious Disease 
consults  
Re-assess at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new symptoms  
Withhold avelumab 
therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤ 1, taper steroids 
over at least 1 month, and then resume avelumab 
therapy following steroids taper  
If not improving after 2 weeks or worsening:  
Treat as Grade 3 to 4.  

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prednisone or equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections  
Consider bronchoscopy, 
lung biopsy  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic 
antibiotics for opportunistic 
infections  
Consider bronchoscopy, 
lung biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month  
If not improving after 48 hours or worsening:  
Add additional immunosuppression (for example, 
infliximab, cyclophosphamide, IV immunoglobulin, 
or mycophenolate mofetil)  
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT > ULN to 
3.0 x ULN and/or Total bilirubin > 
ULN to 1.5 x ULN  
Continue avelumab 
therapy 
Continue liver function monitoring  
If worsens:  
 Treat as Grade 2 or 3 to 4.  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 
x ULN  
Withhold avelumab 
therapy 
Increase frequency of 
monitoring to every 3 
days. 
 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume avelumab 
therapy. 
If elevation persists > 5 to 7 days or worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and/or 
total bilirubin > 3 x ULN  
Permanently discontinue 
avelumab therapy  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining 
MRI/CT scan of liver and 
liver biopsy if clinically 
If returns to Grade ≤ 1:  
Taper steroids over at least 1 month  
If does not improve in > 3 to 5 days, worsens or 
rebounds:  
Add mycophenolate mofetil 1 gram (g) twice daily  
If no response within an additional 3 to 5 days, 
consider other immunosuppressants per local 
guidelines. 

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warranted  
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 
1.5 x ULN 
Continue avelumab therapy 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 
6 x ULN 
 
 
 
 
 
Withhold avelumab therapy 
Increase frequency of monitoring to 
every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤1: 
Taper steroids over at least 1 month, and 
resume avelumab therapy following steroids 
taper. 
If worsens:  
Treat as Grade 4. 
Grade 4 
Creatinine increased > 6 x ULN 
 
 
 
 
 
 
 
Permanently discontinue avelumab 
therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g. troponin, CK-
MB, BNP) or cardiac imaging 
abnormalities suggestive of 
myocarditis.  
Withhold avelumab therapy. 
Hospitalize. 
In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and 
arrhythmia management. 
Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis.  
Guideline based supportive 
treatment as per cardiology consult.* 
 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
If 
symptoms 
improve 
and 
immune-mediated etiology is ruled out, 
re-start avelumab therapy. 
 
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune-
mediated etiology is suspected or 
confirmed following cardiology consult, 
manage as immune-mediated myocarditis. 

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Immune-mediated myocarditis 
Permanently discontinue avelumab. 
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.* 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids over at 
least 1 month. 
 
If no improvement or worsening, consider 
additional immunosuppressants (e.g. 
azathioprine, cyclosporine A). 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids 
(for adrenal insufficiency) or insulin 
(for Type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression and monitoring of 
endocrine function as appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids 
(for adrenal insufficiency) or insulin 
(for type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
Resume avelumab once symptoms and/or 
laboratory tests improve to Grade ≤ 1 (with 
or without hormone 
replacement/suppression). 
 
Continue hormone 
replacement/suppression and monitoring of 
endocrine function as appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤ 1 (with 
or without hormone replacement). 
 
In addition, for hypophysitis with abnormal 

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low ACTH): 
• 
Refer to endocrinologist for 
dynamic testing as indicated 
and measurement of other 
hormones (FSH, LH, GH/IGF-
1, PRL, testosterone in men, 
estrogens in women)  
• 
Hormone 
replacement/suppressive 
therapy as appropriate  
• 
Perform pituitary MRI and 
visual field examination as 
indicated 
 
If hypophysitis confirmed: 
• 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
• 
Withhold avelumab if 
moderate, severe or life-
threatening symptoms of 
hypophysitis and/or abnormal 
MRI. Consider hospitalization. 
Initiate corticosteroids (1 to 2 
mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during at 
least 1 month. 
• 
Add prophylactic antibiotics for 
opportunistic infections. 
 
 
 
 
 
MRI, resume avelumab only once 
shrinkage of the pituitary gland on MRI/CT 
scan is documented.  
 
Continue hormone 
replacement/suppression therapy as 
appropriate. 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical 
signs or symptoms 
suggestive of a potential irAE 
Withhold avelumab therapy 
pending clinical investigation 
If irAE is ruled out, manage as appropriate 
according to the diagnosis and consider re-
starting avelumab therapy 
If irAE is confirmed, treat as Grade 2 or 3 
irAE. 
Grade 2 irAE or first 
occurrence of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent   
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month and 
resume avelumab therapy following 
steroids taper. 

