Clinical trial NCT03000179
Conditions: Adenocarcinoma
Keywords: small bowel cancer, small bowel carcinoma
Sponsor: Vanderbilt-Ingram Cancer Center
Start date: 2017-03-03; Completion date: 2021-08-03
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-agent, open label, one-arm phase 2 pilot study of avelumab in patients with advanced or metastatic adenocarcinoma of the small intestine.

Detailed description:
Primary Objectives

* To describe any antitumor activity of avelumab monotherapy, as measured by the response rate in patients with advanced or metastatic small intestinal adenocarcinoma.
* To describe the safety profile of avelumab monotherapy in patients with advanced or metastatic small intestinal adenocarcinoma.

Secondary Objectives

* To determine overall survival, progression-free survival, and duration of response of avelumab monotherapy in patients with advanced small intestinal adenocarcinoma.
* To evaluate the association of tumor PD-L1 and PD-1 expression, MSI status, lymphocytic infiltration, and somatic mutation burden with response.

Arms: arm 1: Participants receive avelumab by IV infusion following pretreatment with H1 blockers and acetaminophen once every 2 weeks.
Interventions: intervention 1: Avelumab
Intervention descriptions: intervention 1: Avelumab through a vein once every 2 weeks

Protocol documents:
Prot_SAP_000.pdf: 
A Pilot Study to Investigate the Safety and Efficacy of  
Avelumab Monotherapy in Patients with  
Advanced or Metastatic Adenocarcinoma of the Small Intestine 
VICC GI 1679 
Principal Investigator 
Dana B. Cardin, MD 
Vanderbilt University Medical Center 
777 Preston Research Building 
2220 Pierce Ave 
Nashville, TN 37232 
Telephone: 615-936-8422 
Fax: 615-875-0040 
dana.cardin@vanderbilt.edu 
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TABLE of CONTENTS 
1.  SYNOPSIS .......................................................................................................................... 5 
2.  STUDY DESIGN .................................................................................................................. 6 
2.1.  SUMMARY ........................................................................................................................................ 6 
2.2.  SCIENTIFIC RATIONALE AND HYPOTHESIS ................................................................................................ 6 
2.3.  TREATMENT AND DOSE RATIONALE ....................................................................................................... 7 
3.  OBJECTIVES ....................................................................................................................... 7 
3.1.  PRIMARY OBJECTIVES.......................................................................................................................... 7 
3.2.  SECONDARY OBJECTIVES...................................................................................................................... 7 
4.  BACKGROUND .................................................................................................................. 8 
4.1.  SMALL INTESTINAL ADENOCARCINOMA .................................................................................................. 8 
4.2.  PD-L1 .............................................................................................................................................. 9 
4.3.  CORRELATIVE SCIENCE ........................................................................................................................ 9 
4.4.  AVELUMAB ..................................................................................................................................... 12 
4.5.  CLINICAL EXPERIENCE WITH AVELUMAB:  SAFETY AND PRELIMINARY EFFICACY ........................................... 13 
5.  PARTICIPANT SELECTION ................................................................................................. 15 
5.1.  ALLOCATION OF SLOTS TO STUDY SITES ................................................................................................ 15 
5.2.  INCLUSION CRITERIA ......................................................................................................................... 15 
5.3.  EXCLUSION CRITERIA......................................................................................................................... 16 
5.4.  INCLUSION OF UNDERREPRESENTED POPULATIONS ................................................................................ 19 
5.5.  NUMBER OF PATIENTS AND REPLACEMENT OF PATIENTS WHO DISCONTINUE EARLY ................................... 19 
6.  REGISTRATION PROCEDURES .......................................................................................... 19 
6.1.  REGISTRATION ................................................................................................................................. 19 
7.  SCHEDULE OF ASSESSMENTS ........................................................................................... 21 
7.1.  STUDY CALENDAR ............................................................................................................................ 21 
7.2.  SCREENING VISIT ASSESSMENTS.......................................................................................................... 23 
7.3.  CYCLE 1, DAY 1 ASSESSMENTS ........................................................................................................... 24 
7.4.  ADDITIONAL CYCLES ASSESSMENTS ..................................................................................................... 24 
7.5.  END-OF-TREATMENT / WITHDRAWAL ASSESSMENTS ............................................................................. 25 
7.6.  FOLLOW-UP VISIT ASSESSMENTS (30-DAY AND 90-DAY) ....................................................................... 25 
7.7.  SURVIVAL FOLLOW-UP ...................................................................................................................... 26 
8.  STUDY PROCEDURES ....................................................................................................... 26 
8.1.  MEDICAL HISTORY ............................................................................................................................ 26 
8.2.  PHYSICAL EXAMINATION .................................................................................................................... 26 
8.3.  EXTENT OF DISEASE ASSESSMENT ....................................................................................................... 26 


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8.4.  COMPLETE BLOOD COUNT ................................................................................................................. 27 
8.5.  BLOOD CHEMISTRY ........................................................................................................................... 27 
8.6.  SERUM PREGNANCY TEST .................................................................................................................. 27 
8.7.  ARCHIVAL AND OPTIONAL FRESH TUMOR SAMPLES ............................................................................... 27 
9.  STUDY TREATMENT......................................................................................................... 28 
9.1.  INFUSION PREMEDICATIONS ............................................................................................................... 28 
9.2  AVELUMAB INFUSION ........................................................................................................................ 28 
9.3.  DURATION OF STUDY TREATMENT ...................................................................................................... 29 
9.4.  DISCONTINUATION OF STUDY TREATMENT ........................................................................................... 29 
9.5.  DURATION OF FOLLOW-UP ................................................................................................................ 30 
9.6.  WITHDRAWAL FROM STUDY .............................................................................................................. 30 
9.7.  TREATMENT AFTER INITIAL EVIDENCE OF RADIOLOGIC DISEASE PROGRESSION ........................................... 30 
10.  CONCOMITANT TREATMENT ......................................................................................... 32 
10.1.  SUPPORTIVE CARE GUIDELINES ......................................................................................................... 32 
10.2.  PROHIBITED AND/OR RESTRICTED MEDICATIONS AND THERAPIES .......................................................... 33 
10.3.  CLARIFICATIONS ABOUT STEROID USE ................................................................................................ 33 
10.4.  HEMATOPOIETIC GROWTH FACTORS AND TRANSFUSIONAL SUPPORT ...................................................... 34 
10.5.  CONCOMITANT RADIOTHERAPY ........................................................................................................ 34 
11.  ADVERSE EVENT MANAGEMENT ................................................................................... 35 
11.1.  CRITERIA FOR HOLDING TREATMENT FOR ADVERSE EVENT POSSIBLY RELATED TO AVELUMAB..................... 35 
11.2.  CRITERIA FOR RESUMING TREATMENT HELD FOR ADVERSE EVENT RELATED TO AVELUMAB ........................ 36 
11.3.  GUIDELINES FOR THE MANAGEMENT OF INFUSION REACTION ................................................................ 37 
11.4.  MANAGEMENT OF SEVERE HYPERSENSITIVITY REACTION AND FLU-LIKE SYMPTOMS .................................. 38 
11.5.  MANAGEMENT OF TUMOR LYSIS SYNDROME ...................................................................................... 39 
11.6.  MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS (IRAES) ........................................................... 39 
12.  DRUG FORMULATION, SUPPLY AND STORAGE ............................................................... 47 
12.1.  DESCRIPTION OF AVELUMAB ............................................................................................................ 48 
12.2.  PACKAGING AND LABELING OF AVELUMAB ......................................................................................... 48 
12.3.  STORAGE OF AVELUMAB ................................................................................................................. 48 
12.4.  ACCOUNTABILITY OF AVELUMAB ....................................................................................................... 48 
13.  MEASUREMENT OF EFFECT............................................................................................ 49 
13.1.  DEFINITIONS .................................................................................................................................. 49 
13.2.  DISEASE PARAMETERS ..................................................................................................................... 49 
13.3.  RESPONSE CRITERIA ........................................................................................................................ 52 
13.4.  DURATION OF RESPONSE ................................................................................................................. 53 
13.5.  IMMUNE-RELATED RESPONSE CRITERIA ............................................................................................. 54 
13.6.  RESPONSE REVIEW AND CENTRAL TUMOR ASSESSMENTS...................................................................... 55 


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14.  SAFETY REPORTING OF ADVERSE EVENTS ...................................................................... 56 
14.1.  GENERAL ...................................................................................................................................... 56 
14.2.  RISKS ASSOCIATED WITH AVELUMAB ................................................................................................. 57 
14.3.  SAFETY PARAMETERS AND DEFINITIONS ............................................................................................. 57 
14.4.  ASSESSMENT OF ADVERSE EVENTS .................................................................................................... 58 
14.5.  REPORTING PROCEDURES ................................................................................................................ 59 
15.  DATA SAFETY AND MONITORING .................................................................................. 65 
15.1.  DATA MANAGEMENT AND REPORTING .............................................................................................. 65 
15.2.  MEETINGS .................................................................................................................................... 66 
15.3.  MONITORING ................................................................................................................................ 66 
15.4.  DATA HANDLING AND RECORD KEEPING ............................................................................................ 67 
16.  REGULATORY CONSIDERATIONS .................................................................................... 68 
16.1.  PRE-STUDY DOCUMENTATION ......................................................................................................... 68 
16.2.  PROTOCOL REVIEW AND AMENDMENTS............................................................................................. 68 
16.3.  INFORMED CONSENT ...................................................................................................................... 69 
16.4.  ETHICS AND GCP ........................................................................................................................... 69 
16.5.  CONFIDENTIALITY ........................................................................................................................... 70 
16.6.  RECORDS RETENTION ...................................................................................................................... 70 
16.7.  STUDY TERMINATION ...................................................................................................................... 70 
17.  STATISTICAL CONSIDERATIONS ..................................................................................... 70 
17.1.  STUDY DESIGN / ENDPOINTS ............................................................................................................ 70 
17.2.  SAMPLE SIZE / ACCRUAL RATE.......................................................................................................... 71 
17.3.  STATISTICAL ANALYSIS PLAN ............................................................................................................ 71 
17.4.  REPORTING AND EXCLUSIONS ........................................................................................................... 72 
18.  REFERENCES .................................................................................................................. 72 
APPENDIX 1 ......................................................................................................................... 75 
APPENDIX 2 ......................................................................................................................... 79 
APPENDIX 3 ......................................................................................................................... 81 
APPENDIX 4 ......................................................................................................................... 82 
APPENDIX 5 ......................................................................................................................... 84 
 
 
 
 
 


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1.  SYNOPSIS 
 
Sponsor 
Vanderbilt University Medical Center 
Protocol Title 
A Pilot Study Investigating the Safety and Efficacy of  
Avelumab Monotherapy in Patients with 
Advanced or Metastatic Adenocarcinoma of the Small Intestine. 
Protocol Number 
VICC LOI 16001 
Phase of Development 
Phase 2 pilot study 
Investigational Product and 
Mechanism 
Avelumab (MSB0010718C), a fully human IgG1 antibody directed against 
the programmed death ligand 1 (PD-L1). 
Treatment Schedule 
10 mg/kg avelumab, as 1-hour intravenous (IV) infusion every 2 weeks 
(Q2W).  
Objectives 
Primary Objective 
• 
To describe any antitumor activity of avelumab monotherapy, as 
measured by the response rate in patients with advanced or 
metastatic small intestinal adenocarcinoma. 
• 
To describe the safety profile of avelumab monotherapy in patients 
with advanced or metastatic small intestinal adenocarcinoma. 
Secondary Objectives 
• 
To determine overall survival, progression-free survival, and 
duration of response of avelumab monotherapy in patients with 
advanced small intestinal adenocarcinoma. 
• 
To evaluate the association of tumor PD-L1 and PD-1 expression, 
MSI status, lymphocytic infiltration, and somatic mutation burden 
with response. 
Trial Design 
This is a single-agent, open label, one-arm phase 2 pilot study of avelumab 
in patients with advanced or metastatic adenocarcinoma of the small 
intestine. 
Estimated Number of Patients 
This investigator-initiated study intends single-site enrollment limited to 
patients at Vanderbilt University Medical Center.  About 25 patients 
evaluable for disease response are anticipated to enroll in about 30 
months. 
Length of Study 
It is intended that patients will be treated until disease progression or 
intolerable toxicity. 
Investigational Product 
Dose/Route/Regimen 
Treatment will consist of Cycles lasting 2 weeks (14 days) each.  
Investigational avelumab will be provided by EMD Serono Research & 
Development Institute, Inc.  Patients will be treated with 10 mg/kg 
avelumab once every 2 weeks (Q2W), which is identical to the dose 
regimen presented in the 2015 American Society of Clinical Oncology 
(ASCO) abstract1 of the avelumab phase I study in advanced solid tumors 
(NCT01772004). 
Study Assessments 
See the Schedule of Assessments in Section 7. 
 
 


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2.  STUDY DESIGN 
2.1.  Summary 
 
This is a single-agent, open label, one-arm, single-institution phase 2 pilot study of avelumab in 
patients with advanced or metastatic adenocarcinoma of the small intestine. 
 
Avelumab (also referred to as MSB0010718C) is a fully human IgG1 antibody directed against the 
programmed death ligand 1 (PD-L1).  Avelumab binds to PD-L1 and blocks the interaction between 
PD-L1 and its receptor PD-1.  Antibody-mediated binding of PD-L1 by avelumab removes the 
suppressive association of the PD-L1 ligand with the PD-1 receptor expressed by anti-tumor CD8+ T 
cells, thus restoring a cytotoxic T cell response. 
 
Our laboratories demonstrated PD-1 and PD-L1 expression in a significant percentage of small 
bowel adenocarcinomas (85% and 45%, respectively).  Additionally, there are a significant number 
of patients with MSI-high phenotype as well as high levels of CD3+, CD4+ and CD8+ T cells.  
Therefore, we propose a pilot study to evaluate the efficacy of the anti-PD-L1 antibody avelumab, 
in patients with advanced small intestinal adenocarcinoma who have received any number of prior 
chemotherapeutic regimens or who have recurrent disease. 
 
Because of the known role of PD-L1 in the suppression of T cell responses and the strong 
correlation between PD-L1 expression and prognosis in cancer, antibody-mediated therapeutic 
blockade of the PD-L1/PD-1 interaction presents a promising strategy for oncologic 
immunotherapy. 
 
2.2.  Scientific Rationale and Hypothesis 
 
We recently presented preliminary data (see Section 4.3 for additional detail) at the 2016 
Gastrointestinal Cancers Symposium suggesting that small intestinal adenocarcinomas might 
benefit from a programmed death 1 (PD-1) pathway inhibitor.2  Immunohistochemistry (IHC) for 
the expression of PD-L1 and PD-1 was performed on archived tissue samples of small intestinal 
adenocarcinomas.  We observed strong PD-L1 expression in 12 of the 26 cases (46%), which is 
similar to a previous study reporting strong PD-L1 staining in 50% of their small intestinal 
adenocarcinoma cohort.3    
 
All tumor samples with strong PD-L1 expression also had tumor surrounding lymphocytes, 
lymphoid aggregates, and tumor infiltrating lymphocytes (TILs) that expressed PD-1.  These results 
suggest that PD-L1 and PD-1 are expressed in a majority of small intestinal adenocarcinomas, and 
that inhibition of PD-L1 might be an attractive treatment option for this patient population where 
effective therapeutic options for advanced disease are limited.  
 
Based on the data suggesting approximately 50% of small intestinal adenocarcinomas exhibit 
strong expression of PD-L1, we propose a pilot study to evaluate efficacy of the PD-L1 antibody 
avelumab in patients with advanced or metastatic small intestinal adenocarcinoma who have 
received any number of prior chemotherapeutic regimens or who have recurrent disease.   
 


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This study will focus on the antitumor activity as measured by response rate, as well as describe the 
safety profile of avelumab monotherapy in this patient population.  Secondary objectives include 
the determination of overall survival and progression-free survival in this population.  Available 
tumor tissue from an archival block or from a medically safe fresh biopsy will be required for study 
entry.  PD-L1 expression levels using immunohistochemistry will be prospectively correlated with 
clinical benefit from avelumab. Microsatellite instability (MSI) status and lymphocyte infiltration 
analysis will also be prospectively correlated with clinical benefit. 
 
It is hypothesized that avelumab monotherapy in patients with advanced or metastatic small 
intestinal adenocarcinoma will be safe and that observed clinical response to avelumab in patients 
with advanced small intestinal adenocarcinoma will not be inferior to standard-of-care 
chemotherapy regimens. 
 
2.3.  Treatment and Dose Rationale 
 
Investigational avelumab will be provided by EMD Serono Research & Development Institute, Inc.   
 
Treatment will consist of cycles lasting 14 days (2 weeks).  Each patient will be treated with 10 
mg/kg avelumab, administered as 1-hour intravenous (IV) infusion once every two weeks (Q2W). 
 
As additionally addressed below in Section 4.5, based on pharmacokinetic, pharmacodynamic, 
receptor occupancy, and preliminary clinical safety and efficacy data, biweekly 10 mg/kg is the 
recommended dose administered to more than 480 patients in the ongoing dose-expansion phase 
of study EMR 100070-001 (NCT01772004):  A Phase I, Open-label, Multiple-ascending Dose Trial to 
Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of Avelumab 
(MSB0010718C) in Subjects With Metastatic or Locally Advanced Solid Tumors and Expansion to 
Selected Indications. 
 
Avelumab will be administered on Day 1 of each cycle after all assessments and procedures have 
been completed as described in the Schedule of Assessments table (Section 7).  In general, it 
intended that patients will be treated until disease progression or intolerable toxicity.  
  
3.  OBJECTIVES 
3.1.  Primary Objectives 
• To describe any antitumor activity of avelumab monotherapy, as measured by the response rate 
in patients with advanced or metastatic small intestinal adenocarcinoma. 
• To describe the safety profile of avelumab monotherapy in patients with advanced or metastatic 
small intestinal adenocarcinoma. 
 
3.2.  Secondary Objectives 
• To determine overall survival, progression-free survival, and duration of response of avelumab 
monotherapy in patients with advanced small intestinal adenocarcinoma. 
• To evaluate the association of tumor PD-L1 and PD-1 expression, MSI status, lymphocytic 
infiltration, and somatic mutation burden with response. 
 


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4.  BACKGROUND 
4.1.  Small Intestinal Adenocarcinoma 
 
Although the small intestine makes up about 75% of the length of the digestive tract and 90% of its 
mucosal surface area, cancer of the small intestine is rare, representing only 5% of all 
gastrointestinal cancers.4  However, according to the United States National Cancer Database, the 
incidence of small intestinal cancers has approximately doubled since the 1970s.5  In the small 
intestine, four histological types of cancers predominate:  adenocarcinomas, neuroendocrine 
tumors, gastrointestinal stromal tumors, and lymphomas.  This clinical trial will focus on 
adenocarcinoma of the small intestine. 
 
Small intestinal adenocarcinoma represents approximately one-third of all small intestinal cancers, 
and it was estimated that approximately 3,200 new cases would be diagnosed in the United States 
in 2015.6  Adenocarcinomas are found throughout the entire small intestine, however more than 
half are located in the duodenum.5,7  Due to the rarity of the disease and anatomical proximity to 
the large bowel, small intestinal adenocarcinomas are frequently grouped with, and thus often 
treated like, large intestinal adenocarcinomas.  However, small intestinal cancers have a very 
different microenvironment compared to large intestinal cancers and will thus most likely respond 
differently to the same therapies thus potentially lowering the efficacy of these treatments. 
 
Patients presenting with localized disease are treated with complete resection of the primary 
tumor with locoregional lymph node resection.  However, due to nonspecificity of symptoms at 
presentation, a majority of the patients are diagnosed with advanced disease, where 5-year 
survival drops from 65% at stage I to 4% for stage IV.8  Furthermore, a study observed that 37% of 
patients with primary tumor resection experienced recurrent disease with a median time to 
recurrence of 1.3 years, and a majority of patients with recurrent disease had distant metastasis.9 
 
Systemic chemotherapy is regarded as the standard treatment option for patients with metastatic 
or recurrent disease despite the lack of prospective, randomized trials evaluating the role of 
palliative chemotherapy for the treatment of this patient population.  A combined analysis of 
several retrospective studies observed a median overall survival of 13 months for patients receiving 
systemic chemotherapy, versus 4 months in those patients treated with best-supportive care 
alone.10  Three prospective studies using three different regimens, all with oxaliplatin as the 
backbone chemotherapy, observed response rates of 39%-50% and median overall survival of 12.7-
20.4 months.11-13  As a second line therapy, FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) was 
shown to have a disease control rate of 52% though response rate was only 20% and median 
progression-free survival was 3.2 months.14 
 
Despite the observed survival advantage, the published studies are not randomized prospective 
trials and suffer from small, heterogeneous patient populations and selection bias.  Additionally, 
the role of targeted agents, such as the anti-EGFR therapies commonly used in colorectal cancer, 
has not been established for the treatment of small intestinal adenocarcinomas.  Furthermore, no 
approved therapies exist, as large-scale phase III studies are problematic due to the rarity of the 
disease.  Exploring innovative clinical trial designs with novel treatment strategies is therefore vital 
to improve clinical outcomes for patients with adenocarcinomas of the small intestine. 
 


