Phase I (Safety Assessment) of Durvalumab (MEDI4736) With Focal Sensitizing Radiotherapy in Platinum Resistant Ovarian, Primary Peritoneal or Fallopian Tube Epithelial Carcinoma
Phase: PHASE1
Conditions: Ovarian Cancer, Primary Peritoneal Carcinoma, Fallopian Tube Cancer
Sponsor: British Columbia Cancer Agency

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
1 
 
 
Drug Substance 
Durvalumab 
Study Number 
ESR-15-10855 
Version Number 
1 
Date 
June 5, 2017 
Research Title: Phase I (Safety Assessment) of Durvalumab (MEDI4736) 
with Focal Sensitizing Radiotherapy in Platinum Resistant Ovarian, 
Primary Peritoneal or Fallopian Tube Epithelial Carcinoma 
Clinical Trial Protocol No: 
Sponsor Protocol No. ESR-15-10855  
Ozmosis Study No. OZM-078 
 
Protocol Version #:  
1.0 
 
 
Protocol Date: 
05-Jun-2017 
 
 
Phase of Study:  
Phase I 
 
Sponsor: 
Dr. Anna Tinker 
 
Sponsor Address: 
 
BC Cancer Agency 
600 West 10th Avenue 
Vancouver, BC,  
V5Z 4E6 Canada 
 
Source of Agent: 
 
Astra Zeneca 
Protocol History 
 
Original: 
Version 1.0; dated 05-Jun-2017 
 
 
 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
2 
 
CONFIDENTIAL 
 
 
 
 
 
 
Principal Investigators: 
 
 
 
 
 
 
 
Dr. Anna Tinker MD, Medical Oncologist 
Dr. Peter Lim MD, Radiation Oncologist 
600 West 10th Avenue, Vancouver B.C., Canada 
Phone: 1-604-877-6000  
Fax: 1-604-877-6217 
Email: atinker@bccancer.bc.ca 
Clinical Trial 
Management 
Company/Clinical Trials 
Specialist/Manager: 
Patricia Christian 
Ozmosis Research Inc. 
65 Queen Street West, Suite 2020Toronto, ON, M5H 2M5 
Main Line: 416-634-8300 
Direct Line: 416-634-8312 
Fax: 416-598-4382 
Email: patricia.christian@ozmosisresearch.ca 
  
  

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
3 
 
Sponsor’s Agreement to Protocol Version 1.0, 05-Jun-2017 
 
 
 
 
 
Name of Authorized Personnel  
(Print) 
 
 
Title of Authorized Personnel  
(Print) 
 
 
Signature of Authorized 
Personnel: 
 
 
______________________________________ 
 
 
 
______________________________________ 
 
 
 
______________________________________ 
 
                    
 
Date of Approval: 
______________________________________ 
 
DD-MMM-YYYY 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
4 
 
SYNOPSIS 
Study Title: 
Phase I (Safety Assessment) of Durvalumab (MEDI4736) with 
Focal Sensitizing Radiotherapy in Platinum Resistant Ovarian, 
Primary Peritoneal or Fallopian Tube Epithelial Carcinoma 
Primary Objectives: 
The primary objective of this study will be to assess the safety 
and tolerability of durvalumab and focal irradiation as defined by 
dose-limiting toxicities (DLTs) and define the maximum 
tolerated dose (MTD), and treatment schedule that can be safely 
used for future study of this therapeutic strategy. 
Secondary Objectives: 
 
The secondary objectives of this study are to evaluate the clinical 
activity of durvalumab and focal radiotherapy as measured by: 
1) Objective Response rate as evaluated by  
a. RECIST (v 1.1) criteria  
b. GCIG CA-125 response criteria  
c. Immune-related response criteria  
2) Progression free survival  
3) Overall survival 
Exploratory Objectives: 
1) To collect blood and tissue samples for analysis of immune 
biomarkers 
2) To investigate the relationship between the presence or 
absence and spatial distribution of lymphocyte subsets within 
the tumor microenvironment and clinical outcomes 
3) To explore biomarkers of radiation and durvalumab efficacy 
4) To analyze biomarkers (e.g. immune, tumor) in different 
cellular compartments (e.g. tumor, immune, serum, blood) 
which may influence and/or prospectively identify patients 
likely to respond to treatment 
Study Design: 
This is a phase I, open label, safety and tolerability assessment of 
the combination of PD-L1 blockade using the mAb, durvalumab, 
with focal irradiation of two selected cancer lesions in patients 
with recurrent, platinum-resistant ovarian cancer.  
Duration: 
Durvalumab will be continued as long as well tolerated, with no 
evidence of clinically significant disease progression, for up to 12 
months duration. 
Planned Total Sample 
Size: 
The minimum number of patients required to complete this study 
will be 3. This would occur if all of the first 3 patients on dose 
level 1 experienced a DLT. The study would then stop accrual. 
The maximum number of patients required to complete this study 
will be 22. This would occur if at each dose level, the cohorts had 
to be fully expanded (n=9), and 2 patients at each dose level had 
to be replaced. 
Test Drug, 
Administration and 
Dose-Escalation 
Patients enrolled in the study will receive 1500 mg of 
durvalumab q 28 days, corresponding to one cycle.  For the first 
2 doses of durvalumab, focal radiation to the two selected target 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
5 
 
Scheme: 
lesions will be delivered 24-36 hours prior to the infusion of 
durvalumab (on Day -1 and 1 of Cycle 1 and Day 28 of Cycle 1 
as well as Day 1 of Cycle 2).   
 
Two radiation targets will be identified per patient. Target 
selection is described in Section 6.2. Each lesion will receive a 
total of 6Gy x 4 fractions. Radiation will be given 24-36 hours 
prior to durvalumab (e.g., both targets will receive 6Gy of 
radiation on days -1 & 1 and of cycle 1,  and then on day 28 of 
Cycle 1, and day 1 of cycle 2). Where possible, radiation should 
precede administration of durvalumab on days when they are 
given together.  
Subjects will be enrolled in cohorts of 3 each. Dose escalations 
for subsequent cohorts will be undertaken as per the dose 
modification tables below following a 3+3+3 design, to establish 
the MTD of the combination of durvalumab and focal radiation. 
Dose 
Level 
Durvalumab 
dose 
Total Radiation dose 
given per target lesion 
(2 targets per patient) 
N 
1 (starting 
dose level) 
1500 mg 
24 Gy 
3+3+3 
2 
1500 mg 
32 Gy 
3+3+3 
 
Three subjects will be treated at an initial dose level of 1500 mg 
of durvalumab q28 days and 24 Gy of radiation (6Gy X 4) to 
both radiation targets (delivered as per the treatment schedule 
shown in Table 1). If 0, 1 or 2/3 subjects experience DLTs during 
cycle one (first 4 weeks of treatment), 3 additional subjects will 
be enrolled at the dose level 1. If at dose level 1, 2/6 experience 
DLTs, then 3 more subjects will be enrolled in the trial at the 
starting dose level. If 0 or 1/6, or <3/9 experience a DLT at dose 
level 1, then dose escalation to dose level 2 will be permitted 
(Table 2). Enrolment onto dose level 2 will follow the same rules 
as described for dose level 1, following a 3+3+3 design to define 
the MTD. If at any time on dose level 1, ≥3 subjects (3/3, 3/6, or 
3/9) experience a DLT the trial will stop accrual and a MTD will 
not be defined due to excessive treatment toxicity. If at dose level 
2, ≥3 subjects (3/3, >3/6, or 3/9) experience a DLT then accrual 
will stop and dose level 1 will be selected as the MTD. If at dose 
level 2, ≤ 1/6 or < 3/9 experience DLTs, then dose level 2 will 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
6 
 
represent the MTD.  
Dose-limiting toxicity will be defined with the use of the 
Common Terminology Criteria for Adverse Events version 4.03 
as any of the following as assessed by the investigator:  
 
any grade ≥3 adverse event suspected to be related to the 
study agent or to the radiation  
o radiation necrosis or radiation recall reactions at 
previously irradiated sites 
o if the radiation field includes bowel, then radiation 
induced bowel perforation 
o any unexpected grade 3 or greater toxicity at the 
site of irradiation 
 
any grade ≥2 allergic or autoimmune event that involves 
vital organ functions 
 
any other grade 3 allergic or autoimmune events that does 
not resolve to grade 1 toxicity before the next scheduled 
dose of antibody. 
Inclusion/Exclusion 
Criteria: 
Inclusion Criteria  
1. Provision of written informed consent prior to any study 
specific procedures 
2. Female patients aged 19 years and older 
3. Platinum-resistant (progression within 6 months of platinum 
based regimen) or platinum-refractory ovarian/fallopian 
tube/peritoneal origin.  
 
High grade serous, endometrioid, clear cell, 
mucinous, malignant mixed Mullerian tumor, and low 
grade serous histotypes are permitted. Non-epithelial 
tumours will not be permitted. 
4. ECOG performance status 0-1. 
5. No more than 2 lines of therapy in the platinum-resistant 
setting. 
6. No bowel obstructions within the preceding 6 months.  
7. Last radiation therapy treatment ≥3 months prior to 
enrollment. 
8. Expected survival >3 months. 
9. All patients much have at least one site of measurable disease 
as defined by RECIST criteria (v.1.1).  
10. All patients must have disease suitable for core biopsy and 
agree to study related biopsies. Disease suitable for biopsy 
can serve as radiation targets, but cannot be used for response 
assessment. 
11. All patients must have at least 2 additional sites of disease 
that serve are suitable radiation targets (see section 6.2.1). 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
7 
 
 Lesions suitable for radiation targeting must meet all of the 
following criteria: 
o each target must be > 4 cc in volume by standard 
imaging techniques, such as CT scan, MRI, or 
radiograph 
o for each lesion, partial treatment of a tumour mass is 
permitted, but the treatment volume cannot be less 
than the equivalent of a 2cm sphere (4cc) and the two 
targets cannot be part of the same contiguous mass  
o must be outside of  previously irradiated fields 
 
12. Adequate organ and marrow function as defined below 
within 14 days of cycle 1 day 1 and prior to first dose of focal 
radiotherapy: 
 Absolute neutrophil count >1.5 x 109/L (1500 per mm3) 
 Platelets >100 x 109/L (100,000 per mm3) 
 Hemoglobin ≥9.0 g/dL (5.59 mmol/L) 
 Serum creatinine CL >40 mL/min by the Cockcroft-
Gault formula [82] or by 24-hour urine collection for 
determination of creatinine clearance: 
 
Females: Creatinine CL as calculated by Cockcroft-Gault 
Formula  
 
 
 
 
GFR = 1.04 x (140 - age in years) x weight (kg)  
 
 
 
 
serum creatinine (micromol/L) 
 
 
 Serum bilirubin ≤1.5 x upper limit of normal (ULN). 
This will not apply to patients with confirmed Gilbert’s 
syndrome (persistent or recurrent hyperbilirubinaemia 
that is predominantly unconjugated in the absence of 
evidence of haemolysis or hepatic pathology) who will 
be allowed in consultation with their physician. 
 AST and ALT ≤2.5 x ULN. 
 
Exclusion Criteria 
1. Participation in another clinical study with an investigational 
agent during the last 4 weeks. 
2. Concurrent enrolment in another clinical study, the only 
exception being observational (non-interventional) clinical 
studies. 
3. History of pneumonitis requiring treatment with steroids, or 
has a history of interstitial lung disease. 
4. Patients who have contraindications to receiving radiation 
therapy, such as: Rheumatoid Arthritis, connective tissue 
disorders, Lupus, scleroderma, CREST syndrome, Crohn’s 
syndrome, Ulcerative colitis, or other conditions identified by 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
8 
 
the Radiation Oncologist as unsuitable for radiation therapy. 
5. Current or prior use of immunosupressive medication within 
28 days before the first dose of the study drug, with the 
exception of intra-nasal and inhaled corticosteroids or 
systemic corticosteroids at physiologic doses, which must not 
exceed 10 mg/day of prednisone, or an equivalent 
corticosteroid. 
6. Prior exposure to an anti-PD-1 or anti-PD-L1 antibody 
(including durvalumab). 
7. History of acute diverticulitis, intra-abdominal abscess, or GI 
obstruction. 
8. Previous severe hypersensitivity reaction to another 
monoclonal antibody (mAb). 
9. Active autoimmune disease or a documented history of 
autoimmune disease or syndrome that requires systemic 
steroids or immunosuppressive agents. Patients with Vitiligo, 
Grave’s disease or psoriasis not requiring systemic treatment 
(within the past 2 years) or those with resolved childhood 
asthma/atopy are not excluded. 
10. Uncontrolled intercurrent illness including: infection 
requiring therapy, symptomatic congestive heart failure, 
uncontrolled hypertension (systolic blood pressure > 150 and 
diastolic blood pressure >100), unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, 
active bleeding diatheses. 
11. Mean QT interval corrected for heart rate (QTc) ≥ 470 ms 
calculated from using Frediricia’s Correction.  
12. Positive for Human Immunodeficiency Virus (HIV), 
Hepatitis B (Hepatitis B Surface Antigen [HBsAg] reactive), 
or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid 
[HCV RNA] (qualitative) is detected).  
13. Previous clinical diagnosis of active tuberculosis. 
14. Receipt of a live attenuated vaccination within 30 days of 
study entry or within 30 days or receiving the study drug.  
15. History of another malignancy, with the exception of: 
 Malignancy treated with curative intent without evidence of 
recurrence for ≥ 5 years 
 Adequately treated non –melanoma skin cancer or lentigo 
maligna without evidence of disease 
 Adequately treated carcinoma in situ without evidence of 
disease e.g. cervical carcinoma in situ 
16.  Female patients who are pregnant, breast-feeding or of 
childbearing potential who are not employing an effective 
method of birth control (see Table 3). 
17.  Any condition that, in the opinion of the investigator, would 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
9 
 
interfere with evaluation of the study drug or interpretation of 
patient safety or study.  
Screening Assessments: 
 Complete medical history  
 Concomitant medication assessment 
 Physical examination and ECOG Performance Status 
 Vital signs  
 Hematology  
 Coagulation 
 Chemistry 
 Urinalysis 
 12-lead ECG 
 HIV test 
 Hepatitis B & C test 
 Serum pregnancy test (for non-sterile women of childbearing 
potential) 
 Tumour measurement 
 Core needle biopsy 
 Peripheral blood for immune marker analysis 
 Baseline symptoms 
Treatment 
and 
Post-
Treatment Assessments: 
Treatment Assessments: 
 Physical examination and ECOG Performance Status 
 Concomitant medication assessment 
 Vital signs  
 Hematology  
 Coagulation 
 Chemistry 
 Urinalysis 
 12-lead ECG 
 Tumour measurement 
 Core needle biopsy 
 Peripheral blood for immune marker analysis 
 Adverse event assessment 
 
End of Treatment Visit: 
 Physical examination and ECOG Performance Status 
 Concomitant medication assessment 
 Vital signs  
 Hematology  
 Coagulation 
 Chemistry 
 Urinalysis 
 12-lead ECG 
 Tumour measurement 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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 Core needle biopsy 
 Peripheral blood for immune marker analysis 
 Adverse event assessment 
 
Follow up Assessments: 
 Tumor measurement 
 Adverse event assessment 
 Survival status 
Response: 
RECIST 1.1 criteria will be used to assess patient response to 
treatment by determining PFS, ORR, and DoR.  
Safety Variables & 
Analysis: 
The primary objective of this trial is to assess the safety and 
tolerability of durvalumab combined with focal radiotherapy, and 
hence determine the MTD of this combination. Safety endpoints 
will include DLTs, AEs, SAEs and deaths.  
 
Secondary endpoints will include clinical measures of treatment 
outcome: ORR (as measured by RECIST v 1.1, GCIG CA125 
response, and immune related response criteria), PFS and OS. 
Exploratory Samples: 
Core needle biopsy and peripheral blood will be collected at the 
protocol-specified timepoints and analyzed for immune markers 
as outlined below: 
Exploratory objectives  
Outcome measures 
To collect blood and tissue 
samples for analysis of 
immune biomarkers 
Biomarker analysis to assess 
exploratory markers include 
but are not limited to: immune 
cell gene expression profiles in 
the peripheral blood and 
tumor, frequency of 
lymphocyte subsets as defined 
by cell surface markers, 
presence of functional markers 
of immune activity, tumor 
associated antibodies 
To investigate the 
relationship between the 
presence or absence and 
spatial distribution of 
lymphocyte subsets within 
the tumor microenvironment 
and outcomes 
Tumor and tumor associated 
expression of immune 
checkpoints and their spatial 
distribution within the tumor 
microenvironment relative to 
OS, PFS, ORR 
To explore biomarkers of 
radiation and durvalumab 
and efficacy 
Biomarkers in the serum and 
tumor before and after 
treatment will be assessed and 
correlated with response to 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
11 
 
treatment and/or tumor 
progression  
To analyze biomarkers (e.g. 
immune, tumor) in different 
cellular compartments (e.g. 
tumor, immune, serum, 
blood) which may influence 
and/or prospectively identify 
patients likely to respond to 
treatment 
Correlate expression of 
biomarkers with response to 
treatment and/or progression 
Statistical Analysis:  
Evaluable for Adverse Events 
For the primary objectives of this study (i.e. safety and MTD), 
the evaluable population will consist of patients who completed 
Cycle 1 of planned therapy, unless a DLT was encountered. 
Patients who did not complete Cycle 1 and did not experience a 
DLT will be replaced. All patients registered to the study who 
receive at least one dose of durvalumab will be assessed of safety 
and toxicity, but may not necessarily be included in the  
evaluable population for the primary endpoints (see definition 
above). For example, if a patient received one dose of 
durvalumab, and then declined further treatment, or had rapid 
disease progression, then they would be assessed for treatment 
toxicity at the time of the end treatment visit. If DLTs were not 
encountered the patient would be replaced in the study. Subjects 
who receive radiation without receiving durvalumab will not be 
included in the safety analysis.  
Evaluable for Response 
The efficacy analysis set will include all evaluable patients 
registered to the study. The evaluable population will consist of 
patients completing planned Cycle 1 of therapy, unless a DLT 
was encountered. Patients who did not complete Cycle 1 and 
came off treatment due to disease progression will not be 
included in the efficacy analysis.  
Methods of Statistical Analysis 
All safety analyses will be performed on the safety population. 
The incidence of events that are new or worsening from the time 
of the first dose of treatment with durvalumab will be 
summarized by dose level, organ system, severity and 
relationship to the study treatment and reported by CTCAE 
grade. Deaths reportable as SAEs and non-fatal SAEs will be 
listed by patient and tabulated by primary system/organ and type 
of adverse event. The analysis of secondary endpoints will be 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
12 
 
descriptive. Time-to-event endpoints (i.e., PFS, OS) will be 
summarized for the aggregated sample. 
The final analysis for the primary objectives will occur after the 
last patient to enroll in the study has completed Cycle 1 of 
therapy. The final analysis for secondary endpoints will occur 
when data are mature or within 6 months of study completion. 
 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
13 
 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
TABLE OF CONTENTS ....................................................................................... 13 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 18 
1. 
INTRODUCTION ................................................................................................. 20 
1.1 
Background ............................................................................................................ 20 
1.1.1 
Ovarian cancer ....................................................................................................... 20 
1.1.2 
Immunotherapy: checkpoint blockade ................................................................... 20 
1.1.3 
Immune system in ovarian cancer .......................................................................... 22 
1.1.4 
PD-1/PD-L1 expression in ovarian cancer ............................................................ 22 
1.1.5 
Clinical trials of checkpoint inhibitors in metastatic cancers ................................ 22 
1.1.6 
Clinical trials of checkpoint inhibitors in recurrent ovarian cancer ....................... 23 
1.1.7 
Durvalumab ............................................................................................................ 24 
1.1.8 
Clinical experience with durvalumab .................................................................... 24 
1.2 
Radiotherapy and Immunogenic Cell Death .......................................................... 25 
1.2.1 
Pre-clinical data of radiotherapy and checkpoint regulators .................................. 26 
1.2.2 
Clinical data of combined focal radiation and checkpoint inhibition .................... 27 
1.2.3 
Selection of radiotherapy dose, fractionation, and timing of checkpoint 
inhibition ................................................................................................................ 27 
1.3 
Research Hypothesis .............................................................................................. 28 
1.4 
Rationale for Conducting This Study .................................................................... 28 
1.5 
Benefit/Risk and Ethical Assessment .................................................................... 29 
2. 
STUDY OBJECTIVES .......................................................................................... 30 
2.1 
Primary Objective .................................................................................................. 30 
2.2 
Secondary Objectives ............................................................................................. 30 
2.3 
Exploratory Objectives .......................................................................................... 30 
3. 
STUDY PLAN AND PROCEDURES .................................................................. 31 
3.1 
Overall Study Design ............................................................................................. 31 
3.2 
Sample Size ............................................................................................................ 32 
3.3 
Enrolment Procedures ............................................................................................ 32 
3.4 
Definition of Dose-Limiting Toxicity (DLT) ........................................................ 32 
3.5 
Dose Escalation Procedures ................................................................................... 33 
3.5.1 
Assessment of Late Toxicity .................................................................................. 34 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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3.5.2 
Safety Cohort Review ............................................................................................ 34 
3.6 
Rationale for the Study Design and Doses............................................................. 35 
3.6.1 
Durvalumab ............................................................................................................ 35 
3.6.2 
Radiation Fractions ................................................................................................ 35 
4. 
SUBJECT SELECTION CRITERIA .................................................................... 36 
4.1 
Inclusion Criteria ................................................................................................... 36 
4.2 
Exclusion Criteria .................................................................................................. 37 
4.3 
Subject Enrollment and Registration ..................................................................... 39 
5. 
STUDY CALENDAR ........................................................................................... 41 
6. 
STUDY TREATMENT ......................................................................................... 44 
6.1 
Durvalumab ............................................................................................................ 44 
6.1.1 
Identity of investigational product(s) ..................................................................... 44 
6.1.2 
Product preparation of durvalumab ....................................................................... 44 
6.1.3 
Reconstitution of investigational product .............................................................. 44 
6.1.4 
Preparation of durvalumab doses for administration with an IV bag .................... 44 
6.1.5 
Study drug administration ...................................................................................... 45 
6.1.6 
Monitoring of dose administration ......................................................................... 45 
6.1.7 
Management of toxicity ......................................................................................... 45 
6.1.8 Missed treatment doses .................................................................................................. 46 
6.1.9 
Immune-related adverse events .............................................................................. 46 
6.1.10 
Durvalumab adverse events of special interest ...................................................... 46 
6.1.10.1 Pneumonitis ............................................................................................................ 47 
6.1.10.2 Hypersensitivity Reactions .................................................................................... 48 
6.1.10.3 Hepatic function abnormalities (hepatotoxicity) ................................................... 48 
6.1.10.4 Gastrointestinal disorders ....................................................................................... 49 
6.1.10.5 Endocrine disorders ............................................................................................... 49 
6.1.10.6 Pancreatic disorders ............................................................................................... 49 
6.1.10.7 Neurotoxicity ......................................................................................................... 49 
6.1.10.8 Nephritis ................................................................................................................. 49 
6.1.11 
Labeling ................................................................................................................. 50 
6.1.12 
Storage ................................................................................................................... 51 
6.2 
Radiation Therapy .................................................................................................. 51 
6.2.1 
Radiation target planning  ...................................................................................... 51 
6.2.2 
Treatment verification/imaging.............................................................................. 52 
6.2.3 
Radiation dose ........................................................ Error! Bookmark not defined. 
6.2.4 
Radiation technique ............................................................................................... 53 
6.3 
Concomitant Medications ...................................................................................... 53 
6.3.1 
Permitted concomitant medications ....................................................................... 53 
6.3.2 
Blood donation ....................................................................................................... 55 
6.3.3 
Prohibited concomitant medications ...................................................................... 55 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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6.4 
Treatment Compliance ........................................................................................... 56 
6.4.1 
Accountability ........................................................................................................ 56 
6.5 
Premature Withdrawal/Discontinuation Criteria ................................................... 56 
6.5.1 Subject replacement rule ............................................................................................... 57 
7 
STUDY PROCEDURES ....................................................................................... 57 
7.1 
Study Visits ............................................................................................................ 57 
7.1.1 
Screening Visit ....................................................................................................... 57 
7.1.2 
Treatment Phase ..................................................................................................... 58 
7.1.3 
End of Treatment ................................................................................................... 58 
7.2 
Description of study procedures ............................................................................ 58 
7.2.1 
Physical examination, electrocardiogram, and vital signs ..................................... 58 
7.2.2 
Clinical laboratory tests ......................................................................................... 58 
8 
MEASUREMENT OF DRUG EFFECT ............................................................... 60 
8.1 
Safety Assessment ................................................................................................. 60 
8.2 
Efficacy Assessment .............................................................................................. 60 
8.2.2 Gynecological Cancer Intergroup (GCIG) Guidelines for Response Using 
CA125 .................................................................................................................... 62 
8.3 
Exploratory Samples .............................................................................................. 63 
9 
SAFETY AND REPORTING REQUIREMENTS ............................................... 65 
9.1 
Definition of Adverse Events ................................................................................. 65 
9.2 
Adverse Event Documentation .............................................................................. 66 
9.3 
Definitions of Serious Adverse Event .................................................................... 66 
9.4 
Reporting of Serious Adverse Events .................................................................... 67 
9.5 
Reporting of Adverse Events of Special Interest ................................................... 68 
9.6 
Procedure for Expedited Reporting........................................................................ 68 
9.6.1 
Responsibility for Reporting Serious Adverse Events to Health Canada .............. 68 
9.6.2 
Responsibility for Reporting Serious Adverse Events to Drug AstraZeneca ........ 69 
9.6.3 
Reporting Serious Adverse Events to Local Research Ethics Boards ................... 69 
9.6.4 
Overdose ................................................................................................................ 69 
9.6.5 
Hepatic function abnormality ................................................................................ 69 
9.6.6 
Pregnancy and Maternal exposure ......................................................................... 70 
9.6.7 
Pregnancy and Paternal exposure .......................................................................... 70 
9.7 
Follow Up of Adverse and Serious Adverse Events .............................................. 71 
9.8 
Relationship ........................................................................................................... 71 
10 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 72 
10.1 
Informed Consent ................................................................................................... 72 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
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10.2 
Ethics Board Approval ........................................................................................... 72 
11 
EVALUATION AND CALCULATION OF VARIABLES ................................. 73 
11.1 
Calculation or derivation of safety variable(s) ....................................................... 73 
11.1.1 
Exposure to investigational product ....................................................................... 73 
11.1.2 
Adverse events, laboratory changes, vital signs .................................................... 73 
11.2 
Calculation or derivation of efficacy variable(s) ................................................... 73 
12 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 74 
12.1 
Description of analysis sets .................................................................................... 74 
12.1.1 
Evaluable for Adverse Events ................................................................................ 74 
12.1.2 
Evaluable for Response .......................................................................................... 74 
12.2 
Methods of statistical analyses ............................................................................... 75 
13 
DOCUMENTATION, RECORD ACCESS AND MAINTENANCE OF 
STUDY RECORDS ............................................................................................... 76 
13.1 
Documentation of Subject’s Participation ............................................................. 76 
13.2 
Regulatory Requirements ....................................................................................... 76 
13.3 
Subject Confidentiality and Access to Source Data/Documents ........................... 76 
13.4 
Confidentiality of the Study ................................................................................... 77 
13.5 
Registration of Clinical Trial ................................................................................. 77 
13.6 
Data Reporting and Data Management .................................................................. 77 
13.7 
Case Report Forms ................................................................................................. 77 
13.8 
Maintenance of Study Records .............................................................................. 77 
14 
QUALITY ASSURANCE AND QUALITY CONTROL ..................................... 79 
15 
ADMINISTRATIVE PROCEDURES .................................................................. 80 
15.1 
Amendments to the Protocol .................................................................................. 80 
15.2 
Protocol Deviations and Violations ....................................................................... 80 
15.3 
Premature Discontinuation of the Study ................................................................ 80 
16 
LEGAL ASPECTS ................................................................................................ 81 
16.1 
Publication Policies and Disclosure of Data .......................................................... 81 
17 
LIST OF REFERENCES ....................................................................................... 82 
18 
LIST OF APPENDICIES ...................................................................................... 90 
APPENDIX 1:  DOSING MODIFICATION AND TOXICITY MANAGEMENT 
GUIDELINES FOR IMMUNE- MEDIATED, INFUSION RELATED, 
AND NON IMMUNE-MEDIATED REACTION ................................................ 91 
APPENDIX 2:  RECIST 1.1 GUIDELINES ........................................................................ 111 