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Recurrence of same Grade 3 
irAEs 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month. 
Grade 4  
 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or 
other immunosuppressant as 
needed 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult. 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
Requirement for 10 mg per 
day or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue avelumab 
therapy 
Specialty consult 
 
 
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB;  CT= computed tomography; FSH=follicle-
stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; irAE=immune related adverse event; IV=intravenous; 
LH=luteinizing hormone; MRI=magnetic resonance imaging; NCI CTCAE=National Cancer Institute Common Terminology Criteria 
for Adverse Events; PRL=prolactin;T4=thyroxine; TSH=thyroid stimulating hormone; ULN=upper limit of normal. 
 

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15.5 Attachment: 5 
 
Factors to Consider in Assessing the Relationship of AEs to 
Avelumab or Infusion Procedure, Study Procedure, or Combination 
Treatment 
 
Is there a reasonable possibility that the event may have been caused by the study drugs or infusion 
procedure, study procedure, or concomitant treatment? 
 
No: 
 
• 
due to external causes such as environmental factors or other treatment/s being administered 
• 
due to the patient’s/subject’s disease state or clinical condition 
• 
do not follow a reasonable temporal sequence following the time of administration of the dose of 
Avelumab, study procedure, or combination treatment 
• 
do not reappear or worsen when dosing with Avelumab, study procedure, or combination 
treatment is resumed 
• 
are not a known response to Avelumab or infusion procedure, study procedure, or combination 
treatment based upon pre-clinical data or prior clinical data 
 
Yes: 
 
• 
could not be explained by environmental factors or other treatment/s being administered 
• 
could not be explained by the patient’s disease state or clinical condition 
• 
follow a reasonable temporal sequence following the time of administration of the dose of 
Avelumab 
• 
resolve or improve after discontinuation of Avelumab, study procedure, or combination treatment 
• 
reappear or worsen when dosing with Avelumab, study procedure, or combination treatment is 
resumed 
• 
are known to be a response to Avelumab or the infusion procedure, study procedure, or 
combination treatment based upon pre-clinical data or prior clinical data 
 
NOTE: This list is not exhaustive. 
 

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15.6 Attachment: 6 
 
Technical Specifications and Structural Considerations for 
Planning Radiotherapy 
Technique: 
Intensity modulated radiotherapy (IMRT) via any method (e.g., VMAT, static field IMRT) or Stereotactic 
Radiotherapy (SRT) is required. Protons are permitted for institutions which have been approved and 
credentialed for protons, as protons may reduce the volume of normal tissue which will be re-irradiated. If 
protons are used, to avoid delays resulting from unplanned equipment availability, photon therapy may be 
administered instead of proton therapy.  
Every attempt must be made to obtain the original radiotherapy treatment plan in order to guide 
re-irradiation treatment planning. 
Dose Specifications 
Photons: Treatment shall consist of 25 Gy delivered in 5 fractions delivered over 5 consecutive treatment 
days. The treatments may extend over the weekend (e.g., 5 treatment days over 8 calendar days.) Target 
coverage and homogeneity limits and deviations are listed in Table A1. 
Protons - Absorbed dose: Doses are expressed in units of RBE-weighted absorbed dose, DRBE. For 
protons the RBE is taken to be 1.1. DRBE = 1.1 x D, where D represents the absorbed dose in Gy. 
Treatment shall consist of 25 Gy(RBE) delivered in 5 fractions. Target coverage and homogeneity limits 
and deviations are listed in the Table A1 below. 
Table A1: Target Coverage and Dose Limits 
Dose Metric 
Per Protocol 
Variation Acceptable 
Deviation 
Unacceptable 
Volume of PTV 
covered by the 
prescription dose of 25 
Gy photons - protons 
25 Gy(RBE) 
Greater than or equal to 
95% of the PTV should 
receive greater than or 
equal to 25 Gy photons 
-  protons 25 Gy(RBE) 
Greater than or equal to 
90% of the PTV 
receiving greater than or 
equal to 25 Gy photons 
- protons 25 Gy(RBE) 
Less than 90% of the 
PTV receiving greater 
than or equal to 25 Gy 
photons - protons 25 
Gy(RBE). Coverage 
less than 90% is 
acceptable in areas of 
OAR/PTV overlap.  
Minimum dose to the 
PTV (0.03 cc) 
Greater than or equal to 
21.25 Gy (85% of the 
prescription dose) 
photons – protons 21.25 
Gy(RBE) 
Greater than or equal to 
20 Gy (80% of the 
prescription dose) 
photons – protons 20 
Gy(RBE); Minimum 
doses of less than 20 
Gy are acceptable if 
they occur due to 
OAR/PTV overlap 
Less than 20 Gy (80% 
of the prescription 
dose) photons – 
protons 20 Gy(RBE); 
Minimum doses of less 
than 20 Gy are 
unacceptable unless 
they occur in regions of 
OAR/PTV overlap 
Maximum dose to the 
PTV (0.03 cc) 
Less than or equal to 30 
Gy (120% Rx Dose) 
Less than or equal to 
32.5 Gy (130% Rx 
Greater than 32.5 Gy 
(130% Rx Dose) 

