Conditions: Recurrent Epithelial Cancer of Ovary Primary Peritoneal Carcinoma Fallopian Tube Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
Programmed death-1 receptor ligand (PD-L1) the ligand for PD-1 is a key therapeutic target in the reactivation of the immune response against multiple cancers. Pharmacologic inhibitors of PD-1 have also demonstrated significant anti-tumor activity and are currently under active clinical exploration. avelumab (MSB0010718C; anti-PD-L1 is a fully human anti-PD-L1 igG1 antibody that has shown promising efficacy and an acceptable safety profile in multiple tumor types.

Radiation therapy (RT) is one of the mainstream treatments of cancer therapy along with surgery and chemotherapy, yet RT is the only treatment that does not leave the patients immunocompromised (unlike chemotherapy) and keeps the dying tumor / antigen depot within the host (unlike surgery), providing an opportunity for antigen presentation. Therefore, RT is a rational choice to combine with immunotherapy for cancer treatment.

Detailed description:
Screening/Baseline Procedures Assessments performed exclusively to determine eligibility for this study will be done only after obtaining informed consent. Assessments performed for clinical indications (not exclusively to determine study eligibility) may be used for baseline values even if the studies were done before informed consent was obtained.

All screening procedures must be performed within 28 days prior to registration unless otherwise stated. The screening procedures include:

* Informed Consent
* Medical history: Complete medical and surgical history, history of infections
* Demographics: Age, gender, race, ethnicity
* Review subject eligibility criteria
* Review previous and concomitant medications
* Physical exam including vital signs, height and weight: Vital signs (temperature, pulse, respirations, blood pressure), height, weight
* Performance status: Performance status evaluated prior to study entry according to Appendix #/letter.
* Adverse event assessment: Baseline adverse events will be assessed. See section 6 for Adverse Event monitoring and reporting.
* Hematology CBC and diff ( within 2 weeks of registration)
* T 4 levels, TSH and CMP as below: Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin. (within 2 weeks of registration)- Pregnancy test (for females of child bearing potential)( within 2 weeks of registration)
* Tumor assessment:Baseline imaging by CT scan of chest , abdomen, and pelvis.

Procedures During Treatment

* Prior to Each Treatment Cycle

  * Physical exam, vital signs
  * Hematology
  * Serum chemistries
* Every 8 weeks after start till end of treatment Serum TSH, pregnancy test and CT chest abdomen and pelvis

  30 days after treatment termination
* Physical exam, vital signs
* Hematology
* Serum chemistries
* additional Immune co-relate lab testing: Prior to cycle 1, cycle 3, cycle 5, cycle 7 and 2 weeks post last cycle.

Follow-up Procedures

* For patients who are still receiving Avelumab: Subject will be followed every eight weeks (+/- 2 weeks) starting from the beginning of treatment for the first year, then every 12 weeks (+/- 2 weeks) till 2 years after last dose of drug The following procedures will be performed at each follow up:

  * Physical exam, PS, vital signs, medication review, AE assessment
  * Blood collection per time table and for labs
  * Radiographic imaging: Tumor assessments will be completed by the investigator using the RECIST criteria as above.

    * CT chest, abdomen and pelvis with IV contrast, if allowable by renal function
    * After that, survival information will be collected every 6 months until patient death.
* For patients who have been discontinued from Avelumab : Subject will be followed 30 days from last dose (±7 days, or may be on date of discontinuation ±7 days if the date of discontinuation is more than 37 days after last dose) and then 3-4 months from last dose.

The following procedures will be performed at the first two visits:

* Physical exam, PS, vital signs, medication review, AE assessment
* Subsequent anti-cancer treatment/s
* For first visit only, or may repeat if study drug related toxicity persists: CBC w/ differential, LFTs, BUN, creatinine, fasting glucose, and TSH

After that, survival information will be collected every 6 months until patient death.

Arms:
arm 1: Avelumab and SABR

Interventions: intervention 1: Avelumab
Intervention descriptions: intervention 1: Avelumab\* (MSB0010718C; anti-PD-L1 is a fully human anti-PD- L1 IgG1 antibody)

Protocol document:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016 
 
 
 
 
 
NCT03312114 
 
 
 
Title: Phase II trial of Concurrent Anti—PD-L1 and SAbR for Patients with 
Persistent or Recurrent Epithelial Ovarian, Primary Peritoneal or Fallopian 
Tube Cancer (with safety lead-in)  
 
 
 
Document Date: 10/17/18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016 
 
 
STU 032017-078 Phase II trial of Concurrent Anti—PD-L1 and SAbR for 
Patients with Persistent or Recurrent Epithelial Ovarian, Primary Peritoneal 
or Fallopian Tube Cancer (with safety lead-in) 
 
 
Principal Investigator: 
 
Kevin Albuquerque, MD  
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd, Dallas, TX 75390 
 
 
 
 
Telephone: (214) 645-7296; Fax: (214) 645-9233 
 
 
 
 
Email: kevin.albuquerque@utsouthwestern.edu 
 
Co-Principal Investigator 
Jayanthi Lea, MD 
 
 
 
 
Division of Gynecologic Oncology 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
 
 
 
Dallas, TX  75390 
 
 
 
 
Telephone: (214) 648-3111 
 
 
 
 
Email: jayanthi.lea@utsouthwestern.edu 
 
Co-Investigator(s): 
 
Raquibul Hannan, MD 
 
 
 
 
David Miller, MD 
 
 
 
 
Matthew Carlson, MD 
 
Biostatistician:  
 
Hong Zhu, Ph.D. 
 
 
 
 
Email: hong.zhu@utsouthwestern.edu 
 
Study Drug/Treatment: MSB0010718C: Avelumab  
 
IND/IDE Number: 
 
135852 
 
IND/IDE Holder Name:  
Kevin Albuquerque, MD  
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
Funding Source:  
Individual Investigator Grant from Pfizer (trial and drug funding) 
 
 
Version: 
 
 
 
 
 
 
 
 
Version 
Date 
Initial 
3/31/2017 
v2 
09/19/2017 
v3 
10/27/2017 
v4 
12/11/2017 
v5 
08/22/2018 
 
 
UT Southwestern Medical Center (UTSW) 
Radiation Oncology 
Attn: Clinical Research Office 
2280 Inwood Rd 


 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016 
 
Dallas, Texas 75235 
 


 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 


 
i 
 
TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS ........................................................................................................................................................ 1 
STUDY SCHEMA .......................................................................................................................................................................... 4 
STUDY SUMMARY ...................................................................................................................................................................... 5 
1.0 
BACKGROUND AND RATIONALE .......................................................................................................................... 6 
1.1 
DISEASE BACKGROUND ................................................................................................................................................................ 6 
1.2 
IMMUNOTHERAPY(IT) AND RECURRENT  OVARIAN CANCER (ROPT) ............................................................................... 6 
1.3 
STUDY  AGENT(S) BACKGROUND AND ASSOCIATED KNOWN TOXICITIES ........................................................................... 7 
1.4 
RATIONALE ................................................................................................................................................................................... 12 
1.5 
CORRELATIVE STUDIES .............................................................................................................................................................. 12 
2.0 
STUDY OBJECTIVES ................................................................................................................................................ 13 
2.1 
PRIMARY OBJECTIVES ................................................................................................................................................................. 13 
    2.2          SECONDARY OBJECTIVES…………………………………………………………………………………………………….     13 
2.3 
EXPLORATORY OBJECTIVES ....................................................................................................................................................... 13 
2.4 
ENDPOINTS ................................................................................................................................................................................... 14 
3.0 
SUBJECT ELIGIBILITY ............................................................................................................................................ 15 
3.1 
INCLUSION CRITERIA .................................................................................................................................................................. 15 
3.2 
EXCLUSION CRITERIA ................................................................................................................................................................. 16 
3.3 
SUBJECT RECRUITMENT AND SCREENING ............................................................................................................................... 17 
3.4 
WHEN AND HOW TO WITHDRAW SUBJECTS .......................................................................................................................... 18 
3.5 
REPLACEMENT OF SUBJECTS ..................................................................................................................................................... 18 
3.6 
TOTAL NUMBER OF SUBJECTS AND SITES ............................................................................................................................... 18 
4.0 
TREATMENT PLAN ................................................................................................................................................. 18 
4.1 
TREATMENT DOSAGE AND ADMINISTRATION ........................................................................................................................ 18 
4.2 
SABR DOSE AND TECHNIQUES ................................................................................................................................................. 19 
4.3 
AVELUMAB: TREATMENT DOSAGE AND ADMINISTRATION ................................................................................................. 23 
4.4 
OTHER MODALITIES OR PROCEDURES .................................................................................................................................... 32 
4.5 
DURATION OF THERAPY ............................................................................................................................................................. 32 
4.6 
DURATION OF FOLLOW UP ........................................................................................................................................................ 32 
5.0 
STUDY PROCEDURES ............................................................................................................................................. 33 
5.1 
SCREENING/BASELINE PROCEDURES ...................................................................................................................................... 33 
5.2 
PROCEDURES DURING TREATMENT ......................................................................................................................................... 34 
5.3 
FOLLOW-UP PROCEDURES ......................................................................................................................................................... 35 
5.2      TIME AND EVENTS TABLE ......................................................................................................................................................... 36 
5.4 
REMOVAL OF SUBJECTS FROM STUDY ...................................................................................................................................... 37 
6.0 
MEASUREMENT OF EFFECT ................................................................................................................................. 38 
6.1 
ANTITUMOR EFFECT- SOLID TUMORS ..................................................................................................................................... 38 
6.2 
SAFETY/TOLERABILITY .............................................................................................................................................................. 42 
7.0 
ADVERSE EVENTS ................................................................................................................................................... 42 
7.1 
SABR ............................................................................................................................................................................................. 42 
7.2 
ADVERSE EVENT MONITORING ................................................................................................................................................ 43 
7.3 
STEPS TO DETERMINE IF AN ADVERSE EVENT REQUIRES EXPEDITED REPORTING ........................................................ 46 
8.0 
DRUG/TREATMENT INFORMATION ................................................................................................................ 47 


 
ii 
 
8.1 
GENERAL PROPERTIES OF DRUG SUBSTANCE ........................................................................................................................ 48 
9.0 
CORRELATIVES/SPECIAL STUDIES ................................................................................................................... 49 
9.1 
METASTATIC TUMOR PROFILE ................................................................................................................................................. 49 
9.2 
SERUM IMMUNE MARKERS ........................................................................................................................................................ 49 
9.3 
SAMPLE COLLECTION GUIDELINES ........................................................................................................................................... 49 
9.4 
SPECIMEN BANKING ................................................................................................................................................................... 50 
10.0 
STATISTICAL CONSIDERATIONS ....................................................................................................................... 50 
10.1 
STUDY DESIGN/STUDY ENDPOINTS ........................................................................................................................................ 51 
10.2 
SAMPLE SIZE AND ACCRUAL ...................................................................................................................................................... 51 
10.3 
DATA ANALYSES PLANS ............................................................................................................................................................. 51 
11.0 
STUDY MANAGEMENT ........................................................................................................................................... 51 
11.1 
CONFLICT OF INTEREST.............................................................................................................................................................. 51 
11.2 
REGISTRATION/RANDOMIZATION PROCEDURES .................................................................................................................. 52 
11.3 
DATA MANAGEMENT AND MONITORING/AUDITING ............................................................................................................ 52 
11.4 
ADHERENCE TO THE PROTOCOL ............................................................................................................................................... 54 
11.5 
AMENDMENTS TO THE PROTOCOL ........................................................................................................................................... 54 
11.6 
RECORD RETENTION .................................................................................................................................................................. 55 
11.7 
OBLIGATIONS OF INVESTIGATORS ............................................................................................................................................ 55 
12.0 
REFERENCES ............................................................................................................................................................. 55 


 
 
1 
 
 
List of Abbreviations 
 
 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or special 
term 
Explanation 
AChE 
Acetylcholine esterase 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
APF12 
Proportion of patients alive and progression free at 12 months from randomization 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-28day 
Area under the plasma drug concentration-time curve from time zero to Day 
28 post-dose 
AUCss 
Area under the plasma drug concentration-time curve at steady state 
BICR 
Blinded Independent Central Review 
BoR 
Best objective response 
BP 
Blood pressure 
C 
Cycle 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
Cmax,ss 
Maximum plasma concentration at steady state 
CR 
Complete response 
CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 
Ctrough,ss 
Trough concentration at steady state 
CXCL 
Chemokine (C-X-C motif) ligand 
DoR 
Duration of response 
EC 
Ethics Committee, synonymous to Institutional Review Board and Independent 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDoR 
Expected duration of response 
EGFR 
Epidermal growth factor receptor 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 


 
 
2 
 
Abbreviation or special 
term 
Explanation 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IFN 
Interferon 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILS 
Interstitial lung disease 
IM 
Intramuscular 
IMT 
Immunomodulatory therapy 
IP 
Investigational product  
imAE 
Immune-mediated adverse event 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
mAb 
Monoclonal antibody 
MDSC 
Myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Minister of Health, Labor, and Welfare 
miRNA 
Micro-ribonucleic acid 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non–small-cell lung cancer 
OAE 
Other significant adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PDx 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
PFS2 
Time to second progression 
PGx 
Pharmacogenetic research 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
q6w 
Every 6 weeks 
q8w 
Every 8 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
RR 
Response rate 
RT-QPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE 
Serious adverse event 


 
 
3 
 
Abbreviation or special 
term 
Explanation 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SD 
Stable disease 
SNP 
Single nucleotide polymorphism 
SoC 
Standard of Care 
sPD-L1 
Soluble programmed cell death ligand 1 
T3 
Triiodothyronine 
T4 
Thyroxine 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
SBRT 
Stereotactic body radiotherapy 
IMRT 
Intensity modulated radiotherapy 
 
 
UTSW:  
University of Texas-Southwestern 
SABR:  
Stereotactic Ablative Radiotherapy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
4 
 
STUDY SCHEMA 
 
 
 
SCHEMA: 
 
(Diagram): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility: Recurrent Ovary, Primary Peritoneal, 
Fallopian Cancer 
Progressed after 2nd/3rd line chemo 
 
Eligible for anti-PD-L1 treatment 
 
Eligible for SAbR to 1-2 lesions 
Additional lesion to measure response 
 
ECOG 0-2 
 
Whole blood collection for baseline 
immunologic assays 
 
Baseline imaging 
o CT CAP-w/PO+IV contrast 
 
Optional metastatic lesion biopsy 
(biological correlates) 
Concurrent anti-PD-L1 
+ SAbR to metastasis 
 
Repeat imaging Q 8 weeks 
beginning after treatment start 
 
Correlative lab studies 
 
Primary End Point: Overall Response Rate and Toxicity 
(Lead-In Phase – 6 pts)-DLT assessed till 8 weeks 
o RECIST 1.1 
 
Secondary Endpoint: OS, PFS 
 
Biomarkers in tumor bx and blood 
 
Continue PD-L1: until progression of disease, toxicity or 9 
cycles (whichever is earlier) 


 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY SUMMARY 
Title 
Phase II trial of Concurrent Anti—PD-L1 and SAbR for Patients with Persistent 
or Recurrent Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer 
(with safety lead-in) 
Short Title 
Avelumab and SABR for Recurrent Ovarian cancer 
Protocol Number 
STU 032017-078 
Phase 
Phase II 
Methodology 
Open label, one-arm, bi-modality, single center trial 
Study Duration 
3 years 
Study Center(s) 
Single-center  
Objectives 
Trial of combined Avelumab (MSB0010718C) anti-PD-L1checkpoint blockade 
with SAbR for  Recurrent Ovarian and  peritoneal, fallopian tube cancer 
(ROPT) to assess overall  clinical response rates per-RECIST, with prior safety 
lead-in 
Number of Subjects 
29 
Diagnosis and Main 
Inclusion Criteria 
Recurrent Ovarian,  peritoneal and fallopian tube cancer (ROPT) 
Study Product(s), Dose, 
Route, Regimen 
Concurrent Anti—PD-L1 (Avelumab) and SAbR. Avelumab will be dosed 
intravenously (IV) over 60 minutes (±10 min) at 10 mg/kg every 2 weeks (± 2 
days) of each treatment cycle until disease progression or 9 cycles. SABR will 
be administered to 1-2 sites of metastatic disease within 15 days after 
commencing the immunotherapy with 3 fractions to a total dose of 24-36 Gy (8-
12 Gy per fraction x 3 fractions) targeted to the largest easily accessible 
metastases based on normal tissue tolerances. 
Duration of administration 
Up to 9 cycles 
Reference therapy 
Avelumab alone  
Statistical Methodology 
Exact binomial method will be used to estimate the Overall Response and 
toxicity rate in patients receiving SAbR+avelumab along with corresponding 
95% confidence interval. Correlation analysis will be performed with tumor 
immune cell PD-L1 and serial serum cytokine estimation.   
 