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APPENDIX 3: GCIC RESPONSE CRITERIA ................................................................... 116 
APPENDIX 4:  IMMUNE-RELATED RESPONSE CRITERIA ........................................ 118 
APPENDIX 5: RADIATION TREATMENT PLANNING CONTRAINTS ...................... 119 
 
LIST OF TABLES 
Table 1. 
Treatment Delivery Overview 
Table 2.  
Dose modification scheme based on treatment related DLTs.  
Table 3.   
Effective methods of contraception (2 methods must be used)  
Table 4.  
Hematology Laboratory Tests 
Table 5.  
Clinical Chemistry Laboratory Tests 
Table 6. 
Urinalysis Tests 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADCC 
antibody-dependent cell mediated cytotoxicity  
AEs 
Adverse events  
AESI 
Adverse event of special interest 
APCs 
antigen presenting cells  
B7-H1 
B7 homolog 1  
B-cells 
B lymphocytes  
cc 
CD 
cubic centimeter 
cluster of differentiation  
CR 
Complete response 
CSR 
Clinical study report 
CT 
computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CTL 
cytotoxic T lymphocytes  
CTLA-4 
cytotoxic T-lymphocyte antigen 4  
DLT 
Dose limiting toxicity 
Dmax 
maximum dose 
DoR 
Duration of response 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration  
GFR  
Glomerular filtration rate  
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GTV 
Gross tumour volume 
HBsAg 
Hepatitis B Surface Antigen  
HGSC 
high grade serous cancer 
HR 
Hazard ratio 
IGTV 
IMRT 
Internal gross tumour volume 
intensity modulated radiotherapy 

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IV 
intravenously  
Kg 
Kilogram 
L 
Liter 
mAb 
Monoclonal antibody  
mCRPC 
Castration resistant prostate cancer (mCRPC)   
MRI  
Magnetic resonance imaging 
MTD 
maximum tolerated dose 
NED 
No evidence of disease 
NSCLC 
non-small cell lung cancer  
OAE 
Other adverse event 
OAR 
organs at risk 
ORR 
Objective response rate 
OS 
Overall survival 
PARP 
poly ADP ribose polymerase 
PD 
Progressive disease 
PD-1 
programmed death -1 
PD-L1 
programmed death ligand 1 
PFS 
Progression free survival 
PK 
pharmacokinetics  
PR 
Partial Response 
PTV 
planning target volume 
q 28 days  
every 28 days  
SAE 
Serious adverse event 
SD 
Stable disease 
TIL 
tumour infiltrating lymphocytes 
V 
Volume 
VMAT 
volumetric modulated arc therapy 
 

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1. 
INTRODUCTION 
Investigators should be familiar with the urvalumab Investigator’s Brochure (IB). 
1.1 
Background 
1.1.1 
Ovarian cancer 
Approximately 27000 women are diagnosed with ovarian/primary peritoneal/fallopian tube 
cancer (henceforth called ovarian cancer) in the US annually. Of these, nearly 60% will have 
high grade serous cancer (HGSC), the most common subtype of this disease. Given the 
absence of effective screening strategies, cancer of the ovary is typically diagnosed in 
advanced stages (stages III and IV). Survival rates have improved; however, cures remain 
elusive for the majority of patients with stage III and IV disease [1]. The standard of care 
remains de-bulking surgery and successive rounds of cytotoxic therapy. Clinical trials of first-
line sequential therapies, maintenance treatments, targeted therapies, amongst other strategies 
have not lead to cures, although modest improvements in survival can be achieved. Other 
emerging treatment options include angiogenesis inhibitors such as bevacizumab [2] and poly 
ADP ribose polymerase (PARP) inhibitors, particularly in tumours deficient in homologous 
repair [3].  
All cases of recurrent ovarian cancer progress to the penultimate state of platinum resistance. 
Patients with platinum resistant disease, defined by disease progression within 6 months of the 
last line of platinum based therapy, have a poor prognosis (medial survival 12-18 mo), with 
standard therapies having minimal activity (10-15% response rate) and none demonstrating an 
improvement in overall survival [4]. The AURELIA trial is the first advance in the treatment 
of platinum refractory carcinoma of the ovary. Bevacizumab added to standard single agent 
chemotherapy improved progression free survival by 4 months, however, overall survival was 
not improved, potentially because of the 40% crossover observed from the standard arm to 
bevacizumab [5]. Radiotherapy in recurrent ovarian cancer is routinely used for palliation, for 
example, in the case of a painful retroperitoneal lymph node, or uncomfortable pelvic mass, 
but does not lead to improved survival due to the systemic nature of advanced disease. 
Therefore, new approaches are urgently needed for the treatment of this highly lethal cancer. 
1.1.2 
Immunotherapy: checkpoint blockade 
 
The immune system can identify tumour-associated antigens and eliminate cancerous cells.  
The observed co-evolution of the tumour and the immune response is termed immunoediting, 
which is purported to have 3 stages [6]: elimination, during which the innate and adaptive 
immune systems detect and eliminate tumour cells; equilibrium, during which the immune 
system eliminates susceptible tumour cells, however, some tumours may evolve mechanisms 
to avoid or attenuate the immune response, and; escape, during which many factors may 
contribute to the failure of the immune system to control tumour growth including the 
expression of immune-inhibitory molecules, presence of immunosuppressive regulatory T 
lymphocytes (T-regs) or immunosuppressive cytokines within the tumour microenvironment, 

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and down-regulation of major histocompatibility molecules and tumour antigens leading to 
reduced antigen presentation and recognition. 
 
Blockade of negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 
(CTLA-4), programmed death -1 (PD-1) and programmed death ligand 1 (PD-L1) have 
shown promising clinical activity in activating immune recognition and elimination of cancers.  
Ipilimumab binds to CTLA-4 and prevents the interaction of CTLA-4 with cluster of 
differentiation (CD) 80 and CD86, resulting in enhanced T-cell activation and proliferation 
[7].  Ipilimumab was granted United States (US) Food and Drug Administration (FDA) 
approval in 2011 for the treatment of metastatic melanoma and is currently under 
investigation for several other malignancies. Nivolumab and pembrolizumab are IgG4 (fully 
human and humanized respectively) antibodies targeting PD-1.  These agents are approved 
by the FDA for treatment of advanced melanoma and squamous non-small cell lung cancer 
(NSCLC). Increased PD-L1 expression was shown to be predictive of response in patients 
with melanoma and NSCLC treated with pembrolizumab [8,9]. However, PD-L1 status was 
not predictive in patients with squamous NSCLC treated with nivolumab [10]. 
PD-L1 (B7 homolog 1 [B7-H1], CD274) is part of a complex system of receptors and 
ligands that are involved in controlling T-cell activation. PD-L1 is normally expressed on T-
cells, B lymphocytes (B-cells), dendritic cells, macrophages, mesenchymal stem cells, bone 
marrow-derived mast cells, as well as various non-haematopoietic cells [11]. The normal 
tissues, PD-L1 acts to repress T-cell activation and induce tolerance through interaction with 
2 receptors, programmed death 1 (PD-1, CD279) and CD80 (B7-1). The expression of PD-1 
is induced on lymphocytes and regarded as an activation marker. However, chronic antigen 
stimulation can cause T cells to retain high levels of PD-1 expression and thereby lose the 
capacity to respond to activation signals, a state known as T cell exhaustion. This 
physiological feedback mechanism limits the potential for hyper-lymphocyte activation and 
tissue damage. Tumours have co-opted the PD-L1/PD-1 axis at multiple sites to help tumours 
evade detection and elimination by the host immune system. For example, PD-L1 expression 
can be innate to cancers (innate immune resistance) or it can be induced by selective pressure 
from the immune system (adaptive immune resistance) [12]. PD-L1 on antigen presenting 
cells (APCs), found in lymph nodes, binds to PD-1 (CD279) or CD80 (B7-1) on activated T-
cells, inhibiting their function [11,13]. Likewise, APCs that express CD80 can bind to PD-L1 
on T-cells, also leading to T-cell inhibition. These interactions reduce T-cell activation and 
lower activated T-cells in the circulation. T-cell inhibition also occurs in the the tumour 
microenvironment, where PD-L1 expressed on tumour cells binds to PD-1 on activated T-
cells [14]. 
In vitro, antibody blockade of PD-L1: PDL-1 receptor interaction can relieve PD-L1-
dependent immunosuppressive effects, leading to enhanced cytotoxic activity of anti-tumour 
T-cells [15]. Several preclinical studies in mouse tumour models also demonstrate that 
antibodies directed against PD-L1, or its receptor PD-1, improves anti-tumour activity [16-
19]. 
 

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1.1.3 
Immune system in ovarian cancer 
There is strong evidence to suggest that the immune system plays a key role in the progression 
of HGSC ovarian cancer. An immune response signature (defined by a set of 49 genes) has 
been associated with improved ovarian cancer survival in a large analysis conducted on 
samples of The Cancer Genome Atlas Repository [20]. Likewise, intra-tumoural infiltration 
by CD8+ and CD3+ T cells (cytotoxic T lymphocytes - CTL) is associated with better 
prognosis in advanced HGSC of the ovary  [21-23] and many factors associated with cytolytic 
T cells (CTLs) are also associated with better survival (e.g. IFN-gamma, IFN-gamma 
receptor, interferon regulatory factor-1, IL-18, TNF-α, MHC class I, MHC class I antigen 
processing machinery) (reviewed in Milne et al. [24]). On the other hand, worse survival has 
been associated with infiltrating regulatory T cells (Tregs) [25,26]. Tregs act to suppress the 
immune response of CTLs by inhibiting proliferation, cytokine production and cytolytic 
activity. Tregs also induce immunosuppressive phenotypes in cells such as macrophages.  
Up to 50% of ovarian HGSCs have CD8+ and CD3+ tumour infiltrating lymphocytes (TIL), 
suggesting that appropriate tumor-derived antigens lead to T-cell priming and immune 
activation. Immune activation is a key step in triggering an immune response; however, the 
presence of TIL is insufficient to eliminate the cancer. This suggests that the TIL are hypo-
reactive. Several immune suppressive pathways have been identified. These include inhibitory 
receptors, e.g. CTLA-4 and PD-1, which, when engaged by their ligands (B7 and PD-L1 
respectively) expressed on an antigen presenting cells or tumor cells, block T -cell activation. 
In many cases, tumors up-regulate the expression of inhibitory ligands, resulting in a state of 
immune tolerance/immune exhaustion.  
1.1.4 
PD-1/PD-L1 expression in ovarian cancer 
PD-L1 is expressed in a broad range of cancers [11,14].  In a number of these cancers, 
including lung [27], renal [28-30], pancreatic [31-33], and ovarian cancers [34], the expression 
of PD-L1 is associated with reduced survival and an unfavourable prognosis.  In ovarian 
cancer, for example, the 5-year survival rate in patients with low levels of PD-L1 was 80.2%, 
compared with 52.6% in patients with high levels of PDL-1. 
PD-L1 expression is observed in the ascites of ovarian cancer patients and is also associated 
with shorter overall survival [35]. A series of pre-clinical studies have demonstrated that PD-1 
blockade, alone or in combination with other immune modulators (e.g. OX40, CTLA-4) 
impairs ovarian cancer growth in model systems and restores T cell function [36-40]. PD-1 is 
expressed by TILs of ovarian cancers. 
1.1.5 
Clinical trials of checkpoint inhibitors in metastatic cancers 
Since the first reports of activity of checkpoint inhibitors in metastatic cancers [41,42] 
progress in clinical immunotherapy research has been rapid. Numerous phase III trials have 
demonstrated the efficacy of anti-CTLA4 therapy [43-45], and anti-PD-1 therapy [46-48] in 
improving progression free survival and overall survival for metastatic melanoma. A 
comparative trial suggests that anti-PD-1 blockade may have superior clinical outcomes and 
better toxicity profiles than anti-CTLA4 therapy for melanoma patients [47]. However, 

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combined anti-PD-1 (nivolumab) and anti-CTLA4 (ipilimumab) therapy showed better 
clinical outcomes (higher response rates, prolonged progression free survival, longer overall 
survival and more complete responses) than either agent alone [49]. As expected, the 
incidence of grade 3 and 4 toxicity was greater in the combination arm. The most common 
adverse events included diarrhea, fatigue, and pruritis.  
Patients with metastatic non-small cell lung cancer (NSCLC) also benefit from checkpoint 
inhibitors. A phase III trial enrolled patients with treatment resistant NSCLC to standard 
docetaxel versus the PD-1 inhibitor, nivolumab and demonstrated an improvement in 
progression free survival on the nivolumab arm [9.3 mo vs 6 mo, (p<0.001, HR, 0.59)] [50]. A 
recently published phase III trial of nivolumab as compared to everolimus for the second-line 
treatment of renal cell carcinoma demonstrated a greater than 5 month improvement in OS of 
the checkpoint inhibitor over the mTOR targeting agent, which was the historic standard [51].  
Phase III trials of PD-1 inhibitors and PDL-1 inhibitors, in the first-line setting compared to 
standard platinum-based therapy and in second-line therapy compared to docetaxel, for 
patients with metastatic NSCLC are ongoing. Other active areas of research include metastatic 
bladder cancer ([52], NCT02451423), and mismatch repair deficient tumours such as 
colorectal cancers [53].  
1.1.6 
Clinical trials of checkpoint inhibitors in recurrent ovarian cancer 
Data on 11 heavily pretreated patients with ovarian cancer receiving therapy with ipilimumab 
[54,55] reported 6 to have clinical benefit - 2 with transient responses, 3 with stable disease of 
2 months duration, and one with confirmed RECIST response.  Treatment related side effects 
did include 2 cases of grade 3 inflammatory toxicity manifesting as diarrhea. Grade 1 rash was 
documented in 7 patients. 
A phase II study of anti-PD-1 therapy with Nivolumab in platinum resistant ovarian cancer 
demonstrated that amongst 10 patients treated at 1 mg/kg, 1 (10%) had a partial response. Ten 
patients received 3 mg/kg dose, and 2 (25%) had a durable complete response, one with 
recurrent HGSC and the other with recurrent clear cell carcinoma of the ovary [56]. The 
patients were heavily pretreated, with a medial of 4 prior therapies. The agent was well 
tolerated; however, dose independent toxicities such as rash, increased liver enzymes, 
hypothyroidism, fever, arthralgia, low albumin, and lymphocytopenia were reported. 
A phase Ib open expansion study of an anti-PD-L1 agent, avelumab, in recurrent ovarian 
cancer [57] reported on efficacy data on the first 23 evaluable patients who were followed for 
at least 2 or more months. Four patients have an unconfirmed partial response (by RECIST 1.1 
criteria [58]) as best overall response, and 2 patients had >30% tumour shrinkage after initial 
progression was reported, one of whom had clear cell carcinoma of the ovary. Reported drug-
related treatment-emergent adverse events were reported in 18 patients (78.3%) with 2 (8.7%) 
experiencing ≥ grade 3 toxicity (increased lipase [n=1] and elevated creatine kinase and 
autoimmune myositis that led to treatment discontinuation [n=1]). No serious drug-related 
treatment-emergent adverse events were observed. The most commonly reported drug-related 
treatment-emergent adverse events (> 10%) were fatigue, nausea, and diarrhea.  

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Therefore, the PD-1/PD-L1 immune regulators warrant further study in ovarian HGSCs. 
 
1.1.7 
Durvalumab  
For full details please refer to the current IB. 
Durvalumab is an engineered human IgG1κ monoclonal antibody (mAb) with high affinity 
and selectivity for PD-L1 [59]. Durvalumab is non-immunogenic at the phase III dose of 
10mg/kg, hence pharmacokinetics (PK) and pharmacodymics (PD) were not affected. Only 
2/196 patients treated at 10mg/kg developed measurable anti-drug antibodies (ADA) [59]. 
Exposure of the drug was sustained throughout the dosing intervals (>1 yr). The engineering 
of the durvalumab Fc domain (which is triply mutated) has removed the antibody-dependent 
cell mediated cytotoxicity (ADCC) activity.  
1.1.8 
Clinical experience with durvalumab 
For full details of the clinical information, please refer to the current IB. 
Durvalumab has been given to humans as part of ongoing studies where it is given either as a 
single drug or in combination with other drugs.  As of September 2015, 1,910 subjects have 
been treated across 30 ongoing durvalumab studies. The majority of the safety data for 
durvalumab have been pooled from 4 durvalumab monotherapy studies (CD-ON-MEDI4736-
1108, D4190C00002, ATLANTIC and D4193C00001 [HAWK])in patients with advanced 
solid tumours, receiving durvalumab at 10 mg/kg Q2W.  1645 are included in the pooled 
analysis. [59-64]. Two hundred and fifty-two patients (252) with NSCLC and 62 with 
squamous cell carcinoma of the head and neck (SCCHN) were treated as part of the phase I 
expansion cohort study [60,61]. Adverse events (AEs) on this trial (including expansion 
cohorts) occur at a rate of 30-60%. The vast majorityof AEs are low grade (Grades 1-2) and 
are easily managed. The most frequently reported (≥10% of subjects) treatment-emergent AEs 
(all grades) include (in decreasing order of frequency): fatigue, nausea, decreased appetite, 
dyspnea, cough, constipation, diarrhea, vomiting, back pain, pyrexia, abdominal pain, anemia, 
arthralgia, peripheral edema, headache, rash, and pruritus.  An newly recognized adverse 
event is the occurrence of serious hemorrhagic events in pateit 
 
AEs of Grade 3 or higher considered related todurvalumab were reported in 164 patients 
(10.0%): of these, 144 patients (8.8%) had events of Grade 3, 12 patients (0.7%) had events of 
Grade 4 and 8 patients (0.5%) had Grade 5 (fatal) events.. 
Grade 3 events occurring in ≥1% of patients were: anaemia (5.5%); dyspnoea (4.4%); 
hyponatraemia (4.1%); fatigue (2.9%); gamma-glutamyltransferase (GGT) increased 
(2.7%); abdominal pain (2.0%); decreased appetite and back pain (1.9% each); pneumonia 
(1.8%); aspartate aminotransferase (AST) increased and dehydration (1.6% each); 
hypertension (1.3%); blood alkaline phosphatase (ALP) increased, hypokalaemia, urinary tract 
infection and vomiting (1.2% each); alanine aminotransferase (ALT) increased and pleural 
effusion (1.1% each); bilirubin increased, asthenia, nausea and pulmonary embolism (1.0% 
each). Grade 3 eventsconsidered related to durvalumab occurring in ≥0.5% patients were 
fatigue (1.2%), GGT increased (0.8%) and AST increased (0.6%). 

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Treatment-related AEs were reported in 49.8% of cases (820/1645).  Grade 3 events occurring 
in ≥1% of patients were: anaemia (5.5%); dyspnoea (4.4%); hyponatraemia (4.1%); fatigue 
(2.9%); gamma-glutamyltransferase (GGT) increased (2.7%); abdominal pain (2.0%); 
decreased appetite and back pain (1.9% each); pneumonia (1.8%); aspartate aminotransferase 
(AST) increased and dehydration (1.6% each); hypertension (1.3%); blood alkaline 
phosphatase (ALP) increased, hypokalaemia, urinary tract infection and vomiting (1.2% 
each); alanine aminotransferase (ALT) increased and pleural effusion (1.1% each); bilirubin 
increased, asthenia, nausea and pulmonary embolism (1.0% each). Grade 3 events 
considered related to durvalumab occurring in ≥0.5% patients were fatigue (1.2%), GGT 
increased (0.8%) and AST increased (0.6%).Grade 4 events considered related to durvalumab 
occurring in ≥2 patients were GGT increased and pneumonitis (0.1% each). Grade 5 event 
considered related to durvalumab occurring in ≥2 patients was pneumonitis (0.1%). 
 
Serious bleeding events have been observed in patients receiving durvalumab, with or without 
tremelimumab across 6 studies of patients with squamous cell carcinoma of the head and 
neck. Eleven of 238 patients (4.6%) monotherapy with durvalumab and episode of 
hemorrhage. When disease-related, or other etiologies were accounted for, 4/238 events of 
bleeding were attributed to durvalumab (1.7%).  Durvalumab combined with tremelimumab 
has also lead to hemorrhages in 14/238 patients (6.9%). Once again, when other etiologies 
were accounted for, treatment related serious bleeding events were seen in 4/238 cases (2%).  
 
Early reports, from phase I and II trials, demonstrate activity of durvalumab in patients with a 
variety of malignancy types, including NSCLC, SCCHN, melanoma, and urothelial 
carcinoma. Responses have included disease stabilization and partial responses, some of 
which have lasted >43 weeks at last reporting [61]. Thus far, no subjects have experienced a 
complete treatment response. Data from phase III trials remain to be reported. 
 