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photons – protons 30 
Gy(RBE). For SRT, this 
represents a plan 
prescribed to the 84% 
or greater Isodose line) 
Dose) photons – 
protons 32.5 Gy(RBE). 
For SRT, this 
represents a plan 
prescribed to the 80% 
isodose line) 
photons – protons 32.5 
Gy(RBE) or an isodose 
line less than 80% for 
a radiosurgical plan) 
Technical Factors (Equipment, Energies) 
Intensity modulated radiotherapy (IMRT) via any method (e.g., VMAT, static field IMRT) or Stereotactic 
Radiotherapy (SRT) is required. Any FDA cleared external beam radiation delivery system may be used 
(including conventional linear accelerators, cyberknife systems, tomotherapy, proton therapy, etc.). 
Treatment at NYULMC will be on Varian LINAC (TrueBeam or Edge) or Eleckta Gamma Knife Perfexion 
Unit. 
Image-guided radiotherapy with cone-beam CT along with daily treatment kV/kV imaging will be 
performed daily. 
Imaging for treatment planning will be obtained with the patient in the same position and immobilization 
device as for treatment. All patients will be positioned via a combination of rigid immobilization and daily 
image guidance to ensure positioning accuracy of 3 mm or better, and of a magnitude that justifies the 
PTV margin applied. 
Localization, Simulation, and Immobilization 
MRI fusion with CT are required for treatment planning. At least 1 of these scans must be of the patient 
immobilized in treatment position, and with image resolution of no worse than 1.5 mm x 1.5 mm x 3 mm. 
MRI sequences should include axial T1 post-contrast stereotactic image (such as MP-RAGE or FSPGR 
BRAVO). Contrast may be omitted if medically indicated. Additionally, a T2 sequence (e.g., FLAIR or T2, 
preferably stereotactic, thin slice, contiguous) is helpful to identify any non-enhancing tumor. 
Immobilization must be rigid (e.g., thermoplastic masks). For daily treatment, localization will include the 
steps of a) immobilization with the same device used for simulation, and b) daily image guidance using at 
a minimum orthogonal pairs of radiographs aligned to DRRs as a computer-assisted process. Daily cone-
beam CT will be used as well. 
Treatment Planning/Target Volumes 
A GTV will be defined using the CT and MRI images. 
The GTV includes the post-operative resection cavity if no residual enhancing or non-enhancing tumor is 
noted. The GTV also includes any non-enhancing tumor as identified on T2/FLAIR. T2/FLAIR signal 
consistent with edema is not included in the GTV. Therefore a distinction is made between T2 edema 
(typically without mass effect, sparing the cortical ribbon, obeying the grey/white junction, etc.) with T2 
tumor (mass effect with sulcal effacement, involvement of the grey/white junction, obliteration of the 
cortical ribbon). Care is made to not include any enhancement or T2 signal on the post-operative scan 
that is due to post-surgical infarct. Fusion of the pre-operative MRI to determine initial extent of the tumor 
is helpful. 
A PTV expansion that is justified based on image guidance and immobilization will be applied. 
Regardless of immobilization and localization methods, the PTV expansion should be no larger than 3 
mm. Therefore, for stereotactic treatment, the PTV is typically 1 mm. For non-stereotactic treatment with 
IGRT, then the PTV is typically 3 mm. 
Critical Structures 
Normal tissues to be contoured will include the brain, brainstem, optic nerves and chiasm. Planning risk 
volume (PRV) expansions the same size as the PTV expansion (e.g. If the PTV is 3 mm, then the PRV is 
3 mm. For stereotactic machines, a PTV of 0 mm is acceptable; therefore the PTV = CTV = GTV + 5 mm 
in this instance) should be utilized for optic nerves and chiasm. 