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4.2.  PD-L1 
The PD-1 receptor is expressed on activated CD4+ and CD8+ T cells.  By interaction with its ligands, 
PD-L1 and PD-L2, PD-1 delivers a series of strong inhibitory signals through its cytoplasmic tail to 
inhibit T cell functions.15-17  PD-L1 (also called B7-H1 and CD274) can be detected on resting and 
activated T cells, B cells, macrophages, dendritic cells, and mast cells; and PD-L1 expression is 
greatly up-regulated after activation or interferon treatment.16  Numerous results from in vitro 
cellular assays have demonstrated that blockade of the PD-1/PD-L1 interaction enhances T cell 
responses, such as increases in proliferation and cytokine production.18-24  In PD-1–/– mice both T 
and/or B cells responses are unregulated resulting in an array of autoimmune pathologies.25,26  
Breaking tolerance via blocking PD-1 interaction with its ligands, and thus PD-1 signaling, can be 
applied to enhance T cell activity towards chronic pathologies such as cancer.27   
 
Immunohistochemistry studies26 have demonstrated that PD-L1 is also expressed by a variety of 
human tumors, both by the tumor cells, as well as by the immune cells that are present in the 
tumor microenvironment.  In contrast to very strong expression on syncytiotrophoblasts in the 
placenta and in cancer cells, low levels of PD-L1 expression were detected in some normal tissues 
including fetal cardiac tissue.20  High levels of PD-L1 expression have been found to be associated 
with disease progression, increased metastasis, poor response to treatment, and decreased 
survival in a number of human cancers.26  Importantly anti-PD-L1 blockade has demonstrated 
therapeutic efficacy in a variety of murine tumor models as monotherapy and has shown 
synergistic effects in combinatorial therapy.19,28-33 
 
4.3.  Correlative Science 
Our preliminary data suggest that inhibition of PD-L1 might be an attractive treatment option in 
small bowel adenocarcinoma (SBA) because PD-L1 and PD-1 are expressed in a majority of small 
intestinal adenocarcinomas.2  We performed immunohistochemistry (IHC) analysis of PD-L1 and 
PD-1 expression on archived tissue samples of small intestinal adenocarcinomas and observed 
strong PD-L1 expression in 12 of the 26 cases (46%) that was localized to the macrophages around 
the tumor invasive front and in some of the tumor cells adjacent to the macrophages (Figure 1).  All 
tumor samples in our cohort with strong PD-L1 expression also had PD-1 expressing tumor 
infiltrating lymphocytes (TILs) and PD-1 positive lymphocytes and lymphoid aggregates surrounding 
the tumor.  These data are consistent with a previous study that reported robust PD-L1 staining in 
50% of small intestinal adenocarcinomas.3  Interestingly, results of a Phase I study of MPDL3280A 
(anti-PD-L1) in patients harboring a wide range of tumors indicated that responses were observed 
in pre-treatment tumors expressing high levels of PD-L1, especially when PD-L1 was expressed by 
TILs.34,35  In that study PD-L1 positive tumor-infiltrating immune cells were more common than PD-
L1 positive tumor cells at baseline.  Based on these data we propose to perform PD-L1 and PD-1 
IHC in SBA (n=25), prior to treatment with avelumab, to test the hypothesis that PD-L1 and PD-1 
positive staining in the tumor and TILs correlates with disease response to PD-L1 inhibition. 
 
In addition to PD-L1 staining, we propose to evaluate the presence of immune cells (e.g. CD3+, 
CD4+, and CD8+) in and surrounding pre-treatment tumors by IHC.  We hypothesize that increased 
TILs at baseline will correlate with response to PD-L1 inhibition.  Results from the MDPL3280A 
phase I study suggests that PD-L1 inhibition is most effective when pre-existing immunity is 
suppressed by PD-L1, and is re-invigorated on antibody treatment.35  Our preliminary data indicate 
that small intestinal adenocarcinomas expressing PD-L1 contained more CD3+, CD4+, and CD8+ 
tumor infiltrating T cells than those without expression of PD-L1 (Figure 1 and Table 1).  In our 


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tumors, there were approximately 3 times more CD4 cells than CD8 cells.  These data are 
consistent with a previous report in melanoma that showed PD-L1 expression associated with a 
higher density of CD3+ TILs.36 In addition to or alternative to immune cell staining, IHC for other cell 
types may also be performed on the tumor specimens if new clinical or pre-clinical data emerge 
that unveil novel biomarkers of response. 
 
 
 
 
 
 
Figure 1.  Small intestinal carcinomas express PD-L1 and have high lymphocyte infiltration. 
(A-F) Microsatellite stable (MSS) carcinoma and (G-L) Microsatellite instability (MSI)-high medullary 
carcinoma:  (A, G) H&E and IHC staining of (B, H) PD-1, (C, I) PD-L1, (D, J) CD3, (E, K) CD4 and (F, L) 
CD8 positive cells.  All images are 10x with the exception of PD-1 which is 20x. 


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Table 1.  PD-L1 positive tumors have a higher lymphocyte infiltrate. 
# of immune cells 
(per hpf)** 
PD-L1 IHC 
P value 
Positive* 
(n=12) 
Negative 
(n=14) 
CD3+ 
433 ± 22 
239 ± 31 
< 0.01 
CD4+ 
283 ± 21 
185 ± 24 
< 0.01 
CD8+ 
151 ± 31 
54 ± 15 
< 0.01 
 
* Tumors were considered PD-L1 positive if >5% of tumor cells or inflammatory cells  
    stained with an anti-PD-L1 antibody; ** hpf, high-powered field. 
 
There is a strong correlation between non-synonymous mutation burden and response to anti PD-1 
therapy in non-small cell lung cancer (NSCLC).37  About 15% of sporadic colorectal cancers (CRC) 
have defects in the DNA mismatch repair (MMR) pathway which leads to a high frequency of 
somatic alterations compared to tumors with intact MMR.38  Our preliminary data estimated that 
27% (7/26) of small bowel adenocarcinomas are microsatellite instability (MSI)-high, consistent 
with a study reporting 24% of small bowel adenocarcinomas (n=37) with MSI-high status.39  In a 
phase II study evaluating the clinical activity of pembrolizumab (anti-PD1) in patients with 
progressive metastatic carcinoma with or without MMR deficiency, the objective response rate and 
immune-related progression-free survival rate were 40% and 78% respectively for MMR-deficient 
colorectal cancer (CRC) and 0% and 11% for MMR-proficient CRC.40  
 
 
Table 2.  MSI-high tumors are more likely to express PD-L1. 
MSI status 
PD-L1 IHC 
Total 
Positive* 
Negative 
MSS** 
5 (26%) 
14 (74%) 
19 
MSI-high 
7 (100%) 
0 (0%) 
7 
Total 
12 (46%) 
14 (54%) 
26 
 
* Tumors were considered PD-L1 positive if >5% of tumor cells or inflammatory cells  
   stained with an anti-PD-L1 antibody.  ** MSS, microsatellite stable. 
 
Patients with MMR-deficient CRC had responses similar to patients with MMR-deficient non-CRC, 
including two patients with MMR-deficient small bowel adenocarcinoma (SBA).  In our study of 26 
small intestinal adenocarcinomas, we noted that 100% (n=7) of MSI high tumors expressed PD-L1 
(Table 2 and Figure 1).  Based on these data, we hypothesize that MSI high SBA will have a better 
response to PD-L1 inhibition than MSS small bowel adenocarcinoma due to a higher non-
synonymous coding mutation burden.  We propose to examine MSI status in SBA in patients, where 
testing has not been performed in the clinic, by utilizing the MSI Analysis System (Promega) or by 
IHC analysis of MLH1, MSH2, MSH6, and PMS2, when DNA is not available.  Furthermore, we will 
determine non-synonymous mutation burden in SBA (n=25) by exome sequencing (PE-100; 100x 
coverage; Illumina HiSeq300) of fresh-frozen, pre-treatment tumor biopsies and matched patient 
blood.  In addition to generating data regarding mutation burden, exome sequencing may uncover 
novel driver mutations since neither exome nor whole genome sequencing has been previously 
reported in this rare disease. In addition to or alternative to exome sequencing, other genetic 


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testing may also be performed on the tumor specimens if new clinical or pre-clinical data emerge 
that unveil novel genomic biomarkers of response. 
 
4.4.  Avelumab 
 
Avelumab (also referred to as MSB0010718C) is a fully human IgG1 antibody directed against PD-
L1.  Avelumab binds PD-L1 with high affinity (0.7 nM) and blocks the interaction between PD-L1 and 
its receptor PD-1.  This removes the suppressive effects of PD-L1 on anti-tumor CD8+ T cells, 
resulting in the restoration of a cytotoxic T cell response.  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 antibody-dependent cell-mediated cytotoxicity 
(ADCC) against target cells expressing PD-L1. 
 
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. 
  
During development, to circumvent the need for a surrogate antibody, the lead candidate antibody 
was specifically selected for cross-reactivity to murine PD-L1 and, as consequence, all of the 
nonclinical studies were conducted in syngeneic murine tumor models in which the immune 
system of the host is fully intact.  It was demonstrated that the inhibition of the PD-1/PD-L1 
interaction restores antitumor CD8+ T cell responses, which results in an anti-tumor activity. 
 
Avelumab has demonstrated significant nonclinical activity as a monotherapy and in various 
combination therapy settings.  In general, the anti-tumor immunotherapy via blockade of the PD-
1/PD-L1 axis seems not to be limited to any specific tumor types, but there is recent evidence that 
PD-L1 tumor expression is a pre-requisite to achieving an objective response upon blockade of the 
PD-1/PD-L1 axis.41  The clinical relevance of PD-1/PD-L1 blockade has been demonstrated in Phase I 
trials performed with antibodies targeting either PD-L1 or PD-1.41,42 
 
Given the important role of PD-L1 in the suppression of T-cell responses, and the mode of action of 
avelumab which blocks the interaction between PD-L1 and its receptors, avelumab is being 
developed as a potential therapy for subjects with various tumors. 
 
Clinical Phase I/II trials with monoclonal antibodies targeting either PD-L1 or PD-1 have shown 
promising hints for clinical efficacy, for example objective tumor response in indications such as 
NSCLC, melanoma, and ovarian cancer.41-43 
 
Avelumab has two main mechanisms of action for exerting anti-tumor effects: 
1. PD-L1 ligand 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, using an 
anti-PD-L1 antibody to block the PD-L1 ligand’s interaction with PD-1 or B7-1, can release T 
cells from immunosuppression and lead to elimination of tumor cells by T cell 
2. Compared with normal tissues, tumor cells may express high levels of PD-L1 on their 
surface. As a fully human IgG1 monoclonal antibody, avelumab has potential for antibody-
dependent cellular cytotoxicity (ADCC).  Upon binding to PD-L1 on tumor cells, and binding 


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of Fc antibody portions to Fc-gamma receptors on leukocytes, avelumab can trigger tumor-
directed ADCC. 
 
Therefore, blocking PD-L1 inhibitory mechanisms by interactions not only with PD-1 but also the 
other ligand, B7-1, avelumab offers unique therapeutic potential compared with monoclonal 
antibodies targeting PD-1. 
 
4.5.  Clinical Experience with Avelumab:  Safety and Preliminary Efficacy  
Avelumab is currently in development by Merck KGaA, Darmstadt, Germany (within the USA, by 
EMD Serono, the biopharmaceutical division of Merck KGaA) and Pfizer, and has not been 
approved for market in any country. 
 
Over 800 patients have received avelumab monotherapy under the JAVELIN clinical trial program as 
part of at least 3 different clinical trials in solid tumors, including: 
• EMR 100070-001 (NCT01772004):   
A Phase I, Open-label, Multiple-ascending Dose Trial to Investigate the Safety, Tolerability, 
Pharmacokinetics, Biological and Clinical Activity of Avelumab (MSB0010718C) in Subjects 
With Metastatic or Locally Advanced Solid Tumors and Expansion to Selected Indications. 
 
• EMR 100070-002 (NCT01943461):   
A Phase I Trial to Investigate the Tolerability, Safety, Pharmacokinetics, Biological and Clinical 
Activity of Avelumab (MSB0010718C) in Japanese Subjects With Metastatic or Locally 
Advanced Solid Tumors, With Expansion Part in Asian Subjects With Gastric Cancer. 
 
• EMR 100070-003 (NCT02155647):   
A Phase II, Open-Label, Multicenter Trial to Investigate the Clinical Activity and Safety of 
Avelumab (MSB0010718C) in Subjects With Merkel Cell Carcinoma. 
The primary objective of the global Phase 1 trial (EMR 100070-001) was to determine the maximum 
tolerated dose (MTD) of avelumab by monitoring dose-limiting toxicities (DLTs).  The DLT 
evaluation period referred to the first 3 weeks after trial treatment during the dose escalation 
phase following a classical 3 + 3 design.   
 
During dose escalation, none of the subjects treated with doses up to 10 mg/kg experienced a dose 
limiting toxicity (DLT).  Out of the 6 subjects who received 20 mg/kg dose of avelumab, 1 DLT was 
observed.  Occurring 18 days after receiving the first dose of 20 mg/kg avelumab, the DLT event 
was a Grade 3 immune-related disorder with creatine kinase (CK) increase, myositis, and 
myocarditis, considered related to trial drug by the investigator.  All patients treated at 10 mg/kg 
had a median trough concentration >1 µg/mL, the necessary concentration for >95% target 
occupancy (TO). 
 
On the basis of safety, pharmacokinetic (PK), pharmacodyamic (PD), and receptor target occupancy 
(TO) observations, a dose of 10 mg/kg once every 2 weeks was determined for subsequent 
expansion involving 16 tumor treatment cohorts. 
 
As of 15 July 2015 (based on data cutoff 01 June 2015), 53 subjects in dose escalation had received 
avelumab (4, 13, 15, and 21 subjects respectively received 1.0, 3.0, 10.0, and 20.0 mg/kg of 


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avelumab), and 717 subjects in the pooled expansion part had received 10 mg/kg avelumab with 
follow-up for at least 4 weeks. 
 
Safety summary data from 717 subjects treated in the pooled treatment expansion cohorts 
includes a summary of subjects treated in the NSCLC, gastric cancer, ovarian cancer, and urothelial 
carcinoma expansion cohorts (184, 120, 75, and 44 subjects, respectively). 
 
Treatment-related treatment emergent adverse events (TEAEs) were observed in 498 (69.5%) 
subjects in the pooled expansion cohort.  The most frequently observed treatment-related TEAEs 
(with an incidence of ≥ 2%) of any grade in the pooled expansion cohort were infusion-related 
reaction (18.7%), fatigue (18.1%), nausea (10.3%), diarrhea (6.8%), chills (6.7%), and decreased 
appetite (5.2%).  Other frequently seen treatment-related TEAEs with an incidence < 5% but ≥ 2% 
included arthralgia, pyrexia, hypothyroidism, pruritus, vomiting, influenza-like illness, rash, anemia, 
AST increased, myalgia, asthenia, headache, ALT increased, dyspnea, and constipation. 
 
Grade ≥ 3 treatment-related TEAEs were observed in 77 subjects (10.7%) in the pooled expansion 
cohort, of which 13.0%, 9.2%, 6.7%, and 4.5% occurred in the NSCLC, gastric cancer, ovarian cancer, 
and urothelial carcinoma expansion cohorts, respectively.  
 
The most frequently observed Grade ≥ 3 treatment-related TEAEs in the pooled expansion cohort 
were gamma-glutamyltransferase increased, infusion-related reaction, and lipase increased (each 
occurred in 7 subjects; 1.0%), followed by anemia (6 subjects; 0.8%), fatigue (5 subjects; 0.7%), and 
AST increased and autoimmune hepatitis (each occurred in 4 subjects; 0.6%).  Other Grade ≥ 3 
treatment-related TEAEs that were observed in ≥ 2 subjects included ALT increased, lymphocyte 
count decreased, and pneumonitis (each in 3 subjects; 0.4%), and asthenia, blood alkaline 
phosphatase increased, blood creatine phosphokinase increased, colitis, constipation, dyspnea, 
hyperglycemia, hypokalemia, hypoxia, myositis, and platelet count decreased (each in 2 subjects; 
0.3%). 
 
Of the 77 subjects (10.7%) who experienced Grade ≥ 3 treatment-related TEAEs, 60 (8.4%) had 
Grade 3 events, and 14 (2.0%) and 4 (0.6%) reported Grade 4 and Grade 5 treatment-related TEAEs, 
respectively. 
 
The 14 subjects reporting Grade 4 treatment-related TEAEs included 7 subjects (3.8%) in the NSCLC 
expansion cohort with the preferred terms (PTs) of infusion-related reaction (2 subjects), amylase 
increased, embolic stroke, frontal lobe epilepsy, monoplegia, syncope, dyspnea, pneumonitis, and 
autoimmune neutropenia (each in 1 subject).  Further Grade 4 treatment-related TEAEs were seen 
in 5 subjects of the metastatic breast cancer (MBC) expansion cohort (3.0%) with the PTs of 
gamma-glutamyltransferase increased, hypokalemia, respiratory failure, anemia, neutropenia, 
thrombocytopenia, and cardiac arrest (each in 1 subject).  The other 2 subjects who reported 
Grade 4 treatment-related TEAEs were 1 subject in the mesothelioma expansion cohort (blood 
creatine phosphokinase increased) and 1 subject in the urothelial carcinoma expansion cohort 
(myositis). 
 
The 4 subjects who experienced Grade 5 treatment-related TEAEs were 2 subjects in the NSCLC 
expansion cohort (radiation pneumonitis and acute respiratory failure) and 2 subjects in the MBC 
expansion cohort (respiratory distress and acute hepatic failure). 


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Preliminary efficacy results of the 184 subjects treated with 10 mg/kg of avelumab once every 2 
weeks in the NSCLC treatment expansion cohort of Phase I Trial EMR 100070-001 with a minimum 
follow-up of at least 6 months as of 15 January 2015, are available.  The objective response rate 
(ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (including confirmed 
and unconfirmed responses) among the 184 NSCLC subjects treated at 10 mg/kg of avelumab was 
13.6%, which includes one complete response (CR) (0.5%) and 24 partial responses (PR) (13.0%).  In 
19 of the 25 responders (with either a CR or PR) (76.0%), the responses were ongoing at the time of 
the data cutoff.  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 the pre-planned interim analysis on the 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). 
 
In the NSCLC expansion cohort, the clinical activity of avelumab was also evaluated by subjects’ 
tumor PD-L1 expression status.  An objective response was observed in 19 of 122 subjects (15.6%) 
who were PD-L1 positive (defined as having at least 1% PD-L1 positive tumor cells) compared with 
2 of 20 subjects (10.0%) who were considered PD-L1 negative (defined as having less than 1% PD-L1 
positive tumor cells).  A longer median progression free survival (PFS) (12.0 vs 5.9 weeks) and 
overall survival (OS) (8.9 vs 4.6 months) were both observed in PD-L1 positive compared to PD-L1 
negative subjects. 
 
5.  PARTICIPANT SELECTION 
5.1.  Allocation of Slots to Study Sites 
This is an investigator-initiated trial with intended single-site enrollment limited to patients 
enrolling at Vanderbilt University. 
 
5.2.  Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study: 
 
1. Signed and dated written informed consent. 
 
2. Male or female ≥ 18 years of age. 
 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
 
4. Histologically confirmed adenocarcinoma of the small intestine that is advanced (not 
amenable to surgery) or metastatic (clinical stage IV).  For the purposes of this study, 
ampullary tumors are considered a part of the duodenum and are classified as 
adenocarcinomas of the small intestine.  
 
5. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 criteria (Appendix 1) that has not been previously irradiated and 
which can be followed by CT or MRI. 
 
6. Adequate organ function including:  


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• 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
 
 
• 
Platelets ≥ 100 × 109/L 
• 
Hemoglobin ≥ 9/g/dL (may have been transfused) 
• 
Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN) 
• 
Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase 
(ALT/SGPT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases are present) 
• 
Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 30 mL/min as 
calculated using the Cockcroft-Gault (CG) equation (Appendix 3). 
 
7. Archival tissue [paraffin block(s) or unstained slides from paraffin block(s)] from the 
primary tumor and/or a metastatic site judged reasonably available prior to initiating 
treatment, or willingness to undergo fresh pre-treatment tumor biopsy.  (Prior to initiating 
treatment, the screening team must have documentation that an archival or fresh tumor 
specimen has been requested from a local or outside facility.  However, physical 
possession of requested tissue or waiting for histological analysis or confirmation that an 
acquired specimen contains tumor tissue sufficient for analysis is not a requirement prior 
to initiating treatment.)  If no archival tissue is available and patient consents to a fresh 
biopsy, but the patient’s lesion is deemed inaccessible to safe biopsy, the patient will be 
allowed to enroll if otherwise eligible.  
 
8. Female patients of childbearing potential and male patients able to father children who 
have female partners of childbearing potential must agree to use one highly effective 
method (defined as less than 1% failure rate per year) and one additional effective 
method of contraception (Appendix 4) from 15 days prior to first trial treatment 
administration until at least 30 days after study participant’s final dose of avelumab.   
Females of childbearing potential are defined as those who are not surgically sterile or 
post-menopausal (i.e. patient has not had a bilateral tubal ligation, a bilateral 
oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months 
without an alternative medical cause).  Post-menopausal status in females under 55 years 
of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within 
laboratory reference range for postmenopausal women.   
 
Male patients able to father children are defined as those who are not surgically sterile 
(i.e. patient has not had a vasectomy). 
 
9. Serum pregnancy test (for females of childbearing potential) negative at screening. 
 
10. Re-enrollment of a subject that has discontinued the study as a pre-treatment screen 
failure (i.e. a consented patient who did not receive avelumab) is permitted.  If re-
enrolled, the subject must be re-consented.  Only the screening procedures performed 
outside of protocol-specified timing must be repeated. 
 