1.2 
Radiotherapy and Immunogenic Cell Death 
A key step in immune system activation is T cell priming through tumour antigen exposure. 
There is compelling evidence that radiation can induce immunogenic tumour cell death 
characterized by signals that promote uptake of dying cells by dendritic cells, cross-
presentation of the tumour-derived antigens to T cells, and activation of anti-tumour T cells 
(Reviewed in [65] and [66]). Radiation can also alter the tumour microenvironment and 
enhance recruitment of anti-tumour T cells [67]. 
A rare phenomenon called the abscopal (Latin ab-scopus, meaning away from) response has 
been observed clinically where patients receiving local radiotherapy experience anti-tumor 
responses at a distant untreated site. This phenomenon has been described in a patient with 
metastatic melanoma demonstrating disease progression while on maintenance ipilimumab. 
Radiation to a symptomatic pulmonary focus lead to systemic disease response and correlates 
of immune activation were observed in the blood following the localized radiation treatment. 
[68]. The proposed mechanism to explain the abscopal effect is that radiation results in both 

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appropriate changes in the tumour microenvironment and T-cell priming. When inhibition is 
weak (rarely in natural setting, but now manipulatable by checkpoint regulatory drugs) the 
delivery of focal radiotherapy may be sufficient to activate local cellular immunity. As the 
active immune cells enter the circulation, they also excerpt their anti-cancer effect on distant 
metastatic sites.  
Therefore, it may be possible to exploit the immune activating properties of focal radiotherapy 
and simultaneously overcome the state of immune tolerance, with the goal of enhancing anti-
tumour immunity. 
1.2.1 
Pre-clinical data of radiotherapy and checkpoint regulators  
There are no pre-clinical studies of localized radiotherapy delivered with anti-PD-1 or PD-L1 
agents. However, studies of focal radiotherapy given with anti-CTLA treatment have been 
conducted, mainly in models of non-ovarian tumor types. Arguably, a valid model of ovarian 
cancer does not exit. The widely used mouse ID8 model, which forms peritoneal disease and 
ascites, is derived from the surface epithelium of the mouse ovary. However, HGSCs of the 
ovary and peritoneum have their origin in the fallopian tube. In addition, unpublished studies 
from our team found that p53 is highly expressed in ID8 tumors. This is in contrast to 
publically available data from the TCGA showing that greater than 10% of all tumors display 
recurrent mutations in p53 (among many other examples). Thus, the mutational landscape of 
murine ID8 tumors differs from HGSC, which may have profound consequences on the 
responses to radiation therapy.  
Using a syngeneic murine breast and colon cancer model, it has been demonstrated that local 
radiotherapy combined with anti-CTLA-4 antibody induces effective systemic anti-tumour 
responses [69,70]. Likewise, using syngeneic murine models, it has been demonstrated that 
fractionated treatment (using 8 Gy x 3 fractions) elicited the greatest response of tumour 
locally and at distant sites as compared to other dose and fractionation schedules and anti-
CTLA-4 therapy alone [71]. Our own studies have uncovered similar synergy between 
radiation and anti-CTLA4 in a prostate tumor mode whereby animals receiving fractionated 
radiation followed by anti-CTLA4 exhibited significantly better survival than animals 
receiving anti-CTLA4 alone. Moreover, the timing of anti-CTLA4 relative to radiation 
treatment was crucial for clinical responses.  Animals that received anti-CTLA4 closest to the 
time of radiation survived longer than animals that received anti-CTLA4 furthest from the 
time of radiation. As preclinical data is limited, and the optimal strategy for combining focal 
XRT with immune modulation remains to be defined. There are data to suggest that radiation 
regimens with minimal tumour cell-kill and tumour growth inhibition may adequately 
sensitize tumours to rejection by cytotoxic T lymphocytes [72]. The goal is to deliver the 
radiation such that it will act as an in situ vaccine [73], allowing release of tumor-associated 
antigens as well as other immunogenic signals (e.g. HMGB1), antigen uptake and cross-
priming by antigen presenting cells. 

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1.2.2 
Clinical data of combined focal radiation and checkpoint inhibition 
The strategy of adding XRT to checkpoint inhibitors to potentiate immune activation is 
currently being explored in multiple tumour types. One phase III trial in patients with 
metastatic castration resistant prostate cancer (mCRPC)  [74] randomized participants in a 1:1 
ratio to receive a single fraction of bone-directed radiation therapy at 8 Gy followed by 
ipilimumab at 10 mg/kg (n=399) or placebo (n=400). The HR for OS on the intervention arm 
changed over time, but was not significant as an assessment of the proportional hazards 
assumption was shown to be violated. An exploratory, post-hoc analysis did demonstrate an 
OS benefit of the ipilimumab arm in patients with the best prognostic factors (absence of 
visceral metastases, absence of anemia, and normal or only mild elevations of alkaline 
phosphatase). However; it is not possible to assess the contribution of the fraction of 
irradiation to the outcomes on treatment, as the control arm received placebo treatment, rather 
than ipilimumab alone. At the present time, there are no other published reports of the 
combination of focal, immune-sensitizing XRT and a checkpoint regulator, although many 
trials are ongoing. PD-1 inhibition (e.g. MK3475/pembrolizumab) combined with focal 
radiation in the setting of metastatic melanoma (NCT02407171, NCT02562625), or in 
metastatic NSCLC (NCT0244741, NCT02407171) is under active study. Anti-CTLA4 therapy 
using ipilimumab combined with focal radiotherapy is also being studied with may trials 
recruiting patients with solid tumours, melanoma, NSCLC (all listed in 
www.clinicaltrials.gov).   
A proof-of principle study has demonstrated an abscopal effect of radiotherapy when given 
with granulocyte-macrophage colony-stimulating factor (GM-CSF) [75]. This phase 2 trial 
gave GM-CSF (an immune adjuvant that can lead to dendritic cell maturation) and focal 
radiotherapy to patients with stable or progressing metastatic solid malignancies (having at 
least 3 distinct measurable sites >1 cm in size). Patients were able to continue on their existing 
chemotherapy or hormonal therapy. Radiotherapy was given to the chosen target lesions in the 
following way: lesion 1 was treated daily, starting on day 1, for 10 consecutive days and a 
total dose of 35Gy; lesion 2 was treated in the same way starting on day 22. Daily GM-CSF 
(125 µg/m2) was given subcutaneously for 14 days, starting one week after each course of 
radiotherapy. Responses were assessed 7-8 weeks after starting the study, and the primary 
outcome was the observation of an abscopal response (defined by a decrease of 30% in any 
measurable non-irradiated lesion). If multiple lesions were measured, the best response was 
reported. Forty-one patients were enrolled, and 37 were assessable for response. Abscopal 
responses were described in 26.8% of cases. This included 2 complete responders. Therefore, 
this area of research has unexplored potential.    
1.2.3 
Selection of radiotherapy dose, fractionation, and timing of checkpoint 
inhibition 
There are no pre-clinical or clinical data to guide the optimal radiation dose or schedule to be 
used in conjunction with durvalumab. Pre-clinical data suggest that fractionation may be 
important, with 8 Gy X 3 over 3 consecutive days being a superior schedule to single fraction 
of 20 Gy, or 5 fractions of 6 Gy over 5 consecutive days when studied with ipilimumab [71].  

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
28 
 
Using a syngeneic mouse model system (melanoma, colon and triple negative breast cancer) 
Dovedi et al. demonstrated that fractionated radiotherapy leads to increased tumour expression 
of PD-L1, which may attenuate the anti-tumour immune response. The effectiveness of 
fractionated radiotherapy (using 2 Gy x 5 fractions) was enhanced when it was combined with 
an anti-PD-L1 mAb, but not when the radiation and anti-PD-L1 therapies were given 
sequentially [76]. The potential benefits of combining radiation and checkpoint inhibitors 
early in the treatment course is also demonstrated in a recently reported trial of patients with 
refractory NSCLC. Ipilumumb (3 mg/kg) was delivered within 24 hrs of the first dose of 
fractionated radiotherapy (6 Gy in 5 daily fractions).  Of 12 evaluable patients, abscopal 
responses to therapy included 3 patients with CR, 4 with PR, and 5 with SD [77]. 
Various dosing strategies are being explored in the clinical trial setting. Many are modeled 
after the mouse model experiments conducted by Dewan et al. [71], with 3-5, 3-10 Gy, daily 
fractions of focal radiotherapy being delivered immediately before the start of the chosen 
checkpoint inhibitor (e.g. NCT02407171, NCT 02562625, NCT 02406183, NCT 01689974).  
We propose a unique radiation strategy to exploit the potential immune system priming and 
immunogenic tumour cell death effects of fractionated radiation combined with the checkpoint 
inhibition of durvalumab. Two distinct and anatomically separate radiation target lesions will 
be identified. Each target lesion will be treated with a total of 24 Gy at the starting radiation 
dose, given as 6Gy x 4 fractions. The radiation will be planned such that there will be NO 
overlap of the 50% isodose between the targets dose between the targets.  Durvalumab will be 
delivered within 24-36 hours of the first radiation fraction and will be delivered intravenously 
every 28 days. 
Delivering fractionated radiation to two separate lesions may increase the likelihood of 
releasing a broader set of new tumour antigens, assuming the presence of tumour 
heterogeneity.  This novel strategy may also overcome the practical limitations that may arise 
if the first radiation target decreases in size in response to the radiotherapy. By fractionating 
the radiation, and limiting the total dose to 24-32 Gy per target lesion, local radiation toxicity 
will be mitigated and will be within tissue constraints.  
1.3 
Research Hypothesis 
1) We hypothesize anti-PD-L1 therapy and focal radiotherapy can be safely combined in 
patients with recurrent platinum resistant ovarian/primary peritoneal or fallopian tube 
cancer.  
2) We hypothesize that radiation-induced immunogenic cell death will enhance the 
antitumor immune responses of an anti-PD-L1 agent in patients with recurrent 
platinum resistant ovarian/primary peritoneal or fallopian tube cancer. 
1.4 
Rationale for Conducting This Study 
Platinum resistant ovarian/primary peritoneal or fallopian tube HGSCS have a poor prognosis, 
with most patients succumbing to progressive disease within 12 months. It has been observed 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
29 
 
that PD-L1 is highly expressed in ovarian cancers [35,78], thereby suppressing PD-1 positive 
T-cells. While the presence of TIL in ovarian cancer has been associated with better clinical 
outcomes, however, is not sufficient to eliminate the disease. 
Durvalumab is a human mAb that selectively binds human PD-L1 with high affinity and 
blocks its interaction with PD-1 and CD80. Normally this interaction leads to T-cell 
inactivation; therefore, interference with this interaction may activate the T-cell to recognize 
and eliminate cancer cells, a concept demonstrated in vitro and with xenograft models. Focal 
radiation has the potential to further augment the immune response.  
By combining the T-cell activating capacity of durvalumab with the potential immune 
augmenting properties of focal radiation therapy, a synergistic effect against malignancies 
may be induced. This effect may spread to areas of disease outside of the radiation field, and 
this desired response is called the abscopal effect. This trial will determine safety of delivering 
a single fraction of focal radiotherapy with each of the first 4 doses of durvalumab (q 28 days) 
in participants with recurrent, platinum resistant ovarian cancer for whom there remain no 
highly active standard therapies. 
1.5 
Benefit/Risk and Ethical Assessment 
Patients with recurrent ovarian cancer face a poor prognosis. All patients reach the 
penultimate state of platinum resistance, and subsequently succumb to this disease. The need 
to find novel, effective therapies is dire. Patients with platinum resistant ovarian cancer are 
frequently offered participation in clinical trials as standard therapeutic options are minimally 
effective [4]. 
Anti-PD-1 and PD-L1 therapy in ovarian cancer has been demonstrated to be safe with the 
common anti-PD-1/anti-PD-L1 toxicities being reported. However, the single agent activity of 
these agents in ovarian cancer, as reported so far, is modest. Methods to augment the 
effectiveness of immune modulation by checkpoint inhibitors are an important area of current 
research. Radiation, with its ability to affect immunogenic cell death and to affect local 
tumour immune suppression, may be enhance the effectiveness of checkpoint inhibitors and 
lead to tumour regression at sites distant to the radiation field: the so called abscopal effect. 
While radiation therapy is not routinely used in the management of recurrent ovarian cancer, 
palliative radiation is often given for the relief of pain or other symptoms (e.g. pelvic 
bleeding, obstructing pelvic disease etc.).  
Pre-clinical models demonstrate that radiotherapy and checkpoint inhibitors (namely CTLA4 
blockade) can be safely combined. Several clinical trials of checkpoint inhibitors, mainly anti-
CTLA4 but also anti-PD-1 inhibitors, are ongoing in metastatic melanoma, and also in lung 
cancer and breast cancer. This will be the first such trial in patients with recurrent, platinum 
resistant ovarian cancer. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
30 
 
2. 
STUDY OBJECTIVES    
This is an open label, phase I study designed to determine the safety and maximum tolerated 
doses (MTD) of durvalumab and of focal irradiation when combined in the treatment of 
patients with recurrent, platinum-resistant ovarian cancer. 
2.1 
Primary Objective 
The primary objective of this study will be to assess the safety and tolerability of durvalumab 
and focal irradiation, as defined by dose-limiting toxicities (DLTs), and define the maximum 
tolerated dose (MTD) and treatment schedule that can be safely used for future study of this 
therapeutic strategy. 
2.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate the clinical activity of durvalumab and 
focal radiotherapy as measured by: 
1) Objective Response rate as evaluated by  
a. RECIST (v 1.1) criteria [79] 
b. GCIG CA-125 response criteria [80] 
c. Immune-related response criteria [81] 
2) Progression free survival  
3) Overall survival 
2.3 
Exploratory Objectives 
Exploratory objectives of this study include: 
 
1) To collect blood and tissue samples for analysis of immune biomarkers 
2) To investigate the relationship between the presence or absence and spatial distribution 
of lymphocyte subsets within the tumor microenvironment and outcomes 
3) To explore biomarkers of radiation and durvalumab and efficacy 
4) To analyze biomarkers (e.g. immune, tumor) in different cellular compartments (e.g. 
tumor, immune, serum, blood) which may influence and/or prospectively identify 
patients likely to respond to treatment 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
31 
 
3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall Study Design  
This is a phase I, open label, safety and tolerability assessment of the combination of PD-L1 
blockade using the mAb, durvalumab, with focal irradiation of two selected cancer lesions in 
patients with recurrent, platinum-resistant ovarian cancer. The treatment delivery of both focal 
radiation and durvalumab is described in Table 1.  
Eligible participants will have up to 28 days to undergo screening. During the screening 
period, they will be confirmed to meet all the study related eligibility criteria and to undergo 
the required baseline testing.  
The study will be conducted as a 3+3+3 dose escalation study of durvalumab and focal 
radiotherapy (Table 2).  Patients enrolled in the study will receive durvalumab according to 
their assigned dose level (see Table 1) by IV infusion q 28 days ±3 days. Radiation will be 
delivered to both target lesions at the same time at the assigned dose level (see Table 2).  
 
The study will commence on Day -1 following confirmation of registration by Ozmosis 
Research Inc. Treatment will start with the first of 2 fractions of focal radiation to the selected 
target lesions on Day -1, and durvalumab will be delivered on Day 1. For the first 2 cycles of 
durvalumab, focal radiation to the selected target lesions will be delivered 24-36 hours prior to 
the infusion of durvalumab on Day 1, Day 1 and 28 of Cycles 1 and days 1 of Cycle 2 (i.e.  
each cycle will be 28 days). 
 
Durvalumab treatment will be continued on a q 28 day schedule as long as well tolerated for a 
maximum duration of 12 months. Study drug should be discontinued prior to 12 months if 
there is confirmed PD (unless the investigator considers the patient continues to receive 
benefit from study drug), initiation of alternative cancer therapy, unacceptable toxicity, 
withdrawal of consent, or other reasons to discontinue study drug occur as outlined in section 
6.5.  
 
Table 1. Treatment Delivery Overview 
Treatment Cycle 
1 
2 
≥ 3* 
Day of 
Treatment 
D-1 
D1 
D28 
D1 
D14 
D15 
D28 
D1 of a 28 day 
cycle 
Durvalumab 
 all dose levels 
 
X 
 
X 
 
 
 
X 
Radiation Dose 
per Target 
24 Gy  
32 Gy 
 
 
6Gy 
8 Gy 
 
 
6 Gy 
8 Gy 
 
 
6 Gy 
8 Gy 
 
 
6 Gy 
8 Gy 
 
 
 
 
 
 
 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
32 
 
Radiation 
Targets treated 
A and B 
A and B 
 
* maximum treatment duration = 12 months 
3.2 
Sample Size 
The minimum number of patients required to complete this study will be 3. This would occur 
if the first 3 patients on dose level 1 experienced DLTs. The study would then stop accrual. 
The maximum number of patients required to complete this study will be 22. This would 
occur if at each dose level, the cohorts had to be fully expanded (n=9), and 2 patients at each 
dose level had to be replaced. 
3.3 
Enrolment Procedures 
The study will be conducted at two Canadian centres. Once 3 subjects are enrolled in a cohort, 
that dose level will be closed to enrolment until safety assessment of all the 3 subjects is 
performed at the end of cycle 1 (4 weeks). This procedure will be performed for each dose 
level cohort. Subjects will be assigned durvalumab and radiation fractionation dose levels 
based on authorization from the Sponsor in collaboration with Ozmosis Research Inc. Higher 
dose levels will be assigned to subjects following the dose escalation rules described in 
Section 3.5 below. 
3.4 
Definition of Dose-Limiting Toxicity (DLT) 
Patients who have received at least one radiation fraction AND one dose of durvalumab will 
be monitored for DLTs. The safety observation period will be 28 days (one cycle length). This 
time period will allow for assessments of acute DLTs. Once all 3 patients have completed the 
observation period, the dose level may be escalated. Patients will be followed long term to 
monitor for emergence of late toxicity (see 3.5.1).  
DLTs will be defined with the use of the Common Terminology Criteria for Adverse Events 
version 4.03 as any of the following as assessed by the investigator:  
• 
any grade ≥3 adverse event suspected to be related to the study agent or to the 
radiation  
o radiation necrosis or radiation recall reactions at previously irradiated sites 
o if the radiation field includes bowel, then radiation induced bowel perforation 
o any unexpected grade 3 or greater toxicity at the site of irradiation 
• 
any grade ≥2 allergic or autoimmune event that involves vital organ functions 
• 
any other grade 3 allergic or autoimmune events that does not resolve to grade 1 
toxicity before the next scheduled dose of antibody. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
33 
 
In rare instances, an event may fall within the definition of a DLT as defined above but the 
event may be considered not a DLT (ie: not clinically meaningful/significant).  If this occurs, 
a meeting with the principal investigator, the sponsor and the Data and Safety Monitoring 
Committee (DSMC) will take place to thoroughly review the event and supporting data and 
the reasons for not considering the event a DLT will be clearly documented with supporting 
rationale. In addition other events may occur which do not meet the definition of a DLT but 
are concerning to the investigators and sponsor and may be then considered to be DLTs. 
3.5 
Dose Escalation Procedures 
Subjects will be enrolled in cohorts of 3 each. Dose escalations/de-escalations for subsequent 
cohorts will be undertaken as per the dose modification tables below following a standard 
3+3+3 design to establish the MTD of the combination of durvalumab and focal radiation. 
Table 2.  Dose modification scheme based on treatment related DLTs 
Dose Level 
Durvalumab dose 
Total Radiation 
dose given per 
target lesion (2 
lesions per patient) 
N 
1 (starting dose level) 
1500 mg 
24 Gy 
3+3+3 
2 
1500 mg 
32 Gy 
3+3+3 
 
Three subjects will be treated at an initial dose level of 1500 mg of durvalumab q28 days and 
24 Gy of radiation (6Gy X 4) to both radiation targets (delivered as per the treatment schedule 
shown in Table 1). If 0, 1 or 2/3 subjects experience DLTs during cycle one (first 4 weeks of 
treatment), 3 additional subjects will be enrolled at the same dose level. If at dose level 1, 2/6 
experience DLTs, then 3 more subjects will be enrolled in the trial at the starting dose level. If 
0 or 1/6, or <3/9 experience a DLT at dose level 1, then dose escalation to dose level 2 will be 
permitted. Enrolment onto dose level 2 will follow the same rules as described for dose level 
1, following a 3+3+3 design to define the MTD. If at any time on dose level 1, ≥3 subjects 
(3/3, 3/6, or 3/9) experience a DLT the trial will stop accrual and a MTD will not be defined 
due to excessive treatment toxicity. If at dose level 2, ≥3 subjects (3/3, >3/6, or 3/9) 
experience a DLT then accrual will stop and dose level 1 will be selected as the MTD. If at 
dose level 2, ≤ 1/6 or < 3/9 experience DLTs, then dose level 2 will represent the MTD.  

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
34 
 
 
Figure 1. 3+3+3 Dose Escalation Procedures 
3.5.1 
Assessment of Late Toxicity  
Patient follow up will continue until patient death or up to a maximum of 2 years. Assessment 
for late adverse events will be included in this follow up in order to identify late treatment 
toxicity (e.g. radiation toxicity such as radiation necrosis, radiation fibrosis, radiation enteritis 
or colitis, or other toxicities felt to be attributable to the focal radiation treatment, or late 
durvalumab toxicity such as immunologic events). Patients will be contacted by the research 
staff every 3 months to assess their status and ask about possible late treatment effects. If 
needed, patient medical records will be reviewed for evidence of potential late toxicities. 
Potential toxicities will be reviewed by the study sponsor, Ozmosis, the study Principal 
Investigator and with the DSMC. If life threatening or severely morbid late toxicities emerge 
in ≥ 1patient enrolled in the trial, the DSMC will have the capacity to suspend enrolment, and 
recommend premature closure of the study following discussion with Ozmosis and the study 
Principal Investigator and the study sponsor.  
3.5.2 
Safety Cohort Review 
At the end cycle 1 of every subject, the following sections of the eCRF and source 
documentation for laboratory results, must be completed and submitted to Ozmosis Research Inc.:  

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
35 
 
• 
Study Drug Administration 
• 
Adverse Events 
• 
Laboratory Results 
• 
Lab normal ranges page, if applicable 
Additional information may also be requested by Ozmosis Research Inc. from the study site.  
It is imperative that the CRF pages listed above are completed as soon as cycle 1 has ended 
(i.e.: within 24 hours after the end of cycle 1), as the information will be used to assess safety 
at the opened dose level and to determine the feasibility of proceeding to a new dose level. 
An “Accrual on Hold” notice will be sent out to sponsor and sites by Ozmosis Research Inc. 
once the study has recruited the required number of subjects per cohort. A Safety Cohort 
Review Meeting will take place between the Principal Investigator, the sponsor, the Data 
Safety Monitoring Committee (DSMC) and Ozmosis Research to review the patient safety 
data for each dose level.  After a decision is made by the sponsor, in collaboration with 
Ozmosis Research, based on the data submitted for a cohort regarding whether the study will 
be re-opened, a cohort will be expanded, or if there will be dose modification/escalation, etc., 
all applicable parties will be notified by Ozmosis Research.  This process for toxicity review 
and cohort view will continue to be repeated and followed until the MTD is reached. 
3.6 
Rationale for the Study Design and Doses  
Recurrent ovarian cancer is a universally fatal disease. See Background for details on the role 
of the immune system in ovarian cancer survival, for preliminary data on the results of 
checkpoint inhibitor trials in recurrent ovarian cancer, and the rationale for combining focal 
radiation therapy with checkpoint (PD-L1) inhibition.   
The 3+3+3 phase 1 design will be used to assess safety and tolerability as defined by DLTs 
and to identify the MTD of both durvalumab and focal irradiation when given as combination 
therapy to patients with platinum-resistant ovarian cancer.  
3.6.1 
Durvalumab 
The starting dose of durvalumab chosen for this trial is 1500 mg given intravenously (IV) 
every 28 day schedule (one cycle of treatment = 28 days). This is a standard fixed dose of 
durvalumab being studied in future trials of durvalumab, including other trials exploring the 
combination of durvalumab with focal radiotherapy (e.g.:NCT02639065).    
3.6.2 
Radiation Fractions 
Two radiation targets will be identified per patient.  Target selection is described in section 
6.2.1.  Inverse-planned, CT-simulated IMRT/VMAT will be delivered to both lesions on days 
-1, 1, and, 28 of Cycle 1 and day 1 of Cycle 2. (see Study Calendar, Section 5).  Where 
possible, radiation should precede administration of durvalumab on days when they are given 
together.     

