Phase I/II Study Assessing Safety & Efficacy of Consolidative Hypofractionated Radiation Therapy for Boosting Residual Primary Lung Cancer With Durvalumab After Definitive Chemoradiation Therapy for Stage III Non-small Cell Lung Cancer
Phase: PHASE1
Conditions: Lung Cancer, Carcinoma, Non-Small Cell Lung
Sponsor: University of Nebraska

 
 
 
Clinical Trials.Gov PRS Cover Sheet 
Official Title: Phase I/II study to assess the safety and efficacy of consolidative 
hypofractionated radiation therapy (hfRT) for boosting the residual primary lung cancer in 
combination with Durvalumab after definitive chemoradiation therapy for stage III non-
small cell lung cancer (NSCLC) 
NCT Number: NCT04748419 
Document Title: Study Protocol Version 1.8  
Document Date: 10 JUN 2024 
 
 

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Title: 
Phase I/II study to assess the safety and efficacy of consolidative 
hypofractionated radiation therapy (hfRT) for boosting the 
residual primary lung cancer in combination with Durvalumab 
after definitive chemoradiation therapy for stage III non-small 
cell lung cancer (NSCLC) 
  
Principal Investigator: Chi Zhang, MD 
 Associate Professor 
 987521 Nebraska Medical Center 
 Omaha, Ne 68198-7521 
 
Phone: 402-552-3147 
Fax: 402-552-3926 
Email: chi.zhang@unmc.edu 
  
UNMC Secondary 
Investigators: Apar Ganti, MD 
 Alissa Marr, MD 
  
  
Astra Zeneca Protocol 
number ESR-18-13876 
  
Biostatistician: Chris Wichman, PhD 
  
Study Drugs: Durvalumab  
  
IND: Exempt 
Clinical Trials.gov # NCT04748419 
NCI-CTRP #: NCI-2021-07137 
IRB approved Protocol 
Version: 
Version 1.3, dated 26Feb2021 
Version 1.4, Dated 10 Sep2021 
Version 1.5, dated 16Nov2021 
Version 1.6, dated 18Apr2022 
Version 1.7, dated 24Aug2022 
Version 1.8, dated 10Jun2024 
 

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  Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
A second CT simulation at radiation oncology will be performed within one week before the second cycle of 
durvalumab for planning of hfRT to be started and completed between the second and third cycle of durvalumab. 
Consolidative hfRT will start from 6.5Gy x 2 fractions and dose escalate to 10Gy x 2 fractions in a 3+3 design. See 
section 5.1.2 
b 
To make it uniform, for patients enrolled either prior to or after dCRT, Day 0 is defined as the date when post-
dCRT restaging imaging (CT or PET/CT) is performed.  
 
AE Adverse event; CR Complete response; PD Progression of disease; PR Partial response; RECIST Response Evaluation 
Criteria In Solid Tumors; SAE Serious adverse event; SD Stable disease. 
Informed Consent/Baseline Evaluation 
Assessments 
Week 2 CT simulation/First blood drawn 
Week 3-9 Definitive chemoradiation therapy (dCRT) 
(RT: 5 days/week on week days) 
 Weekly on-treat visit (every 5±3 days of RT) 
Routine lab tests and blood drawn for proposed studies (section 7.0) 
Post-dCRT tumor assessment with CT or PET/CT to confirm study 
eligibility b 
Optional consent, if not consented previously 
Registration 
Treatment period (assessments per Study Assessment Table) 
Start durvalumab after confirmation of eligibility, within 42 days after finishing definitive CRT, 10mg/kg IV, Q2wk 
Consolidative hypofractionated radiation therapy (hfRT) (investigational) between the second 
and third cycle of durvalumaba 
Tumor assessment using RECIST 1.1 performed at Week 10 and then every 12 weeks thereafter (relative to the date of final enrollment) 
Disease control at the end of 
12 months of treatment 
Discontinuation of durvalumab 
Potential for retreatment of patients who 
have experience disease control. A patient is 
only allowed to restart durvalumab ONCE. 
Due to toxicity or 
other reasons 
Due to confirmed 
progression of disease 
Continue tumor assessment using RECIST 1.1. F/U 
assessments per Study Assessments until confirmed 
Confirmed disease progression 
Follow-up assessments and survival contact 
per Follow up Assessments 

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Abstract 
This study is designed to determine if combining consolidative radiation therapy (RT) using a 
hypofractionated regimen (hfRT) of 10Gy x 2 fractions for boosting the residual primary lung cancer with 
adjuvant anti-PD-L1 therapy concurrently will provide better tumor control locoregionally and distantly 
than either modality alone. For safety reasons, consolidative hfRT will start from 6.5Gy x 2 fractions and 
dose escalate to 10Gy x 2 fractions in a 3+3 design. Consolidative hfRT will be delivered one to two 
months after finishing definitive chemoradiation therapy (dCRT) and concurrently with adjuvant anti-PD-
L1 therapy using durvalumab in stage III non-small cell lung cancer (NSCLC).  
At the final determined consolidative hfRT dose level, a total of thirty-two subjects with pathologically 
documented stage III NSCLC treated with two or more cycles of platinum-based doublet chemotherapy 
concurrently with dCRT will be enrolled for data analyses.  
Follow-up assessments will occur every 3 months during durvalumab therapy and for 1 year following, 
then after 2 years from study day 0 every 4-6 months until confirmed disease progression or death. Primary 
endpoints include toxicities and safety of boost hfRT and anti-PD-L1 therapy adjuvantly following dCRT, 
and the 12-month progression-free survival to compare with historical results.  
 
 

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TABLE OF CONTENTS  
 
 
 
 
 
 
PAGE 
Study Schema…………………………………………………………………….……...2 
Abstract…………………………………………………………………………………. 3 
Abbreviations and definition of terms…………………………………………….….… 5 
1.0 
Study Objectives………………………………………………………………... 7 
2.0 
Introduction………………………………………………………………....…... 9 
3.0 
Patient Selection..……………………………………………………….........…19 
4.0 
Registration  Procedures…………………………………………...…….…. ….24 
5.0 
Treatment Plan……………………………………………………...……….… 25 
6.0 
Measurement Effects………………………………………………………....... 52 
7.0 
Study Parameters…………………………………………………………….… 56 
8.0 
Drug Formulation and Procurement……………………………….....................62 
9.0 
Toxicity Reporting Guidelines……………………………………………….....64 
10.0 
Statistical Considerations………………………………………………...……. 72 
11.0 
Records to Be Kept…………..……………………………………................….75 
12.0 
Patient Consent Form Statement………………………………………….…….76 
13.0 
References……………………………………………………………………....78 
14.0 
Data Forms………………………………………………………………..….…81 
Appendices 
Appendix I – Dosing Modification and Toxicity Management Guidelines…………….82 
Appendix II – Durvalumab Dosing…………………………………………………….111 
Appendix III – Eligibility checklist ……………………………………………………112 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aRP 
acute radiation pneumonitis 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
CR 
Complete response 
ctDNA 
Circulating Tumor DNA 
CTV 
Clinical Tumor Volume 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen-4 
dCRT 
definitive chemoradiation therapy 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FFPE 
Formalin fixed paraffin embedded 
GTV 
Gross Tumor Volume 
HIV 
Human immunodeficiency virus 
hfRT 
hypofractionated radiation therapy 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IL 
Interleukin 
imAE 
Immune-mediated adverse event 
IP 
investigational product 
IRB 
Institutional Review Board 
iSABR 
Immunotherapy stereotactic ablative radiotherapy 

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ITV 
Internal Tumor Volume 
miRNA 
Micro ribonucleic acid 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NED 
No evidence of disease 
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
Q4W 
Every 4 weeks 
Q12W 
Every 12 weeks 
QoL 
Quality of life 
QTcF 
QT interval on ECG corrected using the Frederica’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SD 
Stable disease 
sPD-L1 
Soluble programmed cell death ligand 1 
TNF 
Tumor necrosis factor  
TSH 
Thyroid stimulating hormone 
TTDM 
Time to Death or Distant Metastasis 
ULN 
Upper limit of normal 

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Section 1.0 STUDY OBJECTIVES 
1.1 Primary objective(s) 
Primary objectives 
Outcome measure 
To evaluate the safety of combining 
hfRT and durvalumab 
Adverse events (AEs) will be assessed during the 
entire course of study after study drug start by physical 
examinations, vital signs including blood pressure, 
pulse, electrocardiograms, etc., diagnostic imaging 
including CT, PET/CT, MRI, etc., and laboratory 
findings including clinical chemistry, hematology and 
urinalysis. 
To evaluate 12-month PFS when 
combining hfRT with adjuvant anti-
PD-L1 therapy 
PFS based on assessments according to RECIST 1.1a 
a The co-primary analysis of PFS will be based on programmatically derived PFS using tumor information recorded in the 
clinical database by the investigator according to RECIST 1.1 
PFS Progression-free survival; RECIST Response Evaluation Criteria In Solid Tumors. 
 
1.2 Secondary objective(s) 
Secondary objectives 
Outcome measure 
To evaluate 18-month PFS when 
combining hfRT with adjuvant anti-
PD-L1 therapy 
PFS based on assessments according to RECIST 1.1a 
To evaluate 12-month Overall survival 
(OS) when combining hfRT with 
adjuvant anti-PD-L1 therapy 
OS 
To evaluate the rate of local control 
(LC), locoregional control (LRC), 
DM, TTDM 
LF12, LRF12 and DM12 rates will be calculated at the 
end of 12-month follow-up based on assessments 
according to RECIST 1.1a 
To assess symptoms and health- 
related quality of life in patients 
treated with Durvalumab plus 
hfRT using EORTC QLQ- C30 v3 
and LC13 module 
EORTC QLQ-C30: Time to symptom deterioration 
(fatigue, pain, nausea/vomiting, dyspnea, loss of 
appetite, insomnia, constipation, and diarrhea). Time 
to QoL/function deterioration (physical function; role   
function;     emotional     function;  cognitive function; 
social function and global health status/QoL) 
LC13: Time to symptom deterioration (dyspnea, 
cough, hemoptysis, chest pain, arm/shoulder pain, 
other pain) 
Changes in ECOG Performance Status will also be 
assessed 
a Analysis of LC, LRC and DM will be based upon tumor information recorded in the clinical database by the investigator according 
to RECIST 1.1. 

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Abbreviations: AE Adverse event; DM distant metastasis; LF12 Proportion of patients alive and developed local failure within 12 months 
from day 0; LRF12 Proportion of patients alive and developed locoregional failure within 12 months from day0; DM12 Proportion 
of patients alive and developed distant metastasis within 12 months from day0; TTDM time to death or distant metastasis is defined 
as the time from the day0 until the first date of distant metastasis or death in the absence of distant metastasis; EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire; LC13 Lung Cancer 
Module; QoL Quality of Life; RECIST Response Evaluation Criteria In Solid Tumours. 
 
1.3 Exploratory objective(s) 
Exploratory objectives 
Outcome measure 
To evaluate the effects of combined 
treatment on tumor 
microenvironment 
Biomarker analysis of tissue biopsied after hfRT to 
assess exploratory markers which may include but is 
not limited to: immune cell gene expression profiles 
within the tumoral compartments, the presence of IFN-
γ tumor necrosis factor-α, IL-2, IL-6, IL-8, IL-10, and 
IL-12 as well as expression of PD-L1 and the number 
and phenotype of immune cells such as T-cells, M1 and 
M2 subtypes of macrophage, and dendritic cells by 
immunohistochemistry methods. 
To evaluate the systemic effects of 
combined therapy by testing circulating 
tumor RNA/DNA, and cytokine levels. 
Biomarker analysis of blood collected before dCRT, 
during dCRT, after dCRT and before starting 
durvalumab, after starting durvalumab and before 
hfRT, and after hfRT to assess exploratory markers 
which may include but is not limited to: immune cell 
gene expression profiles in the peripheral blood, the 
presence of IFN-γ tumor necrosis factor-α, IL-2, IL-6, 
IL-8, IL-10, and IL-12 as well as antibodies against 
tumor, self, or viral antigens, and the number and 
differential of immune cells such as neutrophils, T-
cells, B cells, monocytes, etc.. 
To explore potential biomarkers in 
residual biological samples (e.g., tumor, 
plasma and/or serum), which may 
influence the progression of cancer (and 
associated clinical characteristics) 
and/or prospectively identify patients 
likely to respond to Durvalumab/hfRT 
treatment 
Correlation 
of 
biomarkers 
with 
response 
to 
durvalumab/hfRT treatment and/or the progression of 
cancer and/or toxicities 
To evaluate the potential difference 
in pattern and treatment response and 
the potential relationship between 
acute radiation pneumonitis (aRP) 
during dCRT and shortly after hfRT. 
The timing of onset, severity of symptoms, imaging 
features and treatment response to steroids for patients 
who develop aRP during or shortly after dCRT but 
prior to starting of durvalumab will be compared with 
aRP within three months after hfRT. Whether 
developing aRP during dCRT is predictive to aRP after 
hfRT will be explored in this study. 

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a PD-L1 expression determined by immunohistochemistry will be reported in the Clinical Study Report (CSR). Other exploratory 
biomarker research will be reported outside the CSR. 
 