 
 


 
 
6 
 
 
1.0 
Background and Rationale 
1.1 Disease Background 
Epithelial Ovarian cancer (EOC) is the leading cause of gynecologic cancer deaths, and the fifth most 
common cause of cancer deaths in women in the United States. An estimated 14,346 women will die of 
ovarian cancer in the United States in 2015[1]. Although about 75% of patients with epithelial ovarian 
cancer will respond to first-line chemotherapy with platinum and paclitaxel, most patients with advanced 
stage epithelial ovarian cancer will recur. While there are several active cytotoxic agents for the treatment of 
recurrent epithelial ovarian cancer, median survival after recurrence is about 2 years [2]. Like recurrent 
ovarian, most recurrent epithelial cancers of fallopian tube and primary peritoneal origin are genetically 
unstable, aggressive neoplasms accounting for the majority of gynecologic cancer deaths. About 25% of 
patients are platinum resistant (defined as recurring within 6 months of completing platinum-based 
chemotherapy) at the time of first recurrence, and essentially all women with recurrent ovarian cancer 
eventually become platinum-resistant. In a recent trial, chemotherapy alone (weekly paclitaxel, liposomal 
doxorubicin, or topotecan), resulted in a median progression-free survival of 3.4 months. While this 
improved to 6.7 months with the addition of bevacizumab, there was no improvement in median overall 
survival [3] Therefore, there is a need for developing and testing novel agents in this population. 
Some other drugs have single agent activity in refractory cases, but the response rates are low (10–20%) and 
without a clear survival. For example, in a GOG study looking at Gemcitabine , the Overall response rate 
(CR+PR) was 16% and Time to progression was 5.4 months [4] 
A more recent study was conducted The Gynecologic Oncology Group (GOG) to evaluate the impact of the 
histone deacetylase inhibitor, belinostat, in combination with carboplatin in women with platinum-resistant 
ovarian cancer. An ORR of 7.4% with TTP of 3.3 months was obtained highlighting the very poor prognosis 
for these patients. 
1.2 Immunotherapy (IT) and Recurrent Ovarian Cancer (ROPT) 
Studies have demonstrated that ovarian cancers are immunogenic and elicit spontaneous antitumor immune 
responses from immunotherapy.[5, 6]  Preclinical studies have shown that ovarian cancer mouse models 
develop immunosuppressive phenotypes which enable them to evade the immune system, whereas combined 
immune checkpoint blockade reverses this phenotype. Expression of PD-L1 by tumors has been associated 
with decreased intraepithelial TILs and poor overall survival in EOC. In an immune-competent murine 
model of EOC, PD-1 and PD-L1 blockade has led to eradication of tumors through the expected 
reprogramming of the tumor microenvironment, which suggests potential benefit from PD-1/PD-L1 
inhibition for patients with EOC .The presence and  the number of tumor-infiltrating lymphocytes in 
recurrent ovarian cancer has shown to be a significant prognostic factor[7, 8] Programmed death-1 receptor 
ligand (PD-L1) the ligand for PD-1 is a key therapeutic target in the reactivation of the immune response 
against multiple cancers [9]. Pharmacologic inhibitors of PD-1 have also demonstrated significant anti-
tumor activity and are currently under active clinical exploration[10]. FDA approval has been granted to 
biologic agents Nivolumab (BMS936558) and Pembrolizumab (Pembro, MK-3475) for treatment of 
advanced (metastatic) squamous non-small cell lung cancer (NSCLC) and melanoma, respectively. PD-L1 
expression levels have been correlated with poor clinical prognosis in renal, gastric, ovarian, breast and 
esophageal cancers [11-15]. Avelumab* (MSB0010718C; anti-PD-L1 is a fully human anti-PD-L1 IgG1 
antibody that has shown promising efficacy and an acceptable safety profile in multiple tumor types[16]. 
There are now published data showing the activity of avelumab in treatment of patients with Merckel cell 
carcinoma (Kaufman HL et al, 2016, Lancet Oncology) and the drug has received accelerated FDA approval 
for second line treatment of metastatic bladder cancer.   
 
Role of Radiation  in Recurrent Ovarian Cancer The role of radiation in ovarian cancer is controversial 
in the adjuvant setting though ovarian cancer is known to be radio-sensitive[17] . However, there is the 


 
 
7 
 
emerging data that focal radiation is effective in selected patients with Localized Recurrent ovarian 
cancer.[18-21].We have previously shown a benefit for loco-regional control of selected localized ROC   
with involved field radiation therapy (IFRT)[21] In a comparison cohort we demonstrated a 50% 
improvement in OS for radiation  compared to chemotherapy in a limited recurrent setting. 
Radiation therapy (RT) is one of the mainstream treatments of cancer therapy along with surgery and 
chemotherapy, yet RT is the only treatment that does not leave the patients immunocompromised (unlike 
chemotherapy) and keeps the dying tumor / antigen depot within the host (unlike surgery), providing an 
opportunity for antigen presentation. Therefore, RT is a rational choice to combine with immunotherapy for 
cancer treatment. 
 
1.3 Study Agent(s) Background and Associated Known Toxicities 
1.3.1 
Immunotherapy (IT) Avelumab* (MSB0010718C; anti-PD-L1 is a fully human anti-PD- L1 IgG1 
antibody that has shown promising efficacy and an acceptable safety profile in multiple tumor 
types.[5]. Because of the known role of programmed death ligand 1 (PD-L1) in the suppression of 
T cell  responses and the strong correlation between PD-L1 expression and prognosis in cancer, the  
blockade of the PD-L1/programmed death 1 (PD-1) interaction presents a highly promising  
strategy for cancer immunotherapy. Avelumab binds PD-L1 and blocks the interaction between 
PD-L1 and PD-1. This removes the suppressive effects of PD-L1 on anti-tumor CD8+ T cells, 
resulting in the restoration of cytotoxic T cell response. The non-clinical and clinical experience is 
fully described in the current version of the Avelumab Investigator’s Brochure (IB Version 7.0).  
The active pharmaceutical ingredient in avelumab drug product is a fully human antibody 
(calculated molecular weight of 143,832 Dalton) of the immunoglobulin G (IgG) 1 isotype that 
specifically targets and blocks PD-L1, the ligand for PD-1. 
Avelumab binds to human PD-L1 with a high affinity of 0.7 nM and not to any other B7 family 
proteins, and competitively blocks the interaction of PD-L1 with PD-1. The in vitro study results 
have shown that by binding to PD-L1, avelumab effectively enhances T cell activation as measured 
by interleukin (IL)-2 or interferon-gamma (IFN-
 production. In addition, as a fully human IgG1 
antibody, avelumab has the potential to trigger the antibody-dependent cell-mediated cytotoxicity 
(ADCC) against target cells expressing PD-L1. 
1.3.1.1 
Non-clinical studies and Toxicity 
The toxicological profile of avelumab was investigated in vivo in mice, rats, and cynomolgus 
monkeys. In addition, in vitro cytokine release assays in human and cynomolgus monkey whole 
blood and PBMCs as well as tissue cross reactivity studies in normal human and cynomolgus 
monkey tissues were performed. Additionally, data on the UV absorption of avelumab were 
generated. 
On the basis of the binding affinity data, the cynomolgus monkey was selected as relevant species 
for the nonclinical safety testing of avelumab. Signs of hypersensitivity or avelumab-related 
infusion reactions were not observed in cynomolgus monkeys after repeated treatment with 
avelumab at dose levels of 20, 60 and 140 mg/kg. Avelumab was well tolerated systemically and 
accordingly, the NOAEL was established at the high dose of 140 mg/kg in both, the 4-week and the 
pivotal 13-week, repeat-dose monkey studies. 
 
1.3.1.2 
Clinical studies –summary of efficacy and safety 
Several clinical studies have been initiated as detailed in the IB. However, none have been reported 
except in abstract form. Data from 1629 subjects from ongoing Studies EMR100070 001 (20 
November 2015 cut-off date), EMR100070 002 (20 November 2015 cut-off date), and EMR100070 


 
 
8 
 
003 (03 March 2016 cut-off date) were used to estimate PK parameters and to evaluate the PK 
interindividual variability. Safety data is also available from this same dataset.  
Some preliminary individual trial results are as follows: 
The second-line NSCLC expansion cohort in the ongoing Phase I Trial EMR100070-001 had a 
cutoff date of 15 January 2015, 6 months after the start of avelumab treatment of the last subject in 
this expansion cohort (a total of 184 treated subjects). This group of subjects with NSCLC 
presented with a median age of 65.0 years, and all of whom had Stage IIIB or IV NSCLC that had 
progressed after at least 1 line of platinum-containing doublet chemotherapy for metastatic or 
locally advanced disease. As of 15 January 2015, 41 of 184 subjects (22.3%) remained on study 
treatment, and 143 subjects (77.7%) discontinued study treatment at the time of the data cutoff. The 
major reason for treatment discontinuation was disease progression (93 subjects, 50.5%) followed 
by AE (18 subjects, 9.8%). Of 184 patients, 22 had a confirmed objective response, including one 
complete response and 21partial responses, resulting in a confirmed objective response rate of 
12.0% (95% CI: 7.6, 17.5). 
The unconfirmed objective response rate was 14.1% (95% CI: 9.4, 20.0), including one complete 
response and 25 partial responses. Based on confirmed or unconfirmed responses, 10 of 26 
responding patients (39%) had responded by the first assessment at 6 weeks, and 19 of 26 
(73%)had responded by 12 weeks; median duration of response was not reached, with response 
durations ranging from 0.1 to ongoing at 54.1 weeks. Among 22 patients with a confirmed 
response, response was maintained for 24 weeks or longer in 83% of cases (95% CI: 54, 94) by 
Kaplan-Meier estimates. Median PFS was 11.6 weeks (95% CI: 8.4, 13.7), and PFS rates at 24 
weeks and 48 weeks were 26% (95% CI: 20, 33) and 18% (95% CI: 12, 26), respectively. At the 
time of analysis, 139 of184 patients (76%) had a PFS event (progressive disease (116 [63%]) or 
death (23 [13%]). Based on immune-related response criteria, median PFS was 17.6 weeks (95% 
CI: 12.1, 22.9), and rates at 24 and 48 weeks were 39% (95% CI: 31, 46) and 33% (95% CI: 25, 
42), respectively. 
1.3.1.3 
Ovarian Cancer: Recently the first experience with Avelumab in ovarian cancer;  
The JAVELIN Solid Tumor phase IB trial [6] specifically reported safety and clinical activity of 
avelumab in a large series of patients with recurrent/refractory ovarian cancer (OC; 
NCT01772004). Patients received avelumab 10 mg/kg IV Q2W until progression, unacceptable 
toxicity, or withdrawal. Tumors were assessed every 6 wks. (RECIST 1.1). As of Oct 23, 2015, 124 
pts were treated with avelumab (median 12 wks.  [range 2-54]) and followed for a median of 54 
wks. (range 11-101). Median number of prior therapies was 4 (range 1-13). Treatment-related (TR) 
AEs occurred in 82 pts (66.1%); most common (≥10%) were fatigue (13.7%), infusion-related 
reaction (12.1%), and diarrhea (11.3%), all of grade 1/2. Grade 3/4 TRAEs were reported in 8 pts 
(6.5%); of these, only increased lipase occurred in > 1 pt (n = 2). There were no treatment-related 
deaths. ORR was 9.7% Stable disease was observed in 55 pts (44.4%); disease control rate was 
54.0%.The first published phase 2 study by Hamanishi et al [7] from Japan using the PD-1 
checkpoint inhibitors Nivolumab for (with platinum-resistant, recurrent, or advanced ovarian cancer 
to evaluate the safety and antitumor efficacy of nivolumab have been reported show the best ORR 
of 15%. 
1.3.1.4 
Urothelial cancer:  
Trial EMR100070-001 enrolled 2 cohorts of subjects with locally advanced or metastatic UC who 
were either cisplatin ineligible or had PD after at least 1 line of platinum-based therapy (Table 16). 
As of 19 March 2016, a combined 241 subjects had been treated in the 2 UC cohorts, of whom 153 
had at least 6 months of follow-up (all 44 subjects in the secondary UC cohort and 109 of the 197 
subjects in the efficacy UC cohort). Of the 241 subjects, 87 (36.1%) were still on treatment at the 
time of data cut-off. 
In the pooled group of 153 subjects with at least 6 months of follow-up, the confirmed ORR was  
17.6% (95% CI: 12.0, 24.6), consisting of 9 subjects (5.9%) with CR and 18 subjects (11.8%)  with 


 
 