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
36 
 
4. 
SUBJECT SELECTION CRITERIA 
The patient population should be selected without bias.  
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening. 
4.1 
Inclusion Criteria 
For inclusion in the study subjects should fulfill the following criteria: 
1. 
Provision of written informed consent prior to any study specific procedures 
2. 
Female patients aged 19 years and older 
3. 
Platinum-resistant (progression within 6 months of platinum based regimen) or 
platinum-refractory ovarian/fallopian tube/peritoneal origin.  
 High grade serous, endometrioid, clear cell, mucinous, malignant mixed 
Mullerian tumor, and low grade serous histotypes are permitted. Non-
epithelial tumours will not be permitted. 
4. 
ECOG performance status 0-1. 
5. 
No more than 2 lines of therapy in the platinum-resistant setting. 
6. 
No bowel obstructions within the preceding 6 months.  
7. 
Last radiation therapy treatment ≥3 months prior to enrollment. 
8. 
Expected survival >3 months. 
9. 
All patients much have at least one site of measurable disease as defined by 
RECIST criteria (v.1.1) [79]. 
10. 
All patients must have disease suitable for core biopsy and agree to study related 
biopsies. Disease suitable for biopsy can serve as radiation targets, but cannot be 
used for response assessment. 
11. 
All patients must have at least 2 additional sites of disease that serve are suitable 
radiation targets (see section 6.2.11). 
 Lesions suitable for radiation targeting must meet all of the following 
criteria: 
o each target must be > 4 cc in volume by standard imaging 
techniques, such as CT scan, MRI, or radiograph 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
37 
 
o for each lesion, partial treatment of a tumour mass is permitted, but 
the treatment volume cannot be less than the equivalent of a 2cm 
sphere (4cc) and the two targets cannot be part of the same 
contiguous mass  
o must be outside of  previously irradiated fields 
 
12. 
Adequate organ and marrow function as defined below within 14 days of cycle 1 
day 1 and prior to first dose of focal radiotherapy: 
 Absolute neutrophil count >1.5 x 109/L (1500 per mm3) 
 Platelets >100 x 109/L (100,000 per mm3) 
 Haemoglobin ≥9.0 g/dL (5.59 mmol/L) 
 Serum creatinine CL >40 mL/min by the Cockcroft-Gault formula [82]or by 
24-hour urine collection for determination of creatinine clearance: 
 
Females: Creatinine CL as calculated by Cockcroft-Gault Formula  
 
 
 
 
GFR = 1.04 x (140 - age in years) x weight (kg)  
 
 
 
 
serum creatinine (micromol/L) 
 
 
 Serum bilirubin ≤1.5 x upper limit of normal (ULN). This will not apply to 
patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinaemia that is predominantly unconjugated in the absence of 
evidence of haemolysis or hepatic pathology) who will be allowed in 
consultation with their physician. 
 AST and ALT ≤2.5 x ULN. 
4.2 
Exclusion Criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Subjects who cannot meet all the radiation planning constraints will not be eligible 
for this trial. 
2. 
Participation in another clinical study with an investigational agent during the last 4 
weeks. 
3. 
Concurrent enrolment in another clinical study, the only exception being 
observational (non-interventional) clinical studies. 
4. 
History of pneumonitis requiring treatment with steroids, or has a history of 
interstitial lung disease. 
5. 
Patients who have contraindications to receiving radiation therapy, such as: 
Rheumatoid Arthritis, connective tissue disorders, Lupus, scleroderma, CREST 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
38 
 
syndrome, Crohn’s syndrome, Ulcerative colitis, or other conditions identified by 
the Radiation Oncologist as unsuitable for radiation therapy. 
6. 
Current or prior use of immunosupressive medication within 28 days before the first 
dose of the study drug, with the exception of intra-nasal and inhaled corticosteroids 
or systemic corticosteroids at physiologic doses, which must not exceed 10 mg/day 
of prednisone, or an equivalent corticosteroid. 
7. 
Prior exposure to an anti-PD-1 or anti-PD-L1 antibody.(including durvalumab 
8. 
History of acute diverticulitis, intra-abdominal abscess, or GI obstruction. 
9. 
Previous severe hypersensitivity reaction to another monoclonal antibody (mAb). 
10. 
Active autoimmune disease or a documented history of autoimmune disease or 
syndrome that requires systemic steroids or immunosuppressive agents. Patients 
with Vitiligo, Grave’s disease or psoriasis not requiring systemic treatment (within 
the past 2 years) or those with resolved childhood asthma/atopy are not excluded. 
11. 
Uncontrolled intercurrent illness including: infection requiring therapy, 
symptomatic congestive heart failure, uncontrolled hypertension (systolic blood 
pressure > 150 and diastolic blood pressure >100), unstable angina pectoris, cardiac 
arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses. 
12. 
Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from using 
Frediricia’sCorrection.  
13. 
Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B 
Surface Antigen [HBsAg] reactive), or Hepatitis C virus (Hepatitis C Virus 
Ribonucleic Acid [HCV RNA] (qualitative) is detected).  
14. 
Previous clinical diagnosis of active tuberculosis. 
15. 
Receipt of a live attenuated vaccination within 30 days of study entry or within 30 
days or receiving the study drug.  
16. 
History of another malignancy, with the exception of: 
 
Malignancy treated with curative intent without evidence of recurrence for ≥ 5 
years 
 
Adequately treated non –melanoma skin cancer or lentigo maligna without 
evidence of disease 
 
Adequately treated carcinoma in situ without evidence of disease e.g. cervical 
carcinoma in situ 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
39 
 
17. 
 Female patients who are pregnant, breast-feeding or of childbearing potential who 
are not employing an effective method of birth control (see Table 3). 
18. 
 Any condition that, in the opinion of the investigator, would interfere with 
evaluation of the study drug or interpretation of patient safety or study.  
4.3 
Subject Enrollment and Registration 
All patients will be screened by one of the principal investigators or sub-investigators prior to 
entry into this study and before any study-specific procedures are performed. Procedures that 
are part of standard of care may occur before informed consent is obtained. An explanation of 
the study and discussion of the expected side effects and full disclosure of the “informed 
consent” document will take place. Eligible and consented patients will be registered into the 
study.  
 
At the time of screening, the Principal Investigator, or delegate, will refer the potential 
participant to a Radiation Oncologist for consultation and review to determine whether all 
radiation eligibility criteria have been met to initiate treatment planning for focal radiation 
therapy  (see Section 6.2). 
 
Registration will be done through Ozmosis Research Inc. Sites will assign each patient with a 
patient ID number which should be used on all documentation and correspondence.  
 
Prior to registering a patient, each institution must have submitted all necessary regulatory 
documentation to Ozmosis Research Inc. Access to the eCRFs will only be granted once this 
has been received. All sites should call Ozmosis Research Inc. Clinical Trials 
Manager/Specialist (CTM/CTS) at the number listed on the front page to verify study 
availability.  
 
No patient can receive protocol treatment until eligibility has been confirmed and the Patient 
Enrollment Fax has been submitted to Ozmosis Research Inc.  All eligibility criteria must be 
met at the time of enrollment. There will be no exceptions. Any questions should be addressed 
with Ozmosis Research Inc. prior to enrollment.  
 
The Patient Enrollment Fax must be completed, and signed by the investigator prior to 
enrollment of each patient. There are 2 sections to the Patient Enrollment Fax: 
 
 SCREENING (top section): This section is completed by the site and should be faxed 
to Ozmosis at 416-598-4382 at the time of screening. 
 
 ENROLLMENT (middle section): This section is completed by the site at the time of 
enrollment. The site will fax the signed and completed Patient Enrollment Fax to 
Ozmosis Research Inc. at 416-598-4382.  
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
40 
 
 CONFIRMATION OF REGISTRATION (bottom section): Ozmosis Research will 
assign the dose level and return a Confirmation of Registration to the site. Only after 
this has been received can the patient receive study drug. 
 
Protocol treatment should begin within 5 working days of patient registration. All eligible 
patients enrolled into the study will be entered into a patient registration log at Ozmosis 
Research Inc.  
The following information will be required at the time of registration: 
 Trial code  
 Treatment centre and investigator 
 Patient's initials and/or date of birth   
 Completed Patient Enrollment Checklist 
 
Note: It is the responsibility of the investigator in charge to satisfy him or herself that the 
patient is indeed eligible before requesting registration. 
 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
41 
 
5. 
STUDY CALENDAR 
 
 
 
 
Screening1 
Cycle 1 
Cycle 22 
Cycles 3+3 
End of Treatment4  
Follow-up  
Day of Treatment 
Within 28 days of 
C1D1 
D-2 
D-1 D1 
D5 
D15 
D27 
D28 
D1 
D15 
D 28 
D1 
D9 
D28 
±2 days after coming 
off treatment 
±7 days 
window 
Inclusion/ Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm diagnosis and disease 
status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent medications 
X 
 
 
Continuous assessment 
Vital signsa 
X 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
Medical oncologist physical exam 
& ECOGb 
X 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
Hematologyc 
X 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
Coagulationd 
X 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
Chemistrye 
X 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
Urinalysisf 
X 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
ECGg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
HIV testh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B & C test i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Durvalumab infusionk 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
Radiation oncologist reviewl 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
CT Simulationm 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Focal radiationn 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
Tumor measuremento 
X  
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
CA-125p 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Core needle biopsyq 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Peripheral blood for immune 
markersr 
X 
 
 
X 
 
X 
 
 
X 
X 
 
 
X 
 
 
X 
Adverse event evaluation 
 
 
Continuous assessment 
Survival statuss 
 
 
 
 
X 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
42 
 
 
1: Screening: to be performed within 28 days of C1D1 (unless otherwise indicated) and prior to the first dose of focal radiotherapy. Screening procedures 
performed within 72 hours of Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1. 
2:  All pre-treatment assessments as described in a, b, c, d, e, and f can be performed within 48 hours of the durvalumab infusion on day 1 and 15 of each 
cycle. 
3: Patients on treatment >12 months and deemed stable by the treating physician will be required to be seen within 48 hours of D1of each cycle.   
4: End of Treatment visit: Patients who complete study treatment or are discontinued from the study prematurely will complete the End of Treatment visit ±2 
days of coming off treatment. 
 
a: Vitals signs: systolic blood pressure (BP) and diastolic BP, pulse, respiratory rate, body temperature and oxygen saturation. Vitals will be performed within 
30 minutes prior to the start of durvalumab infusion and every 30±5 minutes during infusion and observation periods (1 hour for the first infusion and 
suggested 30 minutes after subsequent infusions provided no clinically significant infusion reactions are observed during or after the first cycle. Refer to 
section 6.1.6).  
b: Physical exam: Complete physical exam including height, weight and ECOG performance status. Height will only be measured at screening.   
c: Hematology: hemoglobin, hematocrit, RBC count, platelet count, absolute neutrophil count and differential WBC count  
d: Coagulation: prothrombin time, activated partial thromboplastin time (APTT) and international normalised ratio (INR).  
e: Chemistry: total protein, albumin, calcium, phosphorous, random plasma glucose, uric acid, creatinine, creatinine clearance, total bilirubin, ALP, sodium, 
potassium, magnesium, bicarbonate, chloride, AST, ALT and LDH.  
f: Urinalysis: specific gravity, pH and excretion of proteins, glucose, ketones and blood in the urine.  
g: 12-lead ECG: to be performed at screening and then as clinically indicated. 
h: HIV test: to be performed if not done in the last 6 months.  
i: Hepatitis B and C test: Hepatitis B (Hepatitis B Surface Antigen [HBsAg] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid [HCV RNA] 
(qualitative) will be performed if not done in the last 6 months.  
j: Serum pregnancy test (βHCG): for subjects of childbearing potential at screening and as clinically indicated. 
k: Durvalumab infusion: Patients enrolled in the study will receive durvalumab according to their assigned dose level by iv infusion q28d ±3 days for a 
maximum of 12 months.  
l: Review with Radiation Oncologist can be on day -2 or -1 as long as the review precedes radiation therapy  
m: CT simulation will occur approximately within 14 days  of day 1 of durvalumab Cycle 1 and Cycle 2.. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
43 
 
n: Focal radiation: For the first 2 doses of durvalumab, focal irradiation to the selected target lesions will be initiated 24-36 hours prior to infusion of 
durvalumab (i.e. on days -1 & 1 of cycle 1 and  day 28 of cycle 1 and day 1 of cycle 2) . Where possible, radiation should precede administration of 
durvalumab on days when they are given together.  
o: Tumour measurement: CT/MRI scans of the chest and abdomen will be performed within 28 days of C1D1 and prior to the first dose of focal radiotherapy.  
Tumour measurement will be repeated every 8 weeks (± 7 days) for the first 12 months after cycle 1 day 1 and every 12 weeks (± 7 days) thereafter until 
confirmed PD, irrespective of the reason for stopping study drug and/or subsequent therapy. 
p: CA-125: at screening and every  8 weeks (± 7 days) for the first 12 months after cycle 1 day 1 and every 12 weeks (± 7 days) thereafter until confirmed PD, 
irrespective of the reason for stopping study drug and/or subsequent therapy. For the purposes of assessing CA-125 response, there must be a baseline CA-125 
drawn within 14 days of starting therapy.  
q: Core needle   : A core needle biopsy on one of the target tumor lesions that is accessible and can be accomplished within reasonable safety will be 
performed at baseline (prior to starting focal radiation), cycle 1 day 5 for immune marker analysis.. Cycle 3 day 9 biopsy will be optional.  
r: Peripheral blood for immune marker analysis: A 30 mL peripheral blood sample will be obtained at baseline, cycle 1 day 15, cycle 2 day 1 and 15,and cycle 
3 day 9.  
s: All patients will be followed for late toxicity and survival status in clinic or by phone once every 3 months (± 7 days) for a maximum of 2 years.  

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
44 
 
6. 
STUDY TREATMENT 
6.1 
Durvalumab  
6.1.1 
Identity of investigational product(s) 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab to the investigator as a lyophilised powder for reconstitution. The saline solution 
for the matching placebo will be sourced locally. 
 
Investigational product 
Dosage form and strength 
Manufacturer 
durvalumab 
Durvalumab will be supplied in glass vials 
containing 500 mg of liquid solution at a 
concentration of 50 mg/mL for intravenous 
(IV) administration 
AstraZeneca 
 
 
 
 
6.1.2 
Product preparation of durvalumab 
 
The dose of investigational product for administration must be prepared by the investigator’s 
or site’s designated investigational product manager using aseptic technique. Commercially 
available water for injection and 0.9% (weight/volume) saline will be supplied by each site. 
Total in-use storage time from reconstitution of durvalumab to the start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2 to 8°C (36 to 46°F). If the 
in-use storage time exceeds these limits, a new dose must be prepared from new vials. 
durvalumab does not contain preservatives and any unused portion must be discarded. 
 
6.1.3 
Reconstitution of investigational product 
Durvalumab requires reconstitution prior to use. The reconstitution should be performed with 
4.0 mL sterile water for injection for each vial with the liquid added gently to the side of the 
vial to minimize product foaming. The vial should be gently rotated or swirled for 5 minutes 
or until dissolution is complete. The vial should not be shaken or vigorously agitated. 
Reconstituted durvalumab should stand undisturbed at room temperature for a minimum of  
5 minutes or until the solution clarifies. The reconstituted solution should appear clear or 
slightly opalescent. A thin layer of bubbles on the liquid surface is considered normal. 
 
6.1.4 
Preparation of durvalumab doses for administration with an IV bag 
Durvalumab 1500 mg will be administered using a 250 mL iv bag containing 0.9% 
(weight/volume) saline and delivered through an iv administration set with a 0.2-μm in-line 
filter. Dextrose may also be used as an alternate diluent. 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
45 
 
No incompatibilities between durvalumab and polyethylene, polypropylene, 
polyvinylchloride, or polyolefin copolymers have been observed. 
 
6.1.5 
Study drug administration 
Following preparation of durvalumab (see Section 6.1.2 – 6.1.4) the entire contents of the iv 
bag should be administered as an iv infusion over approximately 60 minutes (±5 minutes), 
using a 0.2-μm in-line filter. The iv line will be flushed with a volume of normal saline equal 
to the priming volume of the infusion set used after the contents of the iv bag are fully 
administered, or complete the infusion according to institutional policy to ensure the full dose 
is administered and document if the line was not flushed. Since the compatibility of 
durvalumab with other iv medications and solutions, other than normal saline (0.9% 
[weight/volume] sodium chloride for injection), is not known, the solution should not be 
infused through an iv line in which other solutions or medications are being administered. 
The date, start time, interruption, and completion time of study drug administration must be 
recorded in the source documents. 
 
6.1.6 
Monitoring of dose administration 
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the study calendar (section 5).  Patients will be observed for 1 hour after the 
first infusion of durvalumab. If no clinically significant infusion reactions are observed during 
or after the first cycle, a 30 minute observation period is suggested for subsequent infusions; 
however this is at the Investigator’s discretion. 
 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion. For patients with a ≤Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate. 
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications 
per institutional standard may be administered at the discretion of the investigator. If the 
infusion-related reaction is ≥Grade 3 or higher in severity, study drug will be discontinued. 
As with any antibody, allergic reactions to dose administration are possible. Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis. The study 
site must have immediate access to emergency resuscitation teams and equipment in addition 
to the ability to admit patients to an intensive care unit if necessary. 
 
6.1.7 
Management of toxicity 
The following general guidance should be followed for management of toxicities. 
 
1. Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity where required). 
 
2. If the symptoms promptly resolve with supportive care, consideration should be 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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given to continuing study drug along with appropriate continuing supportive care. 
If medically appropriate, dose modifications are permitted (see below). 
 
3. All dose modifications should be documented with clear reasoning and 
documentation of the approach taken. 
 
 
In addition, there are certain circumstances in which study drug should be permanently 
discontinued (see Appendix 1). 
 
6.1.8 Missed treatment doses 
Following the first infusion of study drug, subsequent administration of study drug can be 
modified based on toxicities observed as described in Appendix 1. All toxicities will be 
graded according to CTCAE Version 4.03. Dose reductions are not permitted. Treatment 
delays > 2 weeks will be permitted only after review and approval by the medical monitor. 
 
If during Cycles 1 or 2 a patient receives focal radiation without receiving the corresponding 
durvalumab dose for that dose level, there will be no make-up doses of the durvalumab. The 
patient may continue on therapy as scheduled assuming they remain eligible for treatment. 
 
Dose modifications will not be required for AEs that are clearly not attributed to study drug 
(such as an accident) or for laboratory abnormalities that are not deemed to be clinically 
significant. Dosing may continue despite concurrent vitiligo of any AE grade. 
 
6.1.9 Immune-related adverse events 
Based on the mechanism of action of durvalumab leading to T-cell activation and 
proliferation, there is the possibility of observing irAEs during the conduct of this study. 
Potential irAEs may be similar to those seen with the use of ipilimumab and nivolumab 
including immune-mediated enterocolitis, dermatitis, hepatitis, and endocrinopathies [43,83]. 
Patients should be monitored for signs and symptoms of irAEs. In the absence of an alternate 
aetiology (eg, infection or PD) signs or symptoms of enterocolitis, dermatitis, hepatitis, and 
endocrinopathy should be considered to be immune-related. 
 
Dose modification recommendations and toxicity management guidelines for immune-
mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions are 
detailed in Appendix 1. 
 
6.1.10 Durvalumab adverse events of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product.  
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
47 
 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy. An immune-related adverse event (irAE) is defined as an adverse 
event that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate aetiology. Serologic, immunologic, 
and histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the irAE.  
 
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
 
 Infusion-related Reactions 
 Diabetes Mellitus type I 
 Colitis 
 Pneumonitis 
 ALT/AST increases / hepatitis / hepatotoxicity  
 Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
 Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism, and hypopituitarism) 
 Dermatitis including rash and pruritis 
 Nephritis 
 Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased 
serum amylase)   
 Serious bleeding events 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab Investigator Brochure. 
 
6.1.10.1 
Pneumonitis 
Pneumonitis has been reported in association with the use of anti-PD-L1/anti-PD-1 antibodies 
[41] [42]. It is also seen in 5% to 15% of patients irradiated for breast, lung, and mediastinal 
tumours. The risk of developing radiation pneumonitis is directly related to the volume of 
irradiated lung, the amount of radiation given, and the use of concurrent chemotherapy. 
Additional risk factors include co-morbid lung disease, poor baseline pulmonary function 
testing, and low performance status.  
 
Symptoms of radiation pneumonitis, include low-grade fever, congestion, dry cough, pleuritic 
chest pain, and a sensation of chest fullness.  
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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Initial work-up should include high-resolution CT scan, ruling out infection, and pulse 
oximetry. Pulmonary consultation is highly recommended. Prednisone, in dosages of at least 
50 to 60 mg per day for 1 week followed by an extended taper, has been shown to abate 
symptoms and improve lung function. Bronchodilators and supplemental oxygen may be 
necessary.  
Guidelines for the management of subjects with immune-mediated events including 
pneumonitis are outlined in Appendix 1. 
6.1.10.2 
Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-
PD-L1 and anti-PD-1 therapy [42]. As with the administration of any foreign protein and/or 
other biologic agents, reactions following the infusion of MAbs can be caused by various 
mechanisms, including acute anaphylactic (immunoglobulin E-mediated) and anaphylactoid 
reactions against the MAb, and serum sickness. Acute allergic reactions may occur, may be 
severe, and may result in death. Acute allergic reactions may include hypotension, dyspnea, 
cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, arthralgia, 
bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, vomiting 
and unresponsiveness. 
Guidelines for management of subjects with hypersensitivity (including anaphylactic reaction) 
and infusion related reactions are outlined in Appendix 1. 
6.1.10.3 
Hepatic function abnormalities (hepatotoxicity) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies [42].  Inflammatory hepatitis has been reported in 3% to 9% of subjects treated 
with anti CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical manifestations of 
ipilimumab-treated subjects included general weakness, fatigue, nausea and/or mild fever and 
increased liver function tests such as AST, ALT, alkaline phosphatase, and/or total bilirubin. 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × 
ULN and concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent 
findings are those that derive from a single blood draw or from separate blood draws taken 
within 8 days of each other. Follow-up investigations and inquiries will be initiated promptly 
by the investigational site to determine whether the findings are reproducible and/or whether 
there is objective evidence that clearly supports causation by a disease (e.g., cholelithiasis and 
bile duct obstruction with distended gallbladder) or an agent other than the investigational 
product. Guidelines for management of subjects with hepatic function abnormality are 
outlined in Appendix 1. 
Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may need 
to be reported as SAEs, These cases should be reported as SAEs if, after evaluation they meet 
the criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of 
the SAE criteria. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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6.1.10.4 
Gastrointestinal disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimumab 
is used as monotherapy.  In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.  Guidelines on 
management of diarrhea and colitis in patients receiving durvalumab are provided in 
Appendix 1. 
6.1.10.5 
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- 
and hypothyroidism.  Guidelines for the management of patients with immune-mediated 
endocrine events are provided in Appendix 1. 
6.1.10.6 
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation.  Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Appendix 1. 
6.1.10.7 
Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of 
patients with immune-mediated neurotoxic events are provided in Appendix 1. 
6.1.10.8 
Nephritis 
Consult with Nephrologist.  Monitor for signs and symptoms that may be related to changes in 
renal function (e.g. routine urinalysis, elevated serum BUN and creatinine, decreased 
creatinine clearance, electrolyte imbalance, decrease in urine output, proteinuria, etc)  
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, infections etc.) 
Steroids should be considered in the absence of clear alternative etiology even for low grade 
events (Grade 2), in order to prevent potential progression to higher grade event.   Guidelines 
for the management of patients with immune-mediated neurotoxic events are provided in 
Appendix 1. 
6.1. 10.9 Serious Bleeding Events  
Serious bleeding events have been identified across 6 studies that enrolled patients with head 
and neck squamous cell carcinomas. Durvalumab alone was noted to cause serious bleeding 
events in 11 or 238 patients (4.6%) but when accounting for bleeding related to disease or 
alternative etiologist, the incidence of serious hemorrhage is 4/238 ( 1.7%). Durvalumab used 
with tremelimumab in 238 patients resulted in 14 cases of serious hemorrhage (6.9%), but the 
rate was lower (4/238, 2%) when alternative etiologies were accounted for. 

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Edition Number 1 
Date: June 5, 2017 
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Serious bleeding events much be managed in an emergent fashion, with appropriate medical 
evaluation, patient stabilization, reversal of underlying coagulopathies and emergent 
consultation with appropriate medical specialists to offer appropriate interventions to achieve 
control of bleeding (e.g. surgeons, interventional radiologists, intensive care physicians etc.). 
 
Criteria for Hy’s Law (FDA Guidance 2009) 
 
 The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo 
 
 Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 x ULN, one or more also show elevation of serum 
total bilirubin to >2 x ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
 
 No other reason can be found to explain the combination of increased aminotransferases 
and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or 
another drug capable of causing the observed injury. 
 
6.1.11 Labeling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. Label 
text will be translated into local language. 
 
The label will include the following information: 
 
 Name of sponsor  
 Study drug dosage form, route of administration, and quantity of dosage units 
 Storage conditions 
 Study code 
 Enrolment code 
 Directions for use 
 The name of the Principal Investigator, where applicable (this may be pre-printed or 
 added on the label when the study drug is dispensed) 
 The period of use eg, expiry date. 
 Product Lot Identifier 
 Medication Identity Number 
 For clinical study use only. 
 
 

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Edition Number 1 
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6.1.12 Storage 
All study drugs should be kept in a secure place under appropriate storage conditions and may 
only be dispensed by a pharmacist or a qualified designee. The investigational product label 
on the kit specifies the appropriate storage. durvalumab must be stored at 2°C to 8°C. 
 
6.2 Radiation Therapy 
 
6.2.1 Radiation Target Selection 
The function of radiotherapy in this study is to cause acute release of tumour antigen; response 
of the radiation target is not a primary endpoint of this study whereas safety and potential 
immunogenic tumour response are primary endpoints.  With these goals in mind, two 
radiographically identifiable target lesions will be selected by Radiation Oncologists with 
expertise in treatment of gynecologic cancers.  Target sites in the central nervous system and 
above the neck will not used.  The two targets must not be part of the same contiguous tumour 
mass.  Part or all of each target lesion may be treated but the minimal volume of each target 
that will be treated will be no smaller than the equivalent of a 2cm sphere (4cc); there is no 
upper limit on the size of each target as long as OAR constraints are met.   
GTV will be defined as tumour visible on diagnostic imaging (CT, MRI or PET-scan). 
Two Gross Target Volumes (GTV) will be defined, GTV1 and GTV2.  CTV will not be used. 
The part of each GTV which will be treated will be defined as GTV(t).  The part of GTV1 and 
GTV2 which will be treated will be designated GTV(t)1 and GTV(t)2, respectively. 
Planning Tumour Volume (PTV) margin of 1-5 mm will be added onto GTV (t 
) depending on the site of disease.  If a GTV(t) is >=5mm within the periphery of the tumor, 
then PTV margin may not be necessary to avoid geographical miss, in this case, PTV can be 
GTV(t).  A 5mm margin will be generally used.  The PTV’s associated with GTV1 and GTV2 
will be designated PTV1 and PTV2, respectively. 
Internal GTV (IGTV) can be defined for mobile lesions per institutional standard. 
6.2.2 Immobilization 
Immobilization devices will be tumor (GTV(t)) site specific, institutional standard for SABR. 
6.2.3 Pre-Treatment Simulation 
Simulation will be per institutional standard for SABR and potentially include: 
 
-4DCT for mobile lesions secondary to respiration. 
 
-Planning CT slice thickness <=2.5mm. 