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Special consideration should be given to avoid doses greater than the prescription dose within the scalp 
as well as limiting the exit dose through the oral cavity and mucosa. 
The treatment parameters should be modified to optimize the conformity of the prescription isodose 
volume to the target volume while minimizing dose to critical structures. OAR limits for newly diagnosed 
GBM are given in Table A2. 
Table A2: Normal Dose Limits (5 Fractions) 
Dose Metric 
Per Protocol 
Variation Acceptable 
Deviation Unacceptable 
Scenario (1): Previous radiation to the local area including critical organs at risk 
Maximum Dose (0.03 
cc) to PRV for Optic 
Nerves, Chiasm 
 
Less than or equal to 
20 Gy photons - 20 
Gy(RBE) protons 
 
Greater than 20 Gy 
but less than or equal 
to 25 Gy photons – 25 
Gy(RBE) protons 
Greater than 25 Gy 
photons - 25 Gy(RBE) 
protons 
 
Maximum Dose (0.03 
cc) to Brainstem 
Less than or equal to 
24 Gy photons - 24 
Gy(RBE) protons 
 
Greater than 24 Gy 
but less than or equal 
to 25 Gy photons – 25 
Gy(RBE) protons 
Greater than 25 Gy 
photons - 25 Gy(RBE) 
protons 
 
Scenario (2): No previous radiation to the local area or critical organs at risk 
Maximum Dose (0.03 
cc) to PRV for Optic 
Nerves, Chiasm 
 
Less than or equal to 
25 Gy (the prescription 
dose) photons - 25 
Gy(RBE) protons 
 
Greater than 25 Gy 
but less than or equal 
to 26.25 Gy (105 % of 
the prescription dose) 
photons – 26.25 
Gy(RBE) protons 
Greater than 26.25 Gy 
(105% of the prescription 
dose) photons – 26.25 
Gy(RBE) protons 
Maximum Dose (0.03 
cc) to Brainstem 
Less than or equal to 
25 Gy (the prescription 
dose) photons - 25 
Gy(RBE) protons 
 
Greater than 25 Gy 
but less than or equal 
to 26.25 Gy (105 % of 
the prescription dose) 
photons – 26.25 
Gy(RBE) protons 
Greater than 26.25 Gy 
(105% of the prescription 
dose) photons – 26.25 
Gy(RBE) protons 
Coverage of the PTV will be decreased in order to fulfill these limits. 
The optic structures (chiasm and optic nerves) are kept to <350 cGy per fraction and the brainstem is 
allowed a D05 (the dose encompassing 5% of volume) of 600 cGy per fraction so that no more than 5% 
of the brainstem receives 600 cGy per fraction. 
Radiotherapy dose constraints are based on the radiation therapy dose specifications in RTOG 1205. 
Documentation Requirements 
At the completion of treatment, the following should be forwarded to the overall Principal Investigator 
listed below. Investigators must submit the following information: 
 
Daily treatment record. 
 
Radiotherapy summary.  
 
Pre-study CT or MRI (the Scan used to delineate the target volumes for planning. Submit the 
entire series and specify which one was used for planning). 
 
Isodose distributions displayed on orthogonal planes or, if not possible, on multiple transverse 
slices through each target. 

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Data should be submitted to: 
Sylvia Kurz, MD, PhD 
Laura and Isaac Perlmutter Cancer Center 
NYU Langone Medical Center 
240 East 38th Street, 19th Floor 
New York, NY 10016

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15.7 Attachment: 7 
 
Research Biomarker/Correlative Studies: Background and Rationale 
Note: This study involves collection of required archival tumor tissue and blood specimens for research as 
well as collection of an optional tumor specimen if a biopsy is required during or after protocol therapy.  
All patients will be given the option to have leftover research specimens after study completion and 
completion of protocol-defined research studies banked for future research at the time of informed 
consent. See Section 9.1.1 for details on leftover research samples. 
 
A. Research Specimens to be Collected 
 
1. Archival tumor tissue 
 
A paraffin-embedded or frozen tumor-tissue block with a minimum of 1 cm2 of tumor surface area 
containing at least 20% viable tumor from a tissue specimen that demonstrates one of the two 
criteria specified below (also in Inclusion Criteria 4a). If a tumor block cannot be submitted, then 
20 unstained 5-micron slides from the tumor specimen must be submitted. 
 
(A) Histopathological evidence of glioblastoma (WHO grade IV) on a progressive tumor 
specimen after treatment with temozolomide or PCV chemotherapy. The diagnosis of 
glioblastoma must be confirmed on central review by a study-designated neuropathologist at 
NYU at screening.  
or 
(B) Any progressive glioma with IDH1 or IDH2 mutation, regardless of WHO grade or 
histopathological diagnosis, may be eligible contingent on approval by the overall Principal 
Investigator if the progressive tumor specimen is found to have one of the genetic alterations 
below: 
 
1. ≥20 somatic mutations per Mb by whole-exome DNA sequencing  
2. Mutation in a mismatch repair (MMR) gene or other genes known to be associated with 
hypermutator phenotypes or microsatellite instability, including but not limited to MSH2, 
MSH6, MLH1, POLE, PMS2, POLD as determined by validated methods. 
3. Microsatellite instability (MSI) as identified by polymerase chain reaction (PCR) or other 
validated methods. 
 