9 
 
PR. Onset of response was documented at the first or second tumor assessment for 21 of the  27 
confirmed responses (77.8%), with a median time to response of 11.43 weeks (range: 5.6 to  48 
weeks). Median duration of response was not yet reached (95% CI: 42.14 weeks, not  estimable 
[NE]); the Kaplan-Meier estimate of 24-week durability of response was 92.0% (95%  CI: 71.6, 
97.9). Of the 27 confirmed responses, 24 (88.9%) were ongoing at the time of data cutoff, with 
duration of response ranging from 4.7 to 65.7 weeks.  
1.3.1.5 
Pregnancy: 
Based on its mechanism of action, avelumab can cause foetal harm when administered to a 
pregnant woman. In animal models, the PD-1/PD-L1 signaling pathway is important in the 
maintenance of pregnancy through induction of maternal immune tolerance to foetal tissue. Human 
IgG1 immunoglobulins are known to cross the placenta. Therefore, avelumab has the potential to be 
transmitted from the mother to the developing foetus. Blockade of PD-L1 signaling has been shown 
in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in 
foetal loss. Therefore, potential risks of administering avelumab during pregnancy include 
increased rates of abortion or stillbirth. 
Reported toxicity Treatment-related TEAEs and Grade ≥ 3 treatment-related TEAEs 
The most frequently reported (incidence at least 5 subjects, 0.3%) treatment-related TEAEs (any  
grade) in the pooled safety dataset are summarized in Table 19 of IB v7.0 . The most frequently 
reported  Grade ≥ 3 treatment-related TEAEs in the pooled safety dataset (occurring in at least 3 
subjects,  0.2%) are presented in Table below. 
Treatment-related TEAEs were observed in 1164 (67.0%) subjects in the pooled safety dataset.  
Treatment-related TEAEs with an incidence of ≥0.3% of any grade were fatigue (17.7%), infusion 
related reaction (17.0%), nausea (8.6%), diarrhea (7.1%), chills (6.7%), pyrexia (6.1%), decreased 
appetite (5.2%), and hypothyroidism (5.0%).  
Grade ≥ 3 treatment-related TEAEs were observed in 177 subjects (10.2%) in the pooled safety 
dataset. As shown in table, the most frequently reported (at least 3 subjects, 0.2%) Grade ≥ 3  
treatment-related TEAEs were fatigue, lipase increased (17 subjects each; 1.0%), GGT  increased, 
infusion related reaction (10 subjects; 0.6%), AST increased (8 subjects; 0.5%),  pneumonitis (7 
subjects; 0.4%), anaemia, blood CPK increased (6 subjects each; 0.3%), diarrhea,  asthenia (5 
subjects each; 0.3%), autoimmune hepatitis, ALT increased, amylase increased,  hyponatraemia, 
hypophosphataemia (4 subjects each; 0.2%). Other Grade ≥ 3 treatment-related TEAEs that were 
observed in 3 subjects (0.2%) included lymphopenia, adrenal insufficiency, hypothyroidism, colitis, 
vomiting, autoimmune disorders, lymphocyte count decreased,  transaminase increased, decreased 
appetite and hypokalaemia. 
 
1.3.2 
Most Frequently Reported (at Least 3 Subjects [0.2%]) Grade > 3 Treatment Related TEAEs by 
SOC and PT in the Pooled Safety Dataset 
The table below contains toxicity data from a pooled dataset of patients on several Avelumab studies. The 
1738 subjects comprising the pooled safety dataset includes subjects from 16 tumor  expansion cohorts from 
Study EMR100070-001 as well as from MCC subjects from Part A of  Study EMR100070-003.the data 
refers to Grade ≥ 3 treatment emergent adverse effects reported. Overall, the severe significant toxicity 
appears to be low.  
 


 
 
10 
 
 
 


 
 
11 
 
 
 
1.3.3 
SAbR: Stereotactic ablative body radiation (SAbR) is an emerging treatment paradigm defined in 
the American Society of Therapeutic Radiology and Oncology guidelines as a “treatment method to 
deliver a high dose of radiation to the target, utilizing either a single dose or a small number of 
fractions with a high degree of precision within the body” [22] . Potential indications for SAbR 
include a broad spectrum of tumor types and locations. The safety and efficacy of SAbR to multiple 
sites is excellent as documented in multiple studies [23-25]. Recently, SAbBR was shown to have 
multiple immunogenic properties including induction of an immunogenic tumor cell death and 
initiation of tumor antigen presentation [13, 14]. Since SAbBR is a highly focused therapy, it does 
not inherently immunocompromise the host. It also spares the surrounding lymph nodes which are 
vital for an effective immune response. Furthermore, since SBRT causes local inflammation, 
dendritic cells (DCs) are attracted into the tumor. The antigen- presenting properties and the 
induction of immunogenic cell death by SBRT via the release of danger-associated molecules 
(DAMPS) such as HMGB1, HSP and Calreticulin are well documented [15-17]. 
A recent comprehensive literature review [26] of SAbR for gynecological tumors  between 1993-
2013 identified 12  case series and one phase 2 trial  [27]. This phase 2 II clinical trial evaluated the 
safety and efficacy of SAbR in 50 patients with recurrent cervical, endometrial, ovarian, and vulvar 
cancer. SRS was used to deliver 24 Gy in 3 fractions to a clinical target volume (CTV) that 
included the gross tumor volume (GTV) as well as surrounding fluorodeoxyglucose (FDG)-avid 


 
 
12 
 
areas. Sixty-two percent of patients showed clinical benefit at 6 months. Most toxicity was mild, 
though one patient did experience grade 4 hyperbilirubinemia and another developed an 
enterovaginal fistula. SAbR was considered safe for recurrent gynecological tumors by the authors.   
1.4 Rationale 
Programmed death receptor 1 (PD-1) is a transmembrane protein of the immunoglobulin CD-28 family and 
is expressed on activated immune cells including macrophages, dendritic cells, activated B and T cells [28]. 
Two ligands specific for PD-1 have been identified: PD-L1 and PD-L2. PD-L1 is a member of the B7 family 
costimulatory molecules. Except for some immune cell lineages, human cells do not normally express PD-
L1. In addition, while not commonly expressed in tumor cell lines in vitro, PD-L1 is widely expressed in 
various in vivo tumor tissues. Multiple studies have shown that interferon-gamma (IFN-γ) produced by 
activated T-cells induce the over expression of PD-L1 on tumor cells [29]. Tumor cells, induced by IFN-γ, 
can express high levels of PD-L1, which interacts with PD-1 on immune cells, and through PI3K/Akt 
inhibition, suppresses their immune response by inducing T cell apoptosis, anergy, exhaustion, dendritic cell 
suppression, IL-10 production and Treg induction. PD-L1 and PD-1 interaction also protect tumor cells from 
lysis by cytotoxic T lymphocytes [30]. Given the expression of PD-L1 on host immune cells, anti-body 
mediated PD-L1 inhibition should work in both PD-L1 positive tumors.  
As discussed above, Avelumab* (MSB0010718C; anti-PD-L1) is a fully human anti-PD-L1 IgG1 antibody 
that has shown promising efficacy and an acceptable safety profile in multiple tumor types. Avelumab 
blocks the interaction between PD-1 and PD-L1, and thus activates the immune system in a non-specific 
manner. SABR should be able to provide a specific direction to the immune response by promoting antigen 
presentation. Recruited and activated by the DAMPs and other changes brought onto the tumor 
microenvironment by radiation therapy, the APCs migrate to the lymph node for antigen presentation and T-
cell activation. RT also increases tumor infiltrating lymphocyte (TIL) trafficking within irradiated tumors 
[31, 32]. Typically, TILs produce IFN-γ which promotes antigen presentation but at the same time induces 
PD-L1 expression which is meant to prevent the propagation of the inflammatory response and limit tissue 
damage. In the presence of PD-1 inhibitors, INF-γ will enhance antigen presentation and stimulate the 
immune response without the down-stream effects of PD-1/PD-L1 interaction [33]. Nonetheless, not all PD-
L1 expression on tumor cells is IFN-γ-dependent. Certain tumors intrinsically express PD-L1 and certain 
cancer mutations can also upregulate PD-L1 expression [34, 35]. 
NK cells are part of the immune system’s innate defense against cancer and were first discovered because of 
their anti-tumor activity [36]. In fact, ex vivo expansion and re-infusion of autologous NK cells has shown to 
induce long-term remission in cancer patients [37]. Specific destruction of cancer stem cells has been 
demonstrated by NK cells [38]. Radiation therapy increases expression of retinoic acid early inducible-1 
(RAE-1) in carcinoma cells, which binds to the NKG2D receptor present in NK cells and CTLs and leads to 
their activation [32, 39]. Interestingly, NK cells also express PD-1 and it has been shown that PD-1 
inhibition enhances NK cell response against multiple myeloma [40]. This suggests another possible 
synergistic interaction of Avelumab and SABR in producing an anti-tumor effect mediated by NK cell 
activation.  
1.5 Correlative Studies 
The goal of laboratory correlative studies will be to identify immune-biomarkers to better identify patient 
populations that are more responsive to this regimen.  
Metastatic Tumor Profile. Archival tissue of metastatic site or retrospective primary tumor biopsy slides 
can be used if present.  These tissues will be studied to perform immunologic assays for PD-1, PDL1 and 
TIL levels. Tumor PD-L1 membrane expression and immune cell PD-L1 expression  (≥1% vs. <1% and 
≥5% vs. <5%, ≥10% vs. <10%,) using SP263 IHC will be quantified in sections which have at least 100 
tumor cells as assessed with immunohistochemical staining. It has been shown previously that tumors with 
higher PD-L1 expression have worse outcomes but it remains to be shown whether these tumors respond 
better to anti-PD-L1 therapy in the setting of ovarian cancer and Avelumab treatment. It would be very 
interesting to examine the correlation between PD-L1 expression and tumor response to Avelumab therapy 
[41]. Specific TIL receptor studies will also be performed if feasible. 


 
 
13 
 
Serum Immune Markers Whole blood will be collected pre-treatment and at specific intervals during 
treatment (prior to cycle 1, cycle 3, cycle 5, cycle 7,and two weeks post last cycle*) to perform immunologic 
assays evaluating induction of a tumor-specific adaptive as well as humoral immune response. These blood 
draws will be performed in sync with the routine lab draws for patient care scheduled prior to each cycle so 
not to inconvenience the patient. Cytokines are hormonal messengers responsible for most of the effects in 
the immune system such as activation of innate versus adaptive immune response, cellular versus humoral 
immune response [42, 43]. Serum cytokines from this clinical trial before and after SAbR and at time-points 
of Avelumab  administration as described above will be measured using an extensive array of cytokines to 
explore the specific immune pathways that are initiated/inhibited by our treatments.  
The planned array will measure levels of the different cytokines and correlate with immune response with 
clinical outcomes. 
In addition, live white blood cells will be stored in DMSO to measure tumor-specific immune response and 
its amplification following treatment, pending availability of additional funding. 
 
2.0 
Study Objectives 
Specific hypotheses (SAbR-IT) 
Anti-PD L1 checkpoint inhibition Immunotherapy(IT) combined  with Stereotactic Ablative Radiation 
Therapy (SAbR –IT) in Recurrent Ovarian and  peritoneal ,fallopian tube  Cancer(ROPT) will be well 
tolerated and have increased response rates compared to current second-line treatment options and to Anti-
PDL1 alone. 
2.1 Primary Objectives 
The primary objective of this phase II(with safety lead-in)  trial of combined Avelumab (MSB0010718C) 
anti-PD-L1checkpoint blockade with SAbR for  Recurrent Ovarian and  peritoneal ,fallopian tube cancer 
(ROPT) is to assess overall  clinical response rates per RECIST criteria . This will be after the safety lead-in 
is completed without DLT at 8 weeks from start of Avelumab, to evaluate the safety of Avelumab and 
SABR to an acceptable dose of the site radiated. 
2.2 Secondary Objectives 
2.2.1 
To evaluate the overall survival (OS), which is defined as the time between date of first cycle and 
the date of death due to any cause,  
2.2.2 
To evaluate and compare progression free survival (PFS), which defined as the time between date 
of first cycle and the first date of documented disease progression or date of death due to any cause. 
2.2.3 
To evaluate and compare complete response rate, which is defined as the percentage of patients 
who show complete response as per RECIST criteria 
2.2.4 
To evaluate and compare time to progression (TTP), which is defined as time between date of first 
cycle and date of documented progression. 
2.2.5 
To evaluate and compare median response duration, which is defined as the time between the date a 
response (CR or PR) was first seen until date of progression. 
2.3 Exploratory Objectives 
Biological correlates including Tumor Immune profile, serum cytokines and additional correlates as 
described in section 1.5  
 


 
 
14 
 
  
 
 
 
 
 
*2 weeks post treatment collection optional 
 
2.4 Endpoints 
2.4.1 
Dose limiting Toxicities as assessed via NCI’s CTCAE v4.1 toxicity criteria. Only those Grade 3-4 
AEs which interfere with drug and therapy administration will be considered as detailed below.  
Additional details regarding toxicities are listed in section 7. 
 
 
 
Dose Limiting toxicity will be defined as follows if detected within 8 weeks after initiating Avelumab 
a) Any immune related  Grade 4 AE ( except for single laboratory values out of normal range that are 
unlikely related to study treatment as assessed by the Investigator, do not have any clinical 
correlate, and resolve within 7 days with adequate medical management) 
 
b) Grade 3 hepatitis, pneumonitis colitis for >3 days despite adequate medical management. Also any 
other Grade 3 AEs persisting >5 days despite adequate medical therapy 
c) Any other Grade ≥3 AEs (persisting >5 days despite adequate medical therapy) to be considered a 
DLT; there should not be a reasonable alternative explanation for the AE (e.g. disease progression) 
d) Any Immune –related  Myocarditis  
e) Hematologic AE: 
 
Hematologic: 
 
Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5 x 109/L) lasting 
>7 days; 
 
Febrile neutropenia, defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C 
(>101 degrees F) or a sustained temperature of ≥ 38 degrees C (100.4 degrees F) for more than 1 
hour; 
 
Neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 infection); 
 
Grade ≥ 3 thrombocytopenia (platelet count <50,000 - 25,000/mm3 or <50.0 – 25.0 × 109/L) with 
bleeding; 
 
Grade 4 thrombocytopenia (platelet count <25,000/mm3 or <25.0 x 109/L); 
 
Grade 4 anemia (life-threatening consequences; urgent intervention indicated). 
 
The following  exclusions listed below will not be considered DLT 
o 
Grade 3 fatigue for ≤ 7days 
o 
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.) 
o 
Concurrent vitiligo or alopecia of any AE grade 
o 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
o 
Grade 3 Neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days. Grade 3 or Grade 4 febrile neutropenia 
will be a DLT regardless of duration or reversibility 
o 
Grade 3 or 4 lymphopenia 
o 
Grade 3 thrombocytopenia that is not associated with clinically significant bleeding 
that requires medical intervention, and improves by at least 1 grade within 3 days 


 
 
15 
 
o 
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs 
or symptoms and are reversed with appropriate maximal medical intervention 
within 3 days 
2.4.2 
ORR (objective response rate) will be measured by RECIST v1.1 at weeks 8, 16, and 24.   New 
developing lesions and progression of target and non-target lesions will be assessed by iRECIST 
guidelines before labelling as progressive disease[44]  
    
2.4.3 
Tumor cell and tumor immune cell PD-L1 level,  and (optional) tumor CD8+ and CD8+granzyme 
B+ T lymphocyte density and FoxP3+ Treg density.(TIL markers) also to look at cytokines such as 
TNF-alpha, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, 
3.0 
Subject Eligibility 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. 
3.1 Inclusion Criteria 
1. Female subjects aged ≥ 18 years.   
2. Performance ECOG status of 0-2 
3. Patient is able and willing to comply with protocol and study procedures for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow-up visits. 
4.  Adequate Physiologic function: 
 
Hematologic:  Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and 
hemoglobin ≥ 9 g/dL (may have been transfused)   
 
Hepatic: Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT  
levels ≤ 2.5 × ULN or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic 
disease to the liver). 
 
Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or 
local institutional standard method) 
5. Pregnancy and contraception: 
Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing 
potential.  
Contraception: Highly effective contraception for female subjects and their male partners throughout 
the study and for at least 30 days after last avelumab treatment administration if the risk of conception 
exists. 
 
6. Histologic diagnosis of recurrent epithelial ovarian, fallopian, peritoneal cancer 
7. Patients with platinum sensitive ovarian cancer must have progressed within 6 months of their last 
platinum-containing regimen, consistent with definition of platinum resistant disease. 


 
 
16 
 
8. Patients with platinum resistant ovarian cancer must have progressed through at least one prior 
chemotherapy regimen for recurrent ovarian cancer. 
9. Eligible patients with germline or somatic BRCA mutations must have disease progression after 
treatment with a PARP inhibitor. For patients with unknown BRCA status, it is recommended patients 
undergo the test unless patient refuses. However, non-mutation patients will also be eligible for study 
10. Patients must have received at least one prior chemotherapy regimen and up to any number of prior 
systemic regimens including chemotherapy and molecular targeted therapy other than PD1/ PDL1/ 
PDL2 inhibitors.  
11. Metastatic/Recurrent disease of at least two Non-CNS sites (including the index lesion to be treated) 
measurable by RECIST criteria with at least one site outside of the radiation field and evaluable by 
RECIST criteria for evaluation of response. 
12. Ability to understand and the willingness to sign a written informed consent. 
3.2 Exclusion Criteria 
1. IMMUNOSUPRESSANTS:  “Current use of immunosuppressive medication, EXCEPT for the 
following: a. Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).” 
2. AUTOIMMUNE DISEASE:  “Active autoimmune disease that might deteriorate when receiving an 
immuno-stimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid 
diseases not requiring immunosuppressive treatment are eligible.”  
3. ORGAN TRANSPLANTATION:  “Prior organ transplantation including allogenic stem-cell 
transplantation.”  
4. HIV/AIDS: “Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome.” 
5. HEPATITIS: “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)” 
6. VACCINATION: “Vaccination within 4 weeks of the first dose of avelumab and while on trial is 
prohibited except for administration of inactivated vaccines“ 
7. HYPERSENSITIIVTY TO STUDY DRUG:  “Known prior severe hypersensitivity to 
investigational product or any component in its formulations, including known severe hypersensitivity 
reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)” 
8. CARDIOVASCULAR DISEASE:  “Clinically significant (i.e., active) cardiovascular disease: 
cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months 
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association 
Classification Class II), or serious cardiac arrhythmia requiring medication.” 
9. OTHER PERSISTING TOXICITIES:   “Persisting toxicity related to prior therapy (NCI CTCAE v. 
4.03 Grade > 2); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting 
a safety risk based on investigator’s judgment are acceptable.” 
10. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, 


 
 
17 
 
pneumonitis, pulmonary fibrosis ,Severe COPD requiring > 3 hospitalizations in the past year 
11. Or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; 
or laboratory abnormalities that may increase the risk associated with study participation or study 
treatment administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study.  
12. Concomitant therapy with any of the following: IL2, interferon, or other non-study immunotherapy 
regimens; cytotoxic chemotherapy; immunosuppressive agents; or other investigational therapies; all 
such therapies must have been discontinued >4weeks prior to registration. 
13. Active TB.  
14. Patients with other invasive malignancies, with the exception of non-melanoma skin cancer, who had 
(or have) any evidence of other cancer present within the last 5 years or whose previous cancer 
treatment contraindicates this protocol therapy. 
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
16. Patients must not be pregnant or nursing. 
17. No history of prior treatment with inhibitor of PD-1 or PD-L1 or PDL2. 
18. Major surgery within 2 weeks prior to registration or first dose of drug.  
19. Subjects who have had radiation therapy within 2 weeks prior to first dose of drug. 
20. Uncontrolled adrenal insufficiency or active chronic liver disease. 
21. Any history of CNS metastases not adequately treated (surgery or radiation) >14 days prior to 
registration. 
22. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone 
equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study 
drug. Inhaled steroids and adrenal replacement steroid doses up to 10 mg daily prednisone equivalent 
are permitted (although not encouraged) in the absence of active autoimmune disease.  
 
3.3 Subject Recruitment and screening 
Subjects will be identified by their treating gynecologic oncologist within PMH and UTSW.  The target 
population of participants will include all patients with a known diagnosis of recurrent metastatic ovarian, 
fallopian, peritoneal cancer outlined in Inclusion Criteria.   
3.3.1 
Withdrawal of Subjects 
Patients may be withdrawn at any time at the discretion of the investigator/sponsor for safety, behavioral, 
or administrative reasons, or may withdraw from the trial at any time at their own request. If a patient 
does not return for a scheduled visit, every effort should be made to contact the patient and arrange for a 
scheduled visit to assess for assessment of adverse events. Every effort should be made to document 
patient outcome. The investigator should request the patient to return for a final visit and follow-up 
regarding any unresolved adverse events. If the patient withdraws from the trial and also withdraws 
consent for disclosure of future information, no further evaluations should be performed and no 


 
 
18 
 
additional data should be collected. The investigator-sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
3.3.2 
Withdrawal of consent 
If consent is withdrawn, the subject will not receive any further investigational product or further study 
observation.  
3.4 When and How to Withdraw Subjects from Study Treatment 
An individual subject will not receive any further investigational product if any of the following occur in 
the subject in question: 
 
Withdrawal of consent from the study and or further treatment with investigational product. 
 
Lost to follow-up 
 
Subject is determined to have met one or more of the exclusion criteria for study participation at 
study entry and continuing investigational therapy might constitute a safety risk. 
 
An AE that, in the opinion of the investigator or the sponsor, contraindicates further dosing 
 
Pregnancy or intent to become pregnant 
 
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants withdrawal 
(e.g. refusal to adhere to scheduled visits) 
 
Initiation of alternative anticancer therapy (excluding surgery), including another investigational 
agent. 
 
Dose-limiting toxicity (see definition of DLT) 
 
Grade  3 infusion reaction anaphylaxis, severe dyspnea (see DLT definition) 
 
Confirmation of progressive disease (unless there is evidence of clinical benefit per physician per 
section 4.6.2) 
 
Treatment delayed > 6 weeks (except in cases where the delay is due to the need for a prolonged 
steroid taper to manage drug-related adverse events or the delay is not drug related). 
3.5 Replacement of Subjects 
Subjects in the safety phase may be replaced if for reasons other than toxicity, they do not receive the 
second infusion of Avelumab and continue on study for safety evaluation. Subjects in the second phase that 
fail to initiate any treatment may be replaced. 
3.6 Total Number of Subjects and Sites  
Recruitment will end when approximately 29 patients are enrolled.  
4.0 
Treatment Plan 
4.1 Treatment Dosage and Administration 
 


 
 
19 
 
4.1.1 
In this phase II study (with safety lead-in) we will begin with a 6 patient cohort of PD-L1 blockade 
combined with 3 fractions SABR to an acceptable dose of the site radiated to determine the safety 
and feasibility of this regimen. We will enroll 3 patients at a time, evaluating DLT at week 8 from 
start for the first 3 patients before enrolling an additional 3 patients if 0 or 1/3 patients have a DLT. 
If ≤ 2/6 patients develops a DLT we will open up to an expansion cohort evaluating PDL-1 
inhibition + SABR to assess response rates, PFS, OS and collect further toxicity data. We propose 
treating up to two lesions in different metastatic sites and the largest lesion when appropriate since 
there is tumor microenvironment heterogeneity between metastatic sites and this may further 
augment T-cell mediated responses. 
4.1.2 
Arms/Regimens 
1. The immunotherapy(IT) infusion regimen will be delivered as follows: 
Concurrent Anti—PD-L1 (Avelumab) and SAbR. Avelumab will be dosed intravenously (IV) over 
60 minutes (±10 min) at 10 mg/kg every 2 weeks (± 2 days) of each treatment cycle until disease 
progression or 9 cycles.  The main purpose is studying synergistic effect of radiation with the 
drug and RT is administered in the early part of the treatment –we have included only 9 cycles (as 
per available funding) or progression (whichever is earlier) 
2. SABR will be administered up to 1-2 sites of metastatic disease within 15 days after commencing 
the immunotherapy, given in treatments every other day, completed within 12 workdays. SAbR will 
be given in 3 fractions to a total dose of 24-36 Gy (8-12 Gy per fraction x 3 fractions) targeted to 
the largest easily accessible metastases based on normal tissue tolerances. Patients must have at 
least one untreated metastatic lesion which is completely outside of the radiation treatment field and 
can be followed by RECIST criteria. If treating two metastatic sites patients must have 3 sites of 
metastatic disease. 
4.2 SAbR Dose and Techniques 
Patients should have at least 2 measurable non-CNS lesions. Lesions receiving SAbR will be called 
“radiated” lesions. “Target” lesions will be selected from non-treated lesions. In any case, there should be at 
least one non-CNS measurable lesion for effect measurement. Prior irradiated lesions--outside of the trial 
will be excluded from target lesions.  SABR will be administered to 1-2 sites of metastatic disease within 15 
days after commencing the immunotherapy with 3 fractions to a total dose of 24-36 Gy (8-12 Gy per 
fraction x 3 fractions) targeted to the largest easily accessible metastasesbased on normal tissue tolerances. 
The sites of larger, bulky disease and the sites of symptomatic disease will be prioritized for treatment. 
Due to normal organ toxicity and limits of dose constraints, a three fraction treatment is recommended, the 
treatment course should be completed within 10-15 days (preferably 12 business days).  Radiation dose-
(immune) response studies have shown a linear increase in immune response with increased dose per 
fraction of radiation without demonstration of a plateau [31, 44-46]. Two studies comparing 15Gy x 1 vs 
5Gy x3, and 20Gy x1 vs 5Gy x4 have shown a superior immune response generated by the single fraction 
radiation [31, 44]. Clinical experience with oligometastatic patients treated at 1-5 sites of disease has also 
showed an increase in progression free survival with the increasing radiation dose per fraction [47]. A dose 
of less than 7.5 Gy per fraction has demonstrated lower induction of systemic IFN-γ producing cells [46], 
and a previous phase II study of mRCC patients treated with HD IL-2 and singe fraction of 8Gy irradiation 
to a single lesion did not show an overall improvement in response rate [48]. Therefore 8Gy per fraction is 
the lowest permitted dose for this study and can be used only when administering the three fraction regimen 
as described in the prescription dose table below.  
The SABR prescription dose will be delivered to the periphery of the planning target volume (PTV, see 
below for definitions).  Treating physician will have further discretion in selecting the number and location 
of sites to treat if multiple sites of disease are present (up to 2 sites total).  Physicians will be REQUIRED to 
leave at least one site of disease for the purpose of measuring a radiographic response (see section 6) at a 
non-treated site, as this is part of the primary endpoint. If left untreated, this site can be treated once patient 


 
 
20 
 
meets the definition of progressive disease (PD) (see section 6). To clarify the definition of “site”, each site 
is an area or organ with active extracranial disease (</=3 in the liver = one site and </=3 in the lung= one 
site) identified by CT scan, or PET/CT, within6 weeks prior to initiation of SABR (up to 2 contiguous 
vertebral metastasis will be considered a single site of disease). For example: a patient with 4 right axillary 
lymph nodes, L1-L2 bone metastasis, 3 right lung lesions, 1 left lung lesion, 2 liver lesions, and T2-T3 bone 
metastasis would be defined as having 6 sites of disease. Preference should be given to the largest feasible 
disease site, symptomatic sites and sites where palliative and preventative (i.e. to prevent a pathologic 
fracture in weight bearing bone, impending cord compression, impending SVC compression etc.) indications 
are applicable.  The gross target/tumor volume (GTV) should be at least 2 cm3 in size, corresponding to 
roughly a 1.5 cm diameter tumor. This is to ensure that adequate tumor volume and therefore adequate 
tumor cells (roughly 108 -109 cells/cm3 [49]) are killed for antigen presentation. Treating physicians should 
choose their dose based on established planning guidelines at their center including their ability to respect 
normal tissue tolerance listed below.  It is not required that all targets be treated with the same dose 
fractionation.  A dose from the following table should be used: 
 
 
 
 
Table 4.1.1 Prescription Dose 
 
Total Cumulative Dose 
Encompassing 95% of Planning 
Target Volume (Gy) 
Number 
of 
Fractions 
Protocol 
Compliant 
Deviation 
3 
24-36 Gy** 
<24 Gy or 
>36 G 
 
 
** Based on normal tissue tolerances 
 
Dose tolerance limits should be adhered to for all treatments.  Protocol compliant dose should be used in all 
cases, if possible.  When treating tumors abutting the spinal cord, tolerance limits should not be exceeded.  
To facilitate this requirement, minor deviation dose ranges listed above in the table will be considered fully 
compliant for tumors abutting the spinal cord. 
4.2.1 
SAbR Planning Constraints and Concerns  
The tolerance dose of SABR to the gastrointestinal tract is not established, and patients with 
metastatic disease involving the esophagus, stomach, intestines, or mesenteric lymph nodes will be 
eligible only if no other sites of lesions are present that can be safely targeted, and the treating 
radiation oncologist feels that a sufficiently conservative dose constraints to these organs can be 
met. Patients with renal or adrenal metastases are potentially eligible if normal tissue constraints are 
otherwise met.  
 
It is well established that for palliative effect for a painful bone metastasis, a single dose of 8 Gy is 
usually as effective as 30 Gy [45]. However, in this protocol the goal is not just to relieve pain 
within an osseous metastasis but also to debulk the tumor present and induce in immune response, 
and the higher dose is more likely to accomplish this goal given a higher biological potency [46]. 
Long term survival after bone metastasectomy has been reported [47].  Irradiation of non-spinal 
skeletal sites does not generally require specialized techniques of treatment. Metastases in major 
lower extremity weight-bearing bones should undergo surgical stabilization if there is plain film 
evidence of cortical erosion. 