Clinical Study Protocol 
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-IV contrast or fiducial markers at the discretion of the treating Radiation Oncologist  
6.2.4 Relevant Organs at Risk (OAR) 
The relevant OAR’s will depend on the location of the PTV’s. and will be outlined from the 
planning CT-scan. 
As a general rule, OAR’s within 5cm of the PTV’s should be contoured.   
Please refer to Appendix 5 for a list of structures that should be considered for different sites 
and for OAR constraints. 
6.2.5 Treatment Planning/Technique 
Each doublet of radiation fractions will be separately planned from 2 separate CT-simulations 
done in the 2 weeks prior to each doublet of radiation fractions. 
Radiotherapy will be inverse planned for IMRT/VMAT treatment per institutional standard 
for stereotactic body radiotherapy (SBRT). 
For BCCA, dose calculation algorithm will be type II only (Eclipse AAA or Acuros) with 
inhomogeneity corrections on.  Dose calculation grid in the treatment planning system (TPS) 
must be <=2.5.  
 
6.2.6 PTV Prescription Isodose 
Each patient will have 2 radiotherapy plans for the first and second doublet of 
radiotherapy fractions.  PTV prescription will be per protocol.  OAR constraints for 
each plan will be half of the 4-fraction OAR listed in Appendix 5 (see column for 
constraints to be used for each 2 fraction plan).   
i. For each target PTV, 95% isodose to cover 95% of the PTV (V95%=95%) 
ii. The RECIST defined response target lesion must receive < 25% of prescription dose 
(Dmax<25% prescription) 
iii. PTV hotspot<150%   
iv. All OAR’s will have a higher planning priority than the PTV’s. 
-Planning constraints i – iv about must be met in order for patients to be eligible for treatment. 
At the starting radiation dose, both PTV1 and PTV2 will receive 6Gy x 4 fractions (given as 
doublets) 24-36 hours prior to durvalumab (e.g., targets 1 and 2 will receive 6Gy of radiation 
on days -1 & 1 of Cycle 1, and on day 28 of cycle 1 and day 1 of Cycle 2). Where possible, 
radiation should precede administration of durvalumab on days when they are given together.  

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6.2.7 Treatment Verification and Imaging 
Pre-treatment cone beam CT-scan (CBCT) prior to each fraction.  
. 
6.2.8 Quality Assurance 
GTV, IGTV, PTV and all relevant OAR contours will be reviewed and signed off by a second 
radiation oncologist prior to treatment. 
Dose volume histogram parameters will be evaluated by the planning dosimetrist(s), 
physicist(s) and radiation oncologist(s).  
6.3 Concomitant Medications 
6.3.1 Permitted concomitant medications 
Investigators may prescribe concomitant medications or treatments (eg, acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” in Section 6.3.3  below. 
 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
Female patient of child-bearing potential 
 
Females of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least 1 highly effective method of contraception 
(Table 3) from the time of screening and must agree to continue using such 
precautions for 90 days after the last dose of durvalumab. Non-sterilised male 
partners of a female patient must use male condom plus spermicide throughout 
this period. Cessation of birth control after this point should be discussed with a 
responsible physician.  Not engaging in sexual activity for the total duration of 
the drug treatment and the drug washout period is an acceptable practice; 
however, periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of birth control.  Female patients should also refrain 
from breastfeeding throughout this period. 
Male patients with a female partner of childbearing potential 
 
Non-sterilized males who are sexually active with a female partner of 
childbearing potential must use a male condom plus spermicide from screening 
through 90 days after receipt of the final dose of durvalumab.  Not engaging in 
sexual activity is an acceptable practice; however, occasional abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of 
contraception.  Male patients should refrain from sperm donation throughout 
this period. 

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 
Female partners (of childbearing potential) of male patients must also use a 
highly effective method of contraception throughout this period (Table 3).   
N.B Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-
menopausal.   
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply:  
 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy). 
Highly effective methods of contraception, defined as one that results in a low failure rate (ie, 
less than 1% per year) when used consistently and correctly are described in Table 3.  Note 
that some contraception methods are not considered highly effective (e.g. male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills). 

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Table 3 
Highly Effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine methods 
Hormonal Methods 
 
Copper T intrauterine device 
 
Levonorgesterel-releasing intrauterine system 
(eg, Mirena®)a 
 
 
Etonogestrel implants: e.g. Implanon or 
Norplan 
 
Intravaginal device: e.g. ethinylestradiol 
and etonogestrel 
 
Medroxyprogesterone injection: e.g. 
Depo-Provera  
 
Normal and low dose combined oral 
contraceptive pill 
 
Norelgestromin/ethinylestradiol  
transdermal system 
 
Cerazette (desogestrel) 
a 
This is also considered a hormonal method 
 
6.3.2 Blood donation 
Subjects should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of durvalumab. 
6.3.3 Prohibited concomitant medications 
The following medications are not permitted during the study: 
 
 Any investigational anticancer therapy 
 
 Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal 
therapy for cancer treatment. Concurrent use of hormones for non cancer-related 
conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable. 
NOTE: Local treatment of isolated lesions, excluding target lesions, for palliative 
intent is acceptable (eg, by local surgery or radiotherapy). 
 
 Immunosuppressive medications including, but not limited to systemic 
corticosteroids at doses beyond 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumour necrosis factor alpha blockers. Use of 
immunosuppressive medications for the management of study drug-related AEs in 
patients with contrast allergies is acceptable. In addition, use of inhaled and 
intranasal corticosteroids is permitted. 
 
 Live attenuated vaccines within 30 days of dosing. Inactivated viruses such as those in 
the influenza vaccine are permitted. 
 

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Other medication, which is considered necessary for the patient’s safety and well-being, may 
be given at the discretion of the investigator and recorded in the appropriate sections of the 
eCRF. 
 
6.4 Treatment Compliance 
Treatment compliance will be assured by site reconciliation of medication dispensed. 
 
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF. The investigator or pharmacy must retain records of 
all study drugs administered. The study monitor will check these records to confirm the 
compliance with the protocol administration schedule. 
 
6.4.1 Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all study drugs dispensed to and returned from the 
patient. 
 
Study site personnel will account for all study drugs received at the site, unused study drugs 
and for appropriate destruction. Certificates of delivery and destruction should be signed. 
 
6.5 Premature Withdrawal/Discontinuation Criteria 
Patients may withdraw at any time. Patients who discontinue from the study will be 
encouraged to return for the End of Treatment visit.  
 
At the discretion of the Investigator, the investigator may remove a patient from the study (no 
more clinic visits except for End of Treatment and follow up if patient did not withdraw from 
further follow-up) for the following reasons:  
 
 
Patient decision. The patient is at any time free to discontinue treatment, 
without prejudice to further treatment. 
 
 
Adverse Event, that in the opinion of the investigator or the sponsor, 
contraindicates further dosing 
 
 
Severe non-compliance to study protocol that, in the opinion of the investigator 
or sponsor, warrants withdrawal; e.g., refusal to adhere to scheduled visits 
 
 
Patient is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing study drug might constitute a safety 
risk 
 
 
Initiation of alternative anticancer therapy including another investigational agent 
 

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 
Confirmed PD and investigator determination that the patient is no 
longer benefiting from treatment 
 
 
Pregnancy or intent to become pregnant. 
 
Disease progression requires confirmation. In the absence of clinically significant 
deterioration the investigational site is advised to continue the patient on study drug until 
progression has been confirmed.  If progression is not confirmed, then the patient should 
continue on study drug and on treatment assessments. 
 
6.5.1 Subject replacement rule 
Any patient who withdraws from the study within 28 days after cycle 1 day 1 for any reasons 
other than toxicity will be replaced. 
7 
STUDY PROCEDURES 
7.1 Study Visits 
7.1.1 Screening Visit 
The following procedures will be performed during the Screening Visit: 
 Informed Consent 
 Review of eligibility criteria 
 Medical history and demographics 
 Confirm diagnosis and disease status 
 Review of prior/concomitant medications  
 Vitals signs, weight and height  
 Complete physical exam  
 ECOG Performance Status 
 12-lead ECG (in triplicate [2-5 minutes apart]) 
 Clinical laboratory tests for: 
o Hematology (see Table 4) 
o Coagulation  
o Chemistry (see Table 6) 
o Urinalysis 
o HIV 
o Hepatitis B & C 
o Serum pregnancy test (for women of childbearing potential only) 
o Imaging by CT/MRI 
o CA-125 

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o Core needle biopsy (refer to Section 8.3) 
o Peripheral blood for immune markers (refer to Section 8.3) 
 
7.1.2 Treatment Phase  
Procedures to be conducted during the treatment phase of the study are presented in the Study 
Calendar.  Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) do not need to 
be repeated on C1D1. 
 
7.1.3 End of Treatment   
End of treatment is defined as the last planned dosing visit within the 12-month dosing period. 
For subjects who discontinue durvalumab prior to 12 months, end of treatment is considered 
the last visit where the decision is made to discontinue treatment. Patients who complete study 
treatment or are discontinued from the study prematurely will complete the End of Treatment 
visit ± 2 days of coming off treatment.  
All patients will be followed for survival status in clinic or by phone once every 3 months (± 7 
days) for a maximum of 2 years. 
7.2 Description of study procedures 
7.2.1 Physical examination, electrocardiogram, and vital signs 
Physical examinations will be performed on study days noted in the Study Calendar 
A complete physical examination will be performed and will include an assessment of the 
following (as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 
skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-
skeletal (including spine and extremities), genital/rectal, and neurological systems and at 
screening only, height.   
 
An ECG is required during screening and then as clinically indicated during the study.  
 
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on 
study days noted in the Study Calendar. Vitals will be performed within 30 minutes prior to 
the start of durvalumab infusion and every 30±5 minutes during infusion and observation 
periods (1 hour for the first infusion and suggested 30 minutes after subsequent infusions 
provided no clinically significant infusion reactions are observed during or after the first 
cycle. Refer to section 6.1.6)  
 
7.2.2 Clinical laboratory tests 
The following clinical laboratory tests will be performed (see the Study Calendar): 

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 Coagulation parameters:  
o 
prothrombin time, activated partial thromboplastin time (APTT) and international normalised 
ratio (INR).  
 Pregnancy test (female subjects of childbearing potential only):  
o 
Serum beta-human chorionic gonadotropin  
 Other laboratory tests 
o 
Hepatitis B Surface Antigen [HBsAg] reactive  or Hepatitis C Virus Ribonucleic Acid [HCV 
RNA] (qualitative) 
o 
HIV antibody 
o 
CA-125 
 
Table 4. Hematology Laboratory Tests 
Hemoglobin 
Absolute neutrophil count 
Hematocrit 
Differential WBC count 
RBC count 
 
Platelet count 
 
 
Table 5. Clinical chemistry  Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 
Alanine aminotransferase 
 
 
Magnesium 
Aspartate aminotransferase 
Potassium 
Bicarbonate 
Sodium 
Calcium  
Total bilirubin 
Chloride 
Total protein 
Creatinine 
Phosphorus  
Creatinine clearance 
Uric acid 
 

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Table 6. Urinalysis Tests 
 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
 
8 
MEASUREMENT OF DRUG EFFECT 
8.1 Safety Assessment 
The adverse effects durvalumab and radiotherapy will be assessed for dose limiting toxicities, 
AEs, vital signs and by clinically significant changes in the laboratory evaluations and ECGs.  
AEs will use the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE). This study will utilize the CTCAE 
Version 4.03 for adverse event reporting.  
8.2 Efficacy Assessment 
 
8.2.1 RECIST 1.1 Criteria 
RECIST 1.1 criteria will be used to assess patient response to treatment by determining ORR 
and PFS.  The RECIST 1.1 guidelines for measurable, non-measurable, target and non-target 
lesions and the objective tumour response criteria (CR, PR, NED, SD or PD) are presented in 
Appendix 2. 
 
The methods of assessment of tumour burden used at baseline CT/MRI scans of the chest 
and abdomen (including liver and adrenal glands) must be used at each subsequent follow-
up assessment. Additional anatomy should be imaged based on signs and symptoms of 
individual patients, including new lesions at follow-up. 
 
Efficacy for all patients will be assessed by objective tumour assessments every 8 weeks 
for the first 12 months (relative to the date of cycle 1 day 1), then every 12 weeks thereafter  
until confirmed objective disease progression as defined by RECIST 1.1 (irrespective of 
the reason for stopping study drug and/or subsequent therapy).  If an unscheduled 
assessment is performed, and the patient has not progressed, every attempt should be made 
to perform the subsequent assessments at their scheduled visits. 
 
Patients who achieve and maintain disease control (ie, CR, PR, NED, or SD) through to the 
end of the 12-month treatment period may restart treatment with study drug upon evidence 
of PD (according to RECIST 1.1), with or without confirmation, during follow-up. To 
restart study drug the patient must not have received an intervening systemic anti-cancer 

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therapy post-study drug discontinuation.  Patients who restart study drug must have a 
baseline tumour assessment within 28 days of restarting study drug, all further scans should 
occur every 8 weeks (relative to the date of restarting study drug) (maximum of 12 months 
of further treatment). 
 
For patients who discontinue study drug due to toxicity or a reason other than confirmed PD, 
objective tumour assessments should be continued every 8 weeks for 12 months (relative to 
the date of cycle 1 day 1) then every 12 weeks thereafter until confirmed objective disease  
progression. 
 
Disease progression requires confirmation, the confirmatory scan should occur preferably at 
the next scheduled visit and no earlier than 4 weeks after the initial assessment of PD in the 
absence of clinically significant deterioration.  A biopsy (optional biopsy at suspected 
progression) may assist with the differentiation of malignant tumour from post-radiation 
changes and may be of assistance at the investigator sit in confirming the malignant origin of 
regrowth within the radiation field. However, confirmatory radiological assessments should 
still be performed at the next schedule visit to confirm radiological progression.  
 
Administration of study drug will continue between the initial assessment of progression and 
confirmation for progression. For all patients who are treated through progression and patients 
who achieve disease control and restart study drug upon evidence of PD (according to 
RECIST 1.1) during follow-up, the investigator should ensure patients do not have any 
significant, unacceptable or irreversible toxicities that indicate continuing treatment will not 
further benefit the patient, and that the patient still meets all of the inclusion criteria and none 
of the exclusion criteria for this study including re-consenting to continue or restart treatment. 
Patients with rapid tumour progression or with symptomatic progression that requires urgent 
medical intervention (e.g., central nervous system metastasis, respiratory failure due to tumour 
compression, spinal cord compression) will not be eligible to continue to receive study drug. 
Progression, would be considered confirmed if the following RECIST 1.1 criteria are met: 
 
≥20% increase in the sum diameters of target lesions compared with the nadir 
at 2 consecutive visits with an absolute increase of at least 5 mm 
 
The assessment of progression of ≥20% increase in the sum diameters of target 
lesions compared with the nadir is at the first progression time point relative to 
the nadir (the smallest sum of diameters and this may be at baseline or 
subsequent follow-up visit).  The confirmed scan confirms the persistence of the 
≥20% increase relative to the nadir 
 
and/or significant progression (worsening) of non-target lesions or new lesions 
at the confirmatory PD time-point compared with the first time point where 
progression of non-target lesions or new lesions identified 
 
 
and/or additional new unequivocal lesions at the confirmatory PD time-
point compared with the first time point new lesions identified. 
 

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In the absence of clinically significant deterioration the investigator should continue 
the patient on study drug until progression is confirmed. 
If progression is not confirmed, then the patient should continue study drug and on 
treatment assessments. 
If a patient discontinues study drug (and/or receives a subsequent cancer therapy) prior 
to progression then the patient should still continue to be followed until confirmed 
objective disease progression. 
Categorizationz of objective tumour response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD and PD.  Patients with no evidence of disease at follow-up 
in the absence of new lesions will be assigned a response of NED. Target lesion progression 
will be calculated in comparison to when the tumour burden was at a minimum (ie, smallest 
sum of diameters previously recorded on study).  In the absence of progression, tumour 
response (CR, PR) and SD will be calculated in comparison to the baseline tumour 
measurements obtained before starting study drug. 
If the investigator is in doubt as to whether progression has occurred, particularly with 
response to non-target lesion or the appearance of a new lesion, it is advisable to continue 
study drug until the next scheduled assessment or sooner if clinically indicated and reassess 
the patient’s status.  If repeat scans confirm progression, then the date of the initial scan 
should be declared as the date of progression. 
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of 
SD or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to quality for unequivocal progression status. 
Following confirmed progression, patients should continue to be followed up for 
survival every 3 months as outlined in the study calendar.  An exception is patients with 
confirmed PD that continue to receive study drug at the discretion of the investigator 
(following consultation with the sponsor); these patients can receive study drug for a 
maximum of 12 months and will have scans every 8 weeks until study drug is stopped. 
Study drug should be discontinued if there is confirmed progression of disease (PD) 
following a previous response (PR or CR) to study drug. 
 
8.2.2 Gynecological Cancer Intergroup (GCIG) Guidelines for Response Using CA125 
 
To be evaluable for response by CA125 requires two pretreatment samples at least twice 
the upper limit of normal and at least two additional samples after the start of treatment. 
A response to CA125 has occurred if after two elevated levels before therapy there is at 
least a 50% decrease that it is confirmed by a fourth sample [80]. The four samples must 
satisfy the following criteria: 
 

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1. The two pretreatment samples must both be at least twice the upper limit of 
normal and at least 1 day but not more than 3 months apart. 
2. At least one of the two pretreatment samples should be within 2 weeks of 
starting treatment. 
3. The third sample must be ≤ 50% of the second sample. 
4. The confirmatory fourth sample must be ≥ 21 days after sample 3. 
 
Patients are not evaluable by CA 125 if they have received mouse antibodies or if there has 
been medical or surgical interference with their peritoneum or pleura during the previous 
28 days. Patients who have a fall of CA 125 to within the reference range but whose initial 
CA 125 was less than twice the upper limit of the reference range have not had a CA 125 
response and cannot therefore be classified as a CA 125 complete responder. 
 
CA125 response is defined as a 50% reduction in level from a pre-treatment sample. The 
response must be confirmed and maintained for at least 28 days. The date when CA125 
level is first reduced is the date of the CA125 response. Appendix 4 summarized how 
CA125 response is incorporated into response assessment when measurable disease is also 
present. 
 
8.2.3 Immune-related Response Criteria (irRC) 
 
The assessment of the effect of cytotoxic agents has utilized the Response Evaluation Criteria 
in Solid Tumours (RECIST) and the World Health Organization (WHO); however, responses 
to immunotherapeutic agents may occur after disease progression as defined by assessment 
methods used for cytotoxic agents.  A novel method of assessment has been specifically 
adapted for immunotherapeutic agents.  
 
The immune-related response criteria (irRC) is intended to address the response patterns 
observed with immunotherapeutic agents [81]. The irRC is outlined further in Appendix 4. 
Response to therapy will be reported by irRC in addition to RECIST 1.1 criteria. 
8.3 Exploratory Samples 
 
All patients must be available and agree to have a core biopsy performed at pretreatment and 
on Cycle 1 day 5, on one of the target tumor lesions that is accessible and can be 
accomplished within reasonable safety.  The lesion chosen for biopsy can also be chosen as a 
radiation target. A Cycle 3 day 9 biopsy is optional. Core biopsies will be processed for 
immune marker analysis.   
 
A pre-treatment blood sample (100 mL = 10 heparin (green) + 1 SST (tiger) + 1 PST (green 
tiger)) will be obtained during the screening period. Subsequent post-treatment blood samples 
will be collected as follows: Day 5 (50 mL), Day 15 (30 mL), Cycle 2 Day 1 (30 mL), Cycle 2 
Day 15 (50 mL), Cycle 3 Day 9 (50 mL) and follow-up at the end of the study (50 mL).  All 
50 mL collections will be done as: 5 heparin (green) + 1 SST (tiger) + 1 PST (green tiger). 

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Primary preference will be a biopsy from a radiation target lesion and secondary preference to 
another non-targeted metastatic lesion including ascites. 
 
Ascites collection will be performed whenever possible. 
 
Blood specimens will be processed into serum, plasma and peripheral blood mononuclear 
cells (PBMCs) and cryopreserved in vapour nitrogen until analysis. Whenever possible, 
tumor-infiltrating lymphocytes (TILs) or tumor-associated lymphocytes (TALs) will be 
harvested and expanded by standard protocols and cryopreserved for further assessment of 
tumor-reactive T cells. 
 
Exploratory objectives  
Outcome measures 
1. To collect blood and tissue samples for 
analysis of immune biomarkers 
Biomarker analysis to assess exploratory 
markers include but are not limited to: 
immune cell gene expression profiles in the 
peripheral blood and tumor, frequency of 
lymphocyte subsets as defined by cell surface 
markers, presence of functional markers of 
immune activity, tumor associated antibodies 
2. To investigate the relationship between 
the presence or absence and spatial 
distribution of lymphocyte subsets within 
the tumor microenvironment and 
outcomes 
Tumor and tumor associated expression of 
immune checkpoints and their spatial 
distribution within the tumor 
microenvironment relative to OS, PFS, ORR 
3. To explore biomarkers of radiation and 
durvalumab and efficacy 
Biomarkers in the serum and tumor before 
and after treatment will be assessed and 
correlated with response to treatment and/or 
tumor progression  
4. To analyze biomarkers (e.g. immune, 
tumor) in different cellular compartments 
(e.g. tumor, immune, serum, blood) which 
may influence and/or prospectively 
identify patients likely to respond to 
treatment 
 
Correlate expression of biomarkers with 
response to treatment and/or progression 
For items 1-4 above, the following analysis will be performed on the respective tissues/blood 
specimens: 
Profiling of PBMCs: This will include standard flow cytometric analysis of 
lymphocyte subsets.  We will use panel established by the Human Immunology 
Consortium Project (as well as additional in-house markers) to enumerate the 
frequency of lymphocytes before and at various time points post-treatment. In 
particular, we will assess for the frequency of PD-1 positive cells. We will also 
perform T cell receptor beta sequencing (TCR-seq) on tumor-reactive CD8+ and 

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CD4+ T cells. In some cases, we will conduct tetramer analysis to common ovarian 
cancer testis antigens (e.g. NY-ESO-1). 
Serum: We will measure serum markers for immunogenic cell death following 
radiation. This will be assessed by a standard commercial ELISA kit. An assessment of 
new reactive antibodies before and after treatment will also be conducted against 
tumor cell lysates. 
Plasma:  Using protocols established, we will assess for circulating tumor DNA and 
RNA (whenever feasible based on quality of material) to identify mutations that are 
present in both the primary and secondary tumor.  These tumor specific mutations will 
be tracked over the duration of the treatment to ascertain the frequency of mutation 
specific T cells in the periphery and TIL. 
Tumor:  We will assess the presence or absence of different lymphocyte subsets and 
their geographic localization within the tumor by multi-parametric immunostaining (up 
to 5 markers per section). This analysis will include expression of PD-L1 and PD-1.  A 
complete RNA profile will be measured NanoString nCounter Pan Cancer Immune 
Profiling Panel which will include additional markers. 
All of the studies above will be correlated with response to therapy to identify signatures of 
response.  
9 
SAFETY AND REPORTING REQUIREMENTS 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
A DSMC will be formed to review the all DLTs and SAEs and oversee the conduct of the 
trial. The Principal Investigator and 2 independent clinicians will constitute the DSMC. Each 
should have experience in clinical trials, specifically phase I trials. At least one member will 
have experience with immunotherapy and at least one member will have experience with 
radiation therapy. 
9.1 Definition of Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product during the course of a study and which does not necessarily have to 
have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational product, whether or not 
considered related to the medicinal product. 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of 
the product are not considered AEs after administration of the study product unless they 

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reoccur after the subject has recovered from the pre-existing condition or they represent an 
exacerbation in intensity or frequency.  
A laboratory test abnormality considered clinically relevant (e.g. causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations) or 
judged relevant by the Investigator should be reported as an adverse event.   
9.2 Adverse Event Documentation 
Adverse events will use the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE). This study will utilize the CTCAE 
Version 4.03 for adverse event reporting.  
All AEs must be recorded on case report forms (CRFs). Documentation must be supported by 
an entry in the subject’s file.  Each event should be described in detail along with start and 
stop dates, severity, relationship to investigational product as judged by the Investigator, 
action taken and outcome. 
9.3 Definitions of Serious Adverse Event 
A serious adverse event is an AE occurring at any dose that fulfils one or more of the 
following criteria: 
Results in death 
Is immediately life-threatening 
Requires in-patient hospitalization or prolongation of existing hospitalization  
Results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions 
Is a congenital abnormality or birth defect 
Is an important medical event that may not be immediately life threatening or result in death 
or hospitalization, but may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above (example: intensive treatment in an 
emergency room or at home for bronchospasm, convulsions that do not result in 
hospitalization). Medical and scientific judgment should be exercised in deciding whether 
some events should be considered as serious because their quick reporting to the sponsor may 
be of interest for the overall conduct of the study. 
Hospitalization: Any adverse event leading to hospitalization or prolongation of 
hospitalization will be considered as Serious, UNLESS at least one of the following 
exceptions are met: 
 The admission results in a hospital stay of less than 12 hours; or  

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 The admission is pre-planned (i.e., elective or scheduled surgery arranged 
prior to the start of the study or for prophylactic insertion of a gastric 
feeding tube); or   
 The admission is not associated with an adverse event (eg, social 
hospitalization for purposes of respite care). 
However it should be noted that invasive treatment during any hospitalization may fulfil the 
criteria of ‘medically important’ and as such may be reportable as a serious adverse 
event dependent on clinical judgment.  In addition where local regulatory 
authorities specifically require a more stringent definition, the local regulation takes 
precedent. 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
Important medical event: Any adverse event may be considered serious because it may 
jeopardize the subject and may require intervention to prevent another serious 
condition.  
Any death (regardless of cause except if death is due to PD) that occurs from the time of 
administration of the first dose of study therapy until 90 days after the final administration of 
the study drug, and any death occurring after this time that is judged at least possibly related 
to prior treatment with the study drug, will be promptly reported. Death due to PD does not 
need to be reported as a SAE. 
Progressive disease will not be reportable as an SAE in this study. Progression of the underlying 
malignancy is not reported as an adverse event if it is clearly consistent with the suspected 
progression of the underlying cancer and this PD must be documented clearly in the patient’s 
source documents. Clinical symptoms of progression may be reported as an adverse event if the 
symptom cannot be determined as exclusively due to the progression of the underlying 
malignancy or does not fit the expected pattern of progression for the disease under study. If there 
is any uncertainty of an adverse event being due only to the study disease, it should be reported as 
an AE or SAE. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated on the SAE report.  
9.4 Reporting of Serious Adverse Events 
All SAEs defined as per ICH guidelines (see below) and other adverse events must be 
recorded on case report forms. In addition, all serious adverse events must be reported by 
using the SAE form and must be submitted to Ozmosis Research Inc.  
Serious Adverse Event Reporting Instructions 

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All serious adverse events must be reported as follows: 
Within 24 hours: 
Report initial information (on trial specific SAE report form) by 
fax to: 
Ozmosis Research Inc.  
Phone: 416-673-6522 
Fax:  416-598-4382 
 
The initial information should always contain:  
- 
Name of Reporter/Investigator,  
- 
Subject Identification,  
 
- 
Adverse Event Term,  
- 
Study Drug Dose and Start/Stop Dates 
 
On the next working day: 
Fax completed trial-specific Serious Adverse Event form  
 
9.5 Reporting of Adverse Events of Special Interest 
The following AESIs will be subject to the same reporting procedures as described in Section 
8.4: 
 
 Colitis 
 Pneumonitis 
 ALT/AST increases / hepatitis / hepatotoxicity  
 Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
 Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
 Dermatitis 
 Nephritis 
 Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased 
serum amylase)   
 
9.6 Procedure for Expedited Reporting 
9.6.1 Responsibility for Reporting Serious Adverse Events to Health Canada 
Ozmosis Research Inc. will provide expedited reports of SAEs to Health Canada according to 
applicable guidelines and regulations (including the 7-day notification for death and life-
threatening events), i.e. events which are BOTH serious AND unexpected, AND which are 
thought to be related to protocol treatment (or for which a causal relationship with protocol 
treatment cannot be ruled out). 