2. (Optional) Tumor Biopsy 
 
If subjects undergo tumor resections or biopsies during the study period after treatment initiation, 
or after progression on HFRT + Avelumab, a tumor specimen will be collected for research 
purposes. A section of frozen tumor or a FFPE block (surface area of 1 cm2 containing at least 
20% viable tumor, as described above in Section 6.8.2) from the tumor surgery is preferred.  If a 
frozen tumor specimen or a tumor block cannot be provided, then 20 unstained 5-micron slides 
(preferably 10 slides from two different tumor blocks from the same surgery) from the tumor block 
should be sent. 
 
Send all research tumor specimens (archival and optional tumor biopsy) to: 
 
Matija Snuderl, MD 

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Department of Pathology, NYU Langone Medical Center 
560 First Avenue 
Tisch Hospital HW 451 
New York, NY 10016 
Phone: 646-501-5281, Fax: 212-263-7916, Pager: 917-205-5543  
Email: Matija.Snuderl@nyumc.org 
 
3. Research Blood Samples 
 
Research blood samples will be taken at only 2 timepoints: Baseline (prior to Cycle 1, Day 1) 
and at Cycle 2, Day 1, as per the study procedures (Section 6) and the Schedule of Events, 
Attachment 1.  
 
Refer to the study Lab Manual for specific processing, handling and shipping procedures for 
research blood specimens. 
 
Research blood samples will be collected from all subjects as detailed below. 
o 
NYULMC subjects: 40 mL (four 10 mL purple top EDTA tubes) of whole blood will be 
drawn and immediately sent to the below sites: 
 
One (1) 10 mL tube will be sent to the Center for Biospecimen Research and 
Development (CBRD) at NYULMC for acquisition of whole blood, buffy coat, and 
plasma samples. 
 
Three (3) 10 mL tubes will be sent to the Immune Monitoring Core (IMC) at 
NYULMC and immediately processed for isolation of PBMCs.  
o 
Subjects at other sites:  30 mL of whole blood will be collected in two types of Streck 
tubes provided by NYULMC. All tubes will be shipped overnight to the CBRD at NYULMC 
per instructions in the Lab Manual. *Subsites should NOT schedule research blood 
draws on Fridays as the NYU CBRD will not be able to receive specimens on 
weekends. 
• 
10 mL will be drawn into one Streck Cell-Free DNA BCT® collection tube. 
 
30 mL total will be drawn into three 10 mL purple top EDTA tubes and 
immediately sent via overnight shipping to NYULMC. On arrival at NYULMC, the 
tubes will be sent immediately to the Immune Monitoring Core and immediately 
processed for isolation of PBMCs. 
All blood samples from non-NYULMC sites should be sent to the CBRD at NYULMC at the 
address below, per instructions in the Lab Manual. Research blood specimens collected from 
NYULMC subjects will be transported immediately to either the CBRD or the IMC (address below) 
as described above.  *Subsites should NOT schedule research blood draws on Fridays as 
the NYU CBRD will not be able to receive specimens on weekends. 
Center for Biospecimen Research and Development (CBRD) 
NYU Langone Medical Center 
Medical Science Building  
550 First Avenue, Berg 3rd Fl., Rm. 381 
New York, NY 10016 
CBRDResearchRequest@nyumc.org 
1 (646) 501-4268 
The Immune Monitoring Core (IMC) 
NYU Langone Medical Center  

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522 First Avenue 
Medical Science Building, MSB 367 
New York, NY 10016 
Debra.Morrison@nyumc.org 
B. Types of Planned Analyses 
 
I. Studies using Tumor Tissue Samples 
 
Whole-exome deep sequencing to assess hypermutation phenotype, estimation of 
the total mutation-associated neoantigens, and T cell receptor (TCR) diversity. 
 
RNA-Seq to assess expression of predicted mutation-associated neoantigens. 
 
Immunohistochemistry (IHC) to assess intratumoral PD-L1 expression 
 
IHC to determine tumor-infiltrating lymphocytes (TILs) 
 
II. Studies Using Blood Samples 
 
Flow cytometry for quantification of Treg and myeloid-derived suppressor cell (MDSC) 
levels 
 
Genomic DNA for paired tumor sequencing 
 
TCR deep sequencing to determine peripheral clonal T-cell expansion and TCR 
diversity 
 