5.3.  Exclusion Criteria 
 
Patients will be ineligible for enrollment into the study if they meet any of the following criteria: 
1. There is no restriction on the number of prior therapies. However, prior therapy with 
antibody or drug specifically targeting T cell regulatory proteins, including but not limited 
to the following is not allowed:  Prior immunotherapy with IL-2 or IFN-α, or an anti-PD-1 


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(including nivolumab), anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-
associated antigen-4 (CTLA-4) antibody (including ipilimumab), or any other antibody or 
drug specifically targeting T-cell co-stimulation or checkpoint pathways. 
 
2. Within 28 days before first dose of avelumab:   
Anti-cancer treatment, major surgery requiring general anesthesia, or the use of any 
investigational agent.   
 
3. Within 14 days before first dose of avelumab: 
Therapeutic or palliative radiation therapy.   (Subjects receiving bisphosphonate or 
denosumab are eligible provided treatment was initiated at least 14 days before the first 
dose of avelumab.) 
 
4. Current use of immunosuppressive medication, except the following:   
• 
Subjects are permitted the use of corticosteroids with minimal systemic 
absorption (e.g. topical, intra-articular, intranasal, and inhaled); 
• 
Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or 
equivalent are permitted; 
• 
A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. CT scan 
premedication against contrast dye allergy) or for treatment of non-
autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by a 
contact allergen) is permitted. 
 
5. Previous malignant disease other than adenocarcinoma of the small intestine within the 
last 5 years, with the exception of basal or squamous cell carcinoma of the skin or cervical 
carcinoma in situ considered curatively treated (i.e. complete remission achieved at least 
2 years prior to first dose of avelumab AND additional therapy not required while 
receiving study treatment). 
 
6. All subjects with brain metastases, expect those meeting the following criteria: 
• 
Brain metastases that have been treated locally and are clinically stable for at 
least 2 weeks prior to enrollment 
• 
No ongoing neurological symptoms that are related to the brain localization of 
the disease (sequelae that are a consequence of the treatment of the brain 
metastases are acceptable.  
• 
Subjects must be either off steroids or on a stable or decreasing dose of ≤ 10 mg 
daily prednisone (or equivalent) 
 
7. Receipt of any organ transplantation including allogeneic stem-cell transplantation. 
 
8. Significant acute or chronic infections requiring systemic therapy. 
 
9. Known history of testing positive for human immunodeficiency virus (HIV), or acquired 
immunodeficiency syndrome (AIDS). 
 
 


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10. Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection at screening (positive HBV 
surface antigen or HCV RNA if anti-HCV antibody screening test positive). 
 
11. Active autoimmune disease with reasonable possibility of clinically significant 
deterioration when receiving an immuno-stimulatory agent. Subjects with Type 1 diabetes 
mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring 
immunosuppressive treatment are eligible. 
 
12. Interstitial lung disease that is symptomatic or which may interfere with the detection or 
management of suspected drug-related pulmonary toxicity. 
 
13. Uncontrolled asthma [defined as having 3 or more of the following features of partially 
controlled asthma within 28 days prior to starting study treatment:  Daytime symptoms 
more than twice per week, any limitation of activities, any nocturnal symptoms/awaking, 
need for reliever/rescue inhaler more than twice per week, or known lung function (PEF 
or FEV1) without administration of a bronchodilator that is < 80% predicted or personal 
best (if known)]. 
 
14. Current symptomatic congestive heart failure (New York Heart Association ≥ class II), 
unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable 
angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled hypertension 
(systolic > 160 mmHg or diastolic > 100mmHg).  Or any of the following occurring within 6 
months (180 days) prior to first dose of avelumab:  Myocardial infarction, 
coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic 
attack, or serious cardiac arrhythmia requiring medication.  (Use of antihypertensive 
medication to control blood pressure is allowed.) 
 
15. Concurrent treatment with a non-permitted drug (see Section 10). 
 
16. Requirement of anticoagulant therapy with oral vitamin K antagonists such as Coumadin 
(warfarin).  Low-dose anticoagulants for the maintenance of patency in a central venous 
access device or the prevention of deep vein thrombosis or pulmonary embolism is 
allowed.  Therapeutic use of low molecular weight heparin is allowed. 
 
17. Persisting toxicity related to prior therapy that has not reduced to Grade 1 [National 
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.03]; 
however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable. 
 
18. Known severe (Grade ≥ 3 NCI-CTCAE v4.03 ) hypersensitivity reactions to monoclonal 
antibodies, including hypersensitivity to the investigational agent or any component in its 
formulations, or history of anaphylaxis. 
 
19. Vaccination within 28 days of the first dose of avelumab and while on trial is prohibited, 
except for administration of inactivated vaccines (for example, inactivated influenza 
vaccine). 
 
20. Pregnant or breastfeeding females. 
 


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21. Known alcohol or drug abuse 
 
22. Prisoners or subjects who are involuntarily incarcerated. 
 
23. Other severe acute or chronic medical condition, including immune colitis, inflammatory 
bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric condition 
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. 
 
5.4.  Inclusion of Underrepresented Populations 
 
Women and men of all races and ethnic groups are eligible for this trial.  There is no bias towards 
gender, age, or race in the clinical trial outlined.  
 
5.5.  Number of Patients and Replacement of Patients Who Discontinue Early 
 
Approximately 25 patients evaluable for response are anticipated to enroll in this study at 
Vanderbilt University Medical Center. 
 
In general, it intended that patients will be treated until disease progression or intolerable toxicity.  
The criteria for patient discontinuation are listed in Sections 9 and 11. 
 
If a patient discontinues study treatment for reasons clearly not related to study treatment, after 
completing fewer than one planned infusion of avelumab, and/or receiving <75% of the total 
intended dose of avelumab over the first cycle of treatment + an additional 14 days (i.e. first 28 
days after initiating patient’s first dose of avelumab), then that patient will be considered not 
evaluable for response to study treatment and may be replaced with a new patient.   
 
 
6.  REGISTRATION PROCEDURES 
6.1.  Registration 
All patients MUST be registered with the VICC prior to the start of protocol treatment. 
Registration can only be conducted during the business hours of 8AM – 5PM Central Standard 
Time Monday through Friday.  
 
1) All sites must email the VICC CTSR Coordinating Center at Coordinating.Center@Vanderbilt.edu 
to notify of upcoming registration and ensure slot availability. The following information 
should be included in your email: 
• 
Study number 
• 
Patient initials 
• 
Disease type  
• 
Anticipated consent date 


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• 
Anticipated start date  
 
2) Email the following documents to the Coordinating Center for eligibility review and patient 
enrollment (coordinating.center@vanderbilt.edu): 
• 
Copy of the patient’s signed and dated Informed Consent, including documentation of 
the consent process. 
• 
Patient Enrollment Form 
• 
Eligibility supporting documents such as pathology reports, laboratory tests, etc. or EMR 
access. Note: all source documents should be de-identified and screening/subject ID 
number added prior to sending. 
• 
Signed and completed Eligibility Checklist. To be eligible for registration to the study, 
the participant must meet each inclusion and exclusion criterion listed in the eligibility 
checklist.  
 
Note: All study documents should be received 24-48 hours prior to the patient’s anticipated start 
date. Same day treatment registrations will only be accepted with prior notice and discussion with 
the Coordinating Center. Please email the Coordinating Center if enrollment is needed sooner. 
 
Upon satisfactory review of eligibility documents submitted, the Coordinating Center will approve 
enrollment and issue a subject ID number if one was not issued at screening. Once 
registration/enrollment confirmation from Coordinating Center is received, proceed with protocol 
procedures. 
 
Please contact the assigned Study Contact with any questions regarding this process. You can also 
reach out to your assigned Clinical Research Associate (CRA) once the study is activated.  
  
The VICC Coordinating Center will assign Subject ID numbers to all patients whose eligibility has 
been confirmed.  Only patients deemed eligible will be registered to investigational treatment.  
Following registration, eligible participants should begin study treatment consistent with the 
protocol no later than 28 days after registration/enrollment by the VICC Coordinating Center. If a 
participant does not receive protocol therapy following registration within the allowed time period, 
the participant’s registration on the study will be canceled. The Study Contact should be notified of 
cancellations as soon as possible. Patients being re-screened will need to consent to repeated 
procedures. As such, the Coordinating Center will require a new, signed Informed Consent 
document.  
Issues that would cause treatment delays should be discussed with the Protocol Chair.   
 
As is generally accepted, standard of care procedures performed prior to consent, but within the 
protocol defined screening window for each assessment, can be used for study purposes.  All 
research-only procedures must be performed after patient consent.  
 
 
 
 
 
 
 


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7.  SCHEDULE of ASSESSMENTS 
7.1.  Study Calendar  
 
 
 
Protocol  
Activities 
Screening 
 
≤ 28 Days 
Prior to 
First Dose 
Day 1 of 
Cycles ≥ 1 
 
Every 14 days 
(+3 days)11 
Post Treatment 
EOT/ 
Withdrawal14 
Follow-Up17 
Clinical Assessments 
Consent, Medical History & 
Demographics 
X 
 
 
 
Physical Examination and ECOG  
X 
X9 
X 
X16 
Vital Signs1 
X 
X1 
X 
X16 
Con Meds & Adverse Events 
X 
X9 
X 
X16 
Height and Weight2 
X 
X2 
X 
 
Survival Follow-up 
 
 
 
X18 
Laboratory Studies 
Hematology and Blood Chemistry3 
X 
X10 
X 
X16 
HCV and HBV Testing 
X 
 
 
 
Serum Pregnancy Test4 
X 
X4 
X 
 
Free T4 and Thyroid Stimulating 
Hormone (TSH) 
X 
X5 
X 
X5 
Tumor and Pharmacogenetic Assessments 
CT or MRI Scans6 
X6 
X6 
X15 
X19 
Archival Tumor Tissue 
X7 
 
 
 
Fresh Tumor Biopsy 
X8 
 
 
 
Pharmacogenetic Blood Sample 
 
X11 
 
 
Treatment 
Avelumab infusion (10 mg/kg) 
 
X12,13 
 
 
 
Notes: 
1. Vital signs to include heart rate, blood pressure and temperature (oral or tympanic).  On days of each 
avelumab treatment:  Pre-Dose and Post-Dose vitals should respectively be recorded ≤ 10 minutes prior 
to the start of the avelumab infusion (Pre), and ≤ 10 min after the end of the avelumab infusion (EOI).   
Following avelumab infusions, patients must be observed for 30 minutes post infusion for potential 
infusion related reactions.   
2. Height only at baseline.  Weight within 3 days prior to every dose of avelumab.  As per Note 11 below 
and protocol Section 8.2, avelumab dose must be adjusted if patient’s weight changes ± 10%.   
3. Hematology to include:  White blood count (WBC) with differential; hemoglobin, hematocrit and platelet 
count.  Blood chemistry to include:  Sodium, potassium, calcium, chloride, and bicarbonate; BUN, serum 
creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, total protein, and albumin.  
4. Serum pregnancy test required for females of childbearing potential, during Screening and on Cycle 1, 
Day 1 (unless already done within 72 hours prior to first dose of avelumab).  Subsequent serum 
pregnancy tests to be done every 4 weeks on Day 1 of each cycle and at End of Treatment.  Females of 
childbearing potential are defined as those not surgically sterile or not post-menopausal (i.e. patient has 
not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been 
amenorrheic for 12 months without an alternative medical cause).  Postmenopausal status in females 
under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within 
laboratory reference range for postmenopausal women (if a patient’s postmenopausal status is 
considered for childbearing potential and study required contraception).  


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5. Free T4 and TSH levels will be tested at screening, Cycle 3 Day 1, and then every 8 weeks while patients 
are on therapy. Free T4 and TSH levels will also be tested at EOT or at the Follow-up visit (if not 
performed in the previous 8 weeks. 
6. Baseline evaluation of disease status by CT or MRI within 28 days prior to first dose of avelumab.  
Baseline and subsequent scans to include imaging of the chest, abdomen and pelvis.  The first scheduled 
re-scan should be performed and evaluated 7 to 8 weeks after Cycle 1, Day 1 treatment, with 
subsequent scheduled scans intended every 8 to 9 weeks thereafter irrespective of dose delays.  Thus, 
the first re-scan is anticipated during Week 2 of Cycle 4 (with evaluation prior to dosing on Cycle 5, Day 
1).  Additional re-scanning is anticipated during Week 2 of every 4th cycle (i.e. Week 2 of Cycles 8, 12, 16, 
etc) prior to infusion in the subsequent cycle (i.e. re-scanning prior to Day 1 of Cycles 5, 9, 13, 17, etc).  
Scanning on the same day as dosing is discouraged but allowed, provided scan results receive 
appropriate evaluation prior to study treatment (e.g. first re-scan is permitted on Cycle 5, Day 1, prior to 
treatment later that same day).  Additional disease evaluations or increased scan frequency may be 
performed according to the medical judgment of the patient’s study physician. 
7. Archival tissue [paraffin block(s) or unstained slides from paraffin block(s)] from the primary tumor 
and/or a metastatic site judged reasonably available prior to initiating treatment, or willingness to 
undergo fresh pre-treatment tumor biopsy.  Prior to initiating treatment, the screening team must have 
documentation that a paraffin block(s), unstained slides from a paraffin block(s), or a fresh biopsy has 
been requested from a local or outside facility.  (However, physical possession of requested tissue, or 
waiting for histological analysis or confirmation that a certain number of acquired specimen slides are 
known to contain tumor tissue, is not a requirement prior to initiating treatment.)  Please note:  Archival 
or fresh biopsy should be excisional, incisional or core needle; fine needle aspiration is not sufficient.  
Patients without available or sufficient archival tumor samples (if otherwise eligible) will be allowed to 
participate, if they are willing to have a fresh biopsy of a primary or metastatic lesion.  If no archival 
tissue is available and patient consents to a fresh biopsy, but the patient’s lesion is deemed inaccessible 
to safe biopsy, the patient will be allowed to enroll if otherwise eligible.  
8. In addition to the mandatory archival tissue or fresh tissue, an optional fresh biopsy will be requested 
from consenting subjects (including those with pre-existing archival tissue) with primary or metastatic 
lesion judged amenable to medically safe excisional, incisional or core needle biopsy.  
9. On Cycle 1, Day 1:  Physical exam (including ECOG performance status) and review of Con Meds and 
Adverse Events not required if already completed within 7 days prior to first dose of avelumab.  After 
initiation of Cycle 4, physical exams may be performed monthly (i.e. after Cycle 4, Day 1 exam to confirm 
satisfactory completion of Cycle 3, the next regularly scheduled physical exam may occur 4 weeks later, 
on Cycle 6, Day 1; with subsequent monthly physical exams intended every even cycle, on Day 1 of 
Cycles 8, 10, 12, etc). 
10. Hematology and blood chemistry must be collected prior to each avelumab dose, at the end of 
treatment visit, and at 30 days post-treatment safety follow-up. 
11. Pharmacogenetic (PG) blood obtained once, prior to patient’s first avelumab dose on Cycle 1, Day 1. 
12. The avelumab dose will be 10 mg/kg administered as 1-hour intravenous (IV) infusion every 2 weeks 
(Q2W). Every effort should be made to target infusion timing to be as close to 1 hour as possible. 
However, given the variability of infusion pumps, time windows of -10 minutes and +20 minutes is 
permitted (i.e. scheduled avelumab infusion time is 60 minutes:  -10 min/+20 min).  See protocol Section 
9 for recommended infusion pre-medications.  Avelumab dosing will be based on the patient’s weight in 
kilograms (kg).  All patients should be weighed within 3 days prior to each avelumab dose.  If a weight 
loss or gain ≥ 10% is observed (compared to the weight used to calculate the immediately prior dose), 
then the amount of avelumab required for a current dose must be recalculated using the most recent 
weight obtained.  Reduction of avelumab dose for toxicity management is not permitted, however 
avelumab administration may be held due to adverse events, as described in protocol Section 11.   
13. Cycle 2, Day 1 dosing should occur 14 days after Cycle 1, Day 1.  In the absence of delayed dosing (e.g. 
due to an adverse event), every reasonable effort should be made to remain on a consistent schedule of 
14-day cycles; but for purpose of accommodating holidays, scheduling limitations, etc, subsequent cycles 
(i.e. Cycles 3+) may occur up to every 14 days +3 days.  Consecutive doses of avelumab must be 


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separated by no fewer than 14 days and, in the absence of adverse event management, no more than 17 
days. 
14. Reasonable effort should be made to complete End-of-Treatment / Withdrawal procedures on the day it 
is decided that a patient will no longer receive study treatment.  These procedures must be completed 
subsequent to and not later than 21 days after a patient’s final treatment with avelumab (and prior to 
any subsequent anti-cancer therapy). 
15. Unless already done within previous 28 days. 
16. A 1-month follow-up clinic visit is intended 28 days (±7 days) after the preceding End-of-Treatment visit 
(at least 30 days after patient’s final treatment with avelumab).  Documented attempt(s) should be made 
for patient return to the study clinic.  It will not be considered a protocol deviation if the patient is 
physically unable to return for the follow-up visit; such circumstance should be recorded in the study 
documents, and as much of the follow-up information as possible should be obtained via feasible patient 
contact and from local and outside facilities. 
17. Given the potential risk for delayed immune-related toxicities, safety follow-up must be performed up to 
90 days (+3 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 clinic visit or telephone call 
with a subsequent site visit requested in case any concerns noted during the telephone call. 
18. Each patient will be followed for survival every 3 months (± 14 days) after patient’s final 
treatment with avelumab until death, end of the study, or until patient withdraws consent, 
whichever comes first.  Contact can be made via clinic visit, chart review, obituary or similar 
observation (e.g. Social Security death index), or by telephone. 
19. If a patient discontinues the study for reason other than progressive disease confirmed by CT or 
MRI (e.g. adverse event), then CT or MRI scans of the chest, abdomen and pelvis should be 
continued every 8-9 weeks until disease progression is confirmed by imaging. 
 
7.2.  Screening Visit Assessments  
 
Prior to performing any study-based procedures, patient informed consent must be obtained. 
 
The following procedures must be completed ≤ 28 days prior to a patient’s first dose of study 
treatment: 
•  Signed Informed Consent Form 
•  Medical history and Demographics 
•  Physical exam 
•  Vital signs:  heart rate, blood pressure and temperature (oral or tympanic) 
•  Height 
•  Weight 
•  ECOG Performance Status 
• 
Concomitant medications (taken up to 28 days prior to Day 1) and Adverse Events 
•  Complete Blood Count (CBC) with differential 
•  Serum chemistry, including Free T4 and thyroid stimulating hormone (TSH) 
•  Serum Pregnancy test in women of childbearing potential (as defined in Sections 7.1 and 
8.6) 
• 
Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) testing 
•  Extent of disease evaluation (by CT or MRI scan of the chest, abdomen and pelvis), within 28 
days of study treatment 
•  Archival tumor tissue requested and/or fresh biopsy of lesion amenable to safe biopsy (see 
Sections 7.1 and 8.7 for additional detail). 
 


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7.3.  Cycle 1, Day 1 Assessments 
 
On Cycle 1, Day 1, the following procedures must be completed: 
•  CBC 
•  Serum chemistry 
• 
Serum Pregnancy test in women of childbearing potential, unless previously completed ≤ 72 
hours prior to a patient’s first dose of study treatment 
• 
Weight. 
 
On Cycle 1, Day 1, the following procedures must be completed, unless previously completed ≤ 7 
days prior to a patient’s first dose of study treatment: 
•  Physical Exam (including ECOG performance status) and review of Con Meds and Adverse 
Events). 
 
On Cycle 1, Day 1, the following procedures will be completed: 
• 
Pharmacogenetic Blood Sample (pre-dose) 
• 
Vital signs (heart rate, blood pressure, and oral or tympanic temperature):   
Pre-Dose:  ≤ 10 minutes prior to the start of the avelumab infusion 
Post-Dose:  ≤ 10 min after the end 
•  Avelumab infusion. 
• 
Patients must be observed for 30 minutes post infusion for potential infusion related 
reactions. 
 
7.4.  Additional Cycles Assessments 
For patients that continue beyond Cycle 1, the following assessments will occur at the specified 
weeks: 
 
Week 1 of Each Cycle (e.g. Cycle ≥2, Day 1) 
•  Physical exam:  After initiation of Cycle 4, physical exams may be performed monthly.  
(After Cycle 4, Day 1 exam to confirm satisfactory completion of Cycle 3, the next 
regularly scheduled physical exam may occur 4 weeks later, on Cycle 6, Day 1; with 
subsequent monthly physical exams intended every even cycle, on Day 1 of Cycles 8, 10, 
12, etc). 
• 
Vital signs (heart rate, blood pressure, and oral or tympanic temperature):   
Pre-Dose:  ≤ 10 minutes prior to the start of the avelumab infusion 
Post-Dose:  ≤ 10 min after the end of the avelumab infusion 
• 
Serum Pregnancy test in women of childbearing potential: must be performed every 4 
weeks 
• 
Weight (within 3 days prior to every dose of avelumab) 
•  ECOG Performance Status 
• 
Concomitant Medications and Adverse Events 
•  CBC and Serum chemistry: must be performed prior to each avelumab treatment 
•  Free T4 and thyroid stimulating hormone (TSH) on Day 1 of every odd cycle (every 8 
weeks) 
• 
Avelumab infusion. 
• 
Patients must be observed for 30 minutes post infusion for potential infusion related 
reactions. 
 