Section 2.0 INTRODUCTION 
2.1 Disease background 
Worldwide, lung cancer has been the most common cancer in the past few decades. In 2018, there 
were an estimated 2.1 million new cases, representing 11.6% of all new cancers. It was also the 
most common cause of death from cancer, with 1.8 million deaths (18.4% of the total) 
(GLOBOCAN 2018). Non-small cell lung cancer (NSCLC) represents approximately 80% to 85% 
of all lung cancers and 30% of patients present with Stage III disease.  
• Standard treatment for patients with a good performance status and unresectable Stage III 
NSCLC is platinum- based doublet chemotherapy and radiotherapy administered with 
curative intent followed by maintenance durvalumab therapy.  
• Unresectable stage III disease includes unresectable IIIA/B (N2) disease based on bulky (> 
2 cm in short-axis diameter measured by chest CT) and multiple mediastinal nodal 
involvement and IIIB/C disease based on unresectable T4 involvement or any N3-disease 
in mediastinal nodes (Robinson et al 2007; Eberhardt et al 2015).  
A meta- analysis of concurrent versus sequential chemoradiotherapy for unresectable stage III 
disease showed better outcomes with concurrent therapy, but even with concurrent 
chemoradiotherapy 5-year overall survival (OS) is approximately 15% (Butts et al 2014). Recently, 
results from the phase III PACIFIC trial have been reported comparing consolidative durvalumab 
vs. placebo after definitive concurrent chemoradiation therapy (dCRT) in patients with stage III 
unresectable NSCLC (Antonia et al 2017). Significantly improved progression-free survival (PFS) 
was seen for patients who received consolidative durvalumab therapy (17.2 months) compared to 
placebo (5.6 months), as well as 2-year overall survival (66.3% vs. 55.6%) (Antonia et al 2018). 
Although the long term survival data is not available, nearly 50% of patients will experience 
disease progression and/or death within 18 months after dCRT. 
 
Thus exploring other consolidative therapies with durvalumab in an attempt to further extend 
disease control and improve overall survival in patients with stage III NSCLC is warranted. 
 
2.1.1 Immunotherapy 
Cancers are recognized by the immune system, and, under some circumstances,  the  immune  
system  controls  or  even  eliminates  them (Dunn  et al 2004).  PD-L1 is one part of a complex 
system of receptors and ligands involved in controlling T- cell activation. The PD-1 receptor, 
(CD279) expressed on the surface of activated T cells (Keir et al 2008) has 2 known ligands: PD-
L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) (Okazaki and Honjo 2007). When PD-L1 binds 
to PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine production and 
suppresses T-cell proliferation. Tumor cells exploit this immune checkpoint pathway as a 
mechanism to evade detection and inhibit immune response. 
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 2016). 
Importantly, PD-L1 is commonly over-expressed on tumor cells or on non-transformed cells in 
the tumor microenvironment (Pardoll 2012). PD-L1 expressed on the tumor cells binds to PD-1 
receptors on the activated T-cells leading to the inhibition of cytotoxic T cells. These deactivated 
T cells remain inhibited in the tumor microenvironment. The PD-1/PD-L1 pathway represents an 
adaptive immune resistance mechanism that is exerted by tumor cells in response to endogenous 
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The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of 
evading immune detection and elimination. The binding of an anti–PD-L1 agent to the PD- L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on 
immune cells. This activity overcomes PD-L1–mediated inhibition of antitumor immunity. 
While functional blockade of PD-L1 results in T-cell reactivation, this mechanism of action is 
different from direct agonism of a stimulatory receptor such as CD28. 
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti–PD-L1 
antibody could be used therapeutically to enhance antitumor immune responses in patients with 
cancer. Results of non-clinical and clinical studies of monoclonal antibodies (mAbs) targeting 
the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable safety 
profile, supporting the hypothesis that an anti–PD-L1 antibody could be used to therapeutically 
enhance antitumor immune response in cancer patients (Brahmer et al, 2012; Hirano et al, 2005; 
Iwai et al, 2002; Okudaira et al, 2009; Topalian et al, 2012; Zhang et al, 2008) with responses 
that tend to be more pronounced in patients with tumors that express PD-L1 (Powles et al, 2014; 
Rizvi et al 2015; Segal et al 2015). In addition, high mutational burden (e.g., in bladder 
carcinoma [Alexandrov et al, 2013]) may contribute to the responses seen with immune therapy. 
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively expressed by 
regulatory T cells and upregulated on activated T cells. CTLA-4 delivers a negative regulatory 
signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on antigen- presenting cells 
(Fife and Bluestone, 2008). Blockade of CTLA-4 binding to CD80/86 by anti– CTLA-4 antibodies 
results in markedly enhanced T-cell activation and antitumor activity in animal models, including 
killing of established murine solid tumors and induction of protective antitumor immunity. 
Therefore, it is expected that treatment with an anti–CTLA-4 antibody will lead to increased 
activation of the human immune system, increasing antitumor activity in patients with solid 
tumors. 
Pre-clinical data have supplemented a wealth of clinical data showing that blockade of negative 
regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and 
programmed death ligand 1 (PD-L1) has promising clinical activity.  
 
2.2. Durvalumab background/non-clinical and clinical experience 
The non-clinical and clinical experience is fully described in the most current version of the 
durvalumab Investigator’s Brochure. 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1 and has been developed by AstraZeneca/MedImmune for 
use in the treatment of cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document). The 
proposed mechanism of action (MOA) for durvalumab is interference in the interaction of PD-L1 
with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases 
the inhibition of immune responses, including those that may result in tumor elimination. In vitro 
studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary 
human T cells resulting in the restored proliferation of IFN-γ (Stewart et al 2015). In vivo studies 
have shown that durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent 
mechanism (Stewart et al 2015). Based on these data, durvalumab is expected to stimulate the 
patient’s antitumor immune response by binding to PD-L1 and shifting the balance toward an 
antitumor response. Durvalumab has been engineered to reduce antibody- dependent cellular 
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To date durvalumab has been given to more than 9000 patients as part of ongoing studies either 
as monotherapy or in combination with other anti-cancer agents. Details on the safety profile of 
durvalumab monotherapy are summarized in Appendix I. Refer to the current durvalumab 
Investigator’s Brochure for a complete summary of non-clinical and clinical information 
including safety, efficacy and pharmacokinetics. 
 
2.2.1 Clinical data demonstrating efficacy of consolidative durvalumab for stage III 
NSCLC 
In the recently published results from PACIFIC trial, efficacy of durvalumab as consolidative 
therapy after definitive CRT for stage III nonresectable NSCLC has been demonstrated. From 
May 2014 through April 2016, a total of 713 patients underwent randomization, of whom 709 
(99.4%) received at least one dose of durvalumab or placebo after chemoradiotherapy. 
Randomization occurred 1 to 42 days after the patients had received chemoradiotherapy in a 2:1 
ratio to receive durvalumab at a dose of 10 mg per kilogram (mg/kg) of body weight 
intravenously or matching placebo every 2 weeks as consolidation therapy for up to 12 months. 
The 12-month overall survival rate was 83.1% in the durvalumab group, as compared with 
75.3% in the placebo group. The 24-month overall survival rate was 66.3% in the durvalumab 
group, versus 55.6% in the placebo group (two-sided P=0.005). Durvalumab significantly 
prolonged overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 
99.73% CI, 0.47 to 0.997; P=0.0025). The overall survival benefit with durvalumab was 
observed across all the pre-specified subgroups. Progression-free survival was also significantly 
longer with durvalumab than with placebo. The 12-month progression- free survival rate was 
55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 
27.0%.The median progression-free survival from randomization was 17.2 months in the 
durvalumab group, as compared with 5.6 months in the placebo group (stratified hazard ratio for 
disease progression or death, 0.51; 95% CI, 0.41 to 0.63). The overall response rate was 30.0% 
in the durvalumab group, as compared with 17.8% in the placebo group (P<0.001). 12-month 
distant metastasis-free survival was estimated to be 73% in durvalumab group compared with an 
estimated 59% in placebo group. 
 
2.3 Immunostimulatory radiation therapy regimen 
Radiation therapy (RT) has long been indicated to induce immune response as demonstrated by 
the abscopal effect, in which a systemic tumor response has been observed after local RT. 
Although previously thought to be an infrequent event, increasing cases of abscopal effects have 
been reported since immune checkpoint inhibitors were introduced along with recently increased 
use of stereotactic body radiation therapy (SBRT), which raised new interests in exploring 
immunoradiotherapy strategies. A wide variety of RT schemes were used in combination with 
immunotherapy in preclinical research ranging from conventional/low dose fractionation of 1.8 
to 5Gy/fraction, to intermediate dose per fraction (6Gy/fraction x 5 fractions, 8Gy/fraction x 3 
fractions, etc.), to high dose in single fraction (12-30Gy per fraction). In pre-clinical settings 
higher dose per fraction of RT such as the dose regimen used for SBRT is more likely to be 
immunostimulating than conventional fractionated RT (3-6). However, radiation dose and 
fractionation schedules for optimal synergy between radiotherapy and immunotherapy are not 
well defined in clinical settings. In pre- clinical including animal studies, RT was able to induce 
cell surface markers such as Fas, MHC I, ICAM-1, etc. Most of the animal model studies showed 
that the optimal increase in cell surface receptor expression resulted from a relatively large single 
dose of radiation (≥8 Gy) rather than conventional/low dose fractionation. Furthermore, the large 

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single fraction regimen also has a higher likelihood of altering the tumor microenvironment by 
facilitating infiltration of host immune cells such as macrophages, dendritic cells, or tumor 
antigen specific cytotoxic T lymphocytes (CTLs). Schaue et al showed that, when using a mouse 
melanoma model, treatment with single fractions of 7.5Gy or moderately higher doses was 
associated with an increase in anti-tumor CTLs and a decrease in regulatory T cells (Tregs), thus 
being immunosimulatory which is not seen in 5Gy x 1 regimen (Schaue et al 2012). Surprisingly, 
when the single fractional dose increased to 15Gy, RT not only increased the infiltration of anti-
tumor CTLs but also the Tregs which may now in turn dampen the immunostimulation. 
However, when mice were irradiated with 15Gy total dose but fractionated in two, three or five 
fractions, ie., 7.5Gy x 2, 5Gy x3 or 3Gy x5 fractions, the 2-fraction regimen (7.5Gy x2 fractions) 
induced the highest level of anti-tumor CTLs and the lowest level of Tregs in the treated area, 
achieving the best tumor control. The authors hypothesized that the ratio of anti-tumor CTLs to 
Tregs might be a critical factor reflecting the aggregate effect of a particular RT regimen on the 
immunostimulatory and immunosuppressive pathways, with the most immunosimulating 
regimen being most likely ranging from 7.5Gy to 15Gy per fraction. When combining RT with 
immune checkpoint blockade such as using anti-CTLA-4 antibody in a mouse model, the most 
immunostimulating RT fractional dose falls into this range as well as reported by Demaria et al 
(7). In their study using a mouse breast model, tumor cells were injected subcutaneously in mice 
at a primary site which was irradiated and a secondary site that was distal and outside the RT 
field. Mice were randomized to RT alone, anti-CTLA-4 antibody 9H10 alone, or a combination 
of RT and 9H10 antibody. Three different fractionation regimen were tested: 20Gy x 1, 8G x3, 
or 6Gy x 5 fractions. 8Gy x3 in combination with anti-CTLA4 was significantly more effective 
than 6Gy x5 in inhibiting tumor growth at both the primary and secondary sites. 20Gy x 1, 
although showing primary site tumor control, was ineffective in inducing an immune-mediated 
response at the secondary site. As for combining RT with PD- 1/PD-L1 antibody studies, Zeng et 
al also confirmed the efficacy of a RT regimen of 12Gy x 1 fraction, when combined with anti-
PD-1 antibody, produces long-term survival in a mouse glioma model which was not seen in 
either therapy alone (8). This dose regimen induced increased infiltration by cytotoxic T cells 
and decreased Tregs within the tumor microenvironment of gliomas. The same regimen of 12Gy 
x 1 has also shown synergistic inhibitory effects with anti-PD-L1 therapy in TUBO mammary 
carcinoma and colon adenocarcinoma mouse models, indicating the most immunostimulating RT 
dose range (7.5- 15Gy per fraction) shown by Schaue et al is very likely shared among different 
types of primary tumors (Deng et al 2014). We thus propose to conduct a phase I/II clinical trial 
testing a consolidative radiation therapy using a regimen within this range with a concurrent PD-
L1 antibody, Durvalumab, in nonresectable stage III NSCLC, after definitive CRT.  This is a 
trial designed as a follow-up study to the recently completed PACIFIC trial. 
 