Circulating tumor DNA analysis 
 
 
C. Specific Planned Analyses 
 
1. Tumor Tissue Whole-Exome Deep Sequencing 
Objectives: To assess the association between PFS6 and:  
A) Presence of temozolomide-induced hypermutation phenotype;  
B) Total predicted neoantigen load;  
C) T cell receptor (TCR) diversity 
A) Hypermutation phenotype: Patients with lower-grade IDH mutant gliomas (WHO grade II or 
III) that are treated with temozolomide or PCV chemotherapy and later proceed to have 
histopathologic transformation to GBM (WHO grade IV) nearly universally develop hypermutation 
phenotype within their tumors (see Background and Rationale, Section 1.1).  Temozolomide and 
PCV chemotherapy therapy provide selection pressure for clones that have acquired mutations in 
mismatch repair (MMR) genes which then dominate subsequent recurrences and drive 
histopathological transformation to the highest grade (GBM, WHO grade IV).  The hypermutation 
phenotype is a distinct signature consisting of mutations in MMR genes (80-90% of cases have 
MSH6 mutation) and an extremely high mutation frequency (>30 mutations per Mb in 
hypermutant versus 1-2 mutations per Mb in non-hypermutant cases) with a striking 
preponderance of C:G>T:A transitions at CpC dinucleotides.27,33,34  Non-hypermutant progressive 
IDH tumors typically harbor 30-80 nonsynonymous mutations, whereas hypermutant IDH mutant 
GBMs typically harbor between 1,000 - 3,000 nonsynonymous mutations.27,29,34  Notably, these 

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cases are not detectable using a standard five reference panel of microsatellite instability (MSI) 
markers recommended by the NCI.35  
We will compare the association of hypermutation phenotype between tumors that achieve PFS6 
and those that do not.  We will analyze archival transformed GBM tissue from all patients with 
whole-exome deep sequencing and define hypermutation as ≥20 somatic, nonsynonymous 
mutations per Mb with a concomitant preference for C:G>T:A transitions at CpC dinucleotides.  If 
enough archival tumor material is available, we will examine the clonality of hypermutated tumors 
through whole-exome sequencing of multiple spatially distinct tumor samples. If feasible, we will 
assess whether achieving PFS6 is impacted by whether hypermutation occurs subclonally or 
constitutes the majority of the recurrent tumor. 
B) Total predicted neoantigen load: We will compare the potential mutation-associated 
neoantigen load between tumors that achieve PFS6 and those that do not.  Using somatic exome 
data, we will assess the hypermutant cases for their immunogenic potential in the context of each 
patient's major histocompatibility complex (MHC) haplotype.  To assess the potential for mutant 
peptide binding, somatic exome data combined with each individual patient’s class I HLA 
haplotype will be applied to an epitope prediction algorithm,89,90 which provides an estimate of the 
total number of mutation-associated neoantigens in each tumor.  
C) T cell receptor (TCR) diversity:  One strategy to reverse the suppression of tumor immune 
responses involves the use of radiation therapy (RT), which has been shown to augment anti-
cancer immune responses and enhance the efficacy of immune therapies in systemic cancer 
preclinical models and patients.43-49  Preclinical studies examining combined radiotherapy and 
checkpoint inhibition indicate that each activate mostly non-redundant immune stimulating 
mechanisms and the major contribution of radiotherapy appears to be increasing T-cell receptor 
(TCR) diversity.48 RT induces major histocompatibility complex (MHC) class I presentation, 
increases antigen presentation, and increases cytotoxic T cell (CTL) recognition of irradiated 
cells50,51 and enhances the diversity of the TCR repertoire of the expanded peripheral T cell 
clones.48   
We will characterize the baseline pre-treatment intratumoral TCR diversity and use intratumoral 
TCR diversity data (e.g., the top 100 most frequent intratumoral TCR clonotypes) to examine 
TCR clonotype frequencies in pre-treatment (Baseline) and post-treatment (C2D1, 29 days post-
initiation of Avelumab and 21 days after completion of HFRT) blood samples.  Using combined 
tumor tissue and pre-treatment (baseline) blood, we will generate whole-exome sequencing data 
and analyze frequencies/counts of TCR clonotypes to estimate the TCR diversity.  The 
Shannon’s diversity index (DI)91 normalized to the number of reads (DI= –Σ(piln pi)/ln n, where n 
is the number of clones, pi is the clonal frequency of the ith clone, and sigma is summed from i = 
1 to i = n) was calculated for each sample. This gives a value between 0 and 1, where 0 is 
monoclonal and 1 is an even distribution of different clones. 
If Post-treatment tumor tissue is available: Additionally, if patients undergo tumor resections or 
biopsies during study therapy or after progression on HFRT + Avelumab, we will whole-exome 
sequence multiple spatially distinct regions, if possible, of the progressive tumor to determine 
whether alterations in the clonal hypermutation distribution, TCR clonotype distribution or 
predicted neoantigens have occurred. 
 
2. Tumor Tissue RNA-Seq 
Objective: To use tumor tissue RNA-Seq data to evaluate the fraction of predicted mutation-
associated neoantigens derived from somatic whole-exome sequencing data that is expressed 
and assess the association of PFS6 and number of expressed mutation-associated neoantigens. 