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Week 2 of every 4th cycle (i.e. Week 2 of Cycles 4, 8, 12, 16, etc)  
•  Extent of disease evaluation (as per Section 7.1) 
 
7.5.  End-of-Treatment / Withdrawal Assessments 
 
Reasonable effort should be made to complete End-of-Treatment / Withdrawal procedures on the 
day it is decided that a patient will no longer receive study treatment.   
 
The following procedures must be completed not later than 21 days after a patient’s final 
treatment with avelumab (and prior to any subsequent anti-cancer therapy): 
•  Physical exam 
•  Vital signs (heart rate, blood pressure, and oral or tympanic temperature) 
•  Weight 
•  ECOG Performance Status  
•  Concomitant Medications and Adverse Events 
•  CBC 
•  Serum chemistry, including Free T4 and thyroid stimulating hormone (TSH) 
•  Serum Pregnancy test (in women of childbearing potential) 
•  Extent of disease evaluation (if not already performed within the last 28 days). 
 
7.6.  Follow-Up Visit Assessments (30-Day and 90-Day) 
 
A 1-month follow-up clinic visit is intended 28 days (±7 days) after the preceding End-of-Treatment 
visit.  Documented attempt(s) should be made for patient return to the study clinic.  It will not be 
considered a protocol deviation if the patient is physically unable to return for the follow-up visit; 
such circumstance should be recorded in the study documents, and as much of the follow-up 
information as possible should be obtained via feasible patient contact and from local and outside 
facilities. 
 
Documented attempts should be made to have patients return to the clinic 28 days (±7 days) after 
the prior End-of-Treatment visit (at least 30 days after patient’s final treatment with avelumab), in 
order to undergo the following assessments: 
•  Physical exam 
•  ECOG Performance Status 
•  Concomitant Medications and Adverse Events 
• 
CBC and Serum chemistry 
• 
Free T4 and Thyroid stimulating hormone (TSH) if not performed in the previous 8 weeks. 
 
If a patient discontinues the study for reason other than progressive disease confirmed by CT or 
MRI (e.g. adverse event), then CT or MRI scans of the chest, abdomen and pelvis should be 
continued every 8-9 weeks until disease progression is confirmed by imaging. 
 
Given the potential risk for delayed immune-related toxicities, safety follow-up must be performed 
up to 90 days (+3 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. 


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7.7.  Survival Follow-Up 
 
Each patient will be followed for survival every 3 months (± 14 days) after patient’s final treatment 
with avelumab until death, end of the study, or until patient withdraws consent, whichever comes 
first.  Contact can be made via clinic visit, chart review, obituary or similar observation (e.g. Social 
Security death index), or by telephone. 
 
8.  STUDY PROCEDURES 
8.1.  Medical History 
 
A medical history will include all relevant prior medical conditions, surgeries or other medical 
procedures. 
 
8.2.  Physical Examination 
Physical examination:  The physical examination should include an examination of major body 
systems, ECOG performance status, body weight, height (at Screening Visit only), vital signs 
(temperature, blood pressure, pulse rate). 
 
All patients should be weighed within 3 days prior to each avelumab dose.   
 
If a weight loss or gain ≥ 10% is observed (compared to the weight used to calculate the 
immediately prior dose), then the amount of avelumab required for a current dose must be 
recalculated using the most recent weight obtained.  
  
8.3.  Extent of Disease Assessment  
 
Tumor response will be evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1, to establish disease progression by CT or MRI.  In addition, other radiographic or 
scintigraphic procedures (such as radionuclide bone scans), as deemed appropriate by the investigator, 
will be performed to assess sites of neoplastic involvement.  The same method of assessment should be 
used throughout the study.  Investigators should select target and non-target lesions in accordance with 
RECIST v1.1 guidelines.  Follow-up measurements and overall response should also be in accordance 
with these guidelines.  To be assigned a status of confirmed PR or CR, changes in tumor measurements 
should be confirmed by repeated assessments that should be performed ≥30 days after the criteria for 
response are first met.   
 
The extent of disease assessment should be completed until it has been determined the patient has 
progressive disease (in accordance with RECIST v1.1).  In the event the patient discontinues study 
treatment for reasons other than disease progression, an extent of disease assessment should be 
completed as soon as possible relative to the date of study termination to ensure disease 
progression is not present and to assess overall disease status.  In such patients, this assessment 
should occur no later than 28 days after a patient’s last treatment with avelumab (and prior to any 
subsequent anti-cancer therapy). 
 
 


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8.4.  Complete Blood Count 
A complete blood count (CBC) will include a white blood count (WBC) with differential, 
hemoglobin, hematocrit and platelet count. 
 
8.5.  Blood Chemistry  
 
Blood chemistry will include electrolytes (sodium, potassium, calcium, chloride, and bicarbonate), 
BUN, serum creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, total protein, and 
albumin.  Thyroid stimulating hormone (TSH) will be drawn during screening and periodically during 
treatment. See the Schedule of Assessments (Section 7.1) for specific time points. 
 
8.6.  Serum Pregnancy Test 
 
A serum pregnancy test will be obtained for all females of childbearing potential, defined as those 
not surgically sterile or not post-menopausal (i.e. patient has not had a bilateral tubal ligation, a 
bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months 
without an alternative medical cause).  Postmenopausal status in females under 55 years of age 
should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory 
reference range for postmenopausal women (if a patient’s postmenopausal status is considered for 
childbearing potential and study required contraception). 
  
8.7.  Archival and Optional Fresh Tumor Samples 
 
Pre-treatment archival tissue [paraffin block(s) or unstained slides from paraffin block(s)] from the 
primary tumor and/or a metastatic site must be judged to be reasonably available prior to initiating 
treatment, or the patient must be willing to undergo a fresh pre-treatment tumor biopsy.  Prior to 
initiating treatment, the screening team must have documentation that a paraffin block(s), 
unstained slides from a paraffin block(s), or a fresh biopsy has been requested from a local or 
outside facility.  (However, physical possession of requested tissue, or waiting for histological 
analysis or confirmation that a certain number of acquired specimen slides are known to contain 
tumor tissue, is not a requirement prior to initiating treatment.)  Please note:  Archival or fresh 
biopsy should be excisional, incisional or core needle; fine needle aspiration is not sufficient. 
 
Patients (including those with pre-existing archival tissue) may elect to have an optional fresh 
biopsy of a primary or metastatic lesion judged amenable to medically safe excisional, incisional or 
core needle biopsy. 
 
Archival tumor samples obtained at the time of metastasis are preferred over tumor samples 
obtained at the time of primary diagnosis.  Approximately 50 total microns of tumor sample (i.e. 
about 10 slides of 5 microns each) is desired for this purpose – see lab manual for additional 
details.   
 
In cases where both archival and optional fresh tumor biopsy tissue are available, both archival and 
fresh samples will be requested.   
 
Patients without available or sufficient archival tumor samples (if otherwise eligible) will be allowed 
to participate, if they are willing to have a fresh biopsy of a primary or metastatic lesion.  If no 


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archival tissue is available and patient consents to a fresh biopsy, but the patient’s lesion is deemed 
inaccessible to safe biopsy, the patient will be allowed to enroll if otherwise eligible.  
 
9.  STUDY TREATMENT 
9.1.  Infusion Premedications 
 
Subjects will receive avelumab by IV infusion following pretreatment with H1 blockers and 
acetaminophen once every 2 weeks. In order to mitigate infusion-related reactions, premedication 
with an antihistamine plus paracetamol (acetaminophen) approximately 30 to 60 minutes prior to 
the first four infusions of avelumab is mandatory.  For example:  25-50 mg diphenhydramine and 
500-650 mg paracetamol (acetaminophen) IV or oral equivalent.  Premedication should be 
administered for subsequent avelumab infusions based upon clinical judgement and 
presence/severity of prior infusion reactions.  As appropriate, this may be modified based on local 
treatment standards and guidelines provided it does not include systemic corticosteroids.  
 
9.2  Avelumab Infusion 
 
In this clinical trial, the avelumab dose will be 10 mg/kg administered as 1-hour intravenous (IV) infusion 
every 2 weeks (Q2W).  Patient vital signs will be monitored at ≤10 minutes prior to avelumab infusion, 
and ≤10 minutes after avelumab infusion.  Following avelumab infusions, patients must be observed for 
30 minutes post infusion for potential infusion related reactions.    See schedule of assessments (Section 
7.1) for the specific vital signs that will be monitored. 
 
This dose is the recommended dose administered to more than 480 patients in the ongoing dose-
expansion phase of study EMR 100070-001 (see Section 4 for details). 
 
Avelumab will be administered on Day 1 of each cycle after all assessments and procedures have 
been completed as described in the Schedule of Assessments table (Section 7).  
 
Cycle 2, Day 1 dosing should occur 14 days after Cycle 1, Day 1.  In the absence of delayed dosing 
(e.g. due to an adverse event), every reasonable effort should be made to remain on a consistent 
schedule of 14-day cycles; but for purpose of accommodating holidays, scheduling limitations, etc, 
subsequent cycles (i.e. Cycles 3+) may occur up to every 14 days +3 days.  Consecutive doses of 
avelumab must be separated by no fewer than 14 days and, in the absence of adverse event 
management, no more than 17 days. 
 
Every effort should be made to target infusion timing to be as close to 1 hour as possible.  
However, given the variability of infusion pumps, time windows of -10 minutes and +20 minutes 
are permitted (i.e. the scheduled avelumab infusion time is 60 minutes:  -10 min/+20 min).   
 
The exact duration of infusion should be recorded in both source documents and data case report 
forms (CRFs).  Possible modifications of the infusion rate for the management of infusion-related 
reactions are described in Section 11. 
 


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The dose amount required to prepare the avelumab infusion solution will be based on the patient’s 
weight in kilograms (kg).  All patients should be weighed within 3 days prior to every dose of 
avelumab.  
 
If a patient experiences either a weight loss or gain ≥ 10% compared to the weight used to calculate 
the patient’s immediately prior dose, then the amount avelumab required for a current dose must 
be recalculated using the most recent weight obtained.   
 
Avelumab dose reduction for toxicity management is not permitted, however avelumab 
administration may be held due to adverse event as described in Section 11. 
 
Even if treatment is held, the numerical 14-Day “cycle clock” should still keep running as scheduled, 
as an overall indication of time elapsed since the first infusion on Cycle 1, Day 1 (e.g. if treatment is 
withheld on Cycle 2, Day 1, the respective calendar day will still be recorded as Cycle 2, Day 1 and 
not Cycle 1, Day 15, etc).  In the event of treatment interruption, the study records should reflect 
treatment was withheld; other visit procedures, including re-scanning for purpose of monitoring for 
disease progression should still be completed as previously intended by the study calendar.   
 
9.3.  Duration of Study Treatment 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance to study treatment.  In the absence of treatment delays due to adverse event, treatment 
may continue until applicability of a criterion listed in Sections 9.4 and 11. 
 
9.4.  Discontinuation of Study Treatment 
Discontinuation of study treatment will be required if deemed by the investigator to be in the 
subject’s best interest or if subject meets any of the criteria for study withdrawal listed below: 
• 
Disease progression as assessed by RECIST 1.1 criteria (Appendix 1), unless the subject 
meets criteria for treatment beyond progression (Section 9.7); 
• 
Termination of the study by Vanderbilt or relevant regulatory authority; 
• 
Drug availability or study supply discontinued; 
• 
The patient withdraws consent to undergo further treatment; 
• 
The patient is lost to follow-up, refuses further follow-up, or is noncompliant; 
• 
The patient no longer requires treatment (e.g. patients having experienced a tumor 
reduction followed by resection and no longer with evaluable disease); 
• 
Initiation of treatment with another anti-cancer therapy; 
• 
Additional protocol specified reason for discontinuation (e.g. related to adverse event), 
see Section 11. 
In the case of pregnancy, the investigator must immediately notify the EMD Serono medical 
designee of this event.  In most cases, the study drug will be permanently discontinued in an 
appropriate manner.  If the investigator determines a possible favorable benefit/risk ratio warrants 
continuation of study drug, a discussion between the investigator and appropriate internal and 
external entities must occur (e.g. the IRB and the EMD Serono medical designee). 
If a patient does not return for a scheduled visit, every reasonable effort should be made to contact 
the patient.  In any circumstance, every reasonable effort should be made to document subject 
outcome, if possible.  The investigator should inquire about the reason for withdrawal, request the 
patient to return for a final visit, if applicable, and follow-up with the patient regarding any 
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All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 7.  The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (e.g. is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness). 
If study drug is discontinued, the reason for the discontinuation must be documented in the 
subject’s medical records and entered on the appropriate CRF page. 
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information during follow-up, no further study specific evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to use any data collected 
before such withdrawal of consent. 
 
9.5.  Duration of Follow-Up 
In general, it intended that patients will be treated until disease progression or intolerable toxicity.  
The criteria for patient discontinuation are listed in Section 9.4.  Patients should be assessed when 
it is decided that the patient will no longer receive study treatment; and assessed again 28 days (± 
7 days) later – i.e. at least 30 days after patient’s final treatment with avelumab.  
 
Subsequently, each patient will be followed for survival every 3 months (± 14 days) after patient’s final 
treatment with avelumab until death, end of the study, or until patient withdraws consent, whichever 
comes first.  Contact can be made via clinic visit, chart review, obituary or similar observation (e.g. Social 
Security death index), or by telephone. 
 
9.6.  Withdrawal from Study  
 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, or behavioral 
reasons; or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures, or an inability to maintain voluntary informed consent.  Reasons for 
withdrawal from the study might include:  Subject withdraws consent for follow-up, subject is lost 
to follow-up, or study is terminated for any reason. 
 
9.7.  Treatment After Initial Evidence of Radiologic Disease Progression 
 
Immunotherapeutic agents such as avelumab may produce antitumor effects by potentiation of 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, and 
can manifest as a clinical response after an initial increase in tumor burden or even the appearance 
of new lesions. 
 
Subjects treated with avelumab will be permitted to continue treatment beyond initial RECIST 
1.1 defined progressive disease (PD) while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria: 
• 
Investigator-assessed clinical benefit and absence of rapid disease progression 
• 
Tolerating study drug 


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• 
Stable performance status 
• 
Absence of progressive tumor at critical anatomical sites (e.g. cord compression) 
requiring urgent alternative medical intervention. 
The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
subject is clinically deteriorating and unlikely to receive any benefit from continued treatment with 
avelumab.  
 
All decisions to continue treatment beyond initial progression should be documented in the study 
records.  The subject will continue to receive monitoring according to the Schedule of Assessments 
listed in Section 7. 
 
If radiologic imaging shows initial disease progression, repeat scanning and tumor assessment 
should be performed 4 to 6 weeks later in order to confirm the observation, unless an alternative 
rescanning interval is provoked by clinical deterioration.   
 
Assigned study treatment may be continued at the investigator’s discretion while awaiting 
radiologic confirmation of disease progression.  In determining whether or not the tumor burden 
has increased or decreased, investigators should consider all target as well as non-target lesions. 
For subjects continuing avelumab beyond initial progression, further disease progression is 
defined as an additional 10% increase in tumor burden volume from time of initial PD.  This 
includes an increase in the sum of all target lesions and/or the development of new measurable 
lesions.  For subjects with evaluable disease only, further progression is defined as unequivocal 
disease progression of non-target lesions or the development of new measurable lesions from time 
of initial PD.   
 
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 15 
mm).  Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore be included in the tumor burden measurement if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes, which must have an increase in 
short axis to at least 15 mm). 
 
Upon documentation of further disease progression, avelumab treatment should be discontinued 
permanently.  However, according to the investigator’s clinical judgment and after any necessary 
discussion between the investigator and EMD Serono, if a patient with evidence of PD is still 
experiencing clinical benefit, the patient may be eligible for continued treatment with avelumab.  
The investigator’s judgment should be based on the overall benefit-risk assessment and the 
patient’s clinical condition, including performance status, clinical symptoms, adverse events and 
laboratory data. 
 
Patients who stop avelumab treatment and then experience radiologic disease progression 
thereafter will be eligible for re-treatment with avelumab at the discretion of the investigator and 
after IRB approval and any necessary discussion with EMD Serono if:  1) no anti-cancer treatment 
was administered since the last dose of avelumab, 2) the patient does not meet the safety 
withdrawal criteria, and 3) the trial is still open.  Patients will resume avelumab therapy at the 
same dose and schedule applied at the time of discontinuation. 
Global deterioration of health status requiring discontinuation of treatment without 
contemporaneous evidence of objective disease progression should be reported as ‘symptomatic 


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deterioration’.  Every effort should be made to document objective progression (i.e. radiographic 
confirmation) even after discontinuation of treatment. 
 
10.  CONCOMITANT TREATMENT 
10.1.  Supportive Care Guidelines 
Patients should be advised to inform their study doctor of all concomitant medications, including 
over-the-counter medications and dietary supplements. 
All concomitant medications taken within 28 days prior to first dose of study drug treatment and 
during the clinical trial (up to 30 days post-treatment) must be recorded on the appropriate Case 
Report Form. 
 
Subjects are permitted the use of corticosteroids with minimal systemic absorption (e.g. topical, 
ocular, intra-articular, intranasal, and inhaled).   
Adrenal replacement steroid doses including doses > 10 mg daily prednisone are permitted.   
 
A brief (less than 3 weeks) 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 a contact allergen) is permitted.   
 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
• 
Diarrhea:  All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion. 
 
• 
Nausea/Vomiting:  Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic 
therapy according to standard institutional practice.  Patients should be strongly 
encouraged to maintain liberal oral fluid intake. 
 
• 
Anti-infectives:  Patients with a documented infectious complication should receive oral or 
IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice. 
Prophylactic administration should be considered for the cases outlined in Section 11. 
 
• 
Anti-inflammatory or narcotic analgesics may be offered as needed. 
Acetaminophen/paracetamol to a maximum total daily dose of 2 g is permitted.  Daily 
intake over 2 g is prohibited.   
 
• 
Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin.  Monitoring of prothrombin time/international 
normalized ratio (PT/INR) should be performed as appropriate. 
 
 
 
 


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10.2.  Prohibited and/or Restricted Medications and Therapies 
Patients are prohibited from receiving the following therapies during the treatment phase of this 
trial: 
• 
Immunotherapy or immunosuppressive drugs (i.e. chemotherapy or systemic 
corticosteroids) except for short-term treatment of allergic reactions or for the treatment 
of an immune-related adverse event (irAE).  Short-term administration of systemic 
steroids (e.g. for allergic reactions or the management of irAEs) is allowed.  Topical and 
inhaled steroids are allowed. 
 
• 
Systemic corticosteroids > 10 mg daily prednisone equivalent, except as stated in Section 
10.1 or to treat a drug-related AE (e.g. Section 11). 
 
• 
Growth factors (granulocyte colony-stimulating factor or granulocyte-macrophage colony 
stimulating factor) are prohibited.   
 
• 
Vaccination within 28 days of the first dose of avelumab and while on study is prohibited, 
except for administration of inactivated vaccines (for example, inactivated influenza 
vaccines). 
 
• 
Bisphosphonate or denosumab treatment is not allowed unless it has been initiated more 
than 14 days prior to receiving the first administration of avelumab. 
 
• 
Anti-cancer systemic chemotherapy or biological therapy or investigational agents other 
than avelumab. 
 
• 
Surgical resection of tumor. 
• 
Other experimental pharmaceutical products. 
 
• 
Herbal remedies reasonably known to have immunostimulating properties (e.g. mistletoe 
extract) or reasonably known to potentially interfere with major organ function (e.g. 
hypericin). 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
10.3.  Clarifications about Steroid Use 
 
Data indicate that corticosteroids have an adverse effect on T cell function and that they inhibit 
and damage lymphocytes.44,45  Furthermore, as with all immunotherapies intended to augment 
cell-mediated immunity, there is a risk that concomitant immunosuppressives such as steroids 
will counteract the intended benefit of the proposed study treatment.  However, studies with 
anti-CTLA-4 compounds indicate that short-term use of steroids may be employed without 
compromising clinical outcomes.46 
 
Therefore, the use of steroids during this trial is restricted as follows: 


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• 
Therapeutic use:  For treatment of infusion-related reactions and short-term treatment of  
immune-related adverse events (irAEs), steroids are permitted according to the modalities 
outlined in Section 11. 
• 
Physiologic use:  Adrenal replacement steroid doses including doses > 10 mg daily 
prednisone or equivalent is acceptable. 
• 
Prophylactic use (e.g. for the prevention of acute infusion-related reactions) is prohibited, 
except prior to CT or MRI scan, or for the management of immune-related adverse events 
(irAEs) as outlined in Section 11. 
 
10.4.  Hematopoietic Growth Factors and Transfusional Support 
• 
Packed red blood cell and platelet transfusions should be administered only if clinically 
indicated, and should be avoided during the first 28 days after the start of a patient’s first 
avelumab infusion. 
 
• 
Growth factors (granulocyte colony-stimulating factor or granulocyte-macrophage colony 
stimulating factor) are prohibited.   
 
Patients who enter the study on stable doses of erythropoietin or darbepoietin may continue this 
treatment, and patients may start either drug during the study (if necessary, then ideally after 
the first 28 days of study treatment) at the discretion of the treating physician if clinically 
indicated. 
 
10.5.  Concomitant Radiotherapy 
 
The potential for overlapping toxicities with radiotherapy and avelumab is currently unknown.  Per 
eligibility criteria, prior therapeutic or palliative radiation therapy must be completed within 14 
days prior to first dose of avelumab.  After beginning study treatment, palliative radiotherapy is 
generally not recommended while receiving avelumab.  
 