2.3.1 Clinical experience of the feasibility of consolidative lung SBRT after definitive 
chemoradiation therapy 
One of the main concerns of adding consolidative RT with potential immunostimulatory effects 
after definitive CRT is pulmonary toxicity, particularly with anti-PD-L1 therapy. A prospective 
study has been conducted at University of Kentucky on thirty-seven patients with stage IIB/III 
NSCLC who underwent computed tomography (CT) or positron emission tomography–
computed tomography (PET/CT) and were screened approximately 1 month after completion of 
definitive CRT (Kumar et al 2017). Limited residual disease (≤5 cm) within the site of the 
primary tumor received  a  stereotactic  radiation  therapy    boost  of  either  10 Gy × 2  fractions  
or 6.5 Gy × 3 fractions to the primary tumor, to achieve a total Biologically Equivalent Dose 

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(BED) >100 Gy. This study did not include anti-PD-L1 therapy. The long term toxicities were 
reported, five patients (13.5%) experienced grade 3 pneumonitis, four developed acutely within 
three months after SBRT and one late onset. This is comparable to historical “moderate to 
severe” radiation pneumonitis rates of 8.0% to 15.3% per the authors. No grade 4 or 5 
pneumonitis occurred. Predictors for grade 3 pneumonitis included age and mean lung dose 
during definitive CRT. For any grade of pneumonitis, current nonsmoking status was found to be 
protective (P<.01). Two patients experienced fatal bleeds. However, no significant dosimetric 
differences in RT were found between patients who developed a fatal hemorrhage and those who 
did not, with a calculated average maximum pulmonary artery dose of 175 Gy (BED3). Each 
hemorrhage was found to be related to local tumor recurrence in the hilum. Other grade 1 and 2 
toxicities were observed including fatigue (7 patients), chest wall pain (5 patients), and 
esophagitis (4 patients). Hypofractionated RT boost or consolidative RT with SBRT after CRT is 
thus considered a safe treatment. 
 
Possible improvement in local control for locally advanced NSCLC with SBRT boost was 
predicted. With a median follow-up of 25.2 months, overall 22% patients experienced local 
failure, 29% regional failure, 41% locoregional failure, and 65% distant failure. Median PFS was 
6.5 months; 1-, 3-, and 5-year PFS was 30.9%, 16.8%, and 9.4%, respectively for the entire 
cohort. Interestingly, when comparing the outcome of boost dose regimens, although 6.5 Gy x3 
fractions has a slightly lower BED (102.2 Gy including the definitive conventional fractionated 
RT dose) than 10 Gy x 2 fractions (110 Gy), both achieved similar rates of local control (22% vs. 
21%, P=1.0). However, the survival for the 20 Gy boost (10 Gy x 2 fractions) were numerically 
better. Median OS was 19.2 months for the 19.5 Gy boost vs. 26.4 months for the 20 Gy boost 
(P=0.05). Although not statistically significantly different, the PFS curves of 19.5 Gy and 20 Gy 
boost treatment started to separate after 6 months with 20 Gy boost showing much better long-
term disease control. Although no conclusion can be drawn from these data with the small 
number of patients in each group and a nonrandomized design, a possible stronger 
immunostimulatory effect from 10Gy x 2 fractions than 6.5Gy x 3 fractions could partly explain 
the difference.  
 
2.3.2 Clinical evidence of the safety and abscopal effects of combining hfRT/SBRT with 
immunotherapy in lung cancer 
Although no data at all available for combining hfRT/SBRT with immunotherapy after dCRT 
which makes our proposed study novel, there are small scaled prospective studies available on 
current use of immunotherapy including PD-1/PD-L1 inhibitors with SBRT in lung cancer and 
other solid tumors. The following two studies showed abscopal effects and low risks of grade 3 
toxicities combining SBRT and immunotherapy particularly for lung cancer. 
 
The University of Chicago recently completed a phase I study of SBRT followed by 
pembrolizumab (anti-PD-L1) in patients with multiple sites of metastatic solid tumors (Luke et 
al 2018). Two to four metastases were targeted with SBRT to 30–50 Gy in 3–5 fractions, and 
pembrolizumab was initiated 7 days after completion of SBRT. The cohort of 73 patients was 
heavily pre-treated, with a median of five prior therapies. Of the total 151 sites of metastases 
irradiated, 68 were in the lung, 24 in the liver, 28 in other abdomen/pelvis sites, 16 in the bone, 
and 15 near the spine. The abscopal response rate per RECIST criteria of any single non-
irradiated target metastasis was an impressive 26.9%. This off-target effects, or abscopal effects, 
generated by combined SBRT and immunotherapy, if can be reproduced in our study, would 

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potentially significantly improve regional and distal control of stage III NSCLC. Grade 3 toxicity 
was seen in 6 patients (pneumonitis n=3; colitis n=2; hepatic toxicity n=1). So the overall grade 3 
pneumonitis risk is only 4.4%. These promising results in a heterogenous group of tumors 
support further studies combining checkpoint inhibitors with SBRT. 
 
More specifically, the short-term safety of combining thoracic SBRT and immunotherapy was 
recently explored in a combined analysis of two prospective trials ongoing at MD Anderson 
(Verma et al 2018). The first was the phase 1–2 trial testing SBRT with ipilimumab (anti-
CTLA4). The second was another ongoing phase 1–2 trial testing SBRT with concurrent 
pembrolizumab (anti-PD-L1) in metastatic NSCLC. SBRT dose was 50 Gy in 4 fractions or 60 
Gy in 10 fractions. Out of 60 patients with a median follow up of 6.9 months (range, 0.5–30.9 
months), there were no grade ≥4 toxicities. Only 4 patients experienced grade 3 pulmonary 
toxicities with no difference between the ipilimumab and pembrolizumab groups. These short-
term pulmonary toxicity rates were on par with RTOG 0236 which was a phase II study with 
SBRT only for stage I NSCLC, in which 8 of 55 patients developed grade 3 respiratory events 
(Timmerman et al 2010). 
 
 
2.4 Research hypothesis 
We hypothesize that combining consolidative RT using hypofractionated (hfRT) regimen of 
10Gy x 2 fractions for boosting the residual primary lung cancer with adjuvant anti-PD-L1 
therapy will further improve immunostimulation and provide better tumor control locoregionally 
and distantly than either modality alone. Consolidative RT will be delivered one to two months 
after finishing definitive chemoradiation therapy and concurrently with consolidative/adjuvant 
anti-PD-L1 therapy using durvalumab in stage III non-small cell lung cancer (NSCLC). 
Hypofractionated RT will be delivered between the second and third cycle of biweekly 
durvalumab. 
 
2.5 Rationale for conducting this study 
Immunotherapy has drastically changed the treatment of NSCLC and have established a new 
treatment paradigm for these patients. Recently results from the phase III PACIFIC trial have 
been reported comparing consolidative durvalumab vs. placebo after definitive chemoradiation 
therapy (dCRT) in patients with stage III unresectable NSCLC (Antonia et al 2017, 2018). 
Significantly improved PFS and OS were demonstrated for patients who received consolidative 
durvalumab therapy compared to placebo group. The FDA has now approved durvalumab as 
consolidation therapy for stage III NSCLC patients after definitive CRT. However, the PFS at 18 
months was only 44.2% even with durvalumab treatment, which is consistent with the results 
from RTOG 0617 which tested dose escalation of RT without immunotherapy (36.6%). There is 
clearly room for further improvement in tumor control for locally advanced NSCLC.  The 
proposed study of additional hfRT may potentiate/synergize the immunotherapy effects and 
further improve PFS.  
 
2.5.1 Durvalumab monotherapy dose rationale 
A durvalumab dose of 20 mg/kg Q4W is supported by in-vitro data, non-clinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with advanced 
solid tumors and from a Phase I trial performed in Japanese patients with advanced solid tumor 

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(D4190C00002). A durvalumab dose of 10 mg/kg Q2W intravenously was instead used in the 
phase III PACIFIC study. 
 
PK/Pharmacodynamic data 
Based on available PK/dynamics data from ongoing Study 1108 with doses ranging from 0.1 to 
10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear (dose-dependent) PK 
consistent with target-mediated drug disposition. The PK approached linearity at ≥3 mg/kg 
Q2W, suggesting near complete target saturation (membrane-bound and sPD-L1), and further 
shows that the durvalumab dosing frequency can be adapted to a particular regimen given the 
linearity seen at doses higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg Q2W is 
approximately 21 days. A dose-dependent suppression in peripheral sPD-L1 was observed over 
the dose range studied, consistent with engagement of durvalumab with PD-L1. A low level of 
immunogenicity has been observed. No patients have experienced immune-complex disease 
following exposure to durvalumab (For further information on immunogenicity, please see the 
current Investigator’s Brochure (IB)). 
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
Q2W or 15 mg/kg Q3W (Fairman et al 2014). Multiple simulations indicate that a similar overall 
exposure is expected following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as 
represented by AUCss (4 weeks). Median Cmax,ss is expected to be higher with 20 mg/kg Q4W 
(~1.5 fold) and median Ctrough,ss is expected to be higher with 10 mg/kg Q2W (~1.25 fold). 
Clinical activity with the 20 mg/kg Q4W dosing regimen is anticipated to be consistent with 10 
mg/kg Q2W with the proposed similar dose of 20 mg/kg Q4W expected to (a) achieve complete 
target saturation in majority of patients; (b) account for anticipated variability in PK, 
pharmacodynamics, and clinical activity in diverse cancer populations; (c) maintain sufficient 
PK exposure in case of ADA impact; and (d) achieve PK exposure that yielded maximal 
antitumor activity in animal models. 
Given the similar area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both regimens 
maintain complete sPD-L1 suppression at trough, and the available clinical data, the 20 mg/kg 
Q4W and 10 mg/kg Q2W regimens are expected to have similar efficacy and safety profiles. 
 
2.5.2 Rationale for fixed dosing 
A population PK model was developed for durvalumab using monotherapy data from a Phase I 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated a minor impact of body weight (WT) on the PK of durvalumab 
(coefficient of ≤0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg 
Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was 
selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 
patients were simulated using body WT distribution of 40–120 kg. Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady state 
PK concentrations with slightly less overall between-patient variability with fixed dosing 
regimen. 
Similar findings have  been  reported  by  others  (Ng  et  al  2006,  Wang  et al 2009,  Zhang et 
al 2012, Narwal et al 2013).  
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given the expectation of similar pharmacokinetic exposure and 

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variability, we considered it feasible to switch to fixed dosing regimens. Based on average body 
WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) can be 
considered for future studies. 
 
2.5.3 Regimen of durvalumab for current study 
To be able to best compare the results from this proposed clinical trial to the historic results from 
PACIFIC study, IV durvalumab of 10mg/kg Q2W used in the protocol of PACIFIC study will be 
the only regimen used in current study. 
 
2.5.4 Rationale for exploratory research 
Although numerous studies have been performed on tumor microenvironmental and systemic 
response to immunotherapies including PD-L1 blockade, there are scant data particularly from 
the lung cancer patients. The PACIFIC trial, which is the first clinical study that demonstrated 
the clinical benefit of adjuvant PD-L1 blockade after definitive chemoradiation therapy for stage 
III NSCLC, did not study the above mentioned questions which may be very valuable for 
predicting treatment response and important in selecting the right candidates for adjuvant 
immunotherapy both for maximizing the benefit of the treatment and for minimizing toxicities. 
 
We thus propose to perform the exploratory research on both tumor tissues from biopsy of the 
residual lung parenchymal tumor two months after consolidative hfRT and patients’ blood 
specimen.  
 
Blood will be drawn from each patient in this study with the schedule described in section 
5.2.3.2 for exploratory research on biomarker studies including sPD-L1, miRNA/mRNA, and 
cytokines, as well as ctDNA isolation for mutation and tumor burden studies and PBMC 
collection for flow cytometry. 
 
For patients enrolled in the trial who consent to a repeat biopsy of residual lung tumor and/or 
lymph nodes (optional) two months after consolidative hfRT, the fresh tumor tissue from 2-3 
core needle biopsy will be collected and processed to FFPE in a single block for PD-L1 testing 
as described in Section 5.2.3. If additional slides are available after PD-L1 staining, 
immunohistochemistry studies can be performed to study on immune cell infiltration into 
irradiated tumor microenvironment at Dr. Zhang’s laboratory and pertinent core centers at our 
institution.  
 
To evaluate the potential difference in pattern and treatment response and the potential 
correlations between acute radiation pneumonitis (aRP) during dCRT and shortly after hfRT, we 
plan to collect all aRP data from the start of dCRT to right before the first dose of durvalumab, 
and the acute onset of pneumonitis after the first fraction of hfRT and within three months after. 
Pneumonitis occurs three months after hfRT will be difficult to be assigned as late onset 
symptoms after dCRT or subacute after hfRT/immunotherapy thus will not be included in the 
comparison of aRPs caused by dCRT or hfRT, but will be captured for toxicities studies and 
counted as treatment-related AEs/SAEs. The timing of onset counting from the start of the first 
dose of RT (dCRT or hfRT respectively), severity of symptoms, imaging features and treatment 
response to steroids for patients who develop aRP during or shortly after dCRT but prior to 
starting of durvalumab will be compared with aRP within three months after hfRT. Whether 
developing aRP during dCRT is predictive to aRP after hfRT in timing or severity will be 

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explored in this study based on Spearman’s rank correlation coefficients. We expect that no more 
than 20% patients are likely to be enrolled after completion of chemo-radiation (dCRT), in which 
case the effective sample size for correlative purposes will be 26 (80% of 32). We would be able 
to detect a correlation of 0.53 vs no correlation with 80% power using a significance level of 
0.05. 
 
 
2.6 Benefit/risk and ethical assessment 
2.6.1 Potential benefits  
 
2.6.1.1 Durvalumab   
Results from the PACIFIC trial demonstrated the benefit of consolidative durvalumab in patients 
with stage III NSCLC after definitive CRT in DFS, PFS, and OS. 
 