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9.6.2 Responsibility for Reporting Serious Adverse Events to Drug AstraZeneca 
Ozmosis Research Inc. will be responsible for submitting SAE (Initial and/or Follow-up 
reports) and AESIs to Astra Zeneca using the Ozmosis SAE form. The SAE form must be 
faxed to 1-800-267-5743  at the latest by 15 days after the investigator is made aware of the 
SAE. The foregoing is applicable to all SAEs, irrespective of causality.   
9.6.3 Reporting Serious Adverse Events to Local Research Ethics Boards 
Ozmosis Research Inc. will notify all Investigators of all Serious Adverse Events that are 
reportable to regulatory authorities in Canada from this trial or from other clinical trials 
involving durvalumab as reported to AstraZeneca. This includes all serious events that are 
unexpected and related to protocol treatment. Investigators must notify their Research Ethics 
Boards (REBs) and file the report with their Investigator Site File. Documentation that serious 
adverse events (SAEs) have been reported to REBs must be kept on file at Ozmosis Research 
Inc.  
Documentation can be any of the following:  
 letter from the REB acknowledging receipt 
 stamp from the REB, signed and dated by REB chair, acknowledging receipt 
 letter demonstrating the SAE was sent to the board 
 
All expedited serious adverse events occurring within a centre should also be reported to local 
REBs. 
9.6.4 Overdose 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that specified in the 
Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, is required to 
be reported within 24 hours of knowledge of the event to Ozmosis Research, who will in turn notify 
the sponsor and AstraZeneca (using the designated mailbox 
AEMailboxClinicalTrialTCS@astrazeneca.com) . If the overdose results in an AE, the AE must also 
be recorded as an AE (see Section 8.2). Overdose does not automatically make an AE serious, but if 
the consequences of the overdose are serious, for example death or hospitalization, the event is serious 
and must be recorded and reported as an SAE (see Section 8.4). There is currently no specific 
treatment in the event of an overdose of durvalumab. The investigator will use clinical judgment to 
treat any overdose. 
 
9.6.5 Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 6.1.9.3) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” within 24 
hours of knowledge of the event to Ozmosis Research who will in turn notify the sponsor and 
AstraZeneca (using the designated mailbox AEMailboxClinicalTrialTCS@astrazeneca.com), unless a 

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definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is 
unrelated to investigational product has been confirmed. 
 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated 
to investigational product, the decision to continue dosing of the study subject will be based on 
the clinical judgment of the investigator. 
 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and evaluated 
by the sponsor.  
 
9.6.6  Pregnancy and Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.   
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform Ozmosis Research within 24 hours of when he or she becomes aware of it.  
Ozmosis will in turn notify the sponsor and AstraZeneca (using the designated mailbox 
AEMailboxClinicalTrialTCS@astrazeneca.com). 
9.6.7  Pregnancy and Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab monotherapy.   
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 90 days after the last 
dose should, if possible, be followed up and documented.   
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner.  Therefore, the local study 

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team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.   
9.7 Follow Up of Adverse and Serious Adverse Events 
For the SAEs that have been deemed by the investigator as unrelated to protocol treatment, the 
SAE reporting period begins after patient signs informed consent and ends 90 days after 
discontinuation of the study drug.  For the SAEs that have been deemed by the investigator as 
at least possibly related to protocol treatment, the SAE must be reported even if this occurs 30 
days after discontinuation of the study drug.   
SAEs that occur prior to dosing will not be reported in an expedited fashion to any health 
authority, and will be summarized and described in the clinical study report.  The investigator 
shall provide follow-up information as and when available in a new follow-up SAE form.  All 
SAEs must be followed until resolved, become chronic, or stable unless the subject is lost to 
follow up. Resolution status of such an event should be documented on the eCRF.  
The eCRF should capture all AEs occurring from the first dose of focal radiation until 30 days 
after discontinuation of the study drug. In addition, any known untoward event of any severity 
that occurs subsequent to the AE reporting period that the Investigator assesses as at least 
possibly related to the study therapy (i.e., the relationship cannot be ruled out) should also be 
reported as an AE. 
9.8 Relationship 
For all AEs, relationship to study drug will be reported on the appropriate AE eCRF page. The 
PI must judge whether the study drug caused or contributed to the AE in which case it is 
considered to be an ADR, and report it as either: 
Related (definitely, probably or possibly): there is a reasonable possibility that the study 
drug caused or contributed to the AE; this conclusion may be supported by the following 
observations, though these are not required for the determination of relatedness: 
 There is a plausible time sequence between onset of the AE and study drug 
administration; 
 There is a plausible biological mechanism through which study drug may 
have caused or contributed to the AE; 
Not related: It is highly unlikely or impossible that the study drug caused or contributed to 
the AE; this conclusion may be supported by the following observations, though these are not 
required for a determination of not related: 
 another cause of the AE is evident and most plausible; 
 the temporal sequence is inconsistent between the onset of the AE and study drug 
administration; a causal relationship is considered biologically implausible; 

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10 ETHICAL AND REGULATORY REQUIREMENTS 
10.1 Informed Consent 
Subject / Legally acceptable representative (LAR) (as applicable) consent must be obtained 
according to local Institutional and/or University Human Experimentation Committee 
requirements prior to any study-specific screening procedures. It will be the responsibility of 
the local participating investigator to obtain the necessary clearance, and to indicate in writing 
to Ozmosis Research Inc. that such clearance has been obtained, before the trial can 
commence at that centre. Sample English consent forms for the trial will be provided. A copy 
of the initial full board REB approval and approved consent form must be sent to Ozmosis 
Research Inc. The subject/LAR must sign consent prior to registration.  
10.2 Ethics Board Approval  
Each participating centre will have on file with Ozmosis Research Inc., a list indicating the 
composition of its REB consistent with Canadian (applicable) regulatory guidelines. This list 
will be updated as appropriate.  
For Canadian sites, a Health Canada REB Attestation Form must be completed and signed by 
the REB representative. Alternatively, an attestation may be included in the signed local ethics 
approval document. This documentation must be received by Ozmosis Research Inc. before 
the centre can be locally activated. 
Initial approval: All study sites are required to obtain full board local ethics approval of the 
protocol and consent form by the appropriate REB prior to commencement of the clinical trial 
at each site. 
Continuing approval: Annual (or as required by the REB) re-approval may be required for as 
long as subjects are being followed on protocol. It will be investigator’s responsibility to apply 
for and obtain the re-approval. 
Amendment: All protocol amendments will be confirmed in writing and submitted, as 
appropriate, for review by the REB and health authorities.  Amendments will be reviewed and 
approved by applicable regulatory authorities prior to central implementation of the 
amendment, and by REBs prior to local implementation, EXCEPT when the amendment 
eliminates an immediate hazard to clinical trial subjects or when the change(s) involves only 
logistical or administrative aspects of the trial. 
REB Refusals: If an REB refuses to approve this protocol (or an amendment/revision to this 
protocol), Ozmosis Research Inc. must be notified immediately of the date of refusal and the 
reason(s) for the refusal. Notification will then be made to Health Canada. 
Serious Adverse Events, Safety Updates and Investigator Brochure Updates: During the 
course of the study serious adverse events, safety updates or investigator brochure updates 

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may be sent to you for reporting to your REB. If/when this occurs, documentation of REB 
submission of this information must be forwarded to Ozmosis Research Inc. 
11 EVALUATION AND CALCULATION OF VARIABLES 
The primary objective of this trial is to assess the safety and tolerability of durvalumab 
combined with focal radiotherapy, and hence determine the MTD of this combination. Safety 
endpoints will include DLTs, AEs, SAEs and deaths.  
Secondary endpoints will include clinical measures of treatment outcome: ORR (as measured 
by RECIST v 1.1, GCIG CA125 response, and immune related response criteria), PFS and 
OS.  
11.1 
Calculation or derivation of safety variable(s) 
11.1.1 Exposure to investigational product 
 
The total time on study treatment, as well as total exposure to study treatment and amount 
delivered relative to intended amount will be summarized for the radiation and the 
durvalumab components.  
 
11.1.2  Adverse events, laboratory changes, vital signs 
Safety profiles will be assessed in terms of AEs and laboratory data, vital signs, and ECG data 
that will be collected for all patients. Treatment-emergent AEs are defined as any AE which 
initiates on or after the first day of study drug up through 30 days after study drug 
discontinuation.  
 
11.1.3  Other significant adverse events (OAE) 
 
The DSMC and Ozmosis Inc. will routinely review the list of AEs that were not reported as 
SAEs or as AEs leading to discontinuation of treatment. Based on judgment, AEs of particular 
clinical importance may, after consultation with the DSMC, be considered an other adverse 
event (OAE) and reported as such in the study report. A similar review of laboratory, ECG 
and vital sign data will be performed for identification of OAEs. Examples of these are 
marked haematological and other laboratory abnormalities, and certain events that lead to 
intervention (other than those already classified as serious), dose reduction or significant 
additional treatment. 
11.2 
Calculation or derivation of efficacy variable(s) 
ORR will be determined using the evaluable patient population. ORR is defined by the 
percentage of patients who have at least one assessment demonstrating CR or PR prior to 
evidence of disease progression. The best overall response designation (per RECIST V 1.1) 
recorded between the date of the start of trial therapy (day -1, the first day of radiation 

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therapy) and the date of objectively documented disease progression, or study cessation, 
whichever occurs first. Each patient will be assigned a RECIST response of CR, PR, SD, or 
PD depending on the status of their disease compared to baseline and previous assessments. 
The ORR will be the proportion of patients achieving CR or PR as the best response to 
therapy. Radiation target lesions will not be suitable for assessing RECIST response, and will 
not be eligible to be used as baseline target lesions for RECIST based assessment of response. 
GCIC CA125 response will be determined and Immune-Mediated RECIST response criteria 
will also be reported.  
PFS, for the evaluable study population, will be determined from the start of trial treatment 
(day -1, as the first day of radiation therapy) to the date of RECIST 1.1 defined progression or 
death (by any cause in the absence of progression). Those who are alive without disease 
progression follow up will be censored at the date of the last disease assessment without 
progression.  DoR, for the evaluable study population, will be calculated, using the time from 
documented disease response to disease progression, and will be reported for the entire study 
population. OS will be calculated from the date of the start of trial therapy (day -1, as the first 
day of radiation therapy) to the date of death from any cause. Patients lost to follow up, or 
who do not have documentation of death at the time of the final analysis will be censored at 
the date of last assessment. 
12 STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
12.1 Description of analysis sets 
12.1.1 Evaluable for Adverse Events 
For the primary objectives of this study (i.e. safety and MTD), the evaluable population will 
consist of patients who completed Cycle 1 of planned therapy, unless a DLT was encountered. 
Patients who did not complete Cycle 1 and did not experience a DLT will be replaced. 
All patients registered to the study who receive at least one dose of durvalumab will be 
assessed of safety and toxicity, but may not necessarily be included in the  
evaluable population for the primary endpoints (see definition above). For example, if a 
patient received one dose of durvalumab, and then declined further treatment, or had rapid 
disease progression, then they would be assessed for treatment toxicity at the time of the end 
treatment visit. If DLTs were not encountered the patient would be replaced in the study. 
Subjects who receive radiation without receiving durvalumab will not be included in the 
safety analysis. Such patients will receive no more than 8Gy to a single disease target. At this 
radiation dose level, toxicity is not expected from radiation alone.  
12.1.2  Evaluable for Response 
The efficacy analysis set will include all evaluable patients registered to the study. The 
evaluable population will consist of patients completing planned Cycle 1 of therapy, unless a 
DLT was encountered. Patients who did not complete Cycle 1 and came off treatment due to 
disease progression will not be included in the efficacy analysis.  

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12.2 Methods of statistical analyses 
All safety analyses will be performed on the safety population. The incidence of events that 
are new or worsening from the time of the first dose of treatment with durvalumab will be 
summarized by dose level, organ system, severity and relationship to the study treatment and 
reported by CTCAE grade. Deaths reportable as SAEs and non-fatal SAEs will be listed by 
patient and tabulated by primary system/organ and type of adverse event. The analysis of 
secondary endpoints will be descriptive. Time-to-event endpoints (i.e., PFS, OS) will be 
summarized for the aggregated sample 
The final analysis for the primary objectives will occur after the last patient to enroll in the 
study has completed Cycle 1 of therapy. The final analysis for secondary endpoints will  occur 
when data are mature or within 6 months of study completion.The study size will be 
determined by dose escalation following a 3+3+3 design. The minimum number of 
participants in the trial will be 3. This would occur if the first 3 patients enrolled in dose level 
1  experienced DLTs. The study would then stop accrual. The maximum possible study size 
would be 22. This would occur if at each dose level, the cohorts had to be fully expanded 
(n=9) and 2 patients at each dose level had to be replaced.  

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13 DOCUMENTATION, RECORD ACCESS AND MAINTENANCE OF 
STUDY RECORDS 
13.1 Documentation of Subject’s Participation 
A statement acknowledging the participation of a subject in this clinical trial must be 
documented in the subject's medical records along with the signed ICF.  
13.2 Regulatory Requirements 
The following documents are required: 
For participating Canadian centres:  
 
All Investigators must complete and sign the Health Canada Qualified Investigator 
Undertaking form. The completed forms must be returned to the Ozmosis Research 
Inc. prior to any drug shipment. 
 
All applicable regulatory documents as listed in the Protocol Activation Checklist 
provided by Ozmosis Research Inc. to the sites. 
 
Ozmosis Research Inc. will submit via fax to Health Canada a completed Health 
Canada Clinical Trial Site Information Form after local activation of each 
participating Canadian centre. 
13.3 Subject Confidentiality and Access to Source Data/Documents 
Any research information obtained about the subject in this study will be kept confidential. A 
subject will not be identified by name, only by his/her study number. The subject’s name or 
any identifying information will not appear in any reports published as a result of this study. 
However, information obtained from individual subject’s participation in the study may be 
disclosed with his/her consent to the health care providers for the purpose of obtaining 
appropriate medical care. The subject’s medical records/charts, tests will be made available to 
Ozmosis Research Inc., BCCA, its potential eventual partners, the Canadian HPFB/TPD, the 
REB and any other regulatory authorities. This is for the purpose of verifying information 
obtained for this study. Confidentiality will be maintained throughout the study within the 
limits of the law.   
A subject’s name will not be given to anyone except the researchers conducting the study, 
who have pledged an oath of confidentiality. All identifying information will be kept behind 
locked doors, under the supervision of the study Principal Investigator and will not be 
transferred outside of the hospital.  
A subject may take away his/her permission to collect, use and share information about 
him/her at any time. If this situation occurs, the subject will not be able to remain in the study. 
No new information that identifies the subject will be gathered after that date. However, the 
information about the subject that has already been gathered and transferred may still be used 

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and given to others as described above in order to preserve the scientific integrity and quality 
of the study. 
13.4 Confidentiality of the Study 
Data generated as a result of this study are to be available for inspection on request by local 
health authority auditors, the Sponsor’s Study Monitors and other personnel (as appropriate) 
and by the IRB/EC. The Investigator shall permit sponsor, authorized agents of the sponsor, 
CRO and regulatory agency employees to enter and inspect any site where the drug or records 
pertaining to the drug are held, and to inspect all source documents. The protocol and other 
study documents contain confidential information and should not be shared or distributed 
without the prior written permission of sponsor.   
13.5 Registration of Clinical Trial 
Prior to the first subject being registered/enrolled into this study, the Sponsor will be 
responsible for ensuring that the clinical trial is registered appropriately to remain eligible for 
publication in any major peer-reviewed journal, adhering to the guidelines put forth by the 
International Committee of Medical Journal Editors (ICMJE). 
13.6 Data Reporting and Data Management 
The data will be collected on electronic CRFs during this study.  All data for this trial will be 
analyzed using the Medidata Rave database.  Data management will be conducted by Ozmosis 
Research Inc. 
13.7 Case Report Forms 
Electronic CRFs will be used for this study. This also applies to records for those patients who 
fail to complete the study. If a patient is withdrawn from the study because of a treatment-
limiting adverse event, thorough efforts should be made to document the outcome clearly. 
The completed eCRF should be reviewed, signed, and dated by the Investigator in a timely 
fashion. 
Please see the study-specific eCRF completion guidelines which have been provided to your 
site by Ozmosis Research Inc. The timelines and details for submission of eCRFs are included 
in these guidelines. 
13.8 Maintenance of Study Records 
To enable evaluations and/or audits from Regulatory Authorities, Ozmosis Research Inc. or 
the Sponsor, the Investigator agrees to keep records, including the identity of all participating 
subjects (sufficient information to link records, CRFs and hospital records), all original signed 
informed consent forms, copies of all CRFs, source documents, and detailed records of 

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treatment disposition. The Investigator should retain these records for 25 years after study 
close-out as required by Canadian regulations or as specified in the Clinical Trial Agreement, 
whichever is longer. 
 
If the investigator relocates, retires, or for any reason withdraws from the study, then the 
Sponsor should be prospectively notified. The study records must be transferred to an 
acceptable designee, such as another investigator, another institution, or to the Sponsor. The 
investigator must obtain the Sponsor’s written permission before disposing of any records. 
 

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14 QUALITY ASSURANCE AND QUALITY CONTROL 
As per the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), the sponsor will be 
responsible for implementing and maintaining quality assurance and quality control systems. 
On Site Monitoring / Auditing 
Ozmosis Research Inc. will organize on-site monitoring of this study to be conducted twice a 
year at each site depending on accrual. 
 
As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Products and Food Branch Inspectorate.  Other audits may be 
conducted by the study sponsor, Ozmosis Research Inc., and/or the company supplying the 
drug for the study. 

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15 ADMINISTRATIVE PROCEDURES 
15.1 Amendments to the Protocol 
Modifications of the signed protocol are only possible by approved protocol amendments 
authorized by the Sponsor. All protocol amendments will be approved by the REB prior to 
implementation.  The Investigator must not implement any deviation from, or change to the 
protocol, except where it is necessary to eliminate an immediate hazard to trial subject or 
when the change(s) involves only logistical or administrative aspects of the trial. 
15.2 Protocol Deviations and Violations 
All violations or deviations are to be reported to the site’s REB (as per REB guidelines). All 
REB correspondence is to be forwarded to Ozmosis Research.  The site must notify Ozmosis 
Research and/or sponsor immediately of any protocol violations.  
15.3 Premature Discontinuation of the Study 
The Sponsor reserves the right to discontinue the trial for any reason but intends only to 
exercise this right for valid scientific or administrative reasons.  After such a decision, the 
Investigators must contact all participating patients immediately after notification.  Standard 
therapy and follow-up for subjects will be assured and, where required by the applicable 
regulatory requirement(s), the relevant regulatory authority(ies) will be informed. 
The REB will be informed promptly and provided with a detailed written explanation for the 
termination or suspension. 
As directed by the Sponsor, all study materials must be collected and all eCRFs completed to 
the greatest extent possible. 

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16 LEGAL ASPECTS 
16.1 Publication Policies and Disclosure of Data 
For publications, the first author will be the Principal Investigator of the study. Additional 
authors will be those who have made the most significant contribution to the overall success 
of the study. This contribution will be assessed, in part but not entirely, in terms of patients 
enrolled and will be reviewed at the end of the trial by the Principal Investigator.  
 
 
 
 
 

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17 LIST OF REFERENCES 
[1]Lowe KA, Chia VM, Taylor A, O'Malley C, Kelsh M, Mohamed M, et al. An international 
assessment of ovarian cancer incidence and mortality. Gynecol Oncol 2013 Apr 2. 
[2]Oza AM, Perren TJ, Swart AM, Schroder W, Pujade-Lauraine E, Havsteen H, Beale P, 
Cervantes A, Embleton AC, Parmar M, on behalf of the ICON7 investigators. ICON7: Final 
overall survival results in the GCIG phase III randomized trial of bevacizumab in women with 
newly diagnosed ovarian cancer. ECCO 2013. 
[3]Galic V, Coleman RL, Herzog TJ. Unmet needs in ovarian cancer: dividing histologic 
subtypes to exploit novel targets and pathways. Curr Cancer Drug Targets 2013 Jul;13(6):698-
707. 
[4]Davis A, Tinker AV, Friedlander M. "Platinum resistant" ovarian cancer: what is it, who to 
treat and how to measure benefit? Gynecol Oncol 2014 Jun;133(3):624-631. 
[5]Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. 
Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: 
The AURELIA open-label randomized phase III trial. J Clin Oncol 2014 May 1;32(13):1302-
1308. 
[6]Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest 2007 
May;117(5):1137-1146. 
[7]Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. 
Clin Cancer Res 2011 Nov 15;17(22):6958-6962. 
[8]Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab 
for the treatment of non-small-cell lung cancer. N Engl J Med 2015 May 21;372(21):2018-
2028. 
[9]Kefford R, Ribas A, Hamid O, et al. Clinical efficacy and correlation with tumor PD-L1 
expression in patients (pts) with melanoma (MEL) treated with the anti-PD-1 monoclonal 
antibody MK-3475. J Clin Oncol 2014;32(5s):suppe: abstr 2005. 
[10]Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity 
and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with 
advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, 
single-arm trial. Lancet Oncol 2015 Mar;16(3):257-265. 
[11]Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and 
immunity. Annu Rev Immunol 2008;26:677-704. 
[12]Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer 2012 Mar 22;12(4):252-264. 