However, local radiotherapy of isolated lesions with palliative intent (e.g. bleeding, pain, 
compression, etc) is permitted if considered medically necessary by the treating physician.  The 
irradiated area should be as small as possible.  Irradiated lesions will be followed for disease 
progression but will not be accounted for in the evaluation of the response.   
 
Subjects requiring palliative radiotherapy should be assessed for disease progression.  If palliative 
radiotherapy is needed to control pain, the site(s) of disease causing pain should be present at 
baseline; otherwise, painful lesion(s) requiring radiotherapy should be considered as a sign of 
disease progression. 
 
Subjects considered as having progressive disease are required to discontinue study therapy, or if 
appropriate, continue avelumab therapy as treatment beyond progression.  Administration of 
additional avelumab to subjects who experienced disease progression at the time of palliative 
radiotherapy should follow guidelines specified in Section 9.7 (Treatment After Initial Evidence of 
Radiologic Disease Progression). 
 


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If palliative radiotherapy to bone metastases is required, then avelumab should be withheld for at 
least 1 week before, during, and 1 week after radiation.  Subjects should be closely monitored for 
any potential toxicity during and after receiving radiotherapy, and adverse events considered 
related to radiotherapy should resolve to Grade ≤ 1 prior to resuming avelumab. 
 
Only non-target bone lesions that do not include lung tissue in the planned radiation field may 
receive palliative radiotherapy while on study treatment.  Details of palliative radiotherapy should 
be documented in the source records and case report form (CRF).  Details in the source records 
should include:  dates of treatment, anatomical site, dose administered and fractionation 
schedule, and adverse events.   
 
11.  ADVERSE EVENT MANAGEMENT 
11.1.  Criteria for Holding Treatment for Adverse Event Possibly Related to Avelumab 
 
No dose reductions of avelumab are permitted for the management of adverse events 
experienced by individual patients in this study. 
 
As outlined below, treatment delays of up to 4 weeks (28 days) from last dose of avelumab are 
allowed. 
 
Avelumab Treatment Should be DELAYED up to 4 Weeks (28 days) for the following Adverse 
Events if at least Possibly related to Avelumab: 
 
• 
Any Grade ≥ 3 drug-related adverse event, with the exception of alopecia and the following laboratory 
exceptions for lymphopenia, leukopenia, AST, ALT, and total bilirubin: 
 
 Grade 3 lymphopenia or leukopenia do not require a dose delay.   
 If subject had baseline AST, ALT, or total bilirubin within normal limits, then delay dosing for 
drug-related Grade ≥ 2 liver function toxicity. 
 If subject had baseline AST, ALT, or total bilirubin that was Grade 1, then delay dosing for drug-
related Grade ≥ 3 liver function toxicity. 
 
• 
Any AE, laboratory abnormality, or intercurrent illness regardless of severity or attribution to avelumab 
which, in the judgment of the investigator, warrants delaying investigational treatment with avelumab. 
 
 
IMPORTANT:   
The above list does NOT include other events which may require holding study treatment – even in cases of 
severity less than Grade 3 and regardless of attribution to study drug.  Events such as Immune-Related 
Adverse Events (irAEs) of Special Interest, Infusion Reactions, Hypersensitivity, or Tumor Lysis Syndrome (if 
applicable) should be managed according to local institutional practice. 
 
Dose delay criteria apply for drug-related adverse events – i.e. events which in the investigator’s 
opinion are possibly, probably, or definitely related to avelumab.  For adverse events deemed 
unlikely or unrelated to avelumab (e.g. related to disease), the medical judgement of the 
investigator should determine the extent to which a treatment delay is appropriate.   
 


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If avelumab treatment is delayed for > 4 weeks (28 days) from the last dose of avelumab, the 
subject must be permanently discontinued from study therapy, except as may be specified in 
Sections 9.4 and 11.3. 
 
The window for a maximal 4 week (28 day) avelumab treatment delay begins on the calendar day of 
the most recent avelumab treatment preceding an event in question, and concludes on the calendar 
day that an immediately subsequent avelumab treatment is initiated. 
 
In the event of multiple toxicities, treatment delay should be based on the worst toxicity observed. 
 
In general, an adverse event related to study treatment that results in a dose delay should be 
present on the day of intended study treatment (i.e. a delayed toxicity that develops mid-cycle, but 
which is no longer present or has resolved to an acceptable grade on the day of intended dosing, 
generally does not require a delay in treatment). 
 
Patients should be instructed to notify their study team at the first occurrence of any adverse 
symptom.  In addition to dose delays according to protocol guidance, investigators are encouraged 
to employ best supportive care according to local institutional clinical practice. 
 
Even if study drug dosing is interrupted, tumor scans and other visits, assessments and procedures 
should continue per protocol (i.e. per timeline in place prior to the dose interruption). 
 
11.2.  Criteria for Resuming Treatment Held for Adverse Event Related to Avelumab 
 
If a subject’s avelumab treatment is held due to an adverse event that is possibly, probably or 
definitely related to avelumab, the subject may resume treatment with avelumab when the 
related adverse event resolves to ≤ Grade 1 or to patient’s baseline value, with the following 
exceptions: 
 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue or alopecia of any 
grade. 
 
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity 
 
• 
Subjects with a Grade 2 AST/ALT or total bilirubin may resume treatment IF patient’s 
respective baseline AST/ALT or total bilirubin was Grade 1 and the reason for patient’s 
dose delay was NOT due to a 2 or more grade increase in AST/ALT or total bilirubin.   
 
• 
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued 
 
• 
Drug-related pulmonary toxicity or colitis must have resolved to baseline before 
treatment is resumed 
 
• 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment.  
 
The subject’s baseline value is defined as the most recent value preceding initiation of the 
patient’s first dose of avelumab. 
 


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In the event study treatment is held due to an event the investigator feels is unlikely related or not 
related to avelumab (e.g. hold study drug per investigator discretion in order to evaluate 
appropriate attribution to disease versus drug), then resumption of avelumab may proceed 
according to the medical judgement of the investigator (with maintained accordance to other 
protocol sections). 
 
If treatment is delayed > 4 weeks (28 days) from the last dose of avelumab, the subject must be 
permanently discontinued from study therapy, except as may be specified in Sections 9.4, 11.2 
and 11.7. 
 
11.3.  Guidelines for the Management of Infusion Reaction 
 
Since avelumab is administered via intravenous (IV) infusion, an infusion-related reaction may 
occur with symptoms possibly including but not limited to fever, chills, rigors, diaphoresis, and 
headache.  In the event of an actual or suspected infusion reaction, avelumab treatment should 
be modified according to the guidelines listed below in conjunction with any overriding local 
policies and procedures for the management of infusion-related reactions. 
 
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 judgement. The total infusion time for avelumab 
should not exceed 120 minutes. If a subject experiences a Grade 3 or 4 infusion-related reaction 
at any time, the subject must discontinue study drug.  
 
 
Infusion Modifications for Symptoms of Infusion Reaction 
NCI CTCAE 
Severity Grade 
Avelumab 
Treatment Modification 
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 
(e.g. antihistamines, NSAIDs, narcotics, IV fluids);  
 
• Prophylactic medications indicated for ≤ 24 
hours. 
 
• Temporarily discontinue avelumab infusion 
 
• Resume infusion at 50% of previous rate as 
soon as infusion-related reaction has 
resolved or decreased to at least Grade 1 in 
severity 
 
Monitor closely for any recurrence or worsening. 


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Grade 3 or Grade 4 – Severe or Life-threatening 
 
Grade 3:   
• 
Prolonged (e.g. not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion);  
 
• 
Recurrence of symptoms following initial 
improvement;  
 
• 
Hospitalization indicated for clinical 
sequelae. 
 
Grade 4:   
• Life-threatening consequences;  
 
Urgent intervention indicated. 
• Stop the avelumab infusion immediately 
 
• Disconnect bag infusion tubing from the 
patient. 
 
Permanently discontinue avelumab treatment. 
 
IV = intravenous, NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events,  
NSAIDs = Non-steroidal anti-inflammatory drugs. 
 
Additional Modifications for Patients with Grade 2 Infusion-Related Reactions: 
 
In the event a Grade 2 infusion-related reaction does not improve or worsens after 
implementation of the modifications indicated in the above table (including reducing the infusion 
rate by 50%), the investigator may consider treatment with corticosteroids, and the infusion 
should not be resumed for that cycle.  At the next cycle, the investigator may consider the 
addition of H2-blocker antihistamines (e.g. famotidine or ranitidine), meperidine, or ibuprofen in 
supplement to the premedications recommended in Section 9.1.  Prophylactic steroids are NOT 
permitted. 
 
11.4.  Management of Severe Hypersensitivity Reaction and Flu-Like Symptoms 
 
As with all monoclonal antibody therapies, avelumab can induce flu-like symptoms and 
hypersensitivity reactions, including impaired airway, decreased oxygen saturation (<92%), 
confusion, lethargy, hypotension, pale/clammy skin, and cyanosis. 
 
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 dilution), allergy medications (IV antihistamines), bronchodilators, or 
equivalents, and oxygen should be available for immediate access. Subjects should be instructed 
to report any delayed reactions to the Investigator immediately. 
 
For prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable non-steroidal anti-
inflammatory drug (NSAID) dose (e.g. 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 (e.g. paracetamol or ibuprofen) may be given to patients at the 
discretion of the investigator. 


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11.5.  Management of Tumor Lysis Syndrome 
 
Because avelumab can induce antibody-dependent cell-mediated cytotoxicity (ADCC), there is a 
potential risk of tumor lysis syndrome (TLS).  Should this occur, patients should be treated 
according to local guidelines and the management algorithm (Appendix 6) published by Howard et 
al.47 
 
11.6.  Management of Immune-Related Adverse Events (irAEs)  
 
Since inhibition of PD-L1 stimulates the immune system, immune-related adverse events (irAEs) 
may occur.  Any adverse event judged by the investigator to be possibly, probably or definitely 
immune-related should be managed according to the guidance in this section for the 
management of immune-related adverse events, except for circumstances in which local or 
other standards known to exist are felt by the investigator to present a more medically 
appropriate course of management.    
 
Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
• 
Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more frequent 
monitoring 
• 
Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4) 
• 
Grade 3 to 4:  treat with high dose corticosteroids 
 
Some potential irAEs described with anti-PD-L1 drugs such as avelumab may be similar to 
toxicities related to disease (e.g. diarrhea related to adenocarcinoma of the small intestine).  In 
general:  Rule out non-inflammatory causes; if non-inflammatory cause is identified, treat 
accordingly and continue study treatment according to protocol.   
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events.   
Patients treated for irAEs with IV steroids may be switched to an equivalent dose of oral 
corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into 
account when switching to the equivalent dose of oral corticosteroids. 
 
 
MANAGEMENT of GASTROINTESTINAL IMMUNE-RELATED ADVERSE EVENTS (irAEs) 
 
Diarrhea / Colitis 
Management 
Follow-Up 
 
Grade 1 
 
Diarrhea:  
< 4 stools/day over baseline 
 
Colitis: 
Asymptomatic 
• Continue avelumab 
therapy per protocol. 
 
• Symptomatic treatment 
(e.g. loperamide). 
• Close monitoring for worsening 
symptoms.   
 
• Educate patient to immediately report 
worsening. 
 
If worsens: 
• Treat as Grade 2, or Grade 3 to 4. 


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MANAGEMENT of GASTROINTESTINAL IMMUNE-RELATED ADVERSE EVENTS (irAEs) 
 
Diarrhea / Colitis 
Management 
Follow-Up 
Grade 2 
 
Diarrhea:  
4 to 6 stools per day over 
baseline; IV fluids indicated 
< 24 hours; not interfering with 
ADL 
 
Colitis:  
Abdominal pain; blood in 
stool 
• Delay avelumab therapy 
per protocol. 
 
• Symptomatic treatment. 
If improves to Grade ≤1: 
• Resume avelumab therapy per 
protocol. 
 
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 hrs; interfering 
with ADL 
 
Colitis (Grade 3):  
Severe abdominal pain, 
medical intervention indicated, 
peritoneal signs 
 
Grade 4:  
Life-threatening, perforation 
 
 
• Withold avelumab for 
Grade 3 
• Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3 
• 1.0 to 2.0 mg/kg/day 
methlyprednisolone 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 5 mg/kg (if no 
contraindication).  Note:  Infliximab 
should not be used in cases of 
perforation or sepsis. 
 
Opiates/narcotics may mask symptoms of perforation.  Inliximab should not be used in cases of 
perforation or sepsis. 
 
 


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MANAGEMENT of DERMATOLOGIC IMMUNE-RELATED ADVERSE EVENTS (irAEs) 
 
Rash 
Management 
Follow-Up 
Grade 1 to 2 
Covering ≤ 30%  
body surface area  
(BSA) 
 
 
• Continue avelumab 
therapy per protocol. 
• Symptomatic therapy (for 
example, antihistamines, 
topical steroids) 
If persists > 1 to 2 weeks or recurs: 
• withhold avelumab therapy 
• Consider skin biopsy. 
• 
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent.  Once improving, taper 
steroids over at least 1 month, 
consider prophylactic antibiotics 
for opportunistic infections, and 
resume avelumab therapy 
following steroids taper. 
 
If worsens:   
• Treat as Grade 3 to 4. 
Grade 3  
Covering > 30% BSA;  
 
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 
methylprednisolone IV or 
IV equivalent. 
• Add prophylactic 
antibiotics for 
opportunistic infections. 
If improves to Grade ≤ 1:   
• Taper steroids over at least 1 month 
and add prophylactic antibiotics for 
opportunistic infections 
• 
Resume avelumab therapy 
following steroids taper (for initial 
Grade 3). 
 
 
 


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MANAGEMENT of PULMONARY IMMUNE-RELATED ADVERSE EVENTS (irAEs) 
 
Pneumonitis 
Management 
Follow-Up 
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 
methylprednisolone IV 
or IV equivalent. 
 
• Add prophylactic 
antibiotics for 
opportunistic infections 
 
• Consider bronchoscopy, 
lung biopsy. 
• 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 per protocol following 
steroids taper and consider 
prophylactic antibiotics. 
 
If not improving after 2 weeks or worsening:   
• Treat as Grade 3 to 4. 
Grade 3 to 4 
Grade 3: Severe new 
symptoms; 
New / worsening hypoxia; 
 Grade 4: life-threatening 
• Permanently discontinue 
avelumab therapy per 
protocol. 
 
• Hospitalize. 
 
• Pulmonary and 
Infectious Disease 
consults. 
 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone IV 
or IV equivalent. 
 
• Add prophylactic 
antibiotics for 
opportunistic infections. 
 
• Consider bronchoscopy, 
lung biopsy. 
If improves to Grade ≤ 1:   
• Taper steroids over at least1 month. 
 
If not improving after 48 hours or 
worsening:   
• Add additional immunosuppression 
(e.g. infliximab, cyclophosphamide, 
intravenous immunoglobulin, or 
mycophenolate mofetil). 
Evaluate with imaging and pulmonary consultation as appropriate. 


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MANAGEMENT of RENAL IMMUNE-RELATED ADVERSE EVENTS (Renal irAEs 
 
Renal Disorder 
Management 
Follow-Up 
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. 
 
MANAGEMENT of HEPATIC IMMUNE-RELATED ADVERSE EVENTS (irAEs) 
Elevated Liver Function Test (LFT) 
Management 
Follow-Up 
 
Grade 1 
 
AST or ALT 
> ULN to 3.0 x ULN 
 
and/or 
 
total bilirubin 
> ULN to 1.5 x ULN 
• Continue avelumab 
therapy per protocol. 
• Continue liver function monitoring per 
protocol. 
 
If worsens:   
• Treat as Grade 2 or Grade 3 to 4. 
 
Grade 2 
 
AST or ALT 
> 3.0 to ≤ 5 x ULN 
 
and/or 
 
total bilirubin 
> 1.5 to ≤ 3 x ULN 
 
• Delay avelumab therapy 
per protocol. 
 
• Increase frequency of 
monitoring to every 3 
days. 
If returns to Grade ≤ 1:   
• Resume routine monitoring, resume 
avelumab therapy per protocol. 
 
If elevations persist > 5 to 7 days or worsen:   
• Treat as Grade 3 or 4. 
Grade 3-4 
 
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 
methylprednisolone IV or 
IV equivalent. 
 
• Add prophylactic 
antibiotics for 
opportunistic infections. 
 
• Consult 
gastroenterologist/hepat
ologist 
 
• Consider obtaining 
MRI/CT scan of liver and 
liver biopsy if clinically 
warranted. 
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 (BID). 
• If no response within an additional 3 to 5 
days, consider other 
immunosuppressants per local guidelines. 


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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. 
 
 
MANAGEMENT of ENDOCRINE IMMUNE-RELATED ADVERSE EVENTS (irAEs): 
 
Endocrine Disorder 
Management 
Follow-Up 
Grade 1 or 2 endocrinopathies 
(hypothyroidism, hyperthyroidism, 
adrenal insufficiency, type I 
diabetes mellitus) 
• Continue avelumab therapy per 
protocol. 
• 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 functions as 
appropriate. 
 
 
 
 
 
 
 
 
 
 
 


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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 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 MRI in one month 
• 
Withhold avelumab if mild 
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 
• 
Resume avelumab once 
symptoms and hormone tests 
improve to Grade ≤ 1 (with or 
without hormone replacement). 
 
• 
In addition for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the 
pituitary gland on MRI/CT scan is 
documented. 
 
• 
Continue hormone replacement 
therapy suppression as 
appropriate. 


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MANAGEMENT OF CARDIAC IMMUNE-RELEATED ADVERSE EVENTS (irAEs) 
Myocarditis 
Management 
Follow-up 
New onset of cardiac signs or 
symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g. troponin, CK-
MB, BNP) or cardiac imaging 
abnormalities suggestive of 
myocarditis. 
• Withhold avelumab therapy. 
 
• Hospitalize. 
 
• In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility 
experienced in advanced heart 
failure and arrhythmia 
management. 
 
• Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis.  
 
• Guideline based supportive 
treatment as per cardiology 
consult.* 
 
• Consider myocardial biopsy if 
recommended per cardiology 
consult. 
• If symptoms improve and immune-
mediated etiology is ruled out, re-
start avelumab therapy. 
 
• If symptoms do not 
improve/worsen, viral myocarditis 
is excluded, and immune-mediated 
etiology is suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis 
• Permanently discontinue 
avelumab. 
 
• Guideline based supportive 
treatment as appropriate as per 
cardiology consult.* 
 
• Methylprednisolone 1 to 2 
mg/kg/day 
 
• 
Once improving, taper steroids 
over at least 1 month   
 
• 
Prophylactic antibiotics for 
opportunistic infections. 
 
• 
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A) 
 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
 
 
MANAGEMENT OF OTHER irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4) 
Management 
Management 


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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. 
Recurrence of same Grade 3 
irAEs 
• Permanently discontinue 
avelumab therapy 
1.0 to 2.0 mg/kg/dayprednisone 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. 
 
 
 
 
12.  DRUG FORMULATION, SUPPLY AND STORAGE 


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12.1.  Description of Avelumab 
The active pharmaceutical ingredient in avelumab drug product is a fully human antibody 
(calculated molecular weight of 143,832 Daltons) of the immunoglobulin G (IgG) 1 isotype that 
specifically targets and blocks PD-L1, the ligand for PD-1. 
 
Avelumab drug product is a sterile, clear, and colorless concentrate for solution intended for 
intravenous (i.v.) administration.   
 
12.2.  Packaging and Labeling of Avelumab  
Avelumab will be provided by EMD Serono.  Avelumab drug product is a sterile solution intended 
for intravenous (i.v.) administration.   
Avelumab drug product is a sterile, clear, and colorless concentrate for solution typically 
presented at concentrations of 10 mg/mL and 20 mg/mL in single use glass vials closed with a 
rubber stopper and sealed with an aluminum Flip Off® crimp seal closure. 
Each single-use 10 mg/mL vial typically contains 80 mg of avelumab as a preservative-free acetate-
buffered solution (pH 5.5) containing Mannitol, Methionine, and Polysorbate 20 (Tween 20). 
Each single-use 20 mg/mL vial typically contains 200 mg of avelumab as a preservative-free 
acetate-buffered solution (pH 5.2) containing Mannitol and Polysorbate 20 (Tween 20). 
For avelumab drug product, only excipients that conform to the current European Pharmacopeia 
(Ph. Eur.) and/or the current United States Pharmacopeia (USP) are used. 
 
12.3.  Storage of Avelumab 
Avelumab drug product must be stored at 2◦C to 8◦C until use, and it must not be frozen.  
 
Avelumab drug product stored at room (23◦C to 27◦C) or higher temperatures for extended 
periods of time might be subject to degradation.  Rough shaking of the solution must be avoided.  
 
For application in clinical trials, avelumab drug product must be diluted with 0.45% or 0.9% saline 
solution (sodium chloride injection) supplied in an infusion bag.  
 
It is recommended that diluted avelumab solution be used immediately.  The chemical and 
physical in-use stability for the infusion solution of avelumab in 0.45% or 0.9% saline solution has 
been demonstrated for a total of 24 hours at room temperature.  However, from a microbiological 
point of view, the diluted solution should be used immediately and is not intended to be stored 
unless dilution has taken place in controlled and validated aseptic conditions.  If not used 
immediately, in-use storage times and conditions prior to administration are the responsibility of 
the user. 
 