2.6.1.2 Consolidative RT 
Both preclinical and clinical data suggest that the most immunostimulating regimen of RT most 
likely ranges from 7.5Gy to 15Gy per fraction. This effective dose range is likely shared among 
different types of cancer, and has been used commonly in stereotactic body radiation therapy 
(SBRT) or stereotactic ablative radiotherapy (SABR) in early stage lung cancer with excellent 
clinical outcome. Unlike conventional fractionated RT which is usually lower than 4 to 5 Gy per 
fraction, or the super-high fractional dose used in stereotactic radiosurgery (SRS) with 18Gy or 
higher per fraction, this immunostimulating range of dosing will optimally induce expression of 
certain cell surface markers, such as Fas, MHC I, ICAM I, etc., induce cytotoxic T cell 
infiltration and decrease immunosuppressive regulatory T cells, with improved local as well as 
systemic tumor control. These effects have been observed in tumors treated with this 
immunostimulating range of RT alone or when combined with anti-CTLA-4 therapy, anti-PD-1, 
or anti-PD-L1 therapy as described in detail in section 2.3. Emerging data from clinical trials 
combining RT and immunotherapy have also shown promise (Gandhi et al 2015, Monjazeb and 
Schoenfeld 2016, Weichselbaum et al 2017). Particularly, a recent retrospective review has 
examined the OS, incidence of toxicities and the timing of radiation in advanced stage NSCLC 
(including metastatic disease) patients who received nivolumab and external beam radiotherapy 
(iEBRT), nivolumab and stereotactic ablative radiotherapy (iSABR) and nivolumab 
monotherapy (Hegde et al 2018). The study demonstrated a significant 29% absolute 
improvement in 18-month OS with iSABR Sandwich when compared to nivolumab 
monotherapy and no OS improvement with EBRT given prior to initiation of nivolumab. Of 
note, iSABR sandwich group of patients all received conventional fractionated EBRT and 
received SABR during nivolumab therapy (Sandwich). This result indicates that there might be 
synergistic effects of SABR (using the immunostimulating dose range of RT) and immune 
checkpoint blockade drug(s) after conventional fractionated EBRT, but not EBRT only, which 
supports the rationale of current clinical trial as designed. 
 
The dose regimen selected for the consolidative RT in the current trial is unique in that it is not 
designed simply as for dose escalation. We propose to test the potential benefit of this 
immunogenic dosing of consolidative RT for further enhancing or even synergizing 
immunotherapy effects by durvalumab. More specifically, this immunogenic dose of 
consolidative RT to the residual primary tumor may alter the tumor microenvironment in 
residual primary tumor by increasing cytotoxic T cell infiltration to improve locoregional 

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control, as well as to enhance tumor antigen presentation by dendritic cells thus promoting 
immune reaction systemically to decrease distant metastasis, and ultimately improve survival. 
 
2.6.2 Overall risks 
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells. By stimulating the immune system, however, there are potentially 
increased adverse effects on other tissues. 
 
Most adverse drug reactions seen with the immune checkpoint inhibitors are thought to be due to 
the effects of inflammatory cells on specific tissues. These risks are generally events with a 
potential inflammatory or immune mediated mechanism and which may require more frequent 
monitoring and/or unique intervention such as immunosuppressants and/or endocrine therapy. 
These immune mediated effects can occur in nearly any organ system, and are most commonly 
seen as gastrointestinal AEs such as colitis and diarrhea, pneumonitis/interstitial lung disease 
(ILD), hepatic AEs such as hepatitis and liver enzyme elevations, skin events such as rash and 
dermatitis and endocrinopathies including hypo- and hyper-thyroidism. 
 
2.6.2.1 Durvalumab 
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal perforation, 
pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus (which 
may present with diabetic ketoacidosis), hypophysitis and adrenal insufficiency) 
hepatitis/increases in transaminases, nephritis/increases in creatinine, pancreatitis/increases in 
amylase and lipase, rash/pruritus/dermatitis (including pemphigoid), diabetes insipidus, 
encephalitis, myocarditis, myositis/polymyositis, other rare or less frequent inflammatory events 
including neurotoxicities, infusion-related reactions, hypersensitivity reactions and 
infections/serious infections and subcutaneous injection site reaction. 
For information on all identified and potential risks with durvalumab please always refer to the 
current version of the durvalumab IB. 
 
In monotherapy clinical studies, AEs (all grades) reported very commonly (≥ 20% of patients) 
are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back 
pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 10% of patients experienced an AE that resulted in permanent discontinuation of 
durvalumab and approximately 6% of patients experienced an SAE that was considered to be 
related to durvalumab by the study investigator. 
 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated (Appendix I) detailed summary of durvalumab 
monotherapy AE data can be found in the current version of the durvalumab IB.  
 
2.6.2.2 Consolidative RT 
Consolidative RT (10Gy x 2 fractions, QOD) after concurrent CRT with 60Gy of conventional 
fractionated EBRT to the residual lung cancer carries potential risks of increased rate of fatigue, 
chest wall pain, dermatitis, radiation pneumonitis, pneumonia, esophagitis, esophageal stenosis, 

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central airway necrosis, hemoptysis, spinal cord injury, arrhythmia and pericarditis, than 
definitive CRT only. 
A prospective study has been conducted at the University of Kentucky on thirty-seven patients 
with stage IIB/III NSCLC with consolidative RT tested after completion of definitive CRT as 
described in section 2.3.1 (Kumar et al 2017). Limited residual disease (≤5 cm) within the site of 
the primary tumor after definitive CRT received a SBRT boost or consolidative RT of either 10 
Gy × 2 fractions or 6.5 Gy × 3 fractions to the primary tumor, to achieve a total Biologically 
Equivalent Dose (BED) >100 Gy. This study did not include anti-PD-L1 therapy. The long term 
toxicities were reported, and five patients (13.5%) experienced grade 3 pneumonitis. There were 
no grade 4 or 5 pneumonitis events. After long-term follow-up, no additional cases of late fatal 
bleeding were found. Other grade 1 or 2 toxicities were observed including fatigue (7 patients), 
chest wall pain (5 patients), and esophagitis (4 patients). 
Hypofractionated RT boost with SBRT after CRT is thus considered a safe treatment. 
However, with the hypothesis that hfRT using SBRT planning of immunostimulating fractional 
dose range may synergize immunotherapy drug such as durvalumab in tumor control, hfRT 
could potentially increase normal tissue toxicities such as tissues within or adjacent to RT field 
including lung, heart, esophagus, chest wall, spinal cord, etc., as well as distant organs including 
thyroid (thyroiditis), pituitary gland (hypophysitis), rash (dermatitis), gastrointestine 
(gastroenteritis), liver (hepatitis) and other autoimmune disease. 
 
2.6.2.3 Overall benefit-risk 
In summary, the potential for clinical benefit associated with combining hfRT using 
immunostimulating range of dose and inhibitor of PD-1/PD-L1 pathway such as durvalumab, 
supported by numerous preclinical studies and survival benefit observed in earlier clinical studies 
in patients with advanced stage NSCLC, outweighs the known and potential risks based on the 
AEs reported in patients treated with durvalumab and other PD- 1/PD-L1 inhibitors, or 
consolidative RT alone. Thus, the benefit/risk assessment favors the conduct of this proposed 
study. 
 
Section 3.0 PATIENT SELECTION 
3.1 Inclusion criteria 
 
Inclusion Criteria:  
1. 
Pathologically diagnosed NSCLC (squamous cell carcinoma, adenocarcinoma, large- 
cell carcinoma, or non-small-cell lung cancer not otherwise specified), clinical stage 
III (AJCC 8th Ed.) 
 
2. 
At time of consent, potential subjects must be a candidate for dCRT  
OR 
 Must have received dCRT with at least 2 cycles of platinum-based chemotherapy 
 concurrent with conventional fractionated radiation therapy with a total dose of 5700 - 
 6300 cGy 
 
3. 
Patients must be aware of the nature of his/her disease and willingly provide written, 
informed consent. Including compliance with the requirements and restrictions listed 
in the informed consent form (ICF) and in this protocol. Written informed consent 
and any locally required authorization (e.g., Health Insurance Portability and 

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Accountability Act in the US) obtained from the patient/legal representative prior to 
performing any protocol-related procedures, including screening evaluations. 
 
4. 
Age ≥ 19 years at time of study entry 
 
5. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at time of 
enrollment. 
 
6. 
Life expectancy of > 12 weeks 
 
7. 
Adequate normal organ and marrow function as defined below: 
− 
Hemoglobin ≥9.0 g/dL (5.59 mmol/L) (patients can be transfused to meet this 
criterion) 
− 
Absolute neutrophil count (ANC) > 1500 per mm
3 
− 
Platelet count ≥100 x 109/L (>100,000 per mm
3) 
− 
Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not 
apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of 
hemolysis or hepatic pathology), who will be allowed only in consultation with 
their physician. 
− 
AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal. 
− 
Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula 
(Cockcroft and Gault 1976)  
Males: 
Creatinine CL 
(mL/min) 
= Weight (kg) x (140 – Age) 
72 x serum creatinine (mg/dL) 
Females: 
Creatinine CL 
(mL/min) 
= Weight (kg) x (140 – Age) 
x 0.85 
72 x serum creatinine (mg/dL) 
 
8. 
Evidence of post-menopausal status or negative serum pregnancy test for female pre-
menopausal patients. 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 

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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) 
 
9. 
Patient is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including 
follow up 
 
3.2 Exclusion criteria 
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site) 
2. Patients who have received prior anti–PD-1, anti PD-L1 or anti CTLA-4 
3. Participation in another clinical study with an investigational product during the last 4 
weeks 
4. Concurrent enrollment in another clinical study, unless it is an observational (non- 
interventional) clinical study or during the follow-up period of an interventional study 
5. Mixed small cell and non-small cell lung cancer histology 
6. Patients who receive sequential chemoradiation therapy for locally advanced NSCLC 
7. Patients with locally advanced NSCLC who have progressed during definitive platinum 
based, concurrent chemoradiation therapy 
8. Any unresolved toxicity (NCI CTCAE Grade >2) from previous anticancer therapy with the 
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria 
 
a. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician. 
b. Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab may be included only after consultation with the 
Study Physician. For example, post-operative neurological deficits for previous 
benign brain tumors, urinary incontinence from radical prostectomy for prostate 
cancer, peripheral neuropathy from chemotherapy for breast cancer.  
 
9. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer 
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., 
hormone replacement therapy) is acceptable.  
10. Major surgical procedure (as defined by the investigator) within 28 days to the first dose of 
immunotherapy (excluding the placement of vascular access) that would prevent 
administration of study drug or radiation therapy. 
11. History of allogenic organ transplantation. 
12. Active or prior documented autoimmune or inflammatory disorders within the past 2 years 
(including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with 
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis 
hypophysitis, uveitis, etc]). The following are exceptions to this criterion: 
a. Patients with vitiligo or alopecia 
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome stable on 
hormone replacement or Graves’ disease). 

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c. Any chronic skin condition including psoriasis that does not require systemic 
therapy (within the past 2 years). 
d. Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician. 
e. Patients with celiac disease controlled by diet alone. 
13. Known allergy or hypersensitivity to Durvalumab or any excipient. 
14. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions 
associated with diarrhea, or psychiatric illness/social situations that would limit compliance 
with study requirement, substantially increase risk of incurring AEs or compromise the 
ability of the patient to give written informed consent 
15. History of another primary malignancy except for 
a. Malignancy treated with curative intent and with no known active disease ≥5 
years before the informed consent and of low potential risk for recurrence 
b.  Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
c. Adequately treated carcinoma in situ without evidence of disease 
16. History of primary immunodeficiency 
17. Known history or active infection of tuberculosis, hepatitis B (known positive HBV 
surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive 
HIV 1/2 antibodies).  
18. Current or prior use of immunosuppressive medication within 14 days before the first dose 
of durvalumab. The following are exceptions to this criterion: 
a.  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection) 
b. Systemic corticosteroids at doses ≤10 mg/day of prednisone or its equivalent 
c.  Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
d. Systemic steroid administration required to manage toxicities arising from 
radiation therapy delivered as part of the chemoradiation therapy for locally 
advanced NSCLC is allowed. 
19. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccines whilst receiving IP and up to 30 days 
after the last dose of IP. 
20. Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from screening 
to 90 days after the last dose of durvalumab therapy. 
21. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical 
study regardless of treatment arm assignment. 
22. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE >Grade 1. 
23. Previous history of RT (other than RT as part of the dCRT for the current course of 
NSCLC) involving any part of lungs, chest wall, thoracic spine or breast(s). 
24. Judgment by the investigator that the patient is unsuitable to participate in the study for any 
condition and the patient is unlikely to comply with study procedures, restrictions and 
requirements. 

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25. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms. If 
QTcF ≥ 470 ms, the QTcF can be recalculated from 3 ECGs performed 2-5 minute apart. 
Triplicate ECGs should only be performed if screening ECG shows QTcF ≥ 470 ms. 
 