 
 
21 
 
4.2.2 
SABR Treatment Technique 
Simulation, beam arrangements, tumor prescription dose 
Treatment to skeletal lesions and paraspinous lesions may be accomplished with any 3D conformal 
radiotherapy or intensity-modulated radiotherapy (IMRT) technique suitable for this application 
with performance specifications adequate to provide proper tumor dose distribution and normal 
tissue sparing.  
At the time of simulation for patients who will receive SABR to the lung and/or liver, the 
movement of the dome of the diaphragm (superior portion of the liver) is to be observed under 
fluoroscopy or other acceptable means to estimate respiratory movement during treatment if no 
breathing control device is used.  Patients will be assessed for suitability for tolerance of a 
respiratory control device using a breath-hold technique, respiratory gating, or abdominal 
compression to limit diaphragmatic excursion during respiration. Patients with severe lung disease 
and patients who cannot tolerate diaphragmatic or breathing control devices for other reasons will 
be treated without them. A larger margin to account for breathing related intra-fractional organ 
movement is required. 
With the patient is immobilized in a vacuum-type or equivalent body mold, a planning CT scan 
with 2-5 mm slices is performed. Intravenous contrast is recommended for lesions near mediastinal 
structures and lesions within the liver. The form of respiratory control to be used during treatment 
should also be used during the simulation. Oral GI contrast to highlight the stomach and duodenum 
is recommended for patients with medial liver lesions or lesions of the caudate lobe.  
The planning target volume (PTV) is constructed to account for the positional uncertainty of the 
GTV during treatment. The PTV for each contoured GTV should be at least 5mm larger than the 
GTV in the axial plane and 1.0 cm larger than the GTV in the cranio-caudal plane. Larger margins 
may be used in cases where greater motion of the hemi-diaphragm is observed in simulation despite 
standard maneuvers to diminish motion.  For lung SABR the same principles apply; the entire lung 
volumes are contoured, as are each individual GTV within the lung. 
The prescription dose for each lesion is listed in  Table 4.1.1(see section 4.2), prescribed to the 
periphery of the PTV. There is no restriction on the dose “hotspot” except that it must be located 
within the PTV. A Linear Accelerator with effective photon energies of ≥ 6 MV is required. The 
use of a multi-leaf collimator (MLC) or custom blocks are acceptable.  A stereotactic relocalization 
system that relies upon stereoscopic radiographs, implanted fiducials, or near real-time CT based 
verification will be used. The PTV may be treated with any combination of coplanar or non-
coplanar three-dimensional conformal fields, shaped to deliver the specified dose while restricting 
the dose to the normal tissues.  Field arrangements will be determined by the planning system to 
produce the optimal conformal plan in accordance with volume definitions.  
Normal Tissue Dose Constraints 
In accordance with prior Phase I studies [48], certain normal tissue dose constraints must be 
respected. The possibility that SABR-induced fibrosis might cause occlusion of large central 
airways, thus impeding ventilation distal to the occlusion has been well considered [49]. An 
adjustment to the fractionation scheme may be made if, in the opinion of the treating radiation 
oncologist, the following conditions apply: (1) the location of a lung lesion is close enough to a 
large proximal bronchial airway such that occlusion might occur, and (2) compromised ventilation 
to the segment(s) of lung potentially affected would cause clinically significant adverse 
consequences. In such a case, the treating radiation oncologist should discuss any proposed dose 
modifications with the PI to decide whether a regimen of similar biological potency can be safely 
given. 
The same special condition applies in the setting of a patient whose primary disease has been 
irradiated previously and is present as a site of disease. Since re-irradiation toxicity is a concern, 
these patients will be considered by the PI on a case-by-case basis and SABR to a site previously 
irradiated with conventional fractionation within two years is not recommended. Re-irradiation to a 


 
 
22 
 
site that has received previous SABR is not allowed.  Deviations from the intended dose regimen 
will be documented, with calculations of the BED of the applied regimen included in the patient’s 
research chart along with documentation of the discussions pertaining to the idiosyncrasies of the 
case. 
The following table lists the specific organ and dose fractionation constraints on normal tissues and 
also the toxicities. 
Three Fractions  
 
 
 
 
 
 
 
Timmerman 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 
Optic Pathway 
<0.2 cc 
15.3 Gy  
17.4 Gy  
Neuritis 
Cochlea 
 
 
14.4 Gy  
hearing loss 
Brainstem (not medulla) 
<0.5 cc 
15.9 Gy 
23.1 Gy  
cranial neuropathy 
Spinal Cord and medulla 
<0.35 cc 
15.9 Gy 
22.5 Gy 
Myelitis 
Cauda Equina 
<5 cc 
21.9 Gy  
25.5 Gy 
Neuritis 
Sacral Plexus 
<5 cc 
22.5 Gy 
25.5 Gy 
neuropathy 
Esophagus* 
<5 cc 
27.9 Gy 
32.4 Gy 
esophagitis 
Brachial Plexus 
<3 cc 
22 Gy 
26  Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
24 Gy 
30 Gy 
pericarditis 
Great vessels 
<10 cc 
39 Gy 
45 Gy 
aneurysm 
Trachea and Large 
Bronchus* 
<5 cc 
39 Gy 
43 Gy 
impairment of pulmonary 
toilet 
Bronchus- smaller airways 
<0.5 cc 
25.8 Gy 
30 Gy 
stenosis with atelectasis 
Rib 
<5 cc 
40 Gy 
50 Gy 
Pain or fracture 
Skin 
<10 cc 
31 Gy 
33 Gy 
ulceration 
Stomach 
<5 cc 
22.5 Gy 
30 Gy 
ulceration/fistula 
Bile duct 
 
 
36 Gy 
stenosis 
Duodenum* 
<5 cc 
22.5 Gy 
30 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
20.7 Gy 
28.5 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
28.8 Gy 
45 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
43 Gy 
30.3 Gy 
47 Gy 
proctitis/fistula 
Ureter 
 
 
40 Gy 
stenosis 
Bladder wall 
<15 cc 
17 Gy 
33 Gy 
cystitis/fistula 
Penile bulb 
<3 cc 
25 Gy 
 
impotence 
Femoral Heads  
<10 cc 
24 Gy 
 
necrosis 
Renal hilum/vascular trunk 
15 cc 
19.5 Gy 
 
malignant hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc for 
males and 
950cc for 
females*** 
10.8 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
 
 
V-11.4Gy<37% 
Pneumonitis 
Liver 
700 cc*** 
17.7 Gy 
 
Basic Liver Function 
Renal cortex (Right & Left) 
200 cc*** 
14.7 Gy 
 
Basic renal function 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
***or one third of the “native” total organ volume (prior to any resection or volume reducing disease), 
whichever is greater 
 


 
 
23 
 
Exceeding these dose tolerances by more than 2.5% constitutes a minor protocol violation.  
Exceeding these dose tolerances by more than 5% constitutes a major protocol violation 
 
4.3 Avelumab: Treatment Dosage and Administration 
The standard and current guidelines for Avelumab administration will be used for this protocol. It will be 
dosed intravenously (IV) over 60 minutes (±10 min) at 10 mg/kg on day 1 (+2 days) of each treatment cycle 
until disease progression or 9 cycles , unacceptable toxicity or other reasons specified in the protocol. Each 
cycle length is 2 weeks (14 days ( +2 days)). 
All doses should be rounded to the nearest milligram. Dosing calculations will be based on the screening 
body weight. If body weight at a given cycle is changed more than 10% from baseline, the dose will be 
recalculated. If Avelumab dosing is delayed for a drug-related adverse event, treatment may resume when 
the event has resolved to Grade 1 or baseline. If treatment is delayed > 6 weeks, the subject must be 
permanently discontinued from study therapy, except in cases where the delay is due to the need for a 
prolonged steroid taper to manage drug-related adverse events or the delay is not drug related. See details 
AE and indication for modifying Avelumab dose. 
Special Precautions for Administration: 
Premedication: In order to mitigate infusion-related reactions, a premedication with an antihistamine and 
with paracetamol (acetaminophen) 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory 
(for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol IV or oral). Premedication should be 
administered for subsequent avelumab infusions based upon clinical judgment and presence/severity of prior 
infusion reactions. This may be modified based on local treatment standards and guidelines, as appropriate.  
Setting: Avelumab should be administered in a setting that allows for immediate access to an intensive care 
unit or equivalent environment and administration of therapy for anaphylaxis, such as the ability to 
implement immediate resuscitation measures.  Steroids (dexamethasone 10 mg), epinephrine 
(1:1,000 dilution), allergy medications (IV antihistamines), bronchodilators, or equivalents, and oxygen 
should be available for immediate access. 
Observation period:  Following avelumab infusions, patients must be observed for 2 hours post-infusion for 
potential infusion-related reactions with vitals done on discharge. 
Toxicities and Dosing Delays/Dose Modifications 
Each subject will stay on the avelumab assigned dose of 10 mg/kg unless treatment needs to be stopped. 
Dosing modifications (changes in infusion rate) and dose delays are described in the tables below.  There 
will be no dose reductions. 
Table 2. Adverse Drug Reactions requiring avelumab discontinuation or modification 
Any Grade 4 ADRs require treatment discontinuation with avelumab except for single laboratory 
values out of normal range that are unlikely related to study treatment as assessed by the Investigator, do 
not have any clinical correlate, and resolve within 7 days with adequate medical management 
Any Grade 3 ADRs require treatment discontinuation with avelumab except for any of the following:  
 
Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management 
 
Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves to 
Grade ≤ 1  
 
Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test increase) that 
are unlikely related to study treatment according to the Investigator, do not have any clinical 
correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical management 
 
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor 
 
Change in ECOG PS to ≥ 3 that does not resolve to  2 within 14 days (infusions should not be 
given on the following cycle, if the ECOG PS is ≥ 3 on the day of study drug administration) 
Any Grade 2 ADR should be managed as follows: 


 
 
24 
 
 
If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue. 
 
If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle, infusions 
should not be given on the following cycle.  If at the end of the following cycle the event has not 
resolved to Grade 1, the subject should permanently discontinue treatment with a avelumab  
 
ADR (except for hormone insufficiencies, that can be managed by replacement therapy; for these 
hormone insufficiencies, up to 2 subsequent doses may be omitted). 
 
Upon the second occurrence of the same Grade 2 ADR (except for hormone insufficiencies that 
can be managed by replacement therapy) in the same subject, treatment with avelumab has to be 
permanently discontinued. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3. Treatment Modification for Symptoms of Infusion-Related Reactions  
 
NCI-CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease avelumab infusion rate by 50% and 
monitor closely for any worsening. 
 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for  
24 h. 
Temporarily discontinue avelumab infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening. 
Grade 3 or Grade 4 – severe or life-threatening 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; urgent 
intervention indicated. 
Stop avelumab infusion immediately and 
disconnect infusion tubing from the subject. 
Subjects have to be withdrawn immediately from 
study drug treatment and must not receive any 
further study drug treatment. 
-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 
isobserved in the next scheduled infusion, the infusion rate may be returned to baseline at the 
subsequent infusions based on investigator’s medical judgment. 
.- If hypersensitivity reaction occurs, the subject must be treated according to the best available medical 


 
 
25 
 
practice.  
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
 
 
 
 
 
 


 
 
26 
 
Table 4.  Management of Immune-mediated Adverse Reactions 
 
 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (e.g. 
loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2, 3 or 4.  
Grade 2  
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated < 24 
hours; not interfering with ADL 
Colitis: abdominal pain; blood in 
stool  
 
Withhold avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume avelumab therapy 
 
If  persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; IV 
fluids ≥ 24 h; interfering with ADL 
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs 
Grade 4: life-threatening, 
perforation 
Withhold avelumab for 
Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade ≤ 1, then taper 
over at least 1 month; resume avelumab 
therapy following steroids taper (for initial 
Grade 3).  
 
If worsens, persists > 3 to 5 days, or recurs 
after improvement: 
Add infliximab 5mg/kg (if no 
contraindication). Note: infliximab should 
not be used in cases of perforation or sepsis.  


 
 
27 
 
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface area  
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
If persists > 1 to 2 weeks or recurs:  
Withhold avelumab therapy  
Consider skin biopsy  
 
Consider 0.5-1.0 mg/kg/day prednisone or 
equivalent. Once improving, taper steroids 
over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and 
resume avelumab therapy following steroids 
taper. 
If worsens:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: Life threatening 
consequences  
Withhold avelumab for 
Grade 3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume 
avelumab therapy following steroids taper 
(for initial Grade 3). 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider withholding 
avelumab therapy  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-assess at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new symptoms  
Withhold avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
Add prophylactic antibiotics 
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤ 1, taper 
steroids over at least 1 month, and then 
resume avelumab  therapy following steroids 
taper  
If not improving after 2 weeks or worsening:  
Treat as Grade 3 to 4.  


 
 
28 
 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day  
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month  
If not improving after 48 hours or worsening:  
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil)  
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT > ULN to 3.0 
x ULN and/or Total bilirubin > 
ULN to 1.5 x ULN  
Continue avelumab therapy 
Continue liver function monitoring  
If worsens:  
 Treat as Grade 2 or 3 to 4.  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x 
ULN  
Withhold avelumab therapy 
Increase frequency of 
monitoring to every 3 days. 
 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume 
avelumab therapy. 
If elevation persists > 5 to 7 days or worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and/or total 
bilirubin > 3 x ULN  
Permanently discontinue 
avelumab therapy  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically 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  
If no response within an additional 3 to 5 
days, consider other immunosuppressants per 
local guidelines. 


 
 
29 
 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 1.5 x 
ULN 
Continue avelumab therapy 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 6 x 
ULN 
 
 
 
 
 
Withhold avelumab therapy 
Increase frequency of  monitoring to 
every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to  Grade ≤1: 
Taper steroids over at least 1 month, 
and resume avelumab therapy 
following steroids taper. 
If worsens:  
Treat as Grade 4. 
Grade 4 
Creatinine increased > 6 x ULN 
 
 
 
 
 
 
 
Permanently discontinue avelumab 
therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive 
of myocarditis.  
Withhold avelumab therapy. 
Hospitalize. 
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility experienced 
in advanced heart failure and 
arrhythmia management. 
Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis.  
Guideline based supportive 
treatment as per cardiology 
consult.* 
 
Consider myocardial biopsy if 
recommended per cardiology consult. 
If symptoms improve and 
immune-mediated 
etiology is ruled out, 
re-start avelumab therapy. 
 
If symptoms do not 
improve/worsen, viral myocarditis 
is excluded, and immune-mediated 
etiology is suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
 
 
 
 
 
 


 
 
30 
 
Immune-mediated myocarditis 
Permanently discontinue 
avelumab. 
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.* 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper 
steroids over at least 1 
month. 
 
If no improvement or 
worsening, consider 
additional 
immunosuppressants (e.g. 
azathioprine, 
cyclosporine A). 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Resume avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤ 1 (with or without 
hormone replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
Resume avelumab once symptoms 
and hormone tests improve to 
Grade ≤ 1 (with or without 
hormone replacement). 


 
 
31 
 
low ACTH) : 
 
Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women)  
 
Hormone 
replacement/suppressive therapy 
as appropriate  
 
Perform pituitary MRI and visual 
field examination as indicated 
 
If hypophysitis confirmed: 
 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
 
Withhold avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) 
followed by corticosteroids taper 
during at least 1 month. 
 
Add prophylactic antibiotics for 
opportunistic infections. 
 
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/suppression therapy as 
appropriate. 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE 
Withhold avelumab therapy pending 
clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
avelumab therapy 
If irAE is confirmed, treat as Grade 
2 or 3 irAE. 
Grade 2 irAE  or first occurrence 
of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone  or 
equivalent   
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
and resume avelumab therapy 
following steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month. 


 
 
32 
 
Specialty consult as appropriate 
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. 
 