Clinical Study Protocol 
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83 
 
[13]Park JJ, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. B7-
H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell 
tolerance. Blood 2010 Aug 26;116(8):1291-1298. 
[14]Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat 
Rev Immunol 2008 Jun;8(6):467-477. 
[15]Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B, et al. Blockade of PD-L1 
(B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer 2006 Jul 
15;119(2):317-327. 
[16]Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 
and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 
2005 Feb 1;65(3):1089-1096. 
[17]Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on 
tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 
blockade. Proc Natl Acad Sci U S A 2002 Sep 17;99(19):12293-12297. 
[18]Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of 
B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J 
Oncol 2009 Oct;35(4):741-749. 
[19]Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Anti-tumor immunotherapy by 
blockade of the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy 
2008;10(7):711-719. 
[20]Delfino KR, Rodriguez-Zas SL. Transcription Factor-MicroRNA-Target Gene Networks 
Associated with Ovarian Cancer Survival and Recurrence. PLoS One 2013;8(3):e58608. 
[21]Raspollini MR, Castiglione F, Rossi Degl'innocenti D, Amunni G, Villanucci A, Garbini 
F, et al. Tumour-infiltrating gamma/delta T-lymphocytes are correlated with a brief disease-
free interval in advanced ovarian serous carcinoma. Ann Oncol 2005 Apr;16(4):590-596. 
[22]Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. 
Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003 
Jan 16;348(3):203-213. 
[23]Clarke B, Tinker AV, Lee CH, Subramanian S, van de Rijn M, Turbin D, et al. 
Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, 
tumor type, and BRCA1 loss. Mod Pathol 2009 Mar;22(3):393-402. 
[24]Milne K, Kobel M, Kalloger SE, Barnes RO, Gao D, Gilks CB, et al. Systematic analysis 
of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as 
positive prognostic factors. PLoS One 2009 Jul 29;4(7):e6412. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
84 
 
[25]Wolf D, Wolf AM, Rumpold H, Fiegl H, Zeimet AG, Muller-Holzner E, et al. The 
expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is 
associated with poor prognosis in ovarian cancer. Clin Cancer Res 2005 Dec 1;11(23):8326-
8331. 
[26]Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment 
of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced 
survival. Nat Med 2004 Sep;10(9):942-949. 
[27]Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung 
cancer may contribute to poor prognosis and tumor cells immune escape through suppressing 
tumor infiltrating dendritic cells maturation. Med Oncol 2011 Sep;28(3):682-688. 
[28]Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. 
Survivin and b7-h1 are collaborative predictors of survival and represent potential therapeutic 
targets for patients with renal cell carcinoma. Clin Cancer Res 2007 Mar 15;13(6):1749-1756. 
[29]Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, et al. 
Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. 
Cancer 2005 Nov 15;104(10):2084-2091. 
[30]Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor 
B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term 
follow-up. Cancer Res 2006 Apr 1;66(7):3381-3385. 
[31]Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical 
significance and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer 
Lett 2008 Sep 8;268(1):98-109. 
[32]Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance 
and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic cancer. Clin Cancer Res 2007 Apr 1;13(7):2151-2157. 
[33]Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M. Clinical significance of B7-H1 and B7-1 
expressions in pancreatic carcinoma. World J Surg 2010 May;34(5):1059-1065. 
[34]Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. 
Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic 
factors of human ovarian cancer. PNAS 2007 February 27, 2007;104(9):3360-3365. 
[35]Abiko K, Mandai M, Hamanishi J, Yoshioka Y, Matsumura N, Baba T, et al. PD-L1 on 
tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer 
through CTL dysfunction. Clin Cancer Res 2013 Mar 15;19(6):1363-1374. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
85 
 
[36]Guo Z, Wang X, Cheng D, Xia Z, Luan M, Zhang S. PD-1 blockade and OX40 triggering 
synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One 
2014 Feb 27;9(2):e89350. 
[37]Lu L, Xu X, Zhang B, Zhang R, Ji H, Wang X. Combined PD-1 blockade and GITR 
triggering induce a potent antitumor immunity in murine cancer models and synergizes with 
chemotherapeutic drugs. J Transl Med 2014 Feb 7;12:36-5876-12-36. 
[38]Krempski J, Karyampudi L, Behrens MD, Erskine CL, Hartmann L, Dong H, et al. 
Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression 
in ovarian cancer. J Immunol 2011 Jun 15;186(12):6905-6913. 
[39]Duraiswamy J, Freeman GJ, Coukos G. Therapeutic PD-1 pathway blockade augments 
with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian 
cancer. Cancer Res 2013 Dec 1;73(23):6900-6912. 
[40]Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 
combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer 
Res 2013 Jun 15;73(12):3591-3603. 
[41]Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012 
Jun 28;366(26):2443-2454. 
[42]Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and 
activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012 Jun 
28;366(26):2455-2465. 
[43]Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved 
survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010 Aug 
19;363(8):711-723. 
[44]Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus 
dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011 Jun 
30;364(26):2517-2526. 
[45]Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, et al. Five-year survival 
rates for treatment-naive patients with advanced melanoma who received ipilimumab plus 
dacarbazine in a phase III trial. J Clin Oncol 2015 Apr 1;33(10):1191-1196. 
[46]Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. 
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory 
melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015 
Aug;16(8):908-918. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
86 
 
[47]Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in 
previously untreated melanoma without BRAF mutation. N Engl J Med 2015 Jan 
22;372(4):320-330. 
[48]Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab 
versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 
treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 
2015 Apr;16(4):375-384. 
[49]Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined 
Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015 Jul 
2;373(1):23-34. 
[50]Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, et al. 
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer. N 
Engl J Med 2015 07/09; 2015/10;373(2):123-135. 
[51]Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. 
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015 Nov 
5;373(19):1803-1813. 
[52]Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-
L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014 Nov 
27;515(7528):558-562. 
[53]Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade 
in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015 06/25; 
2015/11;372(26):2509-2520. 
[54]Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, et al. Biologic 
activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously 
vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 
2003 Apr 15;100(8):4712-4717. 
[55]Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, et al. Immunologic and 
clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in 
previously vaccinated cancer patients. Proc Natl Acad Sci U S A 2008 Feb 26;105(8):3005-
3010. 
[56]Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, et al. Safety 
and Antitumor Activity of Anti–PD-1 Antibody, Nivolumab, in Patients With Platinum-
Resistant Ovarian Cancer. Journal of Clinical Oncology 2015 September 08. 
[57]Disis ML, Patel MR, Pant S, Infante JR, Lockhart C, Kelly K, Beck JT, Gordon MS, 
Weiss GL, Ejadi S, Taylor MH, von Heydebreck A, Chin KM, Cuillerot J, Gulley J. 
Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
87 
 
recurrent or refractory ovarian cancer: A phase Ib, open-label expansion trial. J Clin Oncol 
2015;33((suppl; abstr 5509)). 
[58]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009 Jan;45(2):228-247. 
[59]Lutzky J, et al. A phase 1 study of MEDI4736, an anti–PD-L1 antibody, in patients with 
advanced solid tumors. J Clin Oncol 2014;32:5s((suppl; abstr 3001)). 
[60]Rizvi NA, et al. Safety and clinical activity of MEDI4736, an anti-programmed cell death-
ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 
2015;33((suppl; abstr 8032)). 
[61]Segal NH, et al. Safety and efficacy of MEDI4736, an anti-PD-L1 antibody, in patients 
from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. J Clin 
Oncol 2015;33((suppl; abst 3011)). 
[62]Segal NH, et al. Preliminary data from a multi-arm expansion study of MEDI4736, an 
anti-PD-L1 antibody. J Clin Oncol 2014;32:5s((suppl; abstr 3002)). 
[63]Igushi H, et al. Phase I study to evaluate the safety and tolerability of MEDI4736, an anti-
programmed cell death ligand-1 (PD-L1) antibody, in Japanese patients with advanced solid 
tumors. J Clin Oncol 2015;33((suppl; abstr 3039)). 
[64]Brahmer JR, et al. Clinical activity and biomarkers of MEDI4736, an anti-PDL1 antibody, 
in patients with NSCLC. J Clin Oncol 2014;32:5s((suppl; abstr 8021)). 
[65]Demaria S, Formenti SC. Radiation as an immunological adjuvant: current evidence on 
dose and fractionation. Front Oncol 2012;2:153. 
[66]Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like 
receptor 4-dependent contribution of the immune system to anticancer chemotherapy and 
radiotherapy. Nat Med 2007 Sep;13(9):1050-1059. 
[67]Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-
Induced IFN-γ Production within the Tumor Microenvironment Influences Antitumor 
Immunity. The Journal of Immunology 2008 March 01;180(5):3132-3139. 
[68]Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, et al. Immunologic 
correlates of the abscopal effect in a patient with melanoma. N Engl J Med 2012 Mar 
8;366(10):925-931. 
[69]Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, et al. Immune-
mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in 
a mouse model of breast cancer. Clin Cancer Res 2005 Jan 15;11(2 Pt 1):728-734. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
88 
 
[70]Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. 
Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect 
when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009 Sep 1;15(17):5379-5388. 
[71]Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. 
Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect 
when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009 Sep 1;15(17):5379-5388. 
[72]Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, et al. 
Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces 
successful antitumor immunotherapy. J Exp Med 2006 May 15;203(5):1259-1271. 
[73]Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol 2009 
Jul;10(7):718-726. 
[74]Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. 
Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant 
prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, 
randomised, double-blind, phase 3 trial. Lancet Oncol 2014 Jun;15(7):700-712. 
[75]Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC. 
Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. 
Oncoimmunology 2014 Apr 25;3:e28518. 
[76]Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, et al. 
Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 
blockade. Cancer Res 2014 Oct 1;74(19):5458-5468. 
[77]Golden EB, Chachoua A, Fenton-Kerimian MB, Demaria S, Formenti SC. Abscopal 
responses in metastatic non-small cell lung cancer (NSCLC) patients treated on a phase 2 
study of combined radiation therapy and ipilimumab: Evidence for the in situ vaccination 
hypothesis of radiation . International journal of radiation oncology biology physics 
2015;93(S66). 
[78]Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. 
Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic 
factors of human ovarian cancer. Proc Natl Acad Sci U S A 2007 Feb 27;104(9):3360-3365. 
[79]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009 Jan;45(2):228-247. 
[80]Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. 
Definitions for response and progression in ovarian cancer clinical trials incorporating 
RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J 
Gynecol Cancer 2011 Feb;21(2):419-423. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
89 
 
[81]Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res 2009 Dec 1;15(23):7412-7420. 
[82]Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41. 
[83] Bentzen SM, Constine S, Deasy JO, Eisbruch A, Jackson A, Marks LB, Ten Haken RK, 
Yorke ED. Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): an 
introduction to the scientific issues. Int J Radiat Oncol Biol Phys 2010, 76(3): Suppl, S3-9. 
 
 

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Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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18 LIST OF APPENDICIES 
Appendix 1  
Dosing Modification and Toxicity Management Guidelines for Immune-
mediated, Infusion Related, and Non Immune-mediated Reactions 
Appendix 2 
RECIST 1.1 Guidelines 
 
Appendix 3 
GCIC Response Criteria 
Appendix 4 
Immune-Related Response Criteria 
Appendix 5  
Radiation Treatment Planning Constraints 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 1:  DOSING MODIFICATION AND TOXICITY 
MANAGEMENT GUIDELINES FOR IMMUNE- MEDIATED, 
INFUSION RELATED, AND NON IMMUNE-MEDIATED 
REACTION 
 
 

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Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions (MEDI4736 
Monotherapy or Combination therapy with Tremelimumab or 
Tremelimumab Monotherapy) 19 August 2016 Version 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study 
regimen will be made to manage potential immune-related 
AEs based on severity of treatment-emergent toxicities graded 
per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of 
study drug/study regimen based on CTC grade/severity (table 
below), permanently discontinue study drug/study regimen for 
the following conditions: 
 
Inability to reduce corticosteroid to a dose of 
≤10 mg of prednisone per day (or equivalent) within 
12 weeks after last dose of study drug/study regimen 
 
Recurrence of a previously experienced Grade 3 
treatment-related AE following resumption of 
dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or 
Grade 4. 
Study drug/study regimen can be resumed once 
event stabilizes to Grade ≤1 after completion of 
steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per 
Investigator or treating physician’s clinical 
judgement. 
3. 
Doses of prednisone are at ≤10 mg/day or 
equivalent. 
Grade 3 
Depending on the individual toxicity, study 
drug/study regimen may be permanently 
discontinued. Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study 
regimen. 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, 
hold study drug/study regimen, and if complete work up shows 
no evidence of pancreatitis, study drug/study regimen may be 
continued or resumed. 
Note: For Grade 3 and above asymptomatic amylase or lipase 
levels hold study drug/regimen and if complete work up shows 
no evidence of pancreatitis, may continue or resume study 
drug/regimen 
It is recommended that management of irAEs follows the 
guidelines presented in this table: 
− 
Patients should be thoroughly evaluated to rule 
out any alternative etiology (eg, disease 
progression, concomitant medications, and 
infections). 
− 
In the absence of a clear alternative etiology, all 
events should be considered potentially immune 
related. 
− 
Symptomatic and topical therapy should be 
considered for low-grade (Grade 1 or 2, unless 
otherwise specified) events. 
− 
For persistent (>3 to 5 days) low-grade (Grade 2) 
or severe (Grade ≥3) events, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If symptoms recur or worsen during 
corticosteroid tapering (28 days of taper), 
increase the corticosteroid dose (prednisone dose 
[eg, up to 2 to 4 mg/kg/day PO or IV equivalent]) 
until stabilization or improvement of symptoms, 
then resume corticosteroid tapering at a slower 
rate (>28 days of taper). 
− 
More potent immunosuppressives such as TNF 
inhibitors (eg, infliximab) (also refer to the 
individual sections of the irAE for specific type 
of immunosuppressive) should be considered for 
events not responding to systemic steroids. 
− 
Discontinuation of study drug/study regimen is 
not mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumor response 
(eg, inflammatory reaction at sites of metastatic 
disease and lymph nodes). Continuation of study 
drug/study regimen in this situation should be 
based upon a benefit/risk analysis for that patient. 
AE  Adverse event; CTC  Common Toxicity Criteria; CTCAE  Common Terminology Criteria for Adverse Events; 
irAE  Immune-related adverse event; IV  intravenous; NCI  National Cancer Institute; PO  By mouth. 

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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/ILD 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and 
symptoms of pneumonitis or ILD 
(new onset or worsening shortness of 
breath or cough). Patients should be 
evaluated with imaging and 
pulmonary function tests, including 
other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical 
evaluation, monitoring of 
oxygenation via pulse oximetry 
(resting and exertion), laboratory 
work-up, and high- resolution CT 
scan. 
Grade 1 
(asymptomatic, 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated) 
No dose modifications 
required. However, 
consider holding study 
drug/study regimen dose 
as clinically appropriate 
and during diagnostic 
work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 
4 days for clinical symptoms, pulse 
oximetry (resting and exertion), and 
laboratory work-up and then as 
clinically indicated. 
− 
Consider pulmonary and infectious 
disease consult. 
Grade 2 
(symptomatic; 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL) 
Hold study drug/study 
regimen dose until Grade 
2 resolution to Grade ≤1. 
 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
 
If toxicity improves 
to Grade ≤1, then the 
decision to reinitiate 
study drug/study 
regimen will be based 
upon treating 
physician’s clinical 
judgment and after 
completion of steroid 
taper. 
For Grade 2 (mild to moderate new 
symptoms): 
− 
Monitor symptoms daily and consider 
hospitalization. 
− 
Promptly start systemic steroids (eg, 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, 
additional workup should be 
considered and prompt treatment with 
IV methylprednisolone 2 to 
4 mg/kg/day started 
− 
If still no improvement within 3 to 5 
days despite IV methylprednisone at 2 
to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as 
TNF inhibitors (eg, infliximab at 
5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer 
to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, or anti-PCP treatment 

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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
(Category 2B recommendation)a 
− 
Consider pulmonary and infectious 
disease consult. 
− 
Consider, as necessary, discussing 
with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; 
limiting self-care 
ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated [eg, 
tracheostomy or 
intubation]) 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life-threatening): 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day 
or equivalent. 
− 
Obtain pulmonary and infectious 
disease consult. 
− 
Hospitalize the patient. 
− 
Supportive care (eg, oxygen). 
− 
If no improvement within 3 to 5 days, 
additional workup should be 
considered and prompt treatment with 
additional immunosuppressive 
therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 
weeks dose) started. Caution: rule out 
sepsis and refer to infliximab label for 
general guidance before using 
infliximab. 
− 
Once the patients is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and, in particular, anti-
PCP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
(Category 2B recommendation).a 
Diarrhea/Enterocolitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be 
related to diarrhea/enterocolitis 
(abdominal pain, cramping, or 
changes in bowel habits such as 
increased frequency over baseline or 
blood in stool) or related to bowel 
perforation (such as sepsis, peritoneal 
signs, and ileus). 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (eg, disease progression, 
other medications, or infections), 
including testing for clostridium 
difficile toxin, etc. 

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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
− 
Steroids should be considered in the 
absence of clear alternative etiology, 
even for low-grade events, in order to 
prevent potential progression to 
higher grade event. 
− 
Use analgesics carefully; they can 
mask symptoms of perforation and 
peritonitis. 
Grade 1 
(stool frequency 
of 
<4 over baseline 
per day) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening 
symptoms. 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (eg, 
American Dietetic Association colitis 
diet), and loperamide. Use probiotics 
as per treating physician’s clinical 
judgment. 
Grade 2 
(stool frequency 
of 4 to 6 over 
baseline per day) 
Hold study drug/study 
regimen until resolution to 
Grade ≤1 
 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
 
If toxicity improves 
to Grade ≤1, then 
study drug/study 
regimen can be 
resumed after 
completion of steroid 
taper. 
For Grade 2: 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (eg, 
American Dietetic Association colitis 
diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 
5 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, GI consult should be 
obtained for consideration of further 
workup, such as imaging and/or 
colonoscopy, to confirm colitis and 
rule out perforation, and prompt 
treatment with IV methylprednisolone 
2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 
days despite 2 to 4 mg/kg IV 
methylprednisolone, promptly start 
immunosuppressives such as 
infliximab at 5 mg/kg once every 2 
weeksa. Caution: it is important to 
rule out bowel perforation and refer to 
infliximab label for general guidance 
before using infliximab. 
− 
Consult study physician if no 
resolution to Grade ≤1 in 3 to 4 days. 
− 
Once the patient is improving, 

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Drug Substance Durvalumab 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
Grade 3 or 4 
(Grade 3: stool 
frequency of ≥7 
over baseline per 
day; 
 
Grade 4: life 
threatening 
consequences) 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone 2 to 4 mg/kg/day 
or equivalent. 
− 
Monitor stool frequency and volume 
and maintain hydration. 
− 
Urgent GI consult and imaging and/or 
colonoscopy as appropriate. 
− 
If still no improvement within 3 to 5 
days of IV methylprednisolone 2 to 4 
mg/kg/day or equivalent, promptly 
start further immunosuppressives (eg 
infliximab at 5 mg/kg once every 2 
weeks). Caution: Ensure GI consult 
to rule out bowel perforation and refer 
to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
Hepatitis (elevated 
LFTs) 
Infliximab should not 
be used for 
management of 
immune-related 
hepatitis. 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function 
test: AST, ALT, ALP, and TB. 
− 
Evaluate for alternative etiologies (eg, 
viral hepatitis, disease progression, 
concomitant medications). 
Grade 1 
AST or ALT > to 
3 × ULN and/or 
TB > to 1.5 × 
ULN) 
No dose modifications. 
 
If it worsens, then 
treat as Grade 2 event. 
For Grade 1: 
− 
Continue LFT monitoring per 
protocol. 
Grade 2 
(AST or ALT > 
3 to 5 × ULN 
and/or TB >1.5 
to 3.0 × ULN) 
Hold study drug/study 
regimen dose until Grade 
2 resolution to Grade ≤1. 
 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
 
If toxicity improves to 
For Grade 2: 
− 
Regular and frequent checking of 
LFTs (eg, every 1 to 2 days) until 
elevations of these are improving or 
resolved. 
− 
If no resolution to Grade ≤1 in 1 to 2 

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Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade ≤1 or baseline, 
resume study 
drug/study regimen 
after completion of 
steroid taper. 
days, discuss with study physician. 
− 
If event is persistent (>3 to 5 days) or 
worsens, promptly start prednisone 1 
to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 
days despite 1 to 2 mg/kg/day of 
prednisone PO or IV equivalent, 
consider additional workup and start 
prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 
days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, promptly start 
immunosuppressives (mycophenolate 
mofetil)a Discuss with study 
physician if mycophenolate mofetil is 
not available. Infliximab should 
NOT be used. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
Grade 3 or 4 
(Grade 3: AST 
or ALT >5 to 
20 × ULN and/or 
TB >3.0 to 10 × 
ULN) 
 
(Grade 4: AST 
or ALT 
>20 × ULN 
and/or TB 
>10 × ULN) 
For Grade 3: 
For elevations in 
transaminases ≤8 × ULN, 
or elevations in bilirubin 
≤5 × ULN: 
 Hold study drug/study 
regimen dose until 
resolution to Grade 
≤1 or baseline 
 Resume study 
drug/study regimen if 
elevations downgrade 
to Grade ≤1 or 
baseline within 
14 days and after 
completion of steroid 
taper. 
 Permanently 
discontinue study 
drug/study regimen if 
the elevations do not 
downgrade to Grade 
≤1 or baseline within 
14 days 
For elevations in 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 
days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, 
promptly start treatment with 
immunosuppressive therapy 
(mycophenolate mofetil). Discuss 
with study physician if 
mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Perform hepatology consult, 
abdominal workup, and imaging as 
appropriate. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 

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Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
98 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
transaminases >8 × ULN 
or elevations in bilirubin 
>5 × ULN, discontinue 
study drug/study regimen. 
Permanently discontinue 
study drug/study regimen 
for any case meeting Hy’s 
law criteria (AST and/or 
ALT >3 × ULN + 
bilirubin >2 × ULN 
without initial findings of 
cholestasis (ie, elevated 
alkaline P04) and in the 
absence of any alternative 
cause.b 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that 
may be related to changes in renal 
function (eg, routine urinalysis, 
elevated serum BUN and creatinine, 
decreased creatinine clearance, 
electrolyte imbalance, decrease in 
urine output, or proteinuria). 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (eg, disease progression or 
infections). 
− 
Steroids should be considered in the 
absence of clear alternative etiology 
even for low-grade events (Grade 2), 
in order to prevent potential 
progression to higher grade event. 
Grade 1 
(Serum 
creatinine > 1 to 
1.5 × baseline; > 
ULN to 1.5 × 
ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and 
any accompanying symptoms. 
 
If creatinine returns to 
baseline, resume its regular 
monitoring per study 
protocol. 
 
If creatinine worsens, 
depending on the severity, 
treat as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
99 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
including hydration, electrolyte 
replacement, and diuretics. 
Grade 2 
(serum creatinine 
>1.5 to 3.0 × 
baseline; >1.5 to 
3.0 × ULN) 
Hold study drug/study 
regimen until resolution to 
Grade ≤1 or baseline.  
 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
 
If toxicity improves to 
Grade ≤1 or baseline, 
then resume study 
drug/study regimen 
after completion of 
steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics. 
− 
Carefully monitor serum creatinine 
every 2 to 3 days and as clinically 
warranted. 
− 
Consult nephrologist and consider 
renal biopsy if clinically indicated. 
− 
If event is persistent (>3 to 5 days) or 
worsens, promptly start prednisone 1 
to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 
5 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should 
be considered and prompt treatment 
with IV methylprednisolone at 2 to 
4 mg/kg/day started. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
− 
When event returns to baseline, 
resume study drug/study regimen and 
routine serum creatinine monitoring 
per study protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
>3.0 × baseline; 
>3.0 to 
6.0 × ULN; 
 
Grade 4: serum 
creatinine >6.0 × 
ULN) 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on 
daily basis. 
− 
Consult nephrologist and consider 
renal biopsy if clinically indicated. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 
5 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should 
be considered and prompt treatment 
with IV methylprednisolone 2 to 
4 mg/kg/day started. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 days 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
100 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI 
CTCAE v 4.03 
for definition of 
severity/grade 
depending on 
type of skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of 
dermatitis (rash and pruritus). 
− 
IF THERE IS ANY BULLOUS 
FORMATION, THE STUDY 
PHYSICIAN SHOULD BE 
CONTACTED AND STUDY DRUG 
DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, 
including oral antipruritics (eg, 
diphenhydramine or hydroxyzine) and 
topical therapy (eg, urea cream). 
Grade 2 
For persistent (>1 to 2 
weeks) Grade 2 events, 
hold scheduled study 
drug/study regimen until 
resolution to Grade ≤1 or 
baseline. 
 
If toxicity worsens, 
then treat as 
Grade 3. 
 
If toxicity improves 
to Grade ≤1 or 
baseline, then 
resume drug/study 
regimen after 
completion of 
steroid taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, 
including oral antipruritics (eg, 
diphenhydramine or hydroxyzine) and 
topical therapy (eg, urea cream). 
− 
Consider moderate-strength topical 
steroid. 
− 
If no improvement of rash/skin 
lesions occurs within 3 to 5 days or is 
worsening despite symptomatic 
treatment and/or use of moderate 
strength topical steroid, discuss with 
study physician and promptly start 
systemic steroids such as prednisone 
1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
Consider skin biopsy if the event is 
persistent for >1 to 2 weeks or recurs. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen until resolution to 
Grade ≤1 or baseline. 
If temporarily holding the 
study drug/study regimen 
does not provide 
improvement of the Grade 
3 skin rash to Grade ≤1 or 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day 
or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of 
Nines]. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
baseline within 30 days, 
then permanently 
discontinue study 
drug/study regimen. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
− 
Consider skin biopsy (preferably 
more than 1) as clinically feasible. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
− 
Discuss with study physician. 
Endocrinopathy 
(eg, hyperthyroidism, 
hypothyroidism, 
hypopituitarism, and 
adrenal insufficiency) 
Any Grade 
(depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE v4.03 
for defining the 
CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Consult endocrinologist. 
− 
Monitor patients for signs and 
symptoms of endocrinopathies. Non-
specific symptoms include headache, 
fatigue, behavior changes, changed 
mental status, vertigo, abdominal 
pain, unusual bowel habits, 
hypotension, and weakness. 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (eg, disease progression 
including brain metastases, or 
infections). 
− 
Monitor and evaluate thyroid function 
tests: TSH, free T3 and free T4 and 
other relevant endocrine labs 
depending on suspected 
endocrinopathy. 
− 
If a patient experiences an AE that is 
thought to be possibly of autoimmune 
nature (eg, thyroiditis, pancreatitis, 
hypophysitis, or diabetes insipidus), 
the investigator should send a blood 
sample for appropriate autoimmune 
antibody testing. 
 