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 3.3 
 
3.3 Withdrawal of subjects from study treatment and/or study 
An individual subject will not receive hfRT if any of the following occur in the subject in 
question: 
1. 
Withdrawal of consent or lost to follow-up 
2. 
 Adverse event from durvalumab prior to start hfRT, in the opinion of the treating 
physician, contraindicates hfRT. The decision whether to discontinue durvalumab will 
be determined separately per Appendix I. 
3. 
Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational hfRT might constitute a 
safety risk 
4. 
Pregnancy or intent to become pregnant, then durvalumab and hfRT (if not delivered or 
partly delivered) should be both permanently stopped 
5. 
Any AE that meets criteria for discontinuation as defined in Section 5.3.3.5. and 
Appendix I 
6. 
Adverse event related to hfRT after the first of the total two fractions, in the opinion of 
the investigator, contraindicates continuation of delivery of the second fraction. 
7. 
Grade ≥3 infusion reaction from durvalumab, then both durvalumab and hfRT will be 
permanently stopped 
8. 
Subject noncompliance that, in the opinion of the investigator, warrants withdrawal; 
e.g., refusal to adhere to scheduled visits, then both durvalumab and hfRT will be 
permanently stopped 
9. 
Initiation of alternative anticancer therapy including another investigational agent, then 
both durvalumab and hfRT will be permanently stopped 
10. 
Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with durvalumab. If that is confirmed prior to start of hfRT, 
cancel RT permanently. The subject(s) will remain in analysis set for toxicities and 
survival 
11. 
Subjects who are permanently discontinued from receiving durvalumab or hfRT will be 
followed for safety per Section 9.2, including the collection of any protocol- specified 
blood specimens, unless consent is withdrawn or the patient is lost to follow-up or 
enrolled in another clinical study. All subjects will be followed for survival. Patients 
who decline to return to the site for evaluations will be offered follow-up by phone 
every 3 months as an alternative 
 
Withdrawal of consent 
Subjects are free to withdraw from the study at any time (durvalumab, hfRT and assessments) 
without prejudice to further treatment. 
 
Subjects who withdraw consent for further participation in the study will not receive any further 
durvalumab or hfRT if not delivered yet or further study observation, with the exception of 
follow- up for survival, which will continue until the end of the study unless the patient has 

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expressly withdrawn their consent to survival follow-up. Note that the patient may be offered 
additional tests or tapering of treatment to withdraw safely. 
 
A subject who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE. This is not mandatory.  Subjects are under no obligation to give a 
reason.  The Investigator will follow up AEs outside of the clinical study. 
 
An individual subject will not receive any further IP (durvalumab therapy or hfRT) if any of the 
following occur in the patient in question: 
• An AE that, in the opinion of the Investigator, contraindicates further dosing 
• Pregnancy or intent to become pregnant 
• Non-compliance with the study protocol that, in the opinion of the Investigator, 
warrants withdrawal from treatment with IP (eg, refusal to adhere to scheduled visits) 
• Initiation of alternative anticancer therapy including another investigational agent 
• Clinical progression, i.e. Investigator determination that the patient is no longer 
benefiting from treatment with IP, with or without radiological progression by RECIST 
1.1. 
• Any AE that meets criteria for discontinuation as defined in the Dosing Modification 
and Toxicity Management Guidelines (Appendix I) 
 
3.4 Replacement of patients 
We estimate 15% withdrawal or discontinuation rate in this trial. It should not change the total 
number of enrollment. 
 
Section 4.0 REGISTRATION PROCEDURES  
Patients with NSCLC referred to the Nebraska Medical Center (NMC) / UNMC are evaluated in 
a multidisciplinary team conference. On initial presentation, a history and physical examination 
are performed, laboratory data obtained, and performance status is assessed. Imaging studies will 
be obtained as clinically indicated. Any pathologic specimens obtained at referring institutions 
are reviewed for accuracy. Patients with suspicious NSCLC will require a biopsy for 
confirmation of malignancy.  
 
Patients with pathologically diagnosed NSCLC will be offered participation in the treatment 
portion of this trial.  
 
The potential subject will be provided assistance by the research nurse coordinator in 
determining if the insurance carrier will decline coverage.  Insurance carriers may or may not 
pay for study related expenses. The potential subject can then decide if he/she wishes to 
participate. 
 
Subjects will be registered by contacting the UNMC Project Coordinator. Study personnel from 
UNMC will contact the IIT Office Research Project Coordinator if a subject appears to meet the 
eligibility criteria. They will email the following information:   
• 
Registration request with Demographics cover sheet (located in the Study site Manual) 
• 
Signed, completed eligibility checklist (Appendix B)  

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4.1 Eligibility Verification/Registration 
The date of study enrollment is the date of consent. Before subjects are registered in the 
investigational treatment portion of the study, an eligibility checklist must be completed to verify 
the subject meets the eligibility criteria. The eligibility checklist will be maintained in the study file as 
source documentation only if it has been reviewed, signed by the treating physician. To make it 
uniform, for patients enrolled either prior to or after dCRT, Day 0 is defined as the date when 
post-dCRT restaging imaging (CT or PET/CT) is performed.  
 
Once the UNMC Research Project Coordinator confirms that the subject meets criteria, and 
target accrual has not been met, approval for the subject will be given and study subject number 
assigned. An email confirmation of study registration will be forwarded by the UNMC Research 
Project Coordinator to the study personnel. The Project coordinator can assign a subject study 
number prior to final registration confirmation of a subject. 
  
Each subject consented to the protocol is loaded into the UNMC Clinical Trial Management 
System (CTMS) within 7 days of consent.  CTMS registration includes entering the required 
demographic information (included on the registration request form) as stated in the SRC 
policies and procedures.  All subjects are CTMS registered (On Study) after the first time 
eligibility verification is complete and the IIT office provided the registration confirmation 
regardless if this occurs prior to or after dCRT. 
 
Instructions for Subjects Who Do Not Start Assigned Protocol Treatment (Screen Failure) 
A study subject number is still assigned to all consented subjects.  If a subject does not receive 
any assigned protocol treatment after consenting, baseline data will still be collected and 
included in the electronic data capture system. 
 
Section 5.0 TREATMENT PLAN 
5.1 Schedule of study procedures  
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined. The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments. Clinical 
evaluations and laboratory studies may be repeated more frequently if clinically indicated. The 
Schedule of Assessments during the screening and treatment period is provided in Section 7.0 of 
the protocol. 
Tumor efficacy (RECIST) assessment dates are not affected by dose delays and remain as 
originally scheduled, as they are based on the Day 0 (not the date of therapy). 
All other scheduled assessments must be performed relative to the start of the dosing 
cycle such that all laboratory procedures, etc., required for dosing should be performed 
within 3 days prior to dosing. 
Subjects may delay durvalumab dosing under certain circumstances. 

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− 
 Dosing may be delayed per Toxicity Management Guidelines, due to 
either an immune or a non-immune-related AE. 
− 
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible 
 
5.1.1 Consent and Standard definitive CRT phase  
All potential subjects must first read, understand, and sign the IRB/REB/IEC- approved ICF 
before any study-specific screening procedures are performed. Most patients will be consented 
prior to start of standard clinical care of definitive chemo-radiation therapy (dCRT).  However, 
informed consent of study procedures may occur within the screening period after dCRT and 
prior to starting of durvalumab. All subjects will only consent to the study one time, however.  
 
All subjects must have tumor pathology available prior to start of dCRT and reviewed at UNMC 
prior to consent. The collection of additional biopsies upon progression is encouraged. If 
laboratory or imaging procedures were performed for alternate reasons prior to signing consent, 
these can be used for screening purposes with consent of the patient. 
 
Initial consult day and CT simulation at radiation oncology usually occur one to two weeks 
before starting the dCRT phase.   
 
For subjects to be consented prior to dCRT, the following procedures will be performed prior to 
the start of dCRT: 
•  Informed Consent 
• Review of eligibility criteria 
• Medical history and demographics 
• Complete physical exam 
• ECOG Performance Status 
• Vitals signs, weight and height 
• 12-lead ECG (triplicate ECGs are done only if QTcF is ≥470 [2-5 minutes apart]), See 
section 5.2.1 
• Tumor biopsy 
• Review of prior/concomitant medications 
• Imaging by CT/MRI/PET 
• Clinical laboratory tests for: 
o Hematology (see section 5.2.2) 
o Clinical chemistry (see section 5.2.2) 
o TSH (Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical 
suspicion of an AE related to the endocrine system.) 
o Coagulation (PT, INR) 
o Creatinine Clearance 
o Serum pregnancy test (for women of childbearing potential only) 
o Urinalysis (see section 5.2.2) 
o Disease-specific tumor markers such as PD-L1 (optional) which can be assessed 
after enrollment 
 
5.1.1.2 Second/Final Eligibility Assessment—post-dCRT  

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This step is mainly a review for study eligibility for hfRT based on residual lung tumor size after 
dCRT phase. Subjects with CR (no target for planning hfRT) or tumor size in lung parenchyma 
>5cm in the largest axis (expecting high toxicities with hfRT) will not be eligible to continue on 
the study.  Ideally final subject eligibility review should be completed after imaging study for 
tumor assessment (day 0). Subject consent should be as soon as possible following day 0. 
Infusion should start no more than 42 days post completion of dCRT.  
 
The eligibility confirmation/assessment should be performed after the completion of dCRT with 
a CT chest/abdomen/pelvis with and without IV contrast or PET/CT (preferred), and ideally as 
close as possible before the start of durvalumab. For subjects who are recovering from toxicities 
associated with prior treatment, imaging for tumor assessments may be delayed by up to 14 days 
from the end of chemoradiation therapy. The eligibility confirmation procedures should be 
performed after the end of chemoradiation therapy.  
 
The following procedures will be performed for the eligibility confirmation after dCRT: 
•  Informed consent 
o If the subject was enrolled after dCRT, then they must sign consent prior to any 
study specific screening procedures are performed. 
o If the subject was consented prior to dCRT phase, they will not sign a consent form 
again.  
• Review of eligibility criteria 
• Medical history and demographics 
• Complete physical exam 
• ECOG Performance Status 
• Vitals signs, weight and height- only for subjects consenting after dCRT 
• 12-lead ECG (triplicate ECGs are done only if QTcF is ≥470 [2-5 minutes apart]), See 
section 5.2.1 
• concomitant medications 
• EORTC QLQ-C30 v. 3 and LC13 module 
• Imaging by CT chest/abdomen/pelvis or PET/CT (day 0) 
• Clinical laboratory tests for: 
o Hematology (see section 5.2.2) 
o Clinical chemistry (see section 5.2.2) 
o TSH (Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical 
suspicion of an AE related to the endocrine system.) 
o Coagulation (PT, INR) 
o Creatinine Clearance 
o Urinalysis (see Section 5.2.2) 
o Serum Pregnancy testing (for women of childbearing potential) 
• Tumor pathology review, confirm NSCLC diagnosis 
• Blood collection for exploratory studies 
 
5.1.2 Treatment phase 
 
Procedures to be conducted during the treatment phase of the study are presented in the Schedule 
of Assessments. Screening lab procedures performed within 72 hours before of Cycle 1 Day 1 

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(C1D1) of durvalumab do not need to be repeated on C1D1. 
 
Initial 3+3 design of dose escalation:  
 
A stepwise dose escalation will be conducted for consolidative hfRT for safety reasons. hfRT 
will start with 6.5Gy x 2 fractions and increase to 10Gy x 2 fractions if Maximum Tolerated 
Dose (MTD) is not reached. Only up to these two dose levels will be tested. Up to six patients 
will be accrued to a given dose level to confirm that the dose level does not exceed MTD. The 
MTD will be defined as the dose below which 2 or more of 6 patients experience dose-limiting 
toxicity (DLT).  
 
DLT includes the following:  
• Any Grade 3+ non-hematologic toxicity. An exception is Grade 3 
nausea/vomiting/diarrhea/electrolyte abnormality that is reduced to < Grade 3 with 
maximal supportive care within 3 days of onset.  
• Any Grade 4 adverse event of any duration.  
• Any Grade 3 adverse event that does not improve to baseline or Grade 1 within 7 days of 
onset.  
• Any Grade 3 or 4 neutropenia associated with sepsis or fever > 38º C.  
• Any Grade 4+ hematologic toxicity. An exception is Grade 4 neutropenia that improves 
to < Grade 4 within ≤ 7 days of onset.  
• Grade 3 thrombocytopenia associated with clinically significant bleeding.  
 
3+3 dose escalation design: 
• If DLT is not seen in any of the 3 patients, 3 new patients will be accrued and treated at 
the next higher dose level. If DLT is seen in 2 or 3 of 3 patients treated at a given dose 
level, then the MTD has been exceeded and the next 3 patients will be treated at the next 
lower dose level (unless there have already been 6 accrued to that lower level).  
• If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 additional patients 
will be enrolled and treated at the same dose level. If DLT is seen in at least one of these 
additional patients (at least 2 of 6), the MTD will have been exceeded. If DLT is not seen 
in any of the three additional patients, 3 new patients will be accrued and treated at the 
next higher dose level.  
• After enrolling 6 patients on a specific dose level, if DLT is observed in at least 2 of 6 
patients, then the MTD will have been exceeded and defined as the previous dose level 
unless only 3 patients were treated at the lower dose level. In that case, 3 additional 
patients will be treated at this lower dose level such that a total of 6 patients are treated at 
the MTD to more fully assess the toxicities associated with the MTD.  
• If a patient fails to complete the initial course of therapy (hfRT) for reasons other than 
dose limiting toxicity defined adverse events, the patient will be regarded as 
uninformative in regard to the MTD goal and an additional patient will be treated at the 
current dose level 
• If the starting dose level (6.5Gy x 2 fractions) already exceed MTD, dose de-escalation 
will NOT be performed due to the reasons as below. 
 