4.4 Other Modalities or Procedures 
SABR- see section 4.2.  
4.5 Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 9 cycles or 
until: 
 
Disease progression (unless the investigator assesses clinical benefit to additional 
cycles) 
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Subject  decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the subject unacceptable 
for further treatment in the judgment of the investigator. 
4.6 Duration of Follow Up 
Subjects will be followed for up to 2 years after removal from treatment..  
 
4.6.1 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 3.4 apply. Notify 
the Principal Investigator, and document the reason for study removal and the date the subject was 


 
 
33 
 
removed in the Case Report Form. The subject should be followed-up per protocol. Subjects 
removed from treatment for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event if extending beyond the follow up period. 
 
4.6.2 
Continued Treatment Beyond Progression of Disease 
As indicated above, we will use the RECIST criteria for tumor measurement and RR determination. 
In addition, accumulating evidence indicates a minority of subjects treated with immunotherapy 
may derive clinical benefit from continued treatment despite initial evidence of progressive disease. 
For this reason, subjects will be permitted to continue study therapy beyond initial investigator-
assessed RECIST progression as long as they meet the 2 criteria listed below at the discretion of the 
treating medical oncologist and NO more than 9 cycles   
- Investigator-assessed clinical benefit, 
  and 
- Subject is tolerating study drug. 
Subjects should discontinue study therapy upon evidence of further progression at the discretion of 
the treating medical oncologist, defined as an additional 10% or greater increase in tumor burden 
from time of initial progression (including all target lesions and new measurable lesions). 
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 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). For statistical analyses that include the investigator-assessed 
progression date, subjects who continue treatment beyond initial investigator-assessed, RECIST 
1.1-defined progression will be considered to have investigator-assessed progressive disease at the 
time of the initial progression event. 
5.0 
Study Procedures 
5.1 Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after obtaining 
informed consent. Assessments performed for clinical indications (not exclusively to determine study 
eligibility) may be used for baseline values even if the studies were done before informed consent was 
obtained. 
All screening procedures must be performed within 28 days prior to registration unless otherwise stated. The 
screening procedures include: 
5.1.1 
Informed Consent 
5.1.2 
Medical history 
Complete medical and surgical history, history of infections 
5.1.3 
Demographics 
Age, gender, race, ethnicity 


 
 
34 
 
5.1.4 
Review subject eligibility criteria 
5.1.5 
Review previous and concomitant medications 
5.1.6 
Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 
Performance status 
Performance status evaluated prior to study  
5.1.8 
Adverse event assessment 
Baseline adverse events will be assessed. See section 7 for Adverse Event monitoring and 
reporting. 
5.1.9 
Hematology CBC and diff (within 2 weeks of registration) 
5.1.10 T 4 levels, TSH and CMP as below (within 2 weeks of registration)  
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), 
glucose, and total bilirubin. 
5.1.11 Hep B and Hep C testing – (within 4 weeks of registration) 
5.1.12 Pregnancy test (for females of child bearing potential) 
(within 2 weeks of registration) 
See section 3.1.5 for definition.  
5.1.13 Tumor assessment (within 6 weeks of registration) 
Baseline imaging by CT scan of chest, abdomen, and pelvis. 
5.2 Procedures During Treatment 
5.2.1 
Prior to Each Treatment Cycle 
 Physical exam, PS, vital signs, medication review, AE assessment 
 
Hematology 
 
Serum chemistries 
5.2.2 
Every 8 weeks after start till end of treatment   
 
Serum TSH 
 
Pregnancy test 
 
CT  chest abdomen and pelvis  
 


 
 
35 
 
5.2.3 
Additional Immune coorelate lab testing: Prior to cycle 1, cycle 3, cycle 5, cycle 7 and optionally 2 
weeks post last cycle. (See section 9) 
5.3 Follow-up Procedures 
5.3.1 
- 
For patients who completed 9 cycles of  Avelumab: 
Subject will be followed every eight weeks (+/- 4 weeks) starting from the final cycle  of treatment for 
the first year, then every 12 weeks (+/- 2 weeks) till 2 years after last dose of drug. This follow-up will 
be performed by Gynecologic Oncologist per patient’s routine accepted followup for cancer. The 
following procedures will be performed at each follow up: 
 Physical exam, PS, vital signs, medication review 
 AE assessment (for 8, 16 and 24 week follow up) 
 Blood collection per time table and for labs  
 Radiographic imaging: Tumor assessments will be completed by the investigator using the 
RECIST criteria as above. 
o 
CT chest, abdomen and pelvis with IV contrast( if indicated per time table), if allowable by renal 
function 
o 
After that, survival information will be collected through record review every 6 months until 
patient death. 
5.3.2 
- 
For patients who discontinue Avelumab early (prior to 9 cycles): 
Subjects will be followed within eight weeks (+/- 4 weeks) from discontinuation of treatment  by the 
treating gynecologic oncologist 
 
The following procedures will be performed at that visit: 
 Physical exam, PS, vital signs, medication review, AE assessment 
 Subsequent anti-cancer treatment/s 
 For first visit only, or may repeat if study drug related toxicity persists: CBC w/ differential, 
LFTs, BUN, creatinine, fasting glucose, and TSH 
 
After that, survival information will be collected through record review every 6 months until patient death. 
Patients may be followed up as per standard routine by their gynecologic oncologist for at least one year 
after the last dose of avelumab.  At subsequent routine follow ups  survival information must be collected 
every six months until patient death.  
 
 
 


 
 
36 
 
5.2 Time and Events Table  
Event 
Pre-Study 
(Day-28 – 
Day 0) 
 
 
Prior to every 
cycle(cycle 
length=2weeks) 
Follow up Post 
therapy per 5.3.1 
(subjects who 
completed 9 
cycles of 
Avelumab) 
Follow up Post 
therapy per 
5.3.2 within 8 
weeks  (subjects 
who discontinue 
Avelumab) 
Informed 
Consent 
X 
 
 
 
Historya 
X 
 
X 
 
Physicala & 
ECOG/PSa 
X 
X 
X 
X 
Vitals Signsb + 
Weight 
X 
X 
X 
X 
Heightc 
X 
 
 
 
Concomitant 
Medication 
Review 
X 
X 
X 
X 
CBC + Diff 
Xd 
X 
 
X 
X 
CMPL +  
Xd 
X  
 
X 
Xm 
Hep B & Hep C  
Xk 
 
 
 
Free T4,TSH  
Xd 
Xi, l 
 
Xi 
Pregnancy Test 
Xe 
Xl 
 
 
Concomitant 
Medications 
X 
 
 
 
Toxicity 
Evaluations 
 
X 
 Xn 
X 
 
CT chest, 
abdomen, pelvis 
Xj 
Xl 
X 
 


 
 
37 
 
 
Event 
Pre-Study 
(Day-28 – 
Day 0) 
 
 
 
Prior to every 
cycle(cycle 
length=2weeks) 
 
Follow up Post 
therapy every 8 
weeks (+/- 4 
weeks) (subjects 
who completed 9 
cycles of 
Avelumab) 
 
SAbR 
 
Xh 
See 4.2 
 
 
 
Avelumab 
 Therapy 
 
X 
 
 
Correlative 
Labsg 
 
X 
 
 
 
aPerformed by physician or advanced practice provider (NP/PA);  
bInclude blood pressure, heart rate, temperature, and respiratory rate  before treatment , and 2 hours after end of 
infusion; 
cObtain Height at Baseline only; 
d within 2 weeks of registration 
eUrine or Serum Pregnancy Test for women of childbearing potential as described Section 3.1.5; 
 fToxicity Assessments will be performed from the first dose of study drug until removal from study,. Use 
CTCAEv4.0 as described Section 7; DLT evaluation will be performed at initial follow up (wk 8). 
gFor correlative studies prior to Cycles 1, 3, 5, 7 (see Section 1.5) 
hSABR commenced after first dose of Avelumab as per protocol 
iTSH only 
jwithin 6 weeks of registration 
kwithin 4 weeks of registration 
levery 8 weeks from first Avelumab infusion to end of treatment 
m LFTs, BUN, creatinine, fasting glucose only 
n toxicity follow up per section 7.2.1 
5.4 Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative reasons. The reason(s) 
for discontinuation will be documented and may include: 


 
 
38 
 
5.4.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.4.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.4.3 
Subject is unable to comply with protocol requirements; 
5.4.4 
Subject demonstrates disease progression (unless continued treatment with study drug/treatment is 
deemed appropriate at the discretion of the investigator); 
5.4.5 
Subject experiences toxicity (DLT) that makes continuation in the protocol unsafe; 
5.4.6 
Treating physician judges continuation on the study would not be in the subject’s best interest; 
5.4.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a serious adverse 
event); 
5.4.8 
Development of second malignancy (except for basal cell carcinoma or squamous cell carcinoma of 
the skin) that requires treatment, which would interfere with this study; 
5.4.9 
An AE that, in the opinion of the investigator or the sponsor, contraindicates further dosing 
5.4.10 Lost to follow-up. If a research subject cannot be located to document survival after a period of 2 
years, the subject may be considered “lost to follow-up.” All attempts to contact the subject during 
the two years must be documented and approved by the Data Monitoring Committee. 
6.0 
Measurement of Effect 
6.1 Antitumor Effect- Solid Tumors 
6.1.1 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000].  Additional criteria for bone lesions and clinical endpoints of pathologic 
fracture and cord compression are added to this study (see Section 6.1.4). Changes in only the 
largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 
criteria outlined in http://www.recist.com/Definitions. 
Before labelling as progressive disease, as indicated above in study endpoints, we will use the 
iRECIST criteria for tumor measurement and RR determination. Accordingly, an initial progression 
on the first set of scans would be labelled as iUPD should be verified by a second set of scans 
before considering it as disease progression and before the decision to discontinue treatment is 
made. ) Progression is confirmed in the target lesion category if the next imaging assessment after 
iUPD (4–8 weeks later) confirms a further increase in sum of measures of target disease from 
iUPD, with an increase of at least 5 mm .If progression is confirmed on the second set of scans, the 
first date will be used in evaluations of PFS.  
 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of their first 
treatment with study therapy. 
Evaluable for objective response.  Only those subjects 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 subjects will have their response classified according to 
the definitions stated below. (Note: Subjects who exhibit objective disease progression prior to the 
end of cycle 1 will also be considered evaluable.) 
 


 
 
39 
 
6.1.2 
Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >10 mm with spiral (Helical) CT scan 
(CT/MRI scan slice thickness should be no greater than 5 mm). All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). For malignant lymph nodes to 
beconsidered pathologically enlarged and measurable, a lymph node must be ≥15 mm 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. 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. 
Note: Previously irradiated lesions are non-measurable except in cases of documented progression 
of the lesion since the completion of radiation therapy. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan) and lymph nodes 
<15 mm, are considered non-measurable disease. Leptomeningeal disease (patients excluded), 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable. Blastic 
bone lesions are non-measurable. 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 subject, these are preferred for selection as 
target lesions. 
Target lesions. All measurable lesions up to a maximum of 3 lesions per organ and 6 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter (LD) (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum LD. 
The baseline sum LD will be used as reference by which to characterize the objective tumor 
response. 
Note: Lesions receiving SABR will be called “radiated lesion” which should not be confused with 
“target lesions” defined here for the for the purpose of radiographic measurement. Radiated lesions 
and target lesions are mutually exclusive lesions. Therefore, radiated lesions will not be used as 
target lesions for evaluating response.   At least 2 non-CNS measurable lesions are required for 
enrollment.  
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 6 target lesions should be identified as non-target lesions and should also be recorded 
at baseline. Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up. 
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements will be done digitally on the PACs system. All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and never more than 28 days before 
the beginning of the treatment. 


 
 
40 
 
Whenever possible, 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 using appropriate 
radiologic imaging.  
CT scan of Chest, abdomen and pelvis with IV contrast (whenever possible) will be performed at 
baseline.  Lesions found on bone scan must be verified with a CT. Bone scans will not be used for 
measuring lesion size.   
Spiral CT and MRI. All CT scans will be Spiral CT and should be performed using a 5 mm 
contiguous reconstruction algorithm.  
6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by two separate 
observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started, or the appearance of one or 
more new lesion, verified by a second scan > 6 weeks apart. In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions 
6.1.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The subjects best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 
 
 
 
 
 
 
 
 
 


 
 
41 
 
Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response 
for this 
Category Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
   PD@ 
 
no prior SD, PR 
or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
 
@ iRECIST criteria will apply to determine progression-and the initial label 
will be iUPD 
 
Appearance of new lesions or increase in size of target /non-target lesions 
Remains iUPD unless iCPD is confirmed on the basis of a further increase in  
previously identified target lesion iUPD sum of measures ≥5 mm, previously 
identified non-target lesion iUPD (does not need to be unequivocal), or an 
increase  in the size or number of new lesions previously identified 
 
Target lesions, non-target lesions, and new lesions defined according to 
RECIST 1.1 principles; if no pseudoprogression occurs, RECIST 1.1 and 
iRECIST categories for complete  response, partial response, and stable disease 
would be the same  
 
Note: 
Subjects 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. 
 
Note: If subjects respond to treatment and are able to have their disease resected, the patient’s 
response will be assessed prior to the surgery. 
Evaluation of Bone Lesions:  
Bone lesions will be evaluated by CT if seen initially on bone scan. Since the size of the lesion is 
difficult to measure in a bone scan, particularly if it is not well visible in CT, the following 
guideline will be used. Any ambiguity will require MRI for resolution:  
Progression of bone lesions will be defined as follows:  
Appearance of 1 or more new bone lesion in Bone scan, confirmed by a repeat bone scan in ≥6 
weeks. 
Response of bone lesions in bone scan will be defined by either a complete resolution (CR) at the 
metastatic sites or partial resolution (PR) of radiotracer uptake by a radiologist.   


 
 
42 
 
Evaluation of Pathologic Fracture:  
Any clinical suspicion of pathologic fracture will prompt radiologic evaluation with plain film, CT 
or MRI as appropriate and if confirmed by a radiologist, will constitute progression, unless it is at a 
treated site, in which case a treatment-related toxicity will be considered. In that case, patients will 
be referred for orthopedics specialist evaluation. 
Evaluation of spinal cord Compression or Cauda Equina compression:  
Any clinical suspicion of cord or cauda equina compression will prompt radiologic evaluation with 
MRI (CT myelography if patient is not eligible for MRI) as appropriate and if confirmed 
6.1.5 
Duration of Response 
Duration of overall response: The duration of overall response 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. 
 