No other drugs should be added to the solution for infusion containing avelumab. 
 
12.4.  Accountability of Avelumab 
Discarded volumes of avelumab should be disposed of as clinical waste.  Partially full and empty 
vials may be destroyed at the site by the appropriate site personnel (e.g. Pharmacist or Study 
Nurse/Coordinator) following local environmental requirements and institutional policies.  All 


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destruction must be fully documented on an Investigational Product Accountability Log (IPAL) or 
similar at the time of destruction.   
 
 
 
13.  MEASUREMENT of EFFECT 
13.1.  Definitions 
 
For purposes of this study, patients should be re-evaluated for response every 8 weeks. Response 
and progression will be evaluated using the international criteria proposed by the revised 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1) and immune-
related response criteria (irRC).   Any evaluable or measurable disease must be documented at 
screening and reassessed at each subsequent tumor evaluation.  If a patient is found to have 
disease progression by RECIST, at the discretion of the treating physician, the patient may remain 
on study.  Baseline evaluation of disease status by CT or MRI required within 28 days prior to first 
dose of avelumab.  The first scheduled re-scan should be performed and evaluated 7 to 8 weeks 
after Cycle 1, Day 1 treatment, with subsequent scheduled scans intended every 8 to 9 weeks 
thereafter.  If progression is confirmed by irRC, the patient should typically be removed from study 
(i.e. in the absence of therapeutic benefit and an alternative agreement and arrangement 
specified by protocol).  If irRC show the patient to not have disease progression, the patient may 
remain on study.   
 
Evaluable for toxicity:  All patients will be evaluable for toxicity from time of their first treatment 
with avelumab.   
 
Evaluable for objective response:  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
 
If a patient discontinues study treatment for reasons clearly not related to study treatment, after 
completing fewer than one planned infusion of avelumab, and/or receiving <75% of the total 
intended dose of avelumab over the first cycle of treatment + an additional 14 days (i.e. first 28 
days after initiating patient’s first dose of avelumab), then that patient will be considered not 
evaluable for response to study treatment and may be replaced with a new patient.   
 
13.2.  Disease Parameters 
13.2.1 Measurable 
Tumor lesions:  Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
• 
10mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 
10mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable). 
• 
20mm by chest X-ray. 
 


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Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph node must 
be ≥15mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed.  
 
13.2.2 Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes with ≥10 
to <15mm short axis) as well as truly non-measurable lesions.  Lesions considered truly non-measurable 
include:  leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques. 
 
13.2.3 Special considerations regarding lesion measurability 
 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions.  However, these techniques can be used to confirm the presence or disappearance 
of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
• 
Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above.  However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.   
 
13.2.4 Specifications by methods of measurements 
 
Measurement of lesions: 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks (28 days) before the beginning of study treatment. 
 
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The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up.  Imaging-based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable 
by clinical exam. 
• 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial and ≥10mm diameter as assessed using calipers (e.g. skin nodules).  For the 
case of skin lesions, documentation by colour photography including a ruler to estimate 
the size of the lesion is suggested.  When lesions can be evaluated by both clinical exam 
and imaging, imaging evaluation should be undertaken since it is more objective and 
may also be reviewed at the end of the study. 
 
• 
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung.  
 
• 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  Guidelines have defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5mm or less.  When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for 
bodyscans).  
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised.  If there is concern about 
radiation exposure at CT, MRI may be used instead of CT in selected instances. 
 
• 
Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response or surgical resection is an endpoint. 
 
• 
Tumor markers:  Tumor markers alone cannot be used to assess objective  tumor 
response.  If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response.  
 
• 
Cytology, histology:  These techniques can be used to differentiate between PR and CR 
in rare cases if required by protocol (for example, residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain).  When effusions 
are known to be a potential adverse effect of treatment (e.g. with certain taxane 
compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic 
origin of any effusion that appears or worsens during treatment can be considered if the 


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measurable tumor has met criteria for response or stable disease, in order to 
differentiate between response (or stable disease) and progressive disease. 
 
13.3.  Response Criteria 
13.3.1 Target lesions 
When more than one measurable lesion is present at baseline:  All lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should be 
identified as target lesions, with repeatable measurements recorded and measured at baseline.  (In 
instances where patients have only one or two organ sites involved, a maximum of two and four lesions 
will respectively be recorded.) 
 
13.3.2 Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
 
• 
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
• 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  (Note: the appearance of one or more new lesions is also 
considered progression.) 
 
• 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
 
13.3.3 Non-target lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’.  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
 
13.3.4 Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of applicable tumor 
marker level.  All lymph nodes must be non-pathological in size (<10mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of 
applicable tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions.  (Note: the 
appearance of one or more new lesions is also considered progression.) 
 
 
 


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13.3.5 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation.  The patient’s 
best overall response assignment will depend on the findings of both target and non-target 
disease; and will also take into consideration the appearance of new lesions, as well as post-
treatment assessments and any new therapy introduced before progression.  Furthermore, 
depending on the nature of the study and the protocol requirements, it may also require 
confirmatory measurement.  Specifically, in non-randomized trials where response is the 
primary endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall 
response’. 
 
Time point response: 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non CR/Non PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non PD or not 
all evaluated 
No 
PR 
SD 
Non PD or not 
all evaluated 
No 
SD 
Not all 
evaluated 
Non PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR= complete response, PR= partial response, PD= progressive disease, SD= stable disease,  
NE= not evaluable. 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
13.4.  Duration of Response 
13.4.1 Duration of overall response 
The duration of response (DOR) is measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded since the 
treatment started).  The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
 
13.4.1 Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started. 
 


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13.5.  Immune-Related Response Criteria 
13.5.1  Increasing clinical experience indicates that traditional response criteria (e.g. Response 
Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health Organization [WHO]) 
may not be sufficient to fully characterize activity in the new era of targeted therapies and/or biologics.  
In studies with cytokines, cancer vaccines, and monoclonal antibodies, complete response, partial 
response, or stable disease have been shown to occur after an initial increase in tumor burden 
characterized as progressive disease according to traditional response criteria.  Therefore, conventional 
response criteria may not adequately assess the activity of immunotherapeutic agents because 
progressive disease (by initial radiographic evaluation) does not necessarily reflect therapeutic failure.  
Long-term effect on the target disease must also be captured.   Immune-related response criteria (irRC) 
attempt to enhance characterization of new response patterns that have been observed with 
immunotherapeutic agents (e.g. ipilimumab and nivolumab).   
 
13.5.2 Glossary of Immune-Related Response Terminology 
 
Term 
Definition 
 
 
SPD 
Sum of the Products of the two largest perpendicular Diameters 
Tumor burden SPDindex lesions + SPDnew, measurable lesions 
Nadir 
minimally recorded tumor burden 
irCR 
immune-related Complete Response 
irPD 
immune-related Progressive Disease 
irPR 
immune-related Partial Response 
irSD 
immune-related Stable Disease 
irBOR 
immune-related Best Overall Response 
 
 
13.5.3 Baseline Assessment Using Immune-Related Response Criteria (irRC) 
• 
Step 1:  Identify the index lesions (five lesions per organ, up to ten visceral lesions and five 
cutaneous lesions).   
 
• 
Step 2:  Calculate the Sum of the Products of the two largest perpendicular Diameters (SPD) of 
all of these index lesions: 
SPD = ෍(Largest diameter of lesion i) x (Second largest diameter of lesion i)
𝑖𝑖
 
 
13.5.4 Post-baseline Assessments Using irRC 
• 
Step 1:  Calculate the SPD of the index lesions. 
 
• 
Step 2:  Identify new, measurable lesions (≥ 5 × 5 mm; up to five new lesions per organ:  
five new cutaneous lesions and ten visceral lesions). 


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• 
Step 3:  Calculate the SPD of the new, measurable lesions. 
 
• 
Step 4:  Calculate the tumor burden: 
 
 
 
Tumor burden =  SPDindex lesions + SPDnew, measurable lesions 
 
• 
Step 5:  Calculate the change in tumor burden relative to baseline and the change in tumor 
burden relative to nadir. 
 
• 
Step 6:  Derive the overall response using the table below: 
Overall Response 
Criterion 
 
 
irCR 
Complete disappearance of all lesions (whether measurable or not, 
and no new lesions) confirmed by a repeat, consecutive assessment 
≥ 4 weeks from the date first documented. 
irPR 
Decrease in tumor burden ≥ 50% relative to baseline confirmed by a 
consecutive assessment ≥ 4 weeks from the date first documented. 
irSD 
Criteria for irCR, irPR, and irPD are not met; does not require 
confirmation. 
irPD 
Increase in tumor burden ≥ 25% relative to nadir confirmed by a 
consecutive assessment ≥ 4 weeks from the date first documented. 
irCR = immune-related complete response; irPD = immune-related progressive disease; 
irPR = immune-related partial response; irSD = immune-related stable disease. 
 
13.5.5 Determination of Immune-Related Best Overall Response (irBOR) 
Once a patient has completed all tumor assessments, his/her irBOR may be determined: 
Condition 
irBOR 
At least one irCR 
irCR 
At least one irPR and no irCR 
irPR 
At least one irSD and no irCR and no irPR 
irSD 
At least one irPD and no irCR, no irPR, and no irSD 
irPD 
irBOR = immune-related best overall response; irCR = immune-related complete response; 
irPD = immune-related progressive disease; irPR = immune-related partial response; 
irSD = immune-related stable disease. 
 
13.6.  Response Review and Central Tumor Assessments 
All responses, if any, may be reviewed by an expert(s) independent of the study at the study’s 
completion.  In addition, at the end of treatment, all scans (baseline and through disease progression) 
may be requested via a CD and sent to the Vanderbilt Cancer Imaging Support Laboratory for central 
review and assessment.  
 


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14.  SAFETY REPORTING of ADVERSE EVENTS  
14.1.  General 
Safety assessments will consist of monitoring and reporting AEs and SAEs that are considered possibly, 
probably or definitely related to avelumab, all events of death, and any study-specific issue of concern. 
 
Adverse event collection and reporting is a routine part of every clinical trial.  Each adverse event 
will be graded according to the NCI’s Common Terminology Criteria for Adverse Events (NCI 
CTCAE), Version 4.03, dated June 14, 2010, currently locatable via the following URL: 
< http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf >. 
 
For events not listed in the CTCAE, severity will be designated as mild, moderate, severe or life 
threatening, or fatal which respectively correspond to Grades 1, 2, 3, 4, and 5 on the NCI CTCAE, 
with the following definitions: 
 
•  Mild:  An event not resulting in disability or incapacity and which resolves without 
intervention; 
•  Moderate:  An event not resulting in disability or incapacity but which requires 
intervention; 
•  Severe:  An event resulting in temporary disability or incapacity and which requires 
intervention; 
•  Life-threatening:  An event in which the patient was at risk of death at the time of the 
event; 
• 
Fatal:  An event that results in the death of the patient. 
 
Information on all adverse events, whether serious or not, whether reported by the participant, 
directly observed, or detected by physical examination, laboratory test or other means, will be 
collected, recorded, followed and reported as described in the following sections.  
 
Reporting period:  Adverse events experienced by participants will be collected and reported 
from initiation of study medication, throughout the study, and within 30 days of the last dose of 
study medication.  Participants who experience an ongoing adverse event related to a study 
procedure and/or study medication beyond 30 days will continue to be contacted by a member 
of the study team until the event is resolved, stabilized, or determined to be irreversible by the 
participating investigator.  
Laboratory and vital sign abnormalities are to be recorded as Adverse Events only if they are 
medically relevant as judged by the investigator (e.g. symptomatic, requiring corrective 
treatment, leading to discontinuation and/or fulfilling a seriousness criterion).  Unless otherwise 
specified by protocol or a patient’s study physician, abnormal laboratory values of Grade 1 and 
Grade 2 will be deemed Not Clinically Significant (NCS) and are not required to be individually 
noted or recorded within the study data.  
 
Baseline disease-related signs and symptoms which are initially recorded as medical history, will 
subsequently be recorded as adverse events during the trial if they worsen in severity or increase 
in frequency. 
 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study.  The investigator should notify the IRB and any other 


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applicable regulatory agency of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to 
the study.  
 
14.2.  Risks Associated with Avelumab 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may 
increase the risk of immune-related adverse events, specifically the induction or enhancement of 
autoimmune conditions.  AEs with potentially immune-related causes, including rash, 
hypothyroidism, hepatitis/transaminitis, colitis, myositis, and myasthenia gravis, have been 
observed in studies involving immunomodulators.   
 
Although most immune-related AEs observed with immunomodulatory agents have been mild 
and self-limiting, such events should be recognized early and treated promptly to avoid potential 
major complications. 
 
A more detailed safety profile of avelumab is provided in the avelumab Investigator’s Brochure. 
 
14.3.  Safety Parameters and Definitions 
14.3.1 Adverse Event (AE) 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use 
of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of 
attribution.  Progressive disease will not be considered an adverse event.  
An adverse event includes the following: 
 
• 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms that were not present prior to the AE reporting 
period. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g. invasive 
procedures such as biopsy). 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention. 
• 
Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
• 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests.  
 
14.3.2 Serious adverse event (SAE) 
 
An AE should be classified as an SAE if the following criteria are met: 
• 
It results in death. 
• 
It is life threatening (i.e. the AE, in the view of the investigator, places the patient at immediate 
risk of death.  It does not include an AE that, had it occurred in a more severe form, might have 
caused death.) 
• 
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• 
It results in persistent or significant disability/incapacity (i.e. the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the investigational product. 
• 
It is considered a significant medical event by the investigator based on medical judgment (e.g. 
may jeopardize the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above). 
 
Events not considered to be serious adverse events are hospitalizations for: 
• 
Routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition, or for elective procedures. 
• 
Elective or pre-planned treatment for a pre-existing condition that did not worsen. 
• 
Emergency outpatient treatment for an event not fulfilling the serious criteria outlined above 
and not resulting in inpatient admission. 
• 
Respite care. 
 
14.4.  Assessment of Adverse Events 
All AEs and SAEs, whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means, will be reported 
appropriately.  Each reported AE or SAE will be described by its duration (i.e. start and end dates), 
regulatory seriousness criteria if applicable, suspected relationship to the study drug (see following 
guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the following 
general guidelines: 
 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of avelumab, 
and the AE cannot be readily explained by the patient’s clinical state, intercurrent illness, or concomitant 
therapies; and/or the AE follows a known pattern of response to avelumab; and/or the AE abates or 
resolves upon discontinuation of avelumab or dose reduction and, if applicable, reappears upon re-
challenge. 
 
No 
Evidence exists that the AE has an etiology other than avelumab (e.g. pre-existing medical condition, 
underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible 
temporal relationship to avelumab administration (e.g. cancer diagnosed 2 days after first dose of study 
drug). 
 
14.4.1  Expectedness 
Expected:  Expected adverse events are those that have been previously identified as resulting from 
administration of the agent.  For the purposes of this study, an adverse event is considered expected 
when it appears in the current adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk. 
• 
Unexpected:  An adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, the 


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Investigator’s Brochure, the package insert or when it is not included in the informed 
consent document as a potential risk. 
 
14.4.2  Attribution 
The investigator must attempt to determine if there exists reasonable possibility that an adverse 
event or serious adverse event is related to the use of the study treatment.  Attribution of 
adverse events should be described as unrelated; or unlikely, possibly, probably, or definitely 
related to the study treatment: 
Attribution   
Description 
Unrelated   
AE is clearly NOT related to the intervention. 
Unlikely  
 
AE is doubtfully related to the intervention. 
Possible  
 
AE may be related to the intervention. 
Probable  
 
AE is likely related to the intervention. 
Definite  
 
AE is clearly related to the intervention. 
 
For additional purpose of any applicable binary regulatory reporting, an event should be 
considered Unrelated to study treatment when its attribution is felt by the investigator to be 
either Unrelated or Unlikely related to study treatment.  Similarly, an event should be considered 
Related to study treatment, when its attribution is felt to be either Possibly, Probably, or 
Definitely related to study treatment. 
 
14.5.  Reporting Procedures 
14.5.1 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations.  All adverse events will be captured on the appropriate 
study-specific case report forms (CRFs).  
 
14.5.2 Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g. record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available.  If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
 
14.5.3 Deaths 
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
will be reported to the appropriate parties.  When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept.  If 
the cause of death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death.”  Deaths that occur during the protocol specified adverse event reporting 
period that are attributed by the investigator solely to progression of disease should be recorded 
only in the study CRF and not reported as an SAE. 
 
14.5.4 Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present prior to initiation of protocol specified 
treatment.  Such conditions should be reported as medical and surgical history.  A pre-existing 


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medical condition should be re-assessed throughout the trial and reported as an AE or SAE only if 
the frequency, severity, or character of the condition worsens during the study.  When reporting 
such events, it is important to convey the concept that the pre-existing condition has changed by 
including applicable descriptors (e.g., “more frequent headaches”). 
 
14.5.5 Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE.  If a patient is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE.  For example, if a patient is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for pre-existing conditions, 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study, or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease 
of the study. 
 
14.5.6 Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant while enrolled in the study. A Pregnancy Report CRF 
should be completed by the investigator immediately (i.e., no more than 24 hours after 
learning of the pregnancy) and submitted via fax or email.  A pregnancy report will be 
generated and sent to EMD Serono Drug Safety.  Pregnancy should not be recorded on the 
Adverse Event CRF.  Unless otherwise agreed to and approved by the Investigator, EMD Serono 
and the IRB, the patient should discontinue study drug.  The investigator or medical designee 
should counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  Any SAEs 
associated with the pregnancy (e.g. an event in the fetus, an event in the mother during or 
after the pregnancy, or a congenital anomaly/birth defect in the child) should be reported on 
the Adverse Event CRF. 
 
A Clinical Trial Pregnancy Reporting Form and cover sheet should be completed and faxed or 
emailed to EMD Serono Drug Safety or its designee immediately (i.e. no more than 24 hours 
after learning of the pregnancy), using contact information provided to investigators. 
14.5.7 Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the informed consent form to immediately inform the 
investigator if their partner becomes pregnant at any point while they are enrolled on the 
study. Male patients who received study treatment should not attempt to father a child until 
end of study.  A Pregnancy Report CRF should be completed by the investigator immediately 
(i.e., no more than 24 hours after learning of the pregnancy) and faxed or emailed to EMD 
Serono Drug Safety.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  The 
pregnant partner will be asked to sign an Authorization for Use and Disclosure of Pregnancy 
Health Information to allow for follow-up on her pregnancy.  Once the authorization has been 
signed, the investigator or designee will update the Pregnancy Report CRF with additional 


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information on the course and outcome of the pregnancy.  An investigator or medical designee 
who is contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed decision in 
cooperation with the treating physician and/or obstetrician. 
 
14.5.8 Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsors consider 
spontaneous abortions to be medically significant events), recorded on the Adverse Event CRF, 
and reported to EMD Serono Drug Safety immediately (i.e. no more than 24 hours after 
learning of the event). 
 
14.5.9 Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner of a 
male patient exposed to study drug should be classified as an SAE, recorded on the Adverse 
Event CRF, and reported to EMD Serono Drug Safety immediately (i.e., no more than 24 hours 
after learning of the event). 
 
14.5.10  Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has completed or 
discontinued study participation if attributed to prior avelumab exposure.  If the investigator 
should become aware of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female patient who participated in the study, this should be reported as 
an SAE.  
 
14.5.11  Safety Reconciliation 
The Sponsor-investigator agrees to conduct reconciliation for the product.  EMD Serono and the 
Sponsor-investigator will agree to the reconciliation periodicity and format, but agree at 
minimum to exchange monthly line listings of cases received by the other party.  If discrepancies 
are identified, the Sponsor-investigator and EMD Serono will cooperate in resolving the 
discrepancies.  The responsible individuals for each party shall handle the matter on a case-by-
case basis until satisfactory resolution. 
 
14.5.12  Adverse Events of Special Interest (AESIs) 
Any adverse event that is suspected to be a potential immune-related adverse event (irAE) is 
considered an AE of special interest (AESI).  Specific guidance for the management of irAEs is 
provided in Section 11.7.  AESIs are reported according to the general AE reporting rules 
specified in Section 14.5. 
 
14.5.13  Serious Adverse Events 
All serious adverse events, regardless of causality to study drug, will be reported to the 
Principal Investigator and/or the Study Coordinator at each institution, and also to the 
Coordinating Center. 
 
All serious adverse events must be reported to the Coordinating Center within 24 hours of the 
investigator becoming aware of the event.  Events should be reported using the OnCore SAE 
form and the Vanderbilt SAE form located in OnCore documents.   
 
The form must be fully completed and emailed (preferred), faxed, or scanned to: 


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ATTN:  VICC CTSR Personnel 
EMAIL:  Coordinating.Center@Vanderbilt.edu 
FAX: (615) 875-0040 
 
If SAE documents are faxed, the Coordinating Center must be notified via email as well. Follow-
up information must also be reported within 24 hours of receipt of the information by the 
investigator. 
 
The Coordinating Center will be responsible for reporting of events to the FDA and supporters, 
as appropriate (outlined below). 
 
14.5.14  Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current 
institutional standards.  If an adverse event requires modification of the informed consent, 
these modifications will be provided to the IRB with the report of the adverse event.  If an 
adverse event requires modification to the study protocol, these modifications will be provided 
to the IRB as soon as is possible. 
 