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because 6.5Gy/fraction is the likely minimal dose per fraction that is required to have 
immunostimulating effects per prior studies, no further dose de-escalation is proposed if 6.5Gy x 
2 fractions exceed MTD. The trial will be stopped. Otherwise we will move on to test 10Gy x 2 
fractions. If this dose exceeds MTD, we will choose the dose of 6.5Gy x 2 fractions for the next 
phase of the study. If 10Gy x 2 fractions regimen does not exceed MTD, we will choose 10Gy x 
2 fractions as consolidative hfRT regimen for the next phase of the study. No additional dose 
escalation will be performed since the next dose level has not been clinically tested even by itself 
without immunotherapy and will likely start to induce immunosuppression per prior studies.  
After each cohort/dose level has been accrued the enrollment will temporarily pause to assess 
DLT status of each patient. An observation period of 4 weeks following completing hfRT is 
required to assess toxicity before enrolling a patient at the next dose level. The decisions to 
resume and at what level to resume the enrollment, are based on standard cohort 3+3 design. 
 
All patients recruited in this step will be followed with biospecimen, ie, peripheral blood, 
collected as scheduled in section 7.0. Final data analyses such as PFS, OS, and exploratory aims 
will not include the patients treated at the dose level that is not selected for the second phase of 
the study. 
 
The second phase of study 
After determining which dose regimen to use for consolidative hfRT after the initial 3+3 dose 
escalation study, we will continue to enroll patients to a goal of 32 patients for final data analyses 
including those treated at the same dose level during dose escalation. Those patients in dose 
escalation step who are treated with the consolidative hfRT dose regimen that is not selected for 
the second phase will be followed in the study the same way as the rest of the cohort but will not 
be included in the final data analyses 
 
Disease Progression: 
Disease progression needs to be confirmed, 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 clinical deterioration. Administration of study drug will continue between the initial assessment 
of progression and confirmation for progression.  
 
For all subjects who are treated through progression, the investigator should ensure subjects do not 
have any significant, unacceptable or irreversible toxicities that indicate continuing treatment will 
not further benefit the subject, and that the subject still meets all of the inclusion criteria and none 
of the exclusion criteria for this study including re- consenting to continue treatment. Subjects with 
rapid tumor progression or with symptomatic progression that requires urgent medical intervention 
(eg, central nervous system metastasis, respiratory failure due to tumor compression, spinal cord 
compression) will not be eligible to continue to receive study drug. 
 
For more details about Follow-up of subjects after Disease progression see section 5.1.5 below. 
 
5.1.3 End of treatment 
 
End of treatment for current trial is defined as the last planned dosing visit within the 12-month 
dosing period of durvalumab. For subjects who discontinue durvalumab prior to 12 months, end 

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of treatment is considered the last visit where the decision is made to discontinue treatment, 
including the subjects who did not receive the second fraction of hfRT.  
 
5.1.4 
Follow Up for Subjects which have completed Durvalumab treatment with Disease 
Control 
Assessments for subjects who have completed durvalumab treatment and achieved disease 
control, or have discontinued durvalumab due to toxicity in the absence of confirmed progressive 
disease are provided in Study Assessment tables (Section 7.0) 
 
5.1.4.1 
Re-treatment of subjects with 12-month disease control 
Subjects who achieve and maintain disease control (ie, CR, PR, no evidence of disease, or SD) 
through to the end of the 12-month treatment period, may restart durvalumab upon evidence of 
confirmed PD (according to RECIST 1.1) during follow-up per treating physician discretion. 
Subjects would be considered off study. 
 
5.1.5   Follow-up for subjects who have Confirmed Disease Progression  
Subjects with confirmed PD that require discontinuing study drug, should have scans conducted 
according to local standard clinical practice (see Section 5.3.2.2.2.) until the subject commences a 
new treatment (these scans are optional). 
 
Subjects with confirmed PD that continue to receive durvalumab at the discretion of the 
Investigator can receive study drug for a maximum of 12 months. For all subjects who are treated 
through progression, the investigator should ensure subjects do not have any significant, 
unacceptable or irreversible toxicities that indicate continuing treatment will not further benefit 
the subject, and that the subject still meets all of the inclusion criteria and none of the exclusion 
criteria for this study including re-consenting to continue study drug. The same exceptions as noted 
in 5.1.2 apply. Subjects will follow the study assessments in Section 7.0 including tumor 
assessments every 12 weeks relative to Day 0 until study drug is stopped. 
 
Assessments for subjects who have discontinued durvalumab treatment due to confirmed PD are 
presented in Study Assessment tables, Section 7.0. 
 
All subjects will be followed for survival until the end of the study regardless of further 
treatments, or until the study ends. 
 
5.2 Description of study procedures  
5.2.1 Medical history and physical examination, electrocardiogram, weight, and vital signs 
Findings from medical history (obtained at screening) and physical examination shall be given a 
baseline grade according to the procedure for AEs. Increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the pre-study grade or below. 
 
Physical examinations or focused physical examinations will be performed on study days noted 
in the Schedule of Assessments. A complete physical examination will be performed and will 
include an assessment of the following (as clinically indicated): general appearance, respiratory, 
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nodes, thyroid, musculoskeletal (including spine and extremities), and neurological systems and 
at screening only, height.  Focused exam is a physical exam with focus on AE reviews. 
 
Resting 12-lead ECGs will be recorded at initial OR second screening (first time eligibility is 
determined) and as clinically indicated throughout the study. ECGs should be obtained after the 
subject has been in a supine position for 5 minutes and recorded while the subject remains in that 
position. In case of clinically significant ECG abnormalities, including a QTcF value ≥ 470 ms, 2 
additional 12-lead ECGs should be obtained over a brief period (e.g., 2-5 minutes apart) to 
confirm the finding. 
 
Situations in which ECG results should be reported as AEs are described in Section 9.1. 
At baseline evaluation, a single ECG will be obtained on which QTcF must be <470 ms. The 
same is required at second screening after dCRT.  In case of clinically significant ECG 
abnormalities, including a QTcF value ≥470 ms, 2 additional 12-lead ECGs should be obtained 
over a brief period (e.g., 2-5 minutes apart) to confirm the finding.  Situations in which ECG 
results should be reported as AEs are described in Section 9. 
 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules.  
 
5.2.2 Clinical laboratory tests 
The following clinical laboratory tests will be performed (see the Schedule of Assessments, for 
the timepoints of each test): 
 
Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
 
Total white cell count 
Mean corpuscular hemoglobin concentration 
 
Note: For coagulation parameters, activated partial thromboplastin time and international normalized ratio are to be assessed at 
baseline on Day 0 (unless all screening laboratory hematology assessments are performed within 3 days prior to 
Day 0), and as clinically indicated. 
a 
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by DM if entered 
as percentage. Total white cell count therefore has to be provided. 
 
Clinical Chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 
Alanine aminotransferase 
Lipaseb 

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Amylaseb 
Magnesium 
Aspartate aminotransferase 
Potassium 
Bicarbonate  
Sodium 
Calcium 
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local practice 
Creatinine Clearancec 
TSH  (Free T3 or free T4)d 
a 
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If 
total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome) then fractionate into direct 
and indirect bilirubin. 
b 
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these parameters 
is routinely measured then either lipase or amylase is acceptable. 
c 
Creatinine Clearance will be calculated by  data  management  using  Cockcroft-Gault  (using  actual  body 
weight). 
d  
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at day 0.  
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related 
to the endocrine system 
 
Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Color and appearance 
a Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for red 
blood cells 
 
If a subject shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN, refer to 
Appendix I for further instructions on cases of increases in liver biochemistry and evaluation of 
Hy’s Law. 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. 
All subjects should have further chemistry profiles performed at 30 days (±3 days), 2 months (±1 
week) and 3 months (±1 week) after permanent discontinuation of IP. 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. Situations in which laboratory safety results should be reported as 
AEs are described in Section 9.2. 
 
All subjects with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from IP must have further tests performed until the laboratory values have returned to Grade 1 or 
2, unless these values are not likely to improve because of the underlying disease. 
 
All the above tests will be performed at local hospital clinical laboratories.  
 
5.2.3. Biomarker/exploratory research and evaluation methods 

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5.2.3.1 PD-L1 testing 
Sample collection for PD-L1 testing 
• Samples should be collected via a core needle of 18 gauge or larger or be collected by an 
incisional or excisional tumor biopsy. Where institutional practice uses a smaller gauge 
needle, samples should be evaluated for tumor cell quantity (i.e., >100 tumor cells) to allow 
for adequate PD-L1 immunohistochemistry analyses. 
• When the collection of a new sample is not clinically appropriate, archival samples may be 
utilized provided the specimen it is not older than 3 years of age. When archival samples are 
used to assess PD-L1 status, the age of the sample / date of collection should be captured. 
• Samples submitted for PD-L1 testing should be formalin fixed and embedded in paraffin. 
Samples from fine needle aspirates (FNA) are not appropriate for PD- L1 analysis. 
 
Sample data collection for PD-L1 testing 
 
The following fields of data should be collected from PD-L1 testing laboratory: 
• Are the negative and positive controls stained correctly 
• Is the H&E material acceptable 
• Is morphology acceptable 
• Total percent positivity of PD-L1 in tumor cells 
• PD-L1 status (positive, negative or NA) in tumor cells 
• Total percent positivity of PD-L1 in infiltrating immune cells 
 
Sample processing and submission process for PD-L1 testing 
Preparing Stored samples for testing 
 
• Where samples already exist, they should be retrieved from the Bio-Bank storage location. 
These blocks should undergo quality review, prior to PD-L1 testing. 
 
Preparing newly acquired samples for PD-L1 testing 
 
• If subjects are undergoing a biopsy procedure that provides the option to submit newly 
acquired samples, this sample should be used to determine PD-L1 status. Where 
clinically acceptable, a minimum of 2 core biopsies should be collected and processed to 
FFPE in a single block. The provision of 2 cores is advised in order to provide sufficient 
tissue for PD-L1 assessment. 
• It is recommended that core needle tumor biopsies are collected using an 18 gauge or 
larger needle and the process should be image-guided. Excisional or incisional samples 
are also adequate. If this is not per the institutions normal practice and a smaller gauge 
needle is used, then the number of cores collected should be increased to allow sufficient 
material for successful PD-L1 testing (>100 tumor cells) and embedded in the same 
block. If available, a single excisional biopsy of at least 4 mm in diameter may substitute 
for all core biopsies. 
 
Fixation of biopsy samples for PD-L1 testing 
 
• Previously frozen tissue is not acceptable for processing to FFPE for PD-L1 testing. To 

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fix newly acquired tissue, place immediately (within 30 min of excision) into an adequate 
volume of 10% v/v neutral buffered formalin (NBF). Samples should remain in fixative 
for 24 – 48 hours at room temperature. 
• It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 10- 
volume excess) and that large specimens (if any) are incised prior to fixation to promote 
efficient tissue preservation. 
 
Embedding in paraffin for PD-L1 testing 
 
• FFPE blocks should be stored at ambient temperature and protected from light at ambient 
temperature. FFPE blocks are stable under these conditions for an indefinite period 
 
Quality control of samples to be used for PD-L1 testing 
 
• Tissue should be assessed by the local pathologist prior to PD-L1 testing. 
• Each sample should be reviewed for: 
• Adequate fixation 
• Good preservation of morphology 
• Presence of tumor tissue 
• Histopathology consistent with indication 
• Greater than 100 tumor cells are required to determine PD-L1 status – tumor 
cell content must be reviewed prior to testing in order for PD-L1 obtain a valid 
result. 
• When submitting sample for PD-L1 testing the recommendation is to deliver the block in 
order for sectioning to occur at the laboratory. Blocks should be delivered - containing 
enough material to be provided to allow a minimum of 5, and preferably 10, sections to 
be cut (each 4-micron thick) to be used for PD-L1 testing. 
 
Sectioning instructions 
 
•   It is recommended that slides are cut freshly prior to PD-L1 testing and they are used within 
90 days of being cut to obtain PD-L1 status. 
 
PD-L1 testing in this trial will be performed at the regional pathology service at Department 
of Pathology at University of Nebraska Medical Center 
 
5.2.3.2 Exploratory research  
 
Blood will be drawn from each subject in this study for exploratory research purpose such as 
biomarker studies including sPD-L1, miRNA/mRNA, and cytokines, as well as ctDNA isolation 
for mutation and tumor burden studies and PBMC collection for flow cytometry. 
 
During standard of care dCRT, 20 cc of blood will be drawn each time at the schedule listed as 
below: 
1. During the screening/baseline timepoint, ideally drawn together for other blood tests, e.g., 
routine pre-chemotherapy lab tests; 

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2. After 5 fractions but prior to the 6th fraction of RT. Draw on the day of the 6th fraction before 
delivery of the dose; 
3. After 15 fractions but prior to the 16th fraction of RT. Draw on the day of the 16th fraction 
before delivery of the dose; 
4. Within 72 hours after the last dose of RT. Prefer within 12 to 36 hours after the last dose. 
 
After completing dCRT, 20cc of blood will be drawn each time at the schedule listed as below: 
 
1. Within 24 hours of the CT simulation but prior to the procedure; 
2. Day of the first fraction of hfRT prior to delivery of the dose; 
3. Day of the second fraction of hfRT prior to the delivery of the dose; 
4. Within 24-72 hours after delivery of the second fraction of hfRT but prior to the start of 
next cycle (the third cycle) of durvalumab; 
5. At each subsequent follow-up visit, +/- 7 days.  Q12w ± 1w for the first 48 weeks (relative 
to Day 0, and thereafter until confirmed objective disease progression/death (whichever 
comes first). The schedule of q12w ± 1 week for and thereafter MUST be followed 
regardless of any delays in dosing. If the visit/blood draw at 8 weeks after study treatment 
start is scheduled prior to one week after finishing of hfRT, then this appointment/blood 
draw can be cancelled. 
 