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.  
6.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of 
progression. 
6.2 Safety/tolerability 
Analyses will be performed for all subjects having received at least one dose of study therapy. The study 
will use the CTCAE version 4.0 for reporting of non-hematologic adverse events 
(http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for hematologic adverse events per 
section 2.4.1. 
7.0 
Adverse Events 
7.1 SAbR 
The contraindications and adverse events for SAbR are mostly related to the treatment site and its radiation 
dose tolerance, as discussed in detail in section 4.2.  
Contraindications:  
Treatment of patients who have received conventional radiation therapy at same site of new metastasis is at 
the discretion of the radiation oncologist. Treatment of patients who have received SAbR at same site of new 
metastasis is contra-indicated. Treatment of patients with scleroderma or active Lupus is at the discretion of 
the radiation oncologist. 
Special Warnings and Precautions for Use: N/A 
Interaction with other medications: None 
Adverse Reactions: Site-specific. Please see Table 4. 
Experimental Therapy 
Avelumab Therapy  


 
 
43 
 
For the most recent safety update, please refer to the current investigator brochure.   
Contraindications 
See exclusion criteria  
Special Warnings and Precautions for Use  
  
See section 4.3 
Interaction with other medications 
No formal pharmacokinetic drug-drug interaction studies have been conducted. 
7.2 Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of subjects enrolled in the studies as well as those who will enroll in future studies using 
similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. 
Additionally, certain adverse events must be reported in an expedited manner to allow for optimal 
monitoring of subject safety and care.  
All subjects experiencing an adverse event, regardless of its relationship to study therapy, will be monitored 
until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse event return to 
baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study therapy for the changes observed; or 
 death. 
 
7.2.1 
Definition  
 
Acute Adverse Events 
 
 
An adverse event is defined as any untoward or unfavorable medical occurrence in a human 
research study participant, including any abnormal sign (for example, abnormal physical exam or 
imaging finding), symptom, clinical event, or disease, temporarily associated with the subject’s 
participation in the research, whether or not it is considered related to the subject’s participation in 
the research. Adverse events occurring in the time period (Defined as occurring from the time of 
signing informed consent, through  8 weeks post treatment) will be considered acute adverse 
events.  All acute adverse events will be assessed and reported as per below. 
 
Late Adverse Events  
Adverse effects occurring in the time period from the end of acute monitoring, through week 24 
post treatment, will be defined as late adverse events. These events will include all adverse events 
reported directly to a member of the study team and will be captured, assessed, graded and 
reported as appropriate.  
In addition, the study team will review encounters in a select specialty category relevant to study 
endpoints: Medical Oncology; Radiation Oncology; any hospital admissions or Emergency 
Department visits.  


 
 
44 
 
Adverse events encompass clinical, physical and psychological harms. Adverse events occur most 
commonly in the context of biomedical research, although on occasion, they can occur in the 
context of social and behavioral research. Adverse events may be expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE) and version number specified in the 
protocol. Adverse events not specifically defined in the NCI CTCAE will be scored on the Adverse 
Event log according to the general guidelines provided by the NCI CTCAE and as outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, occurring at 
any dose, which meets any of the following criteria:  
 
Results in death   
 
Immediately life-threatening  
 
Results in inpatient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above criteria. 
Serious adverse events may or may not be related to the research project. A serious adverse event 
determination does not require the event to be related to the research. That is, both events 
completely unrelated to the condition under study and events that are expected in the context of the 
condition under study may be serious adverse events, independent of relatedness to the study itself. 
As examples, a car accident requiring overnight hospitalization would be a serious adverse event 
for any research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death which occurs during the protocol-specified period of monitoring for 
adverse and serious adverse events would be a serious adverse event, even if the event observed is a 
primary clinical endpoint of the study. 
7.2.2 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The term “unanticipated problem” is found, but not defined in the regulations for the Protection of 
Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. Guidance from the 
regulatory agencies considers unanticipated problems to include any incident, experience, or 
outcome that meets each of the following criteria: 
 
Unexpected (in terms of nature, severity or frequency) AND 
 
Definitely or probably related to participation in the research AND  
 
Serious or a possible unexpected problem in that the research places subjects or others at 
greater risk of harm than was previously known or recognized. Note: Any serious adverse 
event would always suggest a greater risk of harm. 


 
 
45 
 
Follow-up  
All adverse events will be followed up according to good medical practices.   
7.2.3 
Reporting 
The UTSW IRB requires reporting of all UPIRSOs according to the guidance below. For 
participating centers other than UTSW, local IRB guidance should be followed for local reporting 
of serious adverse events. All SAEs occurring during the protocol-specified monitoring period 
should be submitted to the UTSW study team within 2 business days of the center learning of the 
event. 
7.2.3.1 
UPIRSOs occurring on the study require expedited reporting, and are submitted to the 
UTSW IRB through the UTSW eIRB by the UTSW study team and to the SCCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB report; FDA Form #3500A 
forms, or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be submitted to the UTSW study team and will be forwarded to the DSMC 
Coordinator.  The DSMC Coordinator forwards the information onto the DSMC Chairman 
who determines if immediate action is required.  Follow-up eIRB reports, and all subsequent 
SAE documentation that is available are also submitted to the DSMC Chair who determines 
if further action is required. (See Appendix IV of the SCCC DSMC Plan for a template 
Serious Adverse Event Form which may be utilized when a sponsor form is unavailable and 
SAE submission to the eIRB is not required). 
  
All serious adverse events which occur on research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. Hardcopies or electronic versions of the FDA Form #3500A forms, or 
other sponsor forms, if applicable; and/or any other supporting documentation available 
should be forwarded to the DSMC Coordinator.   
 
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Cancer Center, the DOT Manager or lead coordinator ensures that all participating sites are 
notified of the event and resulting action, according to FDA guidance for expedited 
reporting. DSMC Chairperson reviews all serious adverse events upon receipt from the 
DSMC Coordinator.  The DSMC Chairperson determines whether action is required and 
either takes action immediately, convenes a special DSMC session (physical or electronic), 
or defers the action until a regularly scheduled DSMC meeting.  
 
The following instructions section may be modified as needed to ensure clear guidance for 
institutions participating in the trial who will not report directly to the UTSW Institutional 
Review Board. If needed, this reporting may be facilitated by the UTSW study team for 
example.  
 
Telephone reports to: 
(Investigator/study team: Insert names and phone numbers for required 
notifications) 
Kevin Albuquerque, MD 
c/o Clinical Research Manager 
214-648-1892 
 
Written reports to: 
(Investigator/study team: Insert names, fax numbers, an addresses for 
required notifications) 
Kevin Albuquerque, MD 
c/o Clinical Research Manager 
 


 
 
46 
 
2280 Inwood Road 
Dallas, TX 75235 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached 
supporting documentation 
 
1. SAEs 
Serious adverse events (SAEs) for studies where the SCCC DSMC is the DSMC of record 
require reporting to the DSMC coordinator within 2 working days of PI awareness, or as 
described in the protocol.   
2. Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) 
Local Serious Adverse Event UPIRSOs require reporting to the UTSW IRB within 48 hours 
of PI awareness of the event (life threatening or fatal events experienced by subjects enrolled 
by the investigator(s) under UTSW IRB jurisdiction).   
Local UPIRSOs (non-serious events experienced by subjects enrolled by the investigator(s) 
under UTSW IRB jurisdiction) require reporting to the UTSW IRB within 5 business days of 
PI awareness of the event. 
External UPIRSOs including those that occur as non-local events require reporting to the 
UTSW IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for INDs and 
BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM227351.pdf 
7.3 Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: 
Identify the type of adverse event using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol treatment. Any event 
that occurs more than 30 days after the last dose of treatment and is attributed (possibly, probably, or 
definitely) to the agent(s) must also be reported accordingly. 
 
Step 4: 
Determine the prior experience of the adverse event.  


 
 
47 
 
Expected events are those that have been previously identified as resulting from administration of the 
agent. An adverse event is considered unexpected, for expedited reporting purposes only, when either the 
type of event or the severity of the event is not listed in: 
 
the current known adverse events listed in the Agent Information Section of this protocol; 
 
the drug package insert; 
 
the current Investigator’s Brochure 
 
The following reportable events must be submitted to Pfizer within 24 hours (or immediately for death or 
life-threatening events) using the provided Investigator-Initiated Research Serious Adverse Event Form (IIR 
SAE) with the Pfizer Reportable Events Fax Cover Sheet with each SAE submission. 
 
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. 
Detailed guidance on the safety reporting is provided in the Safety Reporting Reference Manual. 
 
Contact information for submission of reportable events to Pfizer: 
 
Fax:  Pfizer U.S. Clinical Trial Department,  Fax 1-866-997-8322.  
 
or 
 
E-mail: USA.AEReporting@pfizer.com, specifying: 
∙             PROTOCOL:        
∙             SUBJECT:              
∙             SITE/PI:                 
∙             SAE/ONSET:        
Stopping Rules: The study will be stopped if the combination treatment of SABR and Avelumab resulted in 
>50% of increased Grade 3-5 toxicity as compared to those reported in the literature for patients receiving 
Avelumab alone in the first 6 patients, or if the regimen is deemed to be unsafe by the Data Safety 
Monitoring Committee. 
8.0 
Drug/Treatment Information 
Avelumab (MSB0010718C) 
Mode of action: Avelumab (company code: MSB0010718C) binds PD-L1 and blocks the interaction 
between PD-L1 and PD-1. This removes the suppressive effects of PD-L1 on anti-tumor CD8+ T cells, 
resulting in the restoration of cytotoxic T cell response. 
 
Storage and stability: 
General Information: The active pharmaceutical ingredient in avelumab drug product is a fully human 
antibody of the IgG1 isotype that specifically targets and blocks the ligand (PD-L1) for PD-1. 


 
 
48 
 
8.1 General Properties of Drug Substance 
The calculated molecular weight of the molecule is 143,832 Dalton. The antibody is produced by 
mammalian cell culture in a serum-free growth medium. The antibody is purified by affinity, ion-exchange, 
and mix-mode chromatography.  The process also includes specific viral inactivation and removal steps. The 
antibody is then transferred into formulation buffer and brought to the desired concentration. 
 
Pharmaceutical Formulation 
 
Introduction 
Avelumab drug product is a sterile solution intended for IV infusion. 
 
Pharmaceutical Properties 
Avelumab drug product is a sterile, clear, and colorless concentrate for solution presented at 
concentration of 20 mg/mL in European Pharmacopeia (Ph. Eur.) and United States Pharmacopeia 
(USP) type I glass vials closed with a rubber stopper and sealed with an aluminum Flip Off® seal 
closure. 
 
Description of the Formulations 
Each single-use vial contains 200 mg of avelumab as a preservative-free acetate-buffered solution 
(pH 5.2) containing Mannitol, and Polysorbate 20 (Tween
20). 
For avelumab drug product, only excipients that conform to the current Ph. Eur. and/or the current 
USP are used. 
 
Instructions for Storage 
Avelumab drug product must be stored at 2°C to 8°C until use. The storage condition is based on 
data from ongoing long term stability studies with avelumab. 
Avelumab drug product stored at room (23°C to 27°C) or higher temperatures for extended 
periods of time might be subject to degradation. Avelumab drug product must not be frozen. 
Rough shaking of the solution must be avoided. 
For administration in clinical trials, avelumab drug product must be diluted with 0.9% saline 
solution (sodium chloride injection) supplied in an infusion bag; alternatively a 0.45% saline 
solution can be used if needed. 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, for purposes of this protocol, diluted solution should be used within 
4 hours if stored at room temperature and used within 24 hours if stored under refrigeration at 2-
8C.. 
No other drugs should be added to the solution for infusion containing avelumab. 
 
Protocol dose: A dose of 10 mg/kg of avelumab, intravenous (iv) once every 2 weeks, was 
selected for the expansion cohorts of Phase I trials, the Phase II pivotal trial (EMR 100070-003), 
and the ongoing Phase III trials based on the preliminary pharmacokinetic (PK), target occupancy, 
and preliminary clinical safety data collected in the clinical trials. 
 
 
Preparation: Avelumab drug product is a sterile, clear, and colorless concentrate for solution 
presented at concentration of 20 mg/mL in European Pharmacopeia (Ph. Eur.) and United States 
Pharmacopeia provided labelled by the sponsor  
 
Route of administration for this study: intravenous 
 
Incompatibilities: NA 
 
Administer the diluted solution over 60 minutes through and intravenous line containing a 
sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron.) 
 
Availability: provided by sponsor Pfizer  
 
Side effects (see section on toxicity) 


 
 
49 
 
 
Nursing implications: As dictated by clinical course 
 
9.0 
Correlatives/Special Studies 
The goal of laboratory correlative studies will be to identify immune-biomarkers to better identify patient 
populations that are more responsive to this regimen.  
9.1 Metastatic Tumor Profile  
Archival tissue of metastatic site or retrospective primary tumor biopsy slides will be studied to perform 
immunologic assays for PD-1,PDL1 and TIL levels(i.e. CD4, CD8, CD68, CD1a, FoxP3).. If a recent tumor 
/metastatic site biopsy is available or has been obtained prior to study entry that tissue can be used for 
immune analysis .Tumor PD-L1 membrane expression and immune cell PD-L1 expression  (≥1% vs. <1% 
and ≥5% vs. <5%, ≥10% vs. <10%,) using SP263 IHC will be quantified in sections which have at least 100 
tumor cells as assessed with immunohistochemical staining. It has been shown previously that tumors with 
higher PD-L1 expression have worse outcomes but it remains to be shown whether these tumors respond 
better to anti-PD-L1 therapy. It would be very interesting to examine the correlation between PD-L1 
expression and tumor response to Avelumab therapy[41]. Specific TIL receptor studies will also be 
performed if feasible. 
9.2 Serum Immune Markers  
Whole blood will be collected pre-treatment and at specific intervals during treatment (prior to cycle 1, cycle 
3, cycle 5, cycle 7, and two weeks post last cycle*) to perform immunologic assays evaluating induction of a 
tumor-specific adaptive as well as humoral immune response. These blood draws will be performed in sync 
with the routine lab draws for patient care scheduled prior to each cycle so not to inconvenience the patient. 
Cytokines are hormonal messengers responsible for most of the effects in the immune system such as 
activation of innate versus adaptive immune response, cellular versus humoral immune response [42, 43]. 
Serum cytokines from this clinical trial before and after SAbR and at time-points of Avelumab  
administration as described above will be measured using an array of cytokines to explore the specific 
immune pathways that are initiated/inhibited by our treatments. The planned array will measure levels of the 
cytokines (Th1 vs Th2, pro- vs anti-inflammatory) and correlate immune response with clinical outcomes. to 
correlate immune response with clinical outcomes. 
In addition, live white blood cells will be stored in DMSO to measure tumor-specific immune response (i.e. 
ELISpot) and its amplification following treatment, pending availability of additional funding  
 
  
*2 week post treatment correlative lab will be optional 
9.3  Sample Processing Guidelines 
Samples will be labeled with the subject’s de-identified study number and collection date and delivered for 
analysis during regular business hours to: NC7: 208; Attn Dr. Raquibul Hannan/pathology lab  
 
Whole blood sample: Patient’s whole blood will be collected in EDTA (Lavender top) tubes for ~ 40-50 ml. 
In addition, ~10 ml will be collected in anti-coagulant-free tubes (Red top) for the collection of sera.  The 
blood will immediately be processed (within 2 hours) by centrifugation (1000 g, 15 min, 4oC), collecting the 
supernatant and freezing at -80oC in 5 aliquots for future experiments. The pellet will be re-suspended in 
PBS and PBMC will be isolated using standard protocol. Briefly, the cell suspension will be carefully placed 
on 10ml polystyrene tube containing 1ml ficoll and centrifuged (400g, 30min, RT).  PBMC region will be 
collected from the ficoll and washed 3x with PBS. Cells will be counted and frozen in 5 aliquots with 10% 
DMSO, 90% FBS at -80oC 