14.5.15  Food and Drug Administration (FDA) 
In this trial, unexpected serious adverse events believed to be definitely, probably, or possibly 
related to avelumab (as determined by the sponsor-investigator) will be reported to the Food 
and Drug Administration via MedWatch 3500A (available at 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf).   
 
Submissions by the sponsor can be submitted via fax or email and must be addressed to the 
Regulatory Project Manager in the FDA review division that has responsibility for review of the 
IND.  The Coordinating Center will be responsible for correspondence regarding adverse events 
with the FDA. 
 
14.5.16  EMD Serono 
The following reportable events must be submitted to EMD Serono within 2 business days or 3 
calendar days (whichever comes first) using the applicable safety report form provided.  The 
Sponsor/Principal Investigator* will assume all responsibility for submitting the reportable 
event(s) to EMD Serono 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. 
 
The completed MedWatch/case report should be faxed or emailed immediately upon 
completion to EMD Serono Drug Safety at: 
 
Fax: +49 6151 72 6914 
or 
E-mail: ICSR_CT_GPS@merckgroup.com 
 


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Specifying: 
• 
Protocol Number and/or Title 
• 
Subject Number 
• 
Site Number/PI Name 
• 
SAE/Onset Date 
 
Relevant follow-up information should be submitted to EMD Serono Drug Safety as soon as it 
becomes available. 
 
Adverse Events of Special Interest (AESIs) will be transmitted to EMD Serono within 15 calendar 
days of the Awareness Date. All non-serious avelumab AEs originating from the study will be 
forwarded to EMD Serono monthly. 
 
Note:  Investigators should also report events to their IRB as required. 
 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event Description 
(item 5) of the MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the AE to each investigational product 
and suspect medication 
 
Follow-Up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up; 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form; 
• 
Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. date of birth, initial, patient number), protocol description and number, if 
assigned, brief AE description, and notation that additional or follow-up information is being 
submitted.  (The patient identifiers are important so that the new information is added to the 
correct initial report.) 
 
Occasionally EMD Serono may contact the reporter for additional information, clarification, or 
current status of the patient for whom and AE was reported.  For questions regarding SAE 
reporting, you may contact the EMD Serono Drug Safety representative noted above or the 
Medical Science Liaison assigned to the study.  Relevant follow-up information should be 
submitted to EMD Serono Drug Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is currently available at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/ucm2007307.htm 
 
 
 


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14.5.17  Additional Reporting Requirements for IND 
 
Events meeting the following criteria need to be submitted to the FDA as expedited IND Safety Reports 
according to the following guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report 
The investigator is required to notify the FDA of any fatal or life-threatening AE that is unexpected and 
assessed by the investigator to be possibly related to the use of avelumab.  An unexpected AE is one 
that is not already described in the avelumab Investigator’s Brochure.  Such reports are to be 
telephoned or faxed to the FDA and EMD Serono within 7 calendar days of first learning of the event. 
 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written IND 
Safety Report, of any serious, unexpected AE that is considered reasonably or possibly related to the use 
of avelumab.  An unexpected AE is one that is not already described in the avelumab Investigator’s 
Brochure.  
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with regulation 21 
CFR § 312.32.  All safety reports previously filed by the investigator with the IND concerning similar 
events should be analyzed and the significance of the new report in light of the previous, similar reports 
commented on. 
 
Written IND safety reports with analysis of similar events are to be submitted to the FDA, EMD Serono, 
and all participating investigators within 15 calendar days of first learning of the event.  The FDA prefers 
these reports on a MedWatch 3500 form, but alternative formats are acceptable (e.g. summary letter).  
 
Contact Information for IND Safety Reports 
FDA fax number for IND safety reports: 
Fax: (800) FDA-0178. 
 
All written IND safety reports submitted to the FDA by the investigator must also be submitted via fax 
or email to the following: 
EMD Serono Drug Safety Fax:  +49 6151 72 6914or Email:  ICSR_CT_GPS@merckgroup.com 
 
For questions related to safety reporting, please contact EMD Serono Drug Safety: 
Fax:  +49 6151 72 6914 
 
Or Email: GlobalDrugSafety@merckgroup..com  
 
14.5.18  IND Annual Reports 
Copies of all IND annual reports submitted to the FDA by the Sponsor-investigator should be sent to the 
EMD Serono Drug Safety designee via fax or email. 
 
14.5.19  Study Close-Out 
Any study report submitted to the FDA by the Sponsor-investigator should be copied to EMD Serono.  
This includes all IND annual reports and the Clinical Study Report (final study report).  Additionally, any 
literature articles that are a result of the study should be sent to EMD Serono.  Copies of such reports 
should be faxed, emailed, or mailed to the assigned Clinical Operations contact for the study. 


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15.  DATA SAFETY AND MONITORING 
15.1.  Data Management and Reporting 
 
Data will be collected using a centralized electronic case report form called ON-line Clinical 
Oncology Research Environment (Oncore), located at  
< http://www.vicc.org/ct/research/oncore.php > . 
 
Oncore is a highly secure, web based, cancer specific, and customizable system that provides fully 
integrative clinical data management and study administration capabilities developed in an 
ongoing collaborative effort with NCI designated Comprehensive Cancer Centers.  The system is 
capable of storing basic protocol information (e.g. IRB approval dates, dates for annual renewals) 
and clinical trials research data, and it fully integrates study administration functionality including 
protocol tracking, patient registration, NCI reporting, review committee tracking, and SAE 
tracking, with clinical data management functionality including electronic case report forms 
(eCRF) design, clinical data capture, protocol and regulatory compliance monitoring.   
 
Oncore allows the investigator to define specific protocol requirements and generate data 
collection forms.  Creation of the data collection form is done with a single button click after the 
parameters of an individual protocol have been specified.  Oncore permits specification of study 
protocols, management of patient enrollment, clinical data entry and viewing, and the 
generation of patient or study-specific reports based on time stamping.  OnCore is embedded 
with a comprehensive domain repository of standard reference codes and forms to promote 
standardization.  The sources for the repository include CDUS, CTC, CDEs from NCI, ICD, MedDRA 
and various best practices from contributing NCI-designated Comprehensive Cancer Centers.  
OnCore provides several reporting features specifically addressing NCI Summary 3 and Summary 
4 and other reporting requirements.  Data may also be exported in a format suitable for import 
into other database, spreadsheets or analysis systems (such as SPSS).  This system will be used to 
manage all VICCC clinical trials data.  OnCore is maintained and supported in the VICC Clinical and 
Research Informatics Resource.  
 
Specified site members will submit all pertinent regulatory documents to the Coordinating Center 
Data Manager, who will store it in a secure location. 
 
The Principal Investigator or designee will inform EMD Serono as defined in any established 
Safety and Data Exchange Agreement (SDEA) of any serious adverse event, and will inform the 
Vanderbilt IRB in accordance with IRB policy.  The investigator is responsible for the detection 
and documentation of events meeting the criteria and definition of an AE or SAE, as provided in 
this protocol.  During the study when there is a safety evaluation, the treating investigator or site 
staff will be responsible for detecting, documenting, and report AEs and SAEs, as detailed in the 
protocol.  If any problem is identified related to the conduct of this research, the VICC Data 
Safety and Monitoring Committee (DSMC) will be formally asked to review the study and the 
situation that required DSMC intervention. 
 
 
 
 


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15.2.  Meetings 
 
This trial will be monitored by the VICC Gastrointestinal Research Team. The GI research team is 
composed of Medical Oncologists, Research Nurses, Data Managers, and Regulatory Specialists. 
The GI Research Team meets on a monthly basis to discuss all AEs/SAEs, accrual, compliance, 
safety issues, adherence to protocol, reviews, etc. pertaining to all GI team cancer studies.  This 
particular study will be thoroughly reviewed during these meetings.  These monthly meetings 
have minutes recorded which are reviewed on a monthly basis by the Physician Leader of the 
Gastrointestinal Research Team. 
 
15.3.  Monitoring 
 
This trial will be monitored continuously by the study’s Protocol Chair and by the Gastrointestinal 
Research Team at VUMC.  Additionally, the Vanderbilt-Ingram Cancer Center (VICC) oversees 
patient safety and data monitoring for its investigator-initiated and NIH-NCI funded clinical trials 
through its Data and Safety Monitoring Committee (DSMC). The purpose of the DSMC is to 
ensure the efficient implementation and management of VICC Data and Safety Monitoring Plan 
(DSMP). The Committee maintains authority to intervene in the conduct of studies as necessary 
to ensure clinical research performed at VICC achieves the highest quality standards.  
The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety monitoring of 
clinical trials and to oversee the VICC DSMP. Internal audits for compliance with adverse event 
reporting, regulatory and study requirements, and data accuracy and completion are conducted 
according to the VICC DSMP according to study phase and risk. The committee reviews all serious 
adverse events (SAE) on Vanderbilt sponsored, investigator-initiated studies on a quarterly basis 
and provides DSMC SAE review reports to the Vanderbilt IRB. 
 
The investigator will allow the VICC-DSMC designee access to all pertinent medical records, as 
required by federal regulations, in order to allow for the verification of data gathered in the data 
case report forms (CRFs) and for the review of the data collection process.  The VICC-DSMC 
designee will review various aspects of the trial including, but not limited to:  screening and 
enrollment logs; compliance with the protocol and with the principles of Good Clinical Practice; 
completion of case report forms; source data verification; study drug accountability and storage; 
facilities and staff. 
 
The investigator and the investigational site staff must be available to meet with the VICC-DSMC 
designee 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 research compliance coordinator. 
 
Additionally, the Coordinating Center has responsibilities to health authorities to take all 
reasonable steps to ensure the proper conduct of the study as regards to ethics, protocol 
adherence, integrity, validity of the data recorded on the CRFs, and adherence to regulations 
regarding Good Clinical Practice (GCP) and the protection of human subjects. 
 
In accordance with applicable regulations, GCP, and Coordinating Center procedures, sites will be 
contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and Coordinating Center 


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requirements.  
 
During the course of the study, the Coordinating Center will routinely monitor sites for protocol 
compliance, compare CRFs with individual subjects’ original source documents, assess drug 
accountability, and ensure that the study is being conducted according to the pertinent 
regulatory requirements. The review of subjects’ medical records will be performed in a manner 
to ensure that subjects’ confidentiality is maintained. Monitoring visits will primarily be 
conducted remotely, and sites are required to provide the appropriate source documentation in 
order to allow for proper oversight per GCP. Investigators must agree to cooperate with the 
Coordinating Center to ensure that any problems detected are resolved. In addition to the above, 
the FDA may review the conduct or results of the study at the investigational site.  
 
In accordance with HIPAA and associated privacy regulations, a subject’s authorization to use 
personally identifiable health information may be required from each subject before 
commencement of research activities.  This authorization document must clearly specify what 
parties will have access to a subject’s personal health information, for what purpose and for what 
duration. 
 
VICC Multi-Institutional Coordinating Center 
The trial additionally will be monitored by the VICC Multi-Institutional Coordinating Center. The 
actual frequency of monitoring will depend on the enrollment rate and performance of the site. 
Monitoring will be conducted through onsite and remote monitoring, teleconferences with the 
Investigator and site staff, and appropriate communications by mail, fax, email, or telephone. The 
purpose of monitoring is to ensure that the study is conducted in compliance with the protocol, 
standard operating procedures (SOPs), and other written instructions, and to ensure the quality 
and integrity of the data. 
 
During scheduled monitoring visits, investigators and the investigational site staff must be 
available to discuss the progress of the trial, make necessary corrections to case report form 
entries, respond to data clarification requests, provide required regulatory documents, and 
respond to any other trial-related inquiries of the monitor. 
 
15.4.  Data Handling and Record Keeping 
 
An electronic case report form (eCRF) is required and must be completed for each included 
participant.   
 
The investigator or designee may maintain records separate from the case report forms in the 
forms of clinic charts, medical records, original laboratory, radiology and pathology reports, 
pharmacy records, etc.  The investigator will document in the clinic chart or medical record the 
date on which the patient signed informed consent prior to the patient’s participation in the trial.  
Source documents must completely reflect the nature and extent of the patient’s medical care, 
and must be available for source document verification against entries in the case report forms 
when a designee of the Data Safety Monitoring Committee (DSMC) of the Vanderbilt-Ingram 
Cancer Center (VICC) audits the investigational site.  Source documents regarding procedures 
such as scans and laboratory evaluations performed as part of the standard of care prior to 
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information obtained from source documents will be kept in strict confidentiality.  Source data 
sent as supporting documentation to regulatory authorities for serious adverse events will be de-
identified to preserve confidentiality. 
 
To enable evaluations and/or audits from Health Authorities and Vanderbilt the investigator 
agrees to keep records including:  The identity of all participants (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition.  To comply with international regulations, 
the records should be retained by the investigator in compliance with regulations.  
 
During data entry, range and missing data checks will be performed online.  The checks to be 
performed will be documented in the Data Monitoring Plan for the study.  A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRF's will 
be generated and transmitted to the site and the site monitor.  Corrections will be made by the 
study site personnel.  This will be done on an ongoing basis. 
 
16.  REGULATORY CONSIDERATIONS 
 
16.1.  Pre-Study Documentation 
 
Prior to initiating the trial, the investigator will secure the following documents: 
 
• 
A signed FDA Form 1572 
• 
A current curriculum vitae for the Principal Investigator and each sub-investigator listed 
on the FDA Form 1572 
• 
A copy of the current medical license for the investigator and each sub-investigator 
listed on the FDA Form 1572 
• 
A letter from the IRB stipulating approval of the protocol, the informed consent 
document and any other material provided to potential trial participants with 
information about the trial (e.g. advertisements) 
• 
A copy of the IRB-approved informed consent document 
• 
The current IRB membership list for the reviewing IRB 
• 
A completed financial disclosure form for the investigator and all sub- investigators 
• 
Current laboratory certification for the reference laboratory and curriculum vitae of the 
laboratory director 
• 
A list of current laboratory normal values for the reference laboratory. 
 
16.2.  Protocol Review and Amendments 
 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per current institutional standards. 
 
The trial will not be initiated until there is approval by the local IRB of the protocol, informed 
consent document and any other material used to inform the patient about the nature of the 
trial.  The IRB should be duly constituted according to local regulatory requirements.  The 
investigator will inform the IRB of the progress of the trial at least yearly. 


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Any changes to the protocol will be made in the form of a written amendment and must be 
approved by both EMD Serono and the IRB prior to local implementation.  All amendments will 
also be submitted as necessary to the FDA by the Sponsor. 
 
Protocol changes to eliminate an immediate hazard to a trial patient may be implemented by the 
investigator immediately.  The investigator must then immediately inform the local IRB and the 
FDA. 
The Protocol Chair (or designee) is responsible for the coordination and development of all 
protocol amendments, and will disseminate this information to the institutional participants. 
 
16.3.  Informed Consent 
 
The investigator (or his/her designee) will explain to each subject the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved and any discomfort it may entail.  Each subject will be informed that participation in the 
study is voluntary, that s/he may withdraw from the study at any time, and that withdrawal of 
consent will not affect subsequent medical treatment or relationship with the treating 
physician(s) or institution.  The informed consent will be given by means of a standard written 
statement, written in non-technical language, which will be IRB approved.  The subject should 
read and consider the statement before signing and dating it, and will be given a copy of the 
document.  No subject will enter the study or have study-specific procedures done before his/her 
informed consent has been obtained. 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the written 
informed consent document (or a separate document to be given in conjunction with the 
consent document) will include a subject authorization to release medical information to the 
study sponsor and supporting agencies and/or allow these bodies, a regulatory authority, or 
Institutional Review Board access to subjects’ medical information that includes all hospital 
records relevant to the study, including subjects’ medical history. 
 
16.4.  Ethics and GCP 
 
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described within: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 
1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described within the above 
and thereby to adhere to the principles of Good Clinical Practice with which the above conform. 
 
 


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16.5.  Confidentiality 
 
It is the responsibility of the investigator to insure that the confidentiality of all patients 
participating in the trial and all of their medical information is maintained.  Case report forms 
(CRFs) and other documents submitted to regulatory authorities must not contain the name of a 
trial patient.  All patients in the trial will be identified by a unique identifier which will be used on 
all CRFs and any other material submitted to regulatory authorities.  All case report forms and 
any identifying information must be kept in a secure location with access limited to the study 
staff directly participating in the trial. 
 
16.6.  Records Retention 
 
The investigator will retain the records of the clinical trial (including, but not necessarily limited 
to, CRFs, source documents, informed consent forms, drug accountability records, IRB 
correspondence, etc) for at least 2 years after all investigations have been discontinued.  Study 
records must be stored in a safe and secure location permitting timely retrieval, if necessary. 
 
Study records that must be retained include case report forms, signed informed consents, 
correspondence with the IRB, study drug dispensing and inventory records, source documents 
(clinic charts, medical records, laboratory results, radiographic reports) and screening/enrollment 
logs. 
 
16.7.  Study Termination 
 
The investigator reserves the right to terminate the study at any site and at any time.  Reasons 
for study termination may include, but are not limited to, the following: 
 
•  Investigator non-compliance with the protocol, GCP or regulatory requirements 
•  Insufficient enrollment 
•  Safety concerns 
•  Decision by EMD Serono to modify or discontinue the development or manufacture of 
avelumab  
•  A request to discontinue the study by the IRB or FDA. 
 
The investigator will promptly notify EMD Serono, the IRB and FDA if the study is terminated for 
any reason. 
 
 
 
17.  STATISTICAL CONSIDERATIONS   
17.1.  Study Design / Endpoints 
 
The primary objective of this clinical trial is to estimate the objective response rate (ORR) from the 
best response a patient experiences prior to progression (using RECIST v1.1 and irRC).  Twenty-five 
patients will be enrolled on this clinical trial.  This regimen will be considered sufficiently active to 


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warrant further study in more definitive trials if 4 patients experience an objective response 
among 25 treated. 
 
17.2.  Sample Size / Accrual Rate 
This investigator-initiated study intends single-site enrollment limited to patients at Vanderbilt 
University Medical Center.   
 
About 25 patients evaluable for disease response are anticipated to enroll in approximately 24-36 
months.  
 
17.3.  Statistical Analysis Plan  
 
Demographic, baseline patient characteristics, and study outcomes are intended to be 
summarized graphically and numerically.  Adverse events will be classified by type, incidence, 
severity and causality according to CTCAE v4.03.  All adverse events will be summarized by 
patient, and all patients who received at least one cycle of the therapy (or discontinued due to 
treatment-related adverse event) will be included in the safety profile. 
 
Continuous (e.g. age at on-study date) variables will be summarized using the 25th, 50th (median), 
and 75th percentiles, the range, as well as the mean and standard deviation.  Categorical 
variables, (e.g. adverse events) will be reported as frequencies.  95% confidence intervals will be 
reported for all outcomes.  The distribution of PFS and OS will be estimated using the Kaplan-
Meier (product-limit) estimate with standard errors based on Greenwood’s formula.  No 
comparative statistical tests are planned for this study. 
 
The Wilson 95% confidence intervals for 0 to 13 objective responses among 25 patients treated 
are listed in Table 3: 
 
 
 
Table 3.  Ninety-five percent (Wilson) confidence intervals for  
objective response rate among 25 patients. 
Number of 
Objective 
Responses 
Objective Response Rate 
(%) 
Lower Limit 
(%) 
Upper Limit 
(%) 
0 
0 
0 
13.3 
1 
4 
0.2 
19.5 
2 
8 
2.2 
25.0 
3 
12 
4.2 
30.0 
4 
16 
6.4 
34.6 
5 
20 
8.9 
39.1 
6 
24 
11.5 
43.4 
7 
28 
14.3 
47.6 
8 
32 
17.2 
51.6 
9 
36 
20.2 
55.5 
10 
40 
23.4 
59.3 
11 
44 
26.7 
62.9 
12 
48 
30.3 
66.5 
13 
52 
33.5 
70.0 


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Considering the published data47,48 regarding the responses to standard of care chemotherapy 
regimens, we propose that observing the same or better clinical outcomes with avelumab 
monotherapy would warrant further therapeutic study in patients with advanced small intestinal 
adenocarcinoma.   
 
Twenty-five patients will be enrolled on this clinical trial.  We assume a one-sided type I error 
rate of 5% using a one-sample binomial test and desire 80% power to reject the null hypothesis 
that this regimen is ineffective if it elicits an objective response rate of 5%.  Twenty-five patients 
provide 80% power to reject the null hypothesis if the true objective response rate (ORR) of this 
regimen is 21% or greater.  This regimen will be considered sufficiently active to warrant further 
study in more definitive trials if 4 or more patients among 25 treated experience an objective 
response.  
 
17.4.  Reporting and Exclusions 
 
All patients included in the study must be assessed for safety, tolerability, and response to 
treatment, even if there are major protocol treatment deviations or if they are ineligible.  Each 
patient will be assigned one of the following response categories:  1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 
6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not 
assessable, insufficient data).  
 
All patients meeting the eligibility criteria and received study drug for 2 weeks should be included 
in the main analysis of the clinical benefit rate.  Patients in above response categories 4-9 should 
be considered to have a treatment failure (disease progression).  Thus, an incorrect treatment 
schedule or drug administration should not result in exclusion from the analysis of the response 
and clinical benefit rate. 
  