5.2.3.3 Estimate of volume of blood to be collected 
 
The total volume of blood that will be drawn from each subject in this study depends on the length 
of time that the subject receives durvalumab. The table below is a guide to the approximate volume 
of blood that will be drawn from each subject, based on the assumption that each subject remains 
in the study on treatment for 3 months after starting and attends all the planned visits, with 
additional volumes planned in before and during dCRT period prior to screening. 
 
 Volume of Blood to be Drawn From Each Subject 
Assessment 
Sample 
volume (mL) 
No. of 
samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
1.0 
11 
11.0 
Hematology 
2.0 
11 
22.0 
 
 
 
 
Thyroid 
1.0 
10 
10.0 
Coagulation 
3.0 
2 
6.0 
Biomarkers 
Soluble PD-L1 (to assess target 
engagement) 
5.0 
10* 
50.0 
Circulating soluble factors (to assess 
cytokines, chemokines, growth factors 
and antibodies against tumor and self 
antigens in circulation) 
5.0 
10 
50.0 
miRNA/mRNA (to examine immune 
cell gene expression profiles in 
circulation) 
5.0 
10 
50.0 
ctDNA  
5.0 
5 
25.0 

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PBMC 
Flow cytometry** 
--- 
-- 
--- 
Total 
37 mL 
76 
220.5 mL 
HIV Human immunodeficiency virus; miRNA Micro RNA; mRNA Messenger RNA; PD-L1 Programmed death ligand 1. 
 
* number of samples are estimated based on 12 months follow-up after Day 0.  
** Cells for flow cytometry will be used from blood collected for the biomarkers.  
 
5.2.3.4 Archival tumor samples and fresh tumor biopsies use beyond PD-L1 
 
For subjects who consent to a repeat biopsy of residual lung tumor and/or lymph nodes (optional) 
two months after hfRT, the fresh tumor tissue from 2-3 core needle biopsy will be collected and 
processed to FFPE in a single block for PD-L1 testing as described in section 5.2.3. If additional 
slides are available after PD-L1 staining, immunohistochemistry studies can be performed to study 
on immune cell infiltration into irradiated tumor microenvironment if funding is available. The 
fresh specimen will be used up or disposed of after analyses or formalin-fixed and retained for 
further use as described here. 
 
5.2.3.5 Withdrawal of informed consent for donated biological samples 
 
If a subject withdraws consent to the use of donated samples, the samples will be disposed 
of/destroyed, and the action documented.  
 
The Principal Investigator: 
• Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
• Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/destroyed, the action documented and 
the signed document returned to the study site 
• Ensures that the subject is informed about the sample disposal. 
 
5.2.4  Quality of Life questionnaire 
A health-related Quality of Life questionnaire will be used throughout this study.  For this study 
PRO, the European Organization for Research and Treatment of Cancer (EORTC) questionnaire 
to evaluate the quality of life of subjects with malignant disorders will be used.  Nine multi-item 
scales were incorporated into QLQ-C30, including five functional scales (physical, role, cognitive, 
emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), and a global 
health and quality-of-life scale.  The study coordinator will administer the EORTC QLQ-C30 to 
the subject at specific points throughout the study. Questionnaires will be administered at the time 
of screening and at CT simulation. Thereafter, questionnaires will be administered every 12 weeks 
(± 2 weeks) relative to Day 0 until confirmed disease progression or until treatment with 
durvalumab is discontinued. 
 
5.3 Radiation Therapy 
5.3.1 Radiation therapy planning for definitive chemoradiation therapy (standard care) 
 
Eligible subjects should have histologically or cytologically documented stage III NSCLC 
according to the Staging Manual in Thoracic Oncology, version 7, of the International Association 

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for the Study of Lung Cancer. The subjects can be screened and enrolled preliminarily prior to 
starting the phase of definitive chemoradiation therapy (dCRT) and re-evaluated after the follow- 
up imaging post-dCRT (Day 0.) If no signs of disease progression with residual lung cancer size 
≤5cm in largest axis, the subject will complete screening and be registered. The subject will start 
consolidative/adjuvant durvalumab within 42 days after the end of dCRT phase at 10mg/kg body 
weight intravenously every two weeks. Consolidative hfRT to the residual lung mass will be 
delivered between the second and third cycle of durvalumab. No specific dates are required for 
delivering hfRT between the two cycles. 
 
Subjects should receive a course of dCRT prior to the final study eligibility confirmation. Subjects 
should receive treatment 5 days per week, one fraction per day, 1.8-2 Gy per fraction to a total 
dose of 59.8 to 60 Gy which is strongly recommended dosing although a total dose of 57 to 63 Gy 
is allowed for subjects to be enrolled to current trial. 3D conformal radiation therapy (3DCRT) or 
intensity modulated radiation therapy (IMRT) can be used per physician’s choice for RT planning. 
Chemotherapy should be given concurrently with radiation therapy per standard care and 
institutional preference. More specifically, these subjects should receive two or more cycles 
(defined according to local practice) of platinum-based doublet chemotherapy (containing 
etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently 
with RT. No adjuvant chemotherapy after concurrent CRT is allowed. 
 
Meeting the following dose constraints with conventional fractionated RT as part of the definitive 
chemoradiation is mandatory for eligibility of the current trial. 
 
a 
V20 Gy < 30%: no more than 30% of the volume of total lung minus the CTV should receive 20 Gy or more dose; CTV 
clinical tumor volume; PD prescribed dose; 
Normal tissue constraints shall be prioritized in the following order for treatment planning: 1=spinal cord, 2=lungs, 3=esophagus, 
4=brachial plexus, and 5=heart 
 
5.3.2 Consolidative hypofractionated radiation therapy (investigational therapy) 
5.3.2.1 Dose specifications 
5.3.2.1.1 Stereotactic targeting and treatment 
 
SBRT has now been formally defined and described in a published guideline from the American 
College of Radiology and American Society for Therapeutic Radiology and Oncology (Potters 
2004). This protocol will respect that guideline. NOTE: 3-D conformal and intensity modulated 
radiation therapy (IMRT) are both allowed for planning of this step. The same planning method 
as in the course of dCRT is strongly recommended for medical billing purpose but not mandated. 
 
5.3.2.1.2 Dose fractionation 
Critical Organ 
Max Dose Limit 
Volume/Dose constraint 
Total Lung-CTV 
< 110% of PD 
V20 Gy < 30%a (accept < 35%) 
mean dose <15 Gy (accept < 20Gy) 
Esophagus 
<105% of PD 
mean dose <34 Gy 
Cord 
45 Gy 
Heart 
V50 Gy < 25%; V45 Gy < 67%; V40
Gy < 100% 
mean < 35 Gy 
Brachial plexus 
60 Gy preferred, accept 66Gy 

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All subjects will receive the radiation dose determined per the 3+3 dose escalation study (see 
section 5.1.2), with a total dose of either 13 Gy or 20 Gy in 2 fractions to the prescription line at 
the edge of the planning tumor volume (PTV), one fraction per day, every other day with the 
exception that, if the first fraction is delivered on a Friday, the second fraction is allowed on the 
following Monday (see Section 5.3.2.4. for more prescription details). 
 
5.3.2.1.3 Premedications 
 
It is not recommended to prescribe corticosteroid for premedication purpose (e.g., 
Dexamethasone) before or after each hfRT treatment due to concerns of interfering 
immunotherapy drug effects. Steroid use for symptomatic management is allowed as per 
Appendix I. Analgesic premedication to avoid general discomfort during long treatment 
durations also is recommended when appropriate. 
 
5.3.2.2 Technical factors 
5.3.2.2.1 Physical factors  
 
Only photon (x-ray) beams produced by linear accelerators with photon energies of 4-10 MV 
will be allowed. Photon beam energies > 10 MV but not > 15 MV will be allowed only for a 
limited number (≤ 2) beams that must travel more than a cumulative distance of 10 cm through 
soft tissue (not lung) to reach the target. 
 
5.3.2.2.2 Minimum field aperture (field size) dimension  
 
Because of uncertainties in beam commissioning resulting from electronic disequilibrium within 
small beam apertures, a minimum field dimension of 3.5 cm is required for any field used for 
treatment delivery for sites using standard 3-D conformal techniques where nearly all of the PTV 
is encompassed for each beam. It is understood that this may exceed the technical requirements 
listed in Section 5.3.2.4.2 Dosimetry for small lesions (< 2.5 cm axial GTV dimension or < 1.5 
cm craniocaudal GTV dimension). In such cases, the prescription dose is still prescribed to the 
edge of the defined PTV. This minimum field dimension does not apply to IMRT planning with 
a standard multileaf collimator or Tomotherapy or for the CyberKnife® unit where by design the 
entire PTV is not encompassed for each beam. 
 
5.3.2.3 Localization, simulation and immobilization  
5.3.2.3.1 Subject positioning  
 
Subjects will be positioned in a stable position. A variety of immobilization systems may be 
used, including stereotactic frames used in our institute that surround the subject on three sides 
and large rigid pillows (conforming to subjects’ external contours) with reference to the 
stereotactic coordinate system (Potters 2004). Subject immobilization must be reliable enough 
to insure that in combination with the techniques used to inhibit target motion, the gross tumor 
volume (GTV) does not deviate beyond the confines of the planning treatment volume (PTV) 
with any significant probability. 
 
5.3.2.3.2 Inhibition of effects of internal organ motion  

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Special considerations must be made to account for the effect of internal organ motion (e.g., 
breathing) on target positioning and reproducibility. Acceptable maneuvers include reliable 
abdominal compression, accelerator beam gating with the respiratory cycle, tumor tracking, and 
active breath-holding techniques. Internal organ inhibition maneuvers must be reliable enough 
to insure that the GTV does not deviate beyond the confines of the PTV with any significant 
probability (i.e., < 5%). 
 
5.3.2.3.3 Localization 
 
Isocenter or reference point port localization images should be obtained on the treatment unit 
immediately before treatment to ensure proper alignment of the geometric center (i.e., isocenter) 
of the simulated fields. These IGRT images can be obtained with planar kV imaging devices, an 
in-room helical CT device, tomotherapy helical CT, cone-beam CT equipment, of standard EPID 
imaging. In all cases, the RTOG Image Guidance Guidelines must be followed. For treatment 
systems that use kV imaging but also allow EPID imaging using the treatment beam, orthogonal 
images verifying the isocenter also should be obtained. 
 
5.3.2.4 Treatment planning/target volumes  
5.3.2.4.1 Image acquisition 
 
Computed tomography will be the primary image platform for targeting and treatment planning. 
The planning CT scans must allow simultaneous view of the subject anatomy and fiducial system 
for stereotactic targeting. Intravenous (i.v.) contrast during the planning CT is optional provided 
a diagnostic chest CT was done with contrast to delineate the major blood vessels within 12 
weeks of Day 0 on the trial. If not, i.v. contrast should be given during the planning CT; i.v. 
contrast at simulation may be omitted even in this case if contraindicated (e.g. allergy or renal 
insufficiency. Contrast will allow better distinction between tumor and adjacent vessels or 
atelectasis. Axial acquisitions with gantry 0 degrees will be required with spacing ≤ 3.0 mm 
between scans. Images will be transferred to the treatment planning computers via direct lines. 
 
The target lesion will be outlined by an appropriately trained physician and designated the gross 
tumor volume (GTV). The target will generally be drawn using CT pulmonary windows; 
however, soft tissue windows with contrast may be used to avoid inclusion of adjacent vessels, 
atelectasis, or mediastinal or chest wall structures within the GTV. 4-dimensional CT image 
guided GTV delineation to take tumor motion into consideration is mandated. This target will 
not be enlarged whatsoever for prophylactic treatment (including no “margin” for presumed 
microscopic extension); rather, include only abnormal CT signal consistent with gross tumor 
(i.e., the GTV and the clinical target volume [CTV] are identical). 
 
With 4D CT-simulation, an internal target volume (ITV) around the GTV, accounting for tumor 
motion may be defined from the 4D CT dataset. The PTV will include the ITV plus an additional 
0.5 cm margin uniformly applied to the ITV. 
 
5.3.2.4.2 Dosimetry  
 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom designed for 

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each case to deliver highly conformal prescription dose distributions. Non-opposing, 
noncoplanar beams are preferable. Typically, ≥ 10 beams of radiation will be used with roughly 
equal weighting. Generally, more beams are used for larger lesion sizes. When static beams are 
used, a minimum of 7 non- opposing beams should be used. For arc rotation techniques, a 
minimum of 340 degrees (cumulative for all beams) should be utilized. For arc rotation 
techniques, a minimum of 340 degrees (cumulative for all beams) should be utilized. In order to 
obtain acceptable coverage, field aperture size and shape should correspond nearly identically to 
the projection of the PTV along a beam’s eye view (i.e., no additional “margin” for dose buildup 
at the edges of the blocks or MLC jaws beyond the PTV). The only exception should be when 
observing the minimum field dimension of 3.5 cm when treating small lesions (see above). As 
such, prescription lines covering the PTV will typically be the 67-90% line (where the maximum 
dose is 100%); however, higher isodoses (hotspots) must be manipulated to occur within the 
target and not in adjacent normal tissue. The treatment isocenter or setup point in stereotactic 
coordinates will be determined from system fiducials (and can be adjusted pre-treatment 
depending on the results from localization imaging studies) and translated to the treatment 
record. 
 