 
 
50 
 
9.3.1 
Assay Methodology 
a) Specimen Immunohistochemical staining (IHC): Standard immunohistochemistry staining 
procedure for will be performed using the Benchmark XT automated stainer (Ventana) for both 
antibodies. Briefly, formalin-fixed, paraffin-embedded tissue sections will be cut at 3-4 micron and 
air-dried overnight. The sections will be deparaffinized, rehydrated, and subjected to heat-induced 
epitope retrieval. Sections will then be incubated with appropriate primary antibody. For signal 
detection, ultraView universal detection system (Ventana) will be used. The slides will be 
developed using 3-3’-diaminobenzidine chromogen and counterstained with hematoxylin. 
Appropriate positive and negative controls will be utilized for each run of immunostains.  The 
evaluation of the immunostaining will be carried out by a gynecologic pathologist without 
knowledge of any clinicopathologic data. Only nuclear reactivity will be considered positive. 
Tumor PD-L1 membrane expression and immune cell PD-L1 expression  (≥1% vs. <1% and ≥5% 
vs. <5%, ≥10% vs. <10%,) using SP263 IHC will be quantified in sections which have at least 100 
tumor cells as assessed with immunohistochemical staining. An H score will be assigned as the 
product of average intensity of staining (0 for negative, 1 for weakly positive, 2 for moderately 
positive, and 3 for strongly positive) and extent of immunoexpression (0-100% percentage of cells 
staining). In addition,  Dual-antibody ISH will be performed to identify and analyze( if possible)  
TILs, CTL (CD3+,CD8+), Tregs (CD4+FoxP3), DC (CD11c) , NK/T (CD3+, CD1d), neutrophils 
(CD11b, Ly6G} and MDSC (CD14+,CD11b) in the tumor tissue before and after treatment, (when 
available). PD-L1 expression will be quantified from biopsies of tumors prior to treatment. 
b) Serum Cytokine Analysis: Multiplex cytokine analysis in patient’s plasma will be performed in 
precoated 96 well plates (Human TH1/TH2 10 plex ultrasensitive assay, Meso Scale Discovery – 
MSD, Maryland, USA) according to manufacturer’s instructions. 25 µL of diluent 2 is dispersed 
into each well. The plate is sealed and incubated by vigorous horizontal shaking for 30 minutes at 
RT. 25 µL of the patient plasma is added per well and all samples measured in triplicates. Plates are 
sealed and incubated by vigorous horizontal shaking for two hours at RT. Plates are washed three 
times with 0.05% Tween 20 in PBS. 25 µL of 1× detection antibody solution is placed per well and 
sealed plates are incubated by vigorous horizontal shaking for two hours at RT. Plates are washed 
three times with 0.05% Tween 20 in PBS. 150 µL of 2× Read Buffer T is added to each well. Plates 
are analysed using the MSD SECTOR Imager 2400 and Discovery Workbench 3.0 software (both 
from Meso Scale Discovery, USA). The mean value of two wells is taken as the recorded reading, 
provided that the coefficient of variation (CV) was less than 10%. Concentrations recorded lower 
than the standard curve are kept as absolute values. For purposes of logarithmic analysis, readings 
of 0 are adjusted to 0.01 pg/ml.  The following cytokines will be measured before and after 
treatment for each patients at various timepoints(if possible) : Th1/Th2/Th17 cytokines, IFN-γ, IL-
1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, IL-17 TNF-α; pro-inflammatory cytokines: GM-
CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, TNF-α; Chemokines: Eotaxin, MIP-1β, 
TARC, IP-10, IL-8, MCP-1, MCP-4 and others including IL-6, TGF-β and HMGB1  
9.4 Specimen Banking 
Subject samples collected for this study will be retained at the department of pathologyand at the lab of Dr. 
Hannan (NC7. 208). Specimens will be stored labeled with study ID (no identifiers) and frozen in -80oC 
until they are used up or for 10 years (whichever comes first). Only approved study personnel will have 
access to the blood samples for immunologic assays as listed above.  If future use is denied or withdrawn 
by the subject, best efforts will be made to stop any additional studies and to destroy the specimens. We 
will also analyze archival tissue from patients enrolled in this trial obtained from UTSW sources (clinical 
pathology and cancer center tissue repository) or outside institutions (with appropriate institutional release 
forms).” 
10.0 
Statistical Considerations  
 


 
 
51 
 
10.1 Study Design/Study Endpoints 
This is a prospective one arm, single center phase 2 trial of the addition of SABR to Avelumab  with the 
hypothesis that this is a durably effective means of potentiating the effects of PD-L1 blockade in inducing 
higher objective response rate (ORR) eventually leading to improvements in progression-free survival, 
complete response rate, overall survival in the ROPT patient  population.  
 
10.2 Sample Size and Accrual 
In this phase II study (with safety lead-in) we will begin with a 6 patient cohort of PD-LIt blockade 
combined with 3 fraction SABR to an acceptable dose of the site radiated to determine the safety and 
feasibility of this regimen. We will enroll 3 patients at a time, evaluating DLTs at 8 weeks and follow the 
patients for 8 weeks before enrolling an additional 3 patients if 0 or 1/3 patients has a DLT. If ≤2/6 patients 
develops a DLT we will open up to an expansion cohort evaluating PDL-1 inhibition + SABR to assess 
response rates, PFS, OS and collect further toxicity data.  
The  best ORR for ROCC with anti pD-1 inhibitor was 10-15 % from the Japanese reported phase 2 
study[50].The additional  estimated benefit from SAbR-IT is 25 %  based upon data from Oregon phase 1 
study[51] and also the UTSW RCC study. 
For efficacy evaluation, we plan to enroll 23 patients for the phase II part of this protocol.  
Simon's two-stage design will be used for the phase II study. The null hypothesis that the true response rate 
is 15% will be tested against a one-sided alternative. In the first stage, 11 patients will be accrued (6 of the 
lead-in patients will be evaluated for response and included in the first stage). If there are 2 or fewer 
responses in these 11 patients, the study will be stopped. Otherwise, 18 additional patients will be accrued 
for a total of 29. The null hypothesis will be rejected if 8 or more responses are observed in 29 patients.  
This design yields a type I error rate of 0.05 and power of 85% when the true response rate is 40%. 
 
10.3 Data Analyses Plans 
Safety data (all AEs and SAEs) will be tabulated for both phase I and II parts. Rates of AEs and 
SAEs will also be calculated along with their exact 95% confidence intervals. 
For efficacy, response rate will be calculated along with its exact 95% confidence intervals, and 
compared with historical response rate of 15% using normal approximation test (one-sided).  
Tumor biopsy TIL assay and tumor PD-L1 levels will be assayed and correlated with response 
using Spearman rank-correlation. 
 
11.0 
Study Management 
11.1 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by the UTSW 
COI Committee and IRB according to UTSW Policy on Conflicts of Interest.  All investigators will follow 
the University conflict of interest policy. 
11.1.1 Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations. The IRB must approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 


 
 
52 
 
Before recruitment and enrollment onto this study, the subject will be given a full explanation of the 
study and will be given the opportunity to review the consent form. Each consent form must include all 
the relevant elements currently required by the FDA Regulations and local or state regulations. Once this 
essential information has been provided to the subject and the investigator is assured that the subject 
understands the implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the subject  and by the person who conducted the informed consent discussion. 
11.1.2 Required Documentation (for multi-site studies) 
Before the study can be initiated at any site, the following documentation must be provided to the 
Radiation Oncology Clinical Research Office. 
 
 
A copy of the official IRB approval letter for the protocol and informed consent 
 
IRB membership list or Federal wide Assurance letter 
 
CVs and medical licensure for the principal investigator and any associate investigators who will 
be involved in the study 
 
Form FDA 1572 appropriately filled out and signed with appropriate documentation (NOTE: this 
is required if {institution} holds the IND. Otherwise, the affiliate Investigator’s signature on the 
protocol is sufficient to ensure compliance) 
 
A copy of the IRB-approved consent form 
 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
 
Executed clinical research contract 
11.2 Registration/Randomization Procedures 
All subjects must be registered with the Radiation Oncology Clinical Research Office before enrollment to 
study. All subjects consenting to participate in any aspect of the trial must be registered on REDCap before 
initiating protocol activities.  The eligibility checklist and confirming documentation will be entered 
electronically through the system. 
Upon confirmation of eligibility and enrollment new subjects will receive a number beginning with 01 such 
that the first subject consented is numbered 01, the second subject consented receives the number 02, etc 
The subject will be assigned a secondary number in the order of enrollment.  
Each newly registered subject should be numbered using the schema provided above. Upon registration, the 
registrar will assign the additional registration/randomization code according to the numbering schema 
outlined above, which should then be entered as the patient study id in Velos upon updating the status to 
enrolled. 
The numbering schema should clearly identify the site number; the sequential number of the subject enrolled 
as well as the status of the subjects enrolled so that the number of subjects consented versus the number of 
subjects actually enrolled may be easily identified.   
11.3 Data Management and Monitoring/Auditing 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case report forms for this 
and all SCCC Investigator Initiated Trials. REDCap will be used for electronic case report forms in 
accordance with Simmons Comprehensive Cancer Center requirements. 
Trial monitoring will be conducted no less than annually and refers to a regular interval review of trial 
related activity and documentation performed by the DOT, which includes but is not limited to accuracy of 
case report forms, protocol compliance, timeless and accuracy of Velos entries and AE/SAE management 


 
 
53 
 
and reporting. Documentation of trial monitoring will be maintained along with other protocol related 
documents and will be reviewed during internal audit.   
Toxicity reviews will be performed at 6 monthly intervals. These reviews will be documented by electronic 
method and will be distributed to the sponsor and SCCC-DSMC.) 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring Committee (DSMC) 
is responsible for monitoring data quality and patient safety for all UTSW SCCC clinical trials.  As part of 
that responsibility, the DSMC reviews all local serious adverse events and UPIRSOs in real time as they are 
reported and reviews adverse events on a quarterly basis.  The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to ensure data integrity and 
regulatory compliance.  A copy of the DSMC plan is available upon request. 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of ongoing clinical trials, 
for which it serves as the DSMC of record. The QAC works as part of the DSMC to conduct regular audits 
based on the level of risk. Audit findings are reviewed at the next available DSMC meeting.  In this way, 
frequency of DSMC monitoring is dependent upon the level of risk.  Risk level is determined by the DSMC 
Chairman and a number of factors such as the phase of the study; the type of investigational agent, device or 
intervention being studied; and monitoring required to ensure the safety of study subjects based on the 
associated risks of the study. Protocol-specific DSMC plans must be consistent with these principles.  
RADIATION ONCOLOGY DATA SAFETY MONITORING PLAN 
1. The purpose of the Radiation Oncology Data and Safety Monitoring Plan is to ensure that clinical trial 
data is accurate and valid and to ensure the safety of trial participants.  The plan complies with the 
Simmons Cancer Center (SCCC) Data Safety Monitoring Plan and the University of Texas 
Southwestern Medical Center (UTSW) IRB guidelines.   
2. The Radiation Oncology Safety Assurance Committee (ROSAC) is charged with developing, 
implementing, and maintaining the Data and Safety Monitoring Plan. The membership consists of a 
Medical Director of Clinical Research as well as representation from the following groups:  clinical 
research, nursing, regulatory, pharmacy, physicists, radiation therapists, and faculty. Ad hoc members 
are contacted to participate as needed.  
3. All clinical trials are reviewed by ROSAC on a monthly basis for enrollment.  All local SAEs are 
reviewed by ROSAC monthly for severity and attribution. For investigator-initiated trials, SAEs at 
affiliated institutions are monitored as local SAEs.  The principle investigator and study coordinator 
will present a study treatment summary and SAEs for review.  Source documents will be available for 
the ROSAC members during the review. NCI Common Toxicity Criteria Version 4 will be used for 
grading and attributing adverse events.  The documentation of these monthly reviews will be submitted 
to the SCCC DSMC on a monthly basis.   
4. If a related SAE occurs on a multi-institutional clinical trial coordinated by the Radiation Oncology 
Clinical Research Office, the Clinical Research Manager or designee ensures that all participating sites 
are notified of the event and resulting action, within one (1) working day of the determination. 
5. All participating sites will be monitored annually.  At least 5 charts for each site will be reviewed each 
time a site is monitored. Monitoring will include verification of source documentation as per SCC 
DSMC plan.  Results of data monitoring along with any necessary responses, if applicable, will be 
documented and filed within the Department of Radiation Oncology.   These documents are available 
upon request at time of audit.  All monitoring will be performed remotely, however on-site visits may 
be scheduled as necessary per DSMC policy. 
6. In addition the pharmaceutical sponsor will be notified about any SAE per the safety policy outlined in 
the investigator brochure 


 
 
54 
 
11.4 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being of 
the study subject requires alternative treatment, the study shall be conducted exactly as described in 
the approved protocol.  
11.4.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IRB approval.  
For any such emergency modification implemented, an IRB modification form must be completed 
within five (5) business days of making the change. 
11.4.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the IRB. According to the IRB, a protocol deviation is any unplanned variance 
from an IRB approved protocol that:  
 
Is generally noted or recognized after it occurs 
 
Has no substantive effect on the risks to research participants 
 
Has no substantive effect on the scientific integrity of the research plan or the value of the 
data collected  
 
Did not result from willful or knowing misconduct on the part of the investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research participants. 
 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the investigator(s). 
 
Demonstrates serious or continuing noncompliance with federal regulations, State laws, or 
University policies. 
 
If a deviation or violation occurs without prior approval from the Principal Investigator, please 
follow the guidelines below: 
Protocol Deviations: Personnel will report to any sponsor or data and safety monitoring committee 
in accordance with their policies. Deviations should be summarized and reported to the IRB at the 
time of continuing review. 
Protocol Violations: Study personnel should report violations within two (2) weeks of the 
investigator becoming aware of the event using the same IRB online mechanism used to report 
Unanticipated Problems.  
11.5 Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and documented by the 
Principal Investigator.  A summary of changes document outlining proposed changes as well as rationale for 
changes, when appropriate, is highly recommended.  When an amendment to the protocol substantially alters 
the study design or the potential risk to the patient, a revised consent form might be required.  
The written amendment, and if required the amended consent form, must be sent to the IRB for approval 
prior to implementation.  


 
 
55 
 
11.6 Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that the study investigator retain all study 
documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking 
regulatory approval and marketing, these documents shall be retained for at least two years after the last 
approval of marketing application in an International Conference on Harmonization (ICH) region. In all 
other cases, study documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
11.7 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator is 
responsible for personally overseeing the treatment of all study patients. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study staff members, adhere to the 
study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the required data 
will be collected and entered onto the Case Report Forms. Periodically, monitoring visits may be conducted 
and the Principal Investigator will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all case report forms will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the data. 
12.0 
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