Grade  1 
No dose modifications. 
For Grade 1 (including those with 
asymptomatic TSH elevation): 
− 
Monitor patient with appropriate 
endocrine function tests. 
− 
If TSH < 0.5 × LLN, or TSH >2 × 
ULN or consistently out of range in 2 
subsequent measurements, include 
free T4 at subsequent cycles as 
clinically indicated and consider 
endocrinology consult. 
Grade 2 
For Grade 2 
endocrinopathy other than 
For Grade 2 (including those with 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
hypothyroidism, hold 
study drug/study regimen 
dose until patient is 
clinically stable. 
 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
Study drug/study regimen 
can be resumed once event 
stabilizes and after 
completion of steroid 
taper. 
Patients with 
endocrinopathies who may 
require prolonged or 
continued steroid 
replacement can be 
retreated with study 
drug/study regimen on the 
following conditions: 
1. 
The event stabilizes 
and is controlled. 
2. 
The patient is 
clinically stable as 
per investigator or 
treating physician’s 
clinical judgement. 
3. 
Doses of prednisone 
are ≤10 mg/day or 
equivalent. 
symptomatic endocrinopathy): 
− 
Isolated hypothyroidism may be 
treated with replacement therapy 
without treatment interruption and 
without corticosteroids. 
− 
Initiate hormone replacement as 
needed for management. 
− 
Evaluate endocrine function, and as 
clinically indicated, consider pituitary 
scan. 
− 
For patients with abnormal endocrine 
work up, except for those with 
isolated hypothyroidism, consider 
short-term corticosteroids (eg, 1 to 
2 mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation 
of treatment with relevant hormone 
replacement (eg, levothyroxine, 
hydrocortisone, or sex hormones). - 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
− 
For patients with normal endocrine 
workup (laboratory assessment or 
MRI scans), repeat laboratory 
assessments/MRI as clinically 
indicated. 
Grade 3 or 4 
For Grade 3 or 4 
endocrinopathy other than 
hypothyroidism, hold 
study drug/study regimen 
dose until endocrinopathy 
symptom(s) are 
controlled.  
Study drug/study regimen 
can be resumed once event 
stabilizes and after 
completion of steroid 
taper. 
For Grade 3 or 4: 
− 
Consult endocrinologist. 
− 
Isolated hypothyroidism may be 
treated with replacement therapy 
without treatment interruption and 
without corticosteroids. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day 
or equivalent 
− 
Administer hormone replacement 
therapy as necessary. 
− 
For adrenal crisis, severe dehydration, 
hypotension, or shock, immediately 
initiate IV corticosteroids with 
mineralocorticoid activity. 
− 
Once the patient is improving, 
gradually taper immunosuppressive 
steroids over ≥28 days and consider 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to 
current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
− 
Discuss with study physician. 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
Any Grade 
(depending on 
the type of 
neurotoxicity, 
refer to NCI 
CTCAE v4.03 
for defining the 
CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule 
out any alternative etiology (eg, 
disease progression, infections, 
metabolic syndromes, or 
medications). 
− 
Monitor patient for general symptoms 
(headache, nausea, vertigo, behavior 
change, or weakness). 
− 
Consider appropriate diagnostic 
testing (eg, electromyogram and 
nerve conduction investigations). 
− 
Perform symptomatic treatment with 
neurological consult as appropriate. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations 
above. 
Grade 2 
For acute motor 
neuropathies or 
neurotoxicity, hold study 
drug/study regimen dose 
until resolution to Grade 
≤1. 
For sensory 
neuropathy/neuropathic 
pain, consider holding 
study drug/study regimen 
dose until resolution to 
Grade ≤1. 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
Study drug/study regimen 
can be resumed once event 
improves to Grade ≤1 and 
after completion of steroid 
taper. 
For Grade 2: 
− 
Discuss with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (eg, gabapentin or 
duloxetine). 
− 
Promptly start systemic steroids 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If no improvement within 3 to 5 days 
despite 1 to 2 mg/kg/day prednisone 
PO or IV equivalent, consider 
additional workup and promptly treat 
with additional immunosuppressive 
therapy (eg, IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
For Grade 3 or 4: 
− 
Discuss with study physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
104 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Permanently discontinue 
study drug/study regimen 
if Grade 3 irAE does not 
resolve to Grade ≤1 within 
30 days. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day 
or equivalent. 
− 
If no improvement within 3 to 5 days 
despite IV corticosteroids, consider 
additional workup and promptly treat 
with additional immunosuppressants 
(eg, IV IG). 
− 
Once stable, gradually taper steroids 
over ≥28 days. 
Peripheral 
neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-
mediated peripheral neuromotor 
syndromes is important, since certain 
patients may unpredictably 
experience acute decompensations 
that can result in substantial morbidity 
or in the worst case, death. Special 
care should be taken for certain 
sentinel symptoms that may predict a 
more severe outcome, such as 
prominent dysphagia, rapidly 
progressive weakness, and signs of 
respiratory insufficiency or autonomic 
instability. 
− 
Patients should be evaluated to rule 
out any alternative etiology (eg, 
disease progression, infections, 
metabolic syndromes or medications). 
It should be noted that the diagnosis 
of immune-mediated peripheral 
neuromotor syndromes can be 
particularly challenging in patients 
with underlying cancer, due to the 
multiple potential confounding effects 
of cancer (and its treatments) 
throughout the neuraxis. Given the 
importance of prompt and accurate 
diagnosis, it is essential to have a low 
threshold to obtain a neurological 
consult. 
− 
Neurophysiologic diagnostic testing 
(eg, electromyogram and nerve 
conduction investigations, and 
“repetitive stimulation” if myasthenia 
is suspected) are routinely indicated 
upon suspicion of such conditions and 
may be best facilitated by means of a 
neurology consultation. 
− 
It is important to consider that the use 
of steroids as the primary treatment of 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Guillain-Barre is not typically 
considered effective. Patients 
requiring treatment should be started 
with IV IG and followed by 
plasmapheresis if not responsive to IV 
IG. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Discuss with the study physician. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of a 
potential decompensation as 
described above. 
− 
Obtain a neurology consult unless the 
symptoms are very minor and stable. 
Grade 2 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if it does not resolve to 
Grade ≤1 within 30 days 
or if there are signs of 
respiratory insufficiency 
or autonomic instability. 
For Grade 2: 
− 
Discuss with the study physician. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of a 
potential decompensation as 
described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (eg, gabapentin or 
duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to treat 
myasthenia gravis. It is 
important to consider that 
steroid therapy (especially 
with high doses) may result 
in transient worsening of 
myasthenia and should 
typically be administered in 
a monitored setting under 
supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate 
steroids may be candidates 
for treatment with 
plasmapheresis or IV IG. 
Such decisions are best 
made in consultation with a 
neurologist, taking into 
account the unique needs of 
each patient. 
o 
If myasthenia gravis-like 
neurotoxicity is present, 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
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Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
consider starting AChE 
inhibitor therapy in addition 
to steroids. Such therapy, if 
successful, can also serve to 
reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider 
here that the use of steroids 
as the primary treatment of 
Guillain-Barre is not 
typically considered 
effective. 
o 
Patients requiring treatment 
should be started with IV 
IG and followed by 
plasmapheresis if not 
responsive to IV IG. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 irAE does not 
resolve to Grade ≤1 within 
30 days or if there are 
signs of respiratory 
insufficiency or autonomic 
instability. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Discuss with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain 
neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to treat 
myasthenia gravis. They 
should typically be 
administered in a monitored 
setting under supervision of 
a consulting neurologist. 
o 
Patients unable to tolerate 
steroids may be candidates 
for treatment with 
plasmapheresis or IV IG. 
o 
If myasthenia gravis-like 
neurotoxicity present, 
consider starting AChE 
inhibitor therapy in addition 
to steroids. Such therapy, if 
successful, can also serve to 
reinforce the diagnosis. 
 
GUILLAIN-BARRE: 
o 
It is important to consider 
here that the use of steroids 
as the primary treatment of 
Guillain-Barre is not 
typically considered 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
107 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
effective. 
o 
Patients requiring treatment 
should be started with IV 
IG and followed by 
plasmapheresis if not 
responsive to IV IG. 
a 
ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow 
MD. 
b 
FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical 
Evaluation. 
AChE  Acetylcholine esterase; ADL  Activities of daily living; AE  Adverse event; ALP  Alkaline phosphatase test; 
ALT  Alanine aminotransferase; AST  Aspartate aminotransferase; BUN  Blood urea nitrogen; CT  Computed 
tomography; CTCAE  Common Terminology Criteria for Adverse Events; ILD  Interstitial lung disease; 
irAE  Immune-related adverse event; IG  Immunoglobulin; IV  Intravenous; GI  Gastrointestinal; LFT  Liver function 
tests; LLN  Lower limit of normal; MRI  Magnetic resonance imaging; NCI  National Cancer Institute; 
NCCN  National Comprehensive Cancer Network; PCP ; PO  By mouth; T3  Triiodothyronine; T4  Thyroxine; 
TB  Total bilirubin; TNF  Tumor necrosis factor; TSH  Thyroid-stimulating hormone; ULN  Upper limit of normal. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
108 
 
Infusion-related Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the 
discretion of investigator. 
− 
Monitor patients for signs and symptoms of 
infusion-related reactions (eg, fever and/or 
shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, 
dyspnea or chest discomfort, or skin rashes) 
and anaphylaxis (eg, generalized urticaria, 
angioedema, wheezing, hypotension, or 
tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study 
regimen may be decreased by 50% or 
temporarily interrupted until resolution of 
the event. 
 
For Grade 2: 
The infusion rate of study drug/study 
regimen may be decreased 50% or 
temporarily interrupted until resolution of 
the event. 
Subsequent infusions may be given at 
50% of the initial infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be 
administered per institutional standard at the 
discretion of the investigator. 
− 
Consider premedication per institutional 
standard prior to subsequent doses. 
− 
Steroids should not be used for routine 
premedication of Grade ≤2 infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per 
institutional standards (eg, IM epinephrine, 
followed by IV diphenhydramine and 
ranitidine, and IV glucocorticoid). 
CTCAE  Common Terminology Criteria for Adverse Events; IM  Intramuscular; IV  Intravenous; NCI  National Cancer 
Institute. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
109 
 
Non-immune-mediated Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for 
AEs not deemed to be related to study 
treatment (ie, events due to underlying 
disease) or for laboratory abnormalities not 
deemed to be clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution 
to ≤Grade 1 or baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution 
to ≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 2 within 7 
days or resolve to ≤Grade 1 or baseline within 
14 days, resume study drug/study regimen 
administration.  Otherwise, discontinue study 
drug/study regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue 
should be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the Sponsor.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 
2, please discuss with Study Physician.” 
AE  Adverse event; CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute. 
 
In addition to the dose modifications shown in Appendix 1, it is recommended the 
management guidelines for irAEs are followed. 
 
Management of immune-related adverse events 
 
 
1.  Subjects should be thoroughly evaluated to rule out any alternative etiology (eg, 
disease progression, concomitant medications, infections, etc) 
 
2. In the absence of a clear alternative etiology, all events should be considered 
potentially immune related 
 
3. Symptomatic and topical therapy should be considered for low-grade (Grade 1 or 2, 
unless otherwise specified) events 
 
4. Systemic corticosteroids (eg, prednisone or intravenous equivalent) should be 
considered for persistent low-grade or severe (Grade ≥3) events 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
110 
 
5. If symptoms recur or worsen during corticosteroid tapering, increase the corticosteroid 
dose until stabilization or improvement of symptoms, then resume corticosteroid 
tapering at a slower rate 
 
6. More potent immunosuppressives – TNF antagonist class (eg, infliximab) or 
mycophenolate, etc) should be considered for events not responding to systemic 
steroids after discussion with study physician 
 
7. Discontinuation of study drug is not mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumour response (eg, inflammatory reaction at sites of 
metastatic disease, lymph nodes, etc.) 
 
 
 
 
 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
111 
 
APPENDIX 2:  RECIST 1.1 GUIDELINES  
Response Criteria 
Evaluation of target lesions 
Complete Response 
(CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in the short axis to 
<10 mm. 
Partial Response    
(PR) 
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this may include the 
baseline sum). 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. 
Special notes on the assessment of target lesions 
• Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study. When 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even 
if complete response criteria are met since a normal lymph node is defined as having a 
short axis of <10 mm. 
• Target lesions that become ‘too small to measure’. While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small. However, sometimes 
lesions or lymph nodes become so faint on a CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to 
measure’, in which case a default value of 5 mm should be assigned. 
• Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, 
the longest diameters of the fragmented portions should be added together to calculate 
the target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
112 
 
Evaluation of non-target lesions 
Complete Response 
(CR) 
Disappearance of all non-target lesions and normalization of tumor 
marker levels. All lymph nodes must be non-pathological in size (<10 
mm short axis). 
Non-CR-Non-PD/      
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) 
Unequivocal progression of existing non-target lesions. 
When patient has measurable disease. To achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, 
even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. 
When patient has only non-measurable disease. There is no 
measurable disease assessment to factor into the interpretation of an 
increase in non-measurable disease burden. Because worsening in non-
target disease cannot be easily quantified, a useful test that can be 
applied is to consider if the increase in overall disease burden based on 
change in nonmeasurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease. 
Examples include an increase in a pleural effusion from ‘trace’ to 
‘large’ or an increase in lymphangitic disease from localized to 
widespread. 
 
 
New Lesions 
The appearance of new malignant lesions denotes disease progression: 
 
o The finding of a new lesion should be unequivocal (i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor, especially when the patient’s baseline lesions show partial or complete 
response). 
o If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
113 
 
o A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and disease progression. 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until the end 
of treatment taking into account any requirement for confirmation. 
 
Evaluation of Best Overall Response – Patient with Target (+/- non-target) disease 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR-Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD/or not all 
evaluated 
No 
PR 
SD 
Non-PD/or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Evaluation of Best Overall Response – Patient with Non-Target Disease 
Non-Target lesions 
New Lesions 
Overall response 
CR 
No 
CR 
Non-CR-Non-PD 
No 
Non-CR/Non-PD1 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
114 
 
1 Non-CR / non-PD is preferred over ‘Stable Disease’ for non-target disease since SD 
is increasingly used as an endpoint for assessment of efficacy in some trials. To 
assign this category when no lesions can be measured is not advised. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment.  
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status 
of complete response. 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. 
If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point 
response. This would most likely happen in the case of PD. 
Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error. This will 
also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials. 
However, in all other circumstances, (i.e., in randomized phase II or III trials or studies where 
stable disease or progression are the primary endpoints), confirmation of response is not 
required since it will not add value to the interpretation of trial results. However, elimination 
of the requirement for response confirmation may increase the importance of central review to 
protect against bias, in particular in studies which are not blinded.  
In the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general not less than 6–8 weeks) that is defined in the study 
protocol. 
Duration of overall response 
o The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever status is recorded first) until the first date that recurrence or PD 
is objectively documented, taking as reference for PD the smallest measurements recorded 
since the treatment started. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
115 
 
o The duration of overall complete response is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively documented. 
 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
116 
 
APPENDIX 3: GCIC RESPONSE CRITERIA 
Definition of Response 
A CA 125 response is defined as at least a 50% reduction in CA 125 levels from a 
pretreatment sample. The response must be confirmed and maintained for at least 28 days. 
Patients can be evaluated according to CA 125 only if they have a pretreatment sample that is 
at least twice the upper limit of the reference range and within 2 weeks before starting the 
treatment. 
Evaluation of best overall response in patients with measurable disease and who are also 
evaluable by CA 125 
 
Target Lesion* 
Non-
targetNontarget† 
New Lesion 
CA-125 
Overall Best 
Response 
 
CR 
CR 
No 
Normal 
CR 
CR 
Non-CR Non-PD 
No 
Not PD 
PR 
CR 
CR 
No 
PR but not 
normal 
PR 
CR 
NE 
No 
PR 
PR 
PR 
Non-PD or NAE 
No 
Not PD 
PR 
NAE 
Non-PD 
No 
PR 
PR 
PD or New > 28 days from  CA 125 PR‡ 
PR 
PR 
SD§ 
Non-PD 
No 
PR 
PR 
SD§ 
Non-PD 
No 
Not PR or SD 
SD 
PD or New < 28 days from  CA 125 PR‡ 
PR 
PD 
PD 
Any 
Yes or No 
Any 
PD 
NE 
PD 
Yes or No 
Any 
PD 
NE 
Any 
Yes 
Any 
PD 
NE 
Any 
Yes or No 
PD 
PD 
 
*Target lesions include up to 5 measurable lesions (2 per organ) as defined by RECIST 1.1. 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
117 
 
†Nontarget lesions include ascites and peritoneal thickening which are not measurable according to RECIST 1.1. 
‡Patients who have a CA 125 response that occurs more than 28 days from PD according to RECIST 1.1 are 
considered a PR, according to best response, but PD if the RECIST 1.1 PD is within 28 days of CA 125 response. 
§The protocol should specify the minimum time interval between 2 measurements for classification as stable 
disease. 
NE, Not evaluated; NAE, not all evaluated. 
 
 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
118 
 
APPENDIX 4:  IMMUNE-RELATED RESPONSE CRITERIA  
Antitumor response based on total measurable tumor burden: 
For the irRC, only index and measurable new lesions are taken into account (in contrast to 
conventional WHO criteria, which do not require the measurement of new lesions, nor do they 
include new lesion measurements in the characterization of evolving tumor burden). 
At the baseline tumour assessment, the sum of the products of the two largest perpendicular 
diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five 
cutaneous index lesions) is calculated. 
At each subsequent tumour assessment, the SPD of the index lesions and of new, measurable 
lesions (≥ 5 X 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral 
lesions) are added together to provide the total time-point tumour burden: 
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions 
Time-point response assessment using irRC: 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear. At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the change 
in tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed relative 
to baseline measurements (i.e., the SPD of all index lesions at screening). 
Overall response using the irRC: 
The overall response according to the irRCis derived from time-point response assessments 
(based on tumor burden) as follows: 
 irCR, complete disappearance of all lesions (whether measurable or not, and no new 
lesions) confirmation by a repeat, consecutive assessment no less than 4 wk from the date 
first documented 
• irPR, decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive 
assessment at least 4 wk after first documentation 
• irSD, not meeting criteria for irCR or irPR, in absence of irPD 
• irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden) 
confirmation by a repeat, consecutive assessment no less than 4 wk from the date first 
documented 
 
 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
119 
 
 
APPENDIX 5: RADIATION TREATMENT PLANNING CONTRAINTS  
Organ at Risk (OAR) 
Dose 
Constraint 
Dose Constraints 
  
for 4 
Fractions 
for each 2 fraction 
plan 
Spinal Cord PRV 
Dmax ≤ 26Gy 
1   
Dmax ≤ 13Gy 1   
(PRV=2mm on cord) 
V20.8Gy < 
0.35cc 1   
V10.4Gy < 0.35cc 1   
(Canal for lung) 
V13.6Gy < 
1.2cc 1   
V6.8Gy < 1.2cc 1   
(Cord for spine) 
  
  
Brainstem 
Dmax<28Gy *2 
Dmax<14Gy *2 
  
V21 Gy < 
0.5cc  *2 
V11.5 Gy < 0.5cc  *2 
  
  
  
Cauda equina 
Dmax < 29 Gy 
*2 
Dmax < 14.5 Gy *2 
  
V27 Gy < 5 cc 
*2 
V13.5 Gy < 5 cc *2 
  
  
  
Sacral plexus 
Dmax <29 Gy 
*3 
Dmax <14.5 Gy *3 
  
V 27Gy < 5 cc 
*3 
V 13.5Gy < 5 cc *3 
PBT and PT PRV   (prox. Bronchial tree & prox. Trachea) 
Dmax < 34.8 
Gy 1   
Dmax < 17.4 Gy 1   
  
V15.6 Gy < 
4cc 1   
V7.8 Gy < 4cc 1   
  
  
  
  
  
  
  
  
  
Bronchus - smaller airways 
 V38.7Gy < 
0.1cc 4 
 V19.3Gy < 0.1cc 4 
  
  
  
  
  
  
Lungs-GTV 
1500cc < 
11.6Gy  1  
1500cc < 5.8Gy  1  
(Lungs-GTV-PT-PBT) 
1000cc 
<12.4Gy  1   
1000cc <6.2Gy  1   
  
V20 Gy < 
6%6(10% 1,5) 
V10 Gy < 6%6(10% 1,5) 
  
Mean < 6Gy 5 
Mean < 3Gy 5 
  
  
  
Contralateral lung 
Mean < 3.6 
Mean < 1.8 Gy 7 

Clinical Study Protocol 
Drug Substance Durvalumab 
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Gy 7 
Chest wall / Ribs: 
Dmax < 40Gy 
1  
Dmax < 20Gy 1  
  
V32Gy < 1cc  
1   
V16Gy < 1cc  1   
  
V30 Gy < 
30cc 8 
V15 Gy < 30cc 8 
  
  
  
  
  
  
Brachial Plexus 
Dmax < 
23Gy9  
(27.2Gy1) 
Dmax < 11.5Gy9  (13.6Gy1) 
  
V23.6 Gy < 
3cc 1   
V11.8 Gy < 3cc 1   
  
  
  
Heart / Pericardium 
Dmax < 34 Gy 
1   
Dmax < 17 Gy 1   
  
V28 Gy < 
15cc 1   
V14 Gy < 15cc 1   
Great Vessels 
Dmax < 49 Gy 
1   
Dmax < 24.5 Gy 1   
  
V43 Gy < 
10cc  1   
V21.5 Gy < 10cc  1   
  
  
  
Skin 
Dmax < 36 Gy  
1   
Dmax < 18 Gy  1   
  
V33.2 Gy < 
10cc  1   
V16.6 Gy < 10cc  1   
Esophagus 
Dmax < 30 Gy 
1   
Dmax <15 Gy 1   
  
V18.8 Gy < 
5cc 1   
V9.4 Gy < 5cc 1   
Stomach 
Dmax < 27.2  
1   
Dmax < 13.6  1   
  
V17.6 Gy < 
10cc  1   
V8.8 Gy < 10cc  1   
  
  
  
Duodenum 
Dmax < 29 Gy 
*3 
Dmax < 14.5 Gy *3 
  
V 17Gy < 5cc 
*3 
V 8.5Gy < 5cc *3 
  
V 12 Gy < 
10cc *2 
V 6 Gy < 10cc *2 
  
  
  
Jejunum/ileum 
Dmax < 32 Gy 
*3 
Dmax < 16 Gy *3 
  
V18Gy < 5 cc 
*3 
V9Gy < 5 cc *3 
Small Bowel 
Dmax < 28 Gy 
*10 
Dmax < 14 Gy *10 

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
121 
 
  
V28 Gy < 1cc 
V14 Gy < 1cc 
  
V19 Gy < 3cc 
V9.5 Gy < 3cc 
  
V13 Gy < 1cc 
V6.5 Gy < 1cc 
Large Bowel 
Dmax < 32 Gy 
*10 
Dmax < 16 Gy *10 
  
V28 Gy < 3cc 
V14 Gy < 3cc 
  
V22.5 Gy < 
1cc 
V11.2 Gy < 1cc 
Colon 
Dmax < 34 Gy 
*3 
Dmax < 17 Gy *3 
  
V23 Gy < 20 
cc *3 
V11.5 Gy < 20 cc *3 
  
  
  
Rectum 
Dmax < 34 Gy 
*3 
Dmax < 17 Gy *3 
  
V23 Gy < 20 
cc *3 
V22.5 Gy < 20 cc *3 
  
  
  
Kidneys (R&L) 
200 cc < 16.5 
Gy *10 
200 cc < 8.2 Gy *10 
  
  
  
Renal Hilum / Vascular Trunk 
V21 Gy < 55% 
*3 
V10.5 Gy < 55% *3 
  
  
  
Renal Cortex (R & L) 
200cc<16.2Gy 
*3 
200cc<8.12Gy *3 
  
  
  
Liver 
700 cc < 19 
Gy *3 
700 cc < 9.5 Gy *3 
  
  
  
Bladder Wall 
Dmax < 34 Gy 
*3 
Dmax < 17 Gy *3 
  
V 17 Gy < 
15cc *3 
V 8.5 Gy < 15cc *3 
  
  
  
Femoral Heads 
V27 Gy < 10 
cc  *3 
V13.5 Gy < 10 cc  *3 
PRV = Planning organ-at-risk volume 
GTV = Gross tumour volume 
1  RTOG 0915, http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0915  

Clinical Study Protocol 
Drug Substance Durvalumab 
Study Number ESR-15-10855 
Edition Number 1 
Date: June 5, 2017 
122 
 
2 Benedict SH et al., AAPM TG101, Med.Phys 37(9), 2010 (NB: max pt = 0.035cc) 
3   Timmerman RD.,  Seminars in Radiation Oncology 18:215-222, 
2008 
          
4  Karlsson K et al., IJROBP, 87(3): 590-595, 2013 
5  Baker R, IJROBP, 85(1):190-195, 2013  
6 Matsuo Yet al., IJROBP, 83(4): e545-549, 2012. 
7 Bongers EM et al., Radiother Onc, 109: 95-99, 2013 (VU EMC TO 2013)     
8  Dunlap NE et al., IJROBP 76(3): 796-801, 2010 
9  Forquer JA et al., Radiother Onc, 93:408-413,  2009 
10   SABR-COMET Trial, Palma et al, v.1.8, Nov 2013  (NB:max pt = 0.035cc)     
* EQD2 calculation (a/b=3Gy, except spinal cord a/b = 2Gy)