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Expression of predicted mutation-associated neoantigens:  We will estimate the proportion of 
predicted mutation-associated neoantigens that are expressed by RNA-Seq and compare the 
expressed predicted mutation-associated neoantigen load between tumors that achieve PFS6 
and those that do not.  Total RNA will be extracted from FFPE tumor tissue using RNA extraction 
kits, treated to remove genomic DNA, quantified, and analyzed for integrity. RNA-Seq libraries will 
be prepared using standard protocols to purify poly-adenylated mRNA, generate double-stranded 
cDNA and ligate adapters and then submitted for next-generation sequencing 
Clonality of mutation-associated expressed neoantigens: If enough tumor tissue is 
available to assess distinct regions of an individual tumor, we will perform RNA-Seq 
analyses on different regions of each tumor to assess the clonality of expressed 
neoantigens. 
 
3. Tumor Tissue Immunohistochemistry (IHC) 
Objectives:  To assess the association of PFS6 and:  
A) Tumor tissue PD-L1 expression, 
B) baseline density and subtype of TIL populations.  
A) Tumor cell programmed death-ligand 1 (PD-L1) expression:  We will assess the 
association of PFS6 with baseline membranous and diffuse tumor cell PD-L1 expression.  Tumor 
PD-L1 has been associated with response to PD-1 inhibitor therapy in studies of other solid 
cancers (see Rationale and Background, Section 1.1) however the association of tumor tissue 
PD-L1 expression and response to anti-PD-1 or anti-PD-L1 therapy is unknown.  
IHC staining of paraffin-embedded sections for PD-L1 will be performed on archived formalin-
fixed paraffin-embedded archival tumor specimens as previously described.15  The IHC assay for 
PD-L1 will incorporate an anti–PD-L1 rabbit monoclonal antibody (clone 28-8), which was 
developed on an automated platform by Dako North America. Consecutive sections will be 
stained for PD-L1 and a negative control reagent to control for nonspecific staining. A sample will 
be deemed PD-L1 positive for membranous staining if ≥5% of tumor cells, in a minimum of 100 
evaluable tumor cells, have observable PD-L1–positive staining at any intensity. Specificity of the 
28-8 antibody clone has been extensively validated previously.15 
In addition, we will explore the association of Treg (CD4+CD25+FoxP3+) levels in tumor tissue and 
in circulation at baseline.  Circulating Treg levels will be quantified as below, and tumor tissues will 
be stained for CD4 and FoxP3 to assess infiltrating Tregs.  
B) Tumor Infiltrating lymphocytes (TILs):  We will assess the density and subtype of TILs in 
baseline pre-treatment FFPE tumor tissue by IHC using markers such as CD3, CD4, CD8, CD56, 
FoxP3, and PD-1. 
If Post-treatment tumor tissue is available: Additionally, if patients undergo tumor resections or 
biopsies during study therapy or after progression on HFRT + Avelumab, we will assess for 
changes in tumor tissue PD-L1 expression and TIL density and subtype after treatment with 
Avelumab + HFRT. 
 
4. Peripheral Blood Flow Cytometry 
Objectives:  To assess the association of PFS6 and baseline level of Tregs or MDSCs within 
PBMCs or their change at 4 weeks from Avelumab initiation 

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Circulating Tregs and MDSCs in PBMCs: We will test whether the baseline level of circulating 
regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs) within peripheral blood 
mononuclear cells (PBMCs) or their change at 4 weeks from Avelumab initiation (C2D1, also 21 
days after completion of HFRT) are associated with PFS6.  In GBM patients, Treg and MDSC 
populations have been reported to facilitate tumor immune evasion.  Tregs have been found an 
increased fraction of the circulating CD4 compartment in GBM patients and correlates with 
proliferative defects among CD4+ T cells.92  MDSCs are a heterogeneous group of immature 
myeloid-derived cells that are capable of suppressing the immune system and are increased in 
the blood and tumor tissue of patients with various tumors.  Recently, MDSCs were found to be 
increased in the blood of GBM patients compare to healthy controls, while a subset of MDSCs 
[polymorphonuclear MDSCs (PMN-MDSCs)] were highly prevalent in GBM tumor tissue.93 
All subjects will have research blood drawn at baseline and 4 weeks post-Avelumab initiation for 
flow cytometry studies. 30 mL of (EDTA purple top tube) whole blood will be drawn and 
immediately processed at the study sites using Ficoll technique for isolation of PBMCs. 
Processed study samples will be frozen and stored until shipment to NYULMC for analysis. In 
melanoma patients treated with nivolumab, Tregs decreased in responders and stable patients and 
significantly increased in non-responders at 12 weeks.15  At the Immune Monitoring Core at 
NYULMC, PBMCs will be thawed and analyzed by flow cytometry.  Functional and phenotypic 
markers of T cells will be evaluated by flow cytometry using antibodies from BD Biosciences, 
except where indicated.  PBMCs will then be stained with Live/Dead violet dye (Invitrogen) to 
gate on live cells.  Then, cells will be assessed for expression of CD45, CD3, CD4, CD8, PD-1 
(MIH4 from eBioscience), and CTLA-4.  
Tregs will be defined as cells with CD4+CD25+CD127lowFoxP3+ (eBioscience). MDSCs will be 
defined as MHC class II negative, CD33+, CD15+ cells as previously described.93  Cells will be 
assessed for expression of CD33, HLA-DR, -DP, -DQ and CD15 (Becton Dickinson).  Data will be 
acquired on an LSR II flow cytometer (BD Biosciences) and analyzed with Flowjo software 
(TreeStar).   
 