18.  REFERENCES 
 
 
1. 
Kelly K, Patel M, Infante JR, et al: Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with 
metastatic or locally advanced solid tumors: assessment of safety and tolerability in a phase I, open-
label expansion study. J Clin Oncol 33, 2015 (suppl; abstr 3044) 
 
2. 
Shi C, Thota R, Berlin J: Could the PD-1 pathway be a potential target for treating small intestinal 
adenocarcinoma? J Clin Oncol 34, 2016 (suppl 4S; abstr 233) 
 
3. 
Pederson K, Smyrk TC, Harrington S, et al: Programmed death-ligand 1 (PD-L1) expression in small 
bowel adenocarcinomas (SBA). J Clin Oncol 33, 2015 (suppl; abstr 3619) 
 
4. 
Neugut AI, Jacobson JS, Suh S, et al: The epidemiology of cancer of the small bowel. Cancer Epidemiol 
Biomarkers Prev 7:243-51, 1998 
 
5. 
Bilimoria KY, Bentrem DJ, Wayne JD, et al: Small bowel cancer in the United States: changes in 
epidemiology, treatment, and survival over the last 20 years. Ann Surg 249:63-71, 2009 
 
6. 
Siegel RL, Miller KD, Jemal A: Cancer statistics, 2015. CA Cancer J Clin 65:5-29, 2015 
 
7. 
Howe JR, Karnell LH, Menck HR, et al: The American College of Surgeons Commission on Cancer and 
the American Cancer Society. Adenocarcinoma of the small bowel: review of the National Cancer 
Data Base, 1985-1995. Cancer 86:2693-706, 1999 
 
8. 
Reynolds I, Healy P, McNamara DA: Malignant tumours of the small intestine. Surgeon 12:263-70, 
2014 


GI 1679 
 
 
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08 November 2018 
 
 73 of 84 
 
 
9. 
Bakaeen FG, Murr MM, Sarr MG, et al: What prognostic factors are important in duodenal 
adenocarcinoma? Arch Surg 135:635-41; discussion 641-2, 2000 
 
10. Raghav K, Overman MJ: Small bowel adenocarcinomas--existing evidence and evolving paradigms. 
Nat Rev Clin Oncol 10:534-44, 2013 
 
11. Overman MJ, Varadhachary GR, Kopetz S, et al: Phase II study of capecitabine and oxaliplatin for 
advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol 27:2598-603, 2009 
 
12. Xiang XJ, Liu YW, Zhang L, et al: A phase II study of modified FOLFOX as first-line chemotherapy in 
advanced small bowel adenocarcinoma. Anticancer Drugs 23:561-6, 2012 
 
13. McWilliams RR MM, Marchello BT, et al. : Pharmacogenetic dosing by UGT1A1 genotype as first-line 
therapy for advanced small-bowel adenocarcinoma: A North Central Cancer Treatment Group 
(NCCTG) trial. J Clin Oncol 30, 2012 (suppl 4; abstr 314) 
 
14. Zaanan A, Gauthier M, Malka D, et al: Second-line chemotherapy with fluorouracil, leucovorin, and 
irinotecan (FOLFIRI regimen) in patients with advanced small bowel adenocarcinoma after failure of 
first-line platinum-based chemotherapy: a multicenter AGEO study. Cancer 117:1422-8, 2011 
 
15. Chemnitz JM, Parry RV, Nichols KE, et al: SHP-1 and SHP-2 associate with immunoreceptor tyrosine-
based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor 
ligation prevents T cell activation. J Immunol 173:945-54, 2004 
 
16. Keir ME, Butte MJ, Freeman GJ, et al: PD-1 and its ligands in tolerance and immunity. Annu Rev 
Immunol 26:677-704, 2008 
 
17. Riley JL: PD-1 signaling in primary T cells. Immunol Rev 229:114-25, 2009 
 
18. Bennett F, Luxenberg D, Ling V, et al: Program death-1 engagement upon TCR activation has distinct 
effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but 
not CD28, IL-7, and IL-15 responses. J Immunol 170:711-8, 2003 
 
19. Blank C, Brown I, Peterson AC, et al: PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T 
cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 64:1140-5, 2004 
 
20. Brown JA, Dorfman DM, Ma FR, et al: Blockade of programmed death-1 ligands on dendritic cells 
enhances T cell activation and cytokine production. J Immunol 170:1257-66, 2003 
 
21. Dong H, Zhu G, Tamada K, et al: B7-H1, a third member of the B7 family, co-stimulates T-cell 
proliferation and interleukin-10 secretion. Nat Med 5:1365-9, 1999 
 
22. Freeman GJ, Long AJ, Iwai Y, et al: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 
family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027-34, 2000 
 
23. Waeckerle-Men Y, Starke A, Wuthrich RP: PD-L1 partially protects renal tubular epithelial cells from 
the attack of CD8+ cytotoxic T cells. Nephrol Dial Transplant 22:1527-36, 2007 
 
24. Blank C, Kuball J, Voelkl S, et al: Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell 
responses in vitro. Int J Cancer 119:317-27, 2006 
 
25. Okazaki T, Honjo T: The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 27:195-201, 
2006 
 
26. Okazaki T, Honjo T: PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 19:813-
24, 2007 
 
27. Blank C, Gajewski TF, Mackensen A: Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T 
cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol 
Immunother 54:307-14, 2005 
 
28. Hirano F, Kaneko K, Tamura H, et al: Blockade of B7-H1 and PD-1 by monoclonal antibodies 
potentiates cancer therapeutic immunity. Cancer Res 65:1089-96, 2005 
 
29. Iwai Y, Ishida M, Tanaka Y, et al: Involvement of PD-L1 on tumor cells in the escape from host immune 
system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 99:12293-7, 2002 
 
30. Iwai Y, Terawaki S, Honjo T: PD-1 blockade inhibits hematogenous spread of poorly immunogenic 
tumor cells by enhanced recruitment of effector T cells. Int Immunol 17:133-44, 2005 
 
31. Nomi T, Sho M, Akahori T, et al: Clinical significance and therapeutic potential of the programmed 
death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 13:2151-
7, 2007 
 
32. Strome SE, Dong H, Tamura H, et al: B7-H1 blockade augments adoptive T-cell immunotherapy for 
squamous cell carcinoma. Cancer Res 63:6501-5, 2003 


GI 1679 
 
 
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33. Zhang L, Gajewski TF, Kline J: PD-1/PD-L1 interactions inhibit antitumor immune responses in a 
murine acute myeloid leukemia model. Blood 114:1545-52, 2009 
 
34. Powles T, Eder JP, Fine GD, et al: MPDL3280A (anti-PD-L1) treatment leads to clinical activity in 
metastatic bladder cancer. Nature 515:558-62, 2014 
 
35. Herbst RS, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD-L1 antibody 
MPDL3280A in cancer patients. Nature 515:563-7, 2014 
 
36. Berghoff AS, Ricken G, Widhalm G, et al: Tumour-infiltrating lymphocytes and expression of 
programmed death ligand 1 (PD-L1) in melanoma brain metastases. Histopathology 66:289-99, 2015 
 
37. Rizvi NA, Hellmann MD, Snyder A, et al: Cancer immunology. Mutational landscape determines 
sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124-8, 2015 
 
38. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330-7, 
2012 
 
39. Warth A, Kloor M, Schirmacher P, et al: Genetics and epigenetics of small bowel adenocarcinoma: the 
interactions of CIN, MSI, and CIMP. Mod Pathol 24:564-70, 2011 
 
40. Le DT, Uram JN, Wang H, et al: PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J 
Med 372:2509-20, 2015 
 
41. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody 
in cancer. N Engl J Med 366:2443-54, 2012 
 
42. Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 antibody in patients with 
advanced cancer. N Engl J Med 366:2455-65, 2012 
 
43. Hamid O, Robert C, Daud A, et al: Safety and tumor responses with lambrolizumab (anti-PD-1) in 
melanoma. N Engl J Med 369:134-44, 2013 
 
44. Schleimer RP, Jacques A, Shin HS, et al: Inhibition of T cell-mediated cytotoxicity by anti-inflammatory 
steroids. J Immunol 132:266-71, 1984 
 
45. Khan MM: Immunosuppressive Agents. In:  Immunopharmacology. New York, Springer, 2008 
 
46. Weber JS, Kahler KC, Hauschild A: Management of immune-related adverse events and kinetics of 
response with ipilimumab. J Clin Oncol 30:2691-7, 2012 
 
47. Mizushima T, Tamagawa H, Mishima H, et al: The effects of chemotherapy on primary small bowel 
cancer: A retrospective multicenter observational study in Japan. Mol Clin Oncol 1:820-824, 2013 
 
48. Aparicio T, Zaanan A, Svrcek M, et al: Small bowel adenocarcinoma: epidemiology, risk factors, 
diagnosis and treatment. Dig Liver Dis 46:97-104, 2014 
 
49. Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
 
50. Hoos A, Eggermont AM, Janetzki S, et al: Improved endpoints for cancer immunotherapy trials. J Natl 
Cancer Inst 102:1388-97, 2010 
 
51. Hodi FS, Butler M, Oble DA, et al: Immunologic and clinical effects of antibody blockade of cytotoxic T 
lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A 
105:3005-10, 2008 
 
52. Wolchok JD, Hoos A, O'Day S, et al: Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res 15:7412-20, 2009 
 
53. Nishino M, Jagannathan JP, Krajewski KM, et al: Personalized tumor response assessment in the era 
of molecular medicine: cancer-specific and therapy-specific response criteria to complement pitfalls 
of RECIST. AJR Am J Roentgenol 198:737-45, 2012 
 
54. Nishino M, Gargano M, Suda M, et al: Optimizing immune-related tumor response assessment: does 
reducing the number of lesions impact response assessment in melanoma patients treated with 
ipilimumab? J Immunother Cancer 2:17, 2014 
 
 
 
 
 
 


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APPENDIX 1 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Guidelines49 
 
 
CATEGORIZING LESIONS AT BASELINE 
Measurable lesions 
• 
Lesions that can be accurately measured in at least one dimension. 
• 
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm). 
• 
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
• 
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 
• 
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
 
Non-measurable disease 
• 
Non-measurable disease includes lesions too small to be considered measurable 
(including nodes with short axis between 10 and 14.9 mm) and truly non-measurable 
disease such as pleural or pericardial effusions, ascites, inflammatory breast disease, 
leptomeningeal disease, lymphangitic involvement of skin or lung, clinical lesions that 
cannot be accurately measured with calipers, abdominal masses identified by physical 
exam that are not measurable by reproducible imaging techniques. 
• 
Bone disease:  Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 
• 
Previous local treatment:  A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment. 
 
Normal sites 
• 
Cystic lesions:  Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions. 
• 
Normal nodes:  Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease. 
 
NOTE:  The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions. 
 
 
 
 
 
 
 
 


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RECORDING TUMOR ASSESSMENTS 
 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as close as 
possible prior to study start.  For an adequate baseline assessment, all required scans must be done 
within 28 days prior to treatment and all disease must be documented appropriately.  If baseline 
assessment is inadequate, subsequent statuses generally should be indeterminate. 
 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should still be 
recorded. 
Target Lesions 
• 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except 
in the case of pathological lymph nodes for which the short axis should be recorded.  
The sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions at baseline will be the basis for comparison to assessments performed 
on study. 
 
• 
If two target lesions coalesce the measurement of the coalesced mass is used.  If a large 
target lesion splits, the sum of the parts is used. 
 
• 
Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be recorded. 
 
Non-target disease 
• 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but 
rather assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning. If a change needs to be made the case must be 
discussed with the radiologist to determine if substitution is possible. If not, subsequent objective 
statuses are indeterminate. 
Target Lesions 
 
• 
Complete Response (CR): 
Complete disappearance of all target lesions with the  
  
  
 
exception of nodal disease.  All target nodes must  
  
  
 
decrease to normal size (short axis <10 mm).  All target  
  
  
 
lesions must be assessed. 
• 
Partial Response (PR):    
Greater than or equal to 30% decrease under baseline  
  
 
 
 
of the sum of diameters of all target measurable  
  
 
 
 
lesions.  The short diameter is used in the sum for   


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target nodes, while the longest diameter is used in the  
  
 
 
 
sum for all other target lesions.  All target lesions must  
  
 
 
 
be assessed. 
 
• 
Stable:   
 
 
Does not qualify for CR, PR or Progression.  All target   
  
 
 
 
lesions must be assessed.  Stable can follow PR only in   
  
 
 
 
the rare case that the sum increases by less than 20%   
  
 
 
 
from the nadir, but enough that a previously   
  
 
 
 
documented 30% decrease no longer holds. 
 
• 
Objective Progression (PD):   
20% increase in the sum of diameters of target   
  
 
 
 
measurable lesions above the smallest sum observed  
  
 
 
 
(over baseline if no decrease in the sum is observed   
  
 
 
 
during therapy), with a minimum absolute increase  
  
 
 
 
of 5 mm. 
 
• 
Indeterminate:   
 
Progression has not been documented, AND 
 One or more target measurable lesions have not  
  
been assessed; OR 
 Assessment methods used were inconsistent with   
  
those used at baseline; OR 
 One or more target lesions cannot be measured  
  
accurately (e.g. poorly visible unless due to being too  
  
small to measure); OR 
 One or more target lesions were excised or  
  
irradiated and have not reappeared or increased. 
Non-target disease 
• 
CR: 
  
 
Disappearance of all non-target lesions and   
  
  
 
normalization of applicable tumor marker levels. All  
  
  
 
lymph nodes must be ‘normal’ in size (<10 mm short  
  
  
 
axis). 
 
• 
Non-CR/Non-PD:   
 
Persistence of any non-target lesions and/or applicable  
  
 
 
 
tumor marker level above the normal limits. 
 
• 
PD:   
 
 
 
Unequivocal progression of pre-existing lesions.  
  
 
 
 
Generally the overall tumor burden must increase  
  
 
 
 
sufficiently to merit discontinuation of therapy. In the  
  
 
 
 
presence of SD or PR in target disease, progression due  
  
 
 
 
to unequivocal increase in non-target disease should be  
  
 
 
 
rare. 
 
• 
Indeterminate:   
 
Progression has not been determined and one or more  
  
 
 
 
non-target sites were not assessed or assessment  
  
 
 
 
methods were inconsistent with those used at baseline. 
 
New Lesions 


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• 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the 
etiology.  If repeat assessments confirm the lesion, then progression should be recorded 
on the date of the initial assessment. A lesion identified in an area not previously 
scanned will be considered a new lesion. 
 
Supplemental Investigations 
• 
If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate.  If no disease is identified, objective status is CR. 
 
• 
If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
 
Objective/Subjective Progression 
• 
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of 
Health Status.  Every effort should be made to document objective progression even 
after discontinuation of treatment. 
Objective Response Status at each Evaluation: 
 
 
 
 
 
 
 
If the protocol allows enrollment of patients with only non-target disease, the following table will be 
used. 
 
 
Objective Response Status at each Evaluation for Patients with Non-Target Disease Only: 
 
 
 
 
 
 
DETEMINATION OF BEST OVERALL RESPONSE 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest sum on study).  For CR 
and PR, the patient’s best response assignment will depend on the achievement of both measurement 
and confirmation criteria.  CR and PR must be confirmed by 2 measurements at least 4 weeks apart.  In 
the case of SD, follow up measurements must have met the SD criteria at least once after study entry at 
a minimum interval of 6 weeks. 


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APPENDIX 2 
Immune-Related Response Criteria Derived From RECIST 1.1 (irRECIST) 
 
Increasing clinical experience indicates that traditional response criteria may not be sufficient to fully 
characterize activity in this new era of targeted therapies and/or biologics. 
 
This is particularly true for immunotherapeutic agents such as anti-CTLA4 and anti-PD-1/anti-PD-L1 
antibodies which exert the antitumor activity by augmenting activation and proliferation of T cells, thus 
leading to tumor infiltration by T cells and tumor regression rather than direct cytotoxic effects.50,51   
 
Clinical observations of patients with advanced melanoma treated with ipilimumab, for example, 
suggested that conventional response assessment criteria such as Response Evaluation Criteria in Solid 
Tumors (RECIST) and WHO criteria are not sufficient to fully characterize patterns of tumor response to 
immunotherapy because tumors treated with immunotherapeutic agents may show additional response 
patterns that are not described in these conventional criteria.52,53 
 
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) have been reported 
as not capturing the existence of a subset of patients who have an OS similar to those who have 
experienced CR or PR but were flagged as PD by WHO criteria. 52,53 
 
On these grounds, a tumor assessment system has been developed that incorporates these delayed or 
flare-type responses into the RECIST v1.1 (irRECIST).54 
 
For irRECIST, only target and measurable lesions are taken into account.  In contrast to RECIST v1.1, 
irRECIST: 
• 
Requires confirmation of both progression and response by imaging at least 4 weeks 
from the date first documented, and 
 
• 
Does not necessarily score the appearance of new lesions as progressive disease if the 
sum of lesion diameters of target lesions (minimum of 10 mm longest diameter per non-
nodal lesion and 15 mm shortest diameter per nodal lesion, maximum of 5 target 
lesions, maximum of 2 per organ) and measurable new lesions does not increase by ≥ 
20%. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the trial. 
 
Immune-Related Response Evaluation Criteria in Solid Tumours (irRECIST) is defined as follows: 
• 
Overall immune-related complete response (irCR):   
Complete disappearance of all lesions (whether measurable or not) and no new lesions. 
All measurable lymph nodes also must have a reduction in short axis to < 10 mm. 
 
• 
Overall immune-related partial response (irPR):   
Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target 
and new measurable lesions decreases ≥ 30%. 
    
• 
Overall immune-related stable disease (irSD):  


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Sum of the diameters (longest for nonnodal lesions, shortest for nodal lesions) of target 
and new measurable lesions is neither irCR, irPR, (compared to baseline) or immune-
related progressive disease (irPD, compared to nadir). 
 
• 
Overall immune-related progressive disease (irPD):  
Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target 
and new measurable lesions increases ≥ 20% (compared to nadir), confirmed by a 
repeat, consecutive observation at least 4 weeks from the date first documented. 
 
New measurable lesions:  Incorporated into tumor burden (i.e. added to the target lesion 
measurements).  A lymph node has to be ≥ 15 mm in short axis to be a measurable new lesion and its 
short axis measurement is included in the sum.  Up to 2 new lesions per organ and up to 5 new lesions in 
total can be added to the measurements. 
New non-measurable lesions:  Do not define progression but preclude irCR. 
 
Overall responses derived from changes in index, non-index, and new lesions are outlined in the below 
table: 
 
Overall Response Derived from Changes in Index, Non-index and New Lesions: 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3 
Cockcroft-Gault (CG) equation for the estimation of creatinine clearance 
 
 
𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 (𝑚𝑚𝑚𝑚/𝑚𝑚𝑚𝑚𝑚𝑚) = 
(140 −𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦) 𝑥𝑥 (𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑖𝑖𝑖𝑖 𝑘𝑘𝑘𝑘) 𝑥𝑥 (0.85 𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓)
72 𝑥𝑥 (𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑖𝑖𝑖𝑖𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑
⁄
)
 
 
 


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Appendix 4 
Acceptable Contraception 
 
Female patients of childbearing potential and male patients able to father children who have female 
partners of childbearing potential must agree to use at least one highly effective method of 
contraception, defined as methods with a failure rate of less than 1% per year when used consistently 
and correctly, as well as one additional effective method. Appropriate contraceptive methods are 
required at least 15 days prior to starting therapy, throughout the study, and for at least 30 days after 
the study participant’s final dose of avelumab.   
Females of childbearing potential are defined as those who are not surgically sterile or post-menopausal 
(i.e. patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; 
or has not been amenorrheic for 12 consecutive months without an alternative pathological or 
physiological cause).  Postmenopausal status may be confirmed by having a serum follicle-stimulating 
hormone (FSH) level within laboratory reference range for postmenopausal women.   
 
Male patients able to father children are defined as those who are not surgically sterile (i.e. patient has 
not had a vasectomy). 
A study physician or clinical designee shall counsel female patients of childbearing potential and male 
patients able to father children who have female partners of childbearing potential, regarding the 
importance of pregnancy prevention, the implications of an unexpected pregnancy, and the use of 
acceptable contraceptives.   
Subjects must agree to use at least one method of highly effective contraception and one additional 
effective method. The acceptable methods are listed below: 
Highly effective contraceptive methods (must use at least one): 
1. Combined (estrogen and progesterone containing) hormonal contraceptive associated with 
inhibition of ovulation1 (oral, intravaginal, transdermal) 
2. Progesterone-only hormonal contraceptive associated with inhibition of ovulation1 (oral, 
injectable, implantable2) 
3. Intrauterine device (IUD)2 
4. Intrauterine hormone-releasing system (IUS)2 
5. Bilateral tubal occlusion2 
6. Vasectomized partner2,3 
7. Abstinence defined as complete avoidance of heterosexual intercourse 
Complete abstinence is defined as complete avoidance of heterosexual intercourse, when 
consistent with the patient’s preferred and established lifestyle, is an acceptable form of 
contraceptive for purposes of the study.  Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, and post-ovulation methods) and withdrawal are not acceptable forms of 
contraceptive in this study.  In the event the subject chooses to forego complete abstinence, 
acceptable methods of contraceptive (see above lists) must be discussed with the study 
physician or clinical designee.  
 
Notes: 
1Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method 
2Contraception methods in the context of this guidance are considered to have low user dependency 


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3Vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner of the 
woman of childbearing potential trial participant and that the vasectomized partner has received medical assessment of 
the surgical success 
 
Additional effective contraceptive methods (must use at least one if only using one highly effective 
method listed above): 
1. Male condom or female condom used WITH a spermicide (i.e., foam, gel, film, cream, or 
suppository) 
2. Diaphragm 
3. Cervical cap  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 5 
New York Heart Association Functional Classification