5. Peripheral Blood Deep Sequencing 
Objectives: Peripheral blood will be collected for deep sequencing for the purposes of: 
A) Sequencing normal (germline) DNA to identify tumor somatic mutations 
B) Assessing for alterations in TCR clonotype frequencies in pre-treatment and post-
treatment blood,  
C) Exploring the potential of identifying circulating tumor DNA in patients with IDH 
mutant gliomas. 
B) TCR clonotype frequencies (All subjects):  We will determine whether treatment with HFRT 
and Avelumab results in peripheral expansion of TCR clonotypes found in TIL clones identified by 
tumor tissue whole-exome sequencing and alters the TCR repertoire of the most expanded TCR 
clonotypes. Previous studies indicate radiotherapy and immune checkpoint inhibition activate 
non-redundant immune mechanisms and the major contribution of radiotherapy may be 
increasing TCR diversity and shaping the TCR repertoire of the expanded peripheral T cell 
clones.48  DNA will be extracted from peripheral blood cells and analyzed with whole-exome deep 
sequencing to analyze frequencies/counts of the top 100 most frequent TCR clonotypes identified 
in baseline tumor tissue. 
C) Circulating tumor DNA in patients with IDH mutant gliomas: In nearly all cases that have 
been reported, the mutant IDH allele is ubiquitous throughout the tumor mass. In addition, in 
nearly every case reported in gliomas the mutant IDH allele is heterozygous with the wildtype 
allele and genetic amplification has never been reported. Therefore, the mutant IDH allele 
represents an attractive diagnostic and pharmacodynamic biomarker.  We will sequence cell-free 

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fractions of blood to high depths to attempt to detect circulating mutant IDH allele and also 
attempt to compare the changes in the allele fraction between baseline and post-treatment blood. 
All subjects will have research blood drawn at baseline and 4 weeks post-Avelumab initiation 
(C2D1, 29 days post-initiation of Avelumab and 21 days after completion of HFRT). 10 mL of 
whole blood in EDTA tubes (purple top tubes) will be drawn at each timepoint and processed 
according to the study Lab Manual. From the whole blood sample, a 1mL aliquot will be 
immediately taken and frozen separately in a cryovial.  The remaining sample will be spun to 
separate the plasma, buffy coat, and cells.  The buffy coat and plasma will each be separated 
and placed in cyrovials for freezing. Samples will be batch-shipped to the NYULMC Center for 
Biospecimen Research and Development (CBRD).  DNA will be extracted and analyzed with 
whole-exome deep sequencing to analyze frequencies/counts of the top 100 most frequent TCR 
clonotypes identified in baseline tumor tissue. 
 
Statistical Considerations for Correlative Studies 
Correlative biomarker endpoints are exploratory and hypothesis generating. The correlative 
studies are not powered to make a formal test of the prognostic power of any biomarker.  We will 
use non-parametric statistics (e.g. Wilcoxon, Spearman's rank correlation coefficient, Fisher's 
Exact text) to test the association between presence of temozolomide-induced hypermutation and 
PFS6 as well as the fraction of predicted mutation-associated neoantigens, fraction of expressed 
mutation-associated neoantigens, and levels of tumor-infiltrating immune populations identified by 
RNA-Seq between patients that achieve PFS6 and those that do not.  
For the circulating Treg and MDSC biomarker study, we summarize the distributions of levels at 
baseline and changes from baseline at Day 35 using descriptive statistics and graphical displays. 
Changes from baseline will be examined using Wilcoxon signed rank tests for paired 
measurements. Logistic regression will be used to predict PFS6 (binary) based on baseline levels 
and the changes from baseline.  Optimal cutpoints for changes from baseline will be estimated for 
the separation of those patients who are alive and free of progression at 6 months compared to 
those who are not using the Youden Index based on the receiver operating characteristic curve.  
For the tumor tissue PD-L1 and TIL assays, we will use similar descriptive analyses and 
summary displays to assess whether expression of PD-L1 is associated with PFS6. Additional 
analyses will combine all of these key biomarkers in logistic models to identify potential 
combinations of markers to predict PFS6.