For purposes of dose planning and calculation of monitor units for actual treatment, this 
protocol will require tissue density heterogeneity corrections. The particular algorithm used 
for such correction is per institutional protocol. 
 
5.3.2.4.3 Prescription dose constraints for treatment planning 
Successful treatment planning will require accomplishment of all of the following criteria: 
1. 
Maximum dose: The treatment plan should be created such that 100% corresponds to the 
maximum dose delivered to the subject. This point must exist within the PTV. 
2. 
Prescription isodose: The prescription isodose surface must be ≥ 67% and 
< 100% of the maximum dose. 
 
3. 
Prescription Isodose Surface Coverage: The prescription isodose surface will be chosen 
such that 90% close to of the target volume (PTV) is conformally covered by the 
prescription isodose surface (PTV V100Rx = 90%) and 99% of the target volume (PTV) 
receives a minimum of 80% of the prescription dose (PTV V80%Rx > 99%). For ITV, 
V100Rx=95%; V80%Rx=100%. 
 
4. 
High Dose Spillage: 
The cumulative volume of all tissue outside the PTV receiving a dose > 105% of 
prescription dose should be no more than 15% of the PTV volume. 
 
5. 
Intermediate Dose Spillage 
 
The falloff gradient beyond the PTV extending into normal tissue structures must be rapid 
in all directions and meet the following criteria: 
 
a. Location 
The maximum total dose over all fractions in Gray (Gy) to any point 2 cm or greater away 
from the PTV in any direction must be no greater than D2CM where D2CM is given by 
the table below. 

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b. Volume 
The ratio of the volume of 50% of the prescription dose isodose to the volume of the PTV 
must be no greater than R50% where R50% is given in the table below. This table is used 
for all prescription requirements as stated above irrespective of calculation algorithm and 
total treatment dose. 
 
Conformality of Prescribed Dose for Calculations Based on Deposition of Photon Beam 
Energy in Heterogeneous Tissue 
 
Note 1: For values of PTV dimension or volume not specified, linear interpolation between table entries is required. 
Note 2: Protocol deviations greater than listed here as “minor” will be classified as “major” for protocol compliance 
(see Section 5.3.3.4). 
 
5.3.3 Critical structures  
5.3.3.1 Critical organ dose-volume limits 
The following table lists maximum dose limits to a point or volume within several critical 
organs. Except for the rib, these are absolute limits, and treatment delivery that exceeds these 
limits will constitute a protocol violation. The dose is listed as total delivered. These limits were 
formulated using tolerance data with biological equivalent dose (BED) conversion from prior 
SBRT experience including RTOG 0813 and historical data as published by Kumar et al 2017 
from their experience on SBRT boost (without immunotherapy) for post-chemoradiation residual 
disease. 
The esophagus, trachea, bronchi and heart may be situated adjacent to the treated GTV/PTV. As 
such, there is no specified limit as tumors that are immediately adjacent to that organ will not be 
able to be treated to any of the prescription doses without irradiating a small volume of that 
organ to the prescribed dose. In such a case, safety takes priority since the entire tumor has 
received standard dose of RT previously. The planning needs to be done so that all OARs meet 
the dose constraints as shown in the table below, even if that organ is part of the PTV, except for 
skin and rib. In addition, the volume of the OAR in question needs to be minimized, both in 
length and in the width (i.e., circumference), with efforts made to reduce the dose to the 
contralateral wall of the organ. The volume limits (columns 2, 3 and 4) will be scored as 
protocol violations if exceeded by 5%, except for skin and rib which has dose constraints 

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listed in the table below only as suggested for planning. For centrally located tumor, the 
constraints for “trachea & ipsilateral bronchus” is not required. PTV coverage should be 
attempted to meet recommendations with reasonable effort but can be compromised in order to 
meet the normal tissue constraints if needed.  
For tumors that are not immediately adjacent to any OAR, centers are encouraged to observe 
prudent treatment planning principles in avoiding unnecessary radiation exposure to critical 
normal structures; we expect that the OAR doses will be as low as achievable (ideally, < 4 
Gy/fraction). 
Normal tissue constraints for consolidative RT 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose (Gy) 
Avoidance Endpoint 
Spinal Cord 
<0.03 cc 
5.5 Gy (2.75 Gy/fx) 
Myelitis 
Ipsilateral brachial 
plexus 
<0.03 cc 
6 Gy (3 G/fx) 
neuropathy 
Rib* 
<1 cc 
16 Gy (8 Gy/fx) 
17.6 Gy (8.6 Gy/fx) 
Pain or fracture 
Skin* 
<10 cc 
14 Gy (7 Gy/fx) 
12.8 Gy (6.4 Gy/fx) 
ulceration 
Stomach 
<10 cc 
7.2 Gy (3.6 Gy/fx) 
12.8 Gy (6.4 Gy/fx) 
Ulceration/fistula 
 
Parallel Tissue 
Critical Volume 
Critical Volume Dose 
Max (Gy) 
Avoidance Endpoint 
Lung, Total 
1500 cc 
5 Gy (2.5 Gy/fx) 
Basic Lung Function 
Lung, Total 
< 25% 
2.5 Gy (1.25 Gy/fx) 
Pneumonitis 
< 15% 
5 Gy (2.5 Gy/fx) 
< 5% 
10Gy (5 Gy/fx) 
<1.5% 
20Gy (10 Gy/fx) 
1000 cc 
5.4 Gy(2.7Gy/fx) 
Esophagus, non- 
adjacent wall 
< 5 cc 
11 Gy (5.5 Gy/fx) 
16Gy (8 Gy/fx) 
Stenosis/fistula 
Heart/pericardium 
< 15 cc 
12.8 Gy (6.4 Gy/fx) 
16Gy (8 Gy/fx) 
pericarditis 
Trachea 
and 
ipsilateral 
bronchus** 
< 4 cc 
6.6 Gy (3.3 Gy/fx) 
14 Gy (7 Gy/fx) 
Stenosis/fistula 
Trachea 
 and 
ipsilateral 
bronchus, 
non- 
adjacent wall 
< 4 cc 
7.2 Gy (3.6 Gy/fx) 
12 Gy (6 Gy/fx) 
Stenosis/fistula 
Great 
Vessels, 
non-adjacent wall 
12 Gy (6 Gy/fx) 
aneurysm 
PD prescription dose; 
Exceeded any of these limits by 5% is a protocol violation except for skin and rib (*) with dose constraints provided for 
suggested planning. 
** circumferential volume of trachea and ipsilateral bronchus dose constraints are only required for proximally located tumor 
as defined in Section 5.3.3.4. Also see Section 5.3.3. for more details. 
 
In order to verify each of these limits, the organs must be contoured such that appropriate dose 
volume histograms can be generated. Instructions for the contouring of these organs are as follows 
in Section below. 
 
5.3.3.2 Contouring or normal tissue structures 
 

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All structures listed in Sections 5.3.3.2.1 through 5.3.3.2.11 should be contoured in every subject 
irrespective of the location of the PTV. The structures listed in Sections 5.3.3.2.12 through 
5.3.3.2.13 are only required if the named structure lies within 5 cm of the PTV. 
 
5.3.3.2.1 Spinal cord  
The spinal cord will be contoured based on the bony limits of the spinal canal. The spinal cord 
should be contoured starting at least 10 cm above the superior extent of the PTV and continuing 
on every CT slice to at least 10 below the inferior extent of the PTV. 
 
5.3.3.2.2 Esophagus 
The esophagus will be contoured using mediastinal windowing on CT to correspond to the 
mucosal, submucosa, and all muscular layers out to the fatty adventitia. The esophagus should be 
contoured starting at least 10 cm above the superior extent of the PTV and continuing on every 
CT slice to at least 10 below the inferior extent of the PTV. 
 
5.3.3.2.3 Brachial plexus 
The defined ipsilateral brachial plexus originates from the spinal nerves exiting the 
neuroforamina on the involved side from around C5 to T2. However, for the purposes of this 
protocol, only the major trunks of the brachial plexus will be contoured using the subclavian and 
axillary vessels as a surrogate for identifying the location of the brachial plexus. This 
neurovascular complex will be contoured starting proximally at the bifurcation of the 
brachiocephalic trunk into the jugular/subclavian veins (or carotid/subclavian arteries) and 
following along the route of the subclavian vein to the axillary vein ending after the 
neurovascular structures cross the second rib. 
 
5.3.3.2.4 Heart 
The heart will be contoured along with the pericardial sac. The superior aspect (or base) for 
purposes of contouring will begin at the level of the inferior aspect of the aortic arch 
(aortopulmonary window) and extend inferiorly to the apex of the heart. 
 
5.3.3.2.5 Trachea and proximal bronchial tree 
The trachea and proximal bronchial tree will be contoured as two separate structures using 
mediastinal windows on CT to correspond to the mucosal, submucosa and cartilage rings and 
airway channels associated with these structures. For this purpose, the trachea will be divided 
into two sections: the proximal trachea and the distal 2 cm of trachea. The proximal trachea will 
be contoured as one structure, and the distal 2 cm of trachea will be included in the structure 
identified as proximal bronchial tree. Differentiating these structures in this fashion will facilitate 
the eligibility requirement for excluding subjects with tumors within 2 cm of the proximal 
bronchial tree (see Section 5.3.3.2.10 below). 
 
5.3.3.2.6 Proximal trachea 
Contouring of the proximal trachea should begin at least 10 cm superior to the extent of the PTV 
or 5 cm superior to the carina (whichever is more superior) and continue inferiorly to the 
superior aspect of the proximal bronchial tree. 
 
5.3.3.2.7 Proximal bronchial tree 

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The proximal bronchial tree will include the most inferior 2 cm of distal trachea and the proximal 
airways on both sides. The following airways will be included according to standard anatomic 
relationships: the distal 2 cm of trachea, the carina, the right and left mainstem bronchi, the right 
and left upper lobe bronchi, the intermedius bronchus, the right middle lobe bronchus, the 
lingular bronchus, and the right and left lower lobe bronchi. Contouring of the lobar bronchi will 
end immediately at the site of a segmental bifurcation. 
 
5.3.3.2.8 Whole lung 
Both the right and left lungs should be contoured as one structure. Contouring should be carried 
out using pulmonary windows. All inflated and collapsed lung should be contoured; however, 
gross tumor (GTV) and trachea/ipsilateral bronchus as defined above should not be included in 
this structure. 
 
5.3.3.2.9 PTV plus 2 cm 
As part of the QA requirements for “low dose spillage” listed in Section 5.3.3.5, a maximum 
dose to any point 2 cm away in any direction is to be determined. To facilitate this QA 
requirement, an artificial structure 2 cm larger in all directions from the PTV is required. Most 
treatment planning systems have automatic contouring features that will generate this structure 
without prohibitive effort at the time of treatment planning. 
 
5.3.3.2.10 Proximal bronchial tree plus 2 cm 
To differentiate a “centrally located tumor” versus a “peripherally located tumor”, it is 
convenient to define an artificial structure 2 cm larger in all directions from the proximal 
bronchial tree. If any part of the GTV falls within this artificial structure, the subject should be 
treated as “centrally located tumor”. Otherwise the tumor is considered as “peripherally located 
tumor”. Most treatment planning systems have automatic contouring features that will generate 
this structure without prohibitive effort at the time of treatment planning. Defining the tumor as 
“centrally located tumor” versus a “peripherally located tumor” does not change prescription 
dose but affects tracheal and ipsilateral bronchus dose constraint requirement. 
 
5.3.3.2.11 Skin 
The skin will be defined as the outer 0.5 cm of the body surface. As such it is a rind of uniform 
thickness (0.5 cm) which envelopes the entire body in the axial planes. The cranial and caudal 
surface of the superior and inferior limits of the planning CT should not be contoured as skin 
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5.3.3.2.12 Rib 
Ribs within 5 cm of the PTV should be contoured by outlining the bone and marrow. Typically, 
several portions of adjacent ribs will be contoured as one structure. Adjacent ribs, however, 
should not be contoured in a contiguous fashion (i.e., do not include the intercostal space as part 
of the ribs). 
 
5.3.3.2.13 Great vessels 
The great vessels (aorta and vena cava, not the pulmonary artery or vein) will be contoured using 
mediastinal windowing on CT to correspond to the vascular wall and all muscular layers out to 
the fatty adventitia. The great vessel should be contoured starting at least 10 cm above the 
superior extent of the PTV and continuing on every CT slice to at least 10 cm below the inferior 
extent of the PTV. For right sided tumors, the vena cava will be contoured, and for left sided 
tumors, the aorta will be contoured. 
 
5.3.3.2.14 Other structures  
The constraints tables above contain other structure, eg. stomach. These are required if the 
treated lesion is within 5 cm of the PTV. 
 
5.3.3.3 Documentation requirements  
In general, treatment interruptions should be avoided by preventative medical measures and 
nutritional, psychological, and emotional counseling. Treatment breaks, including indications, 
must be clearly documented on the treatment record. 
 
5.3.3.4 Compliance criteria 
5.3.3.4.1 Dosimetry compliance  
Section 5.3.2.4.3 describes appropriate conduct for treatment planning dosimetry for target 
coverage and the dose falloff. The Principal Investigator and co-investigators at radiation 
oncology of local institute will evaluate plans. Criteria for both Per Protocol (listed in the table as 
“None”) and Variations Acceptable (listed under the heading of “Minor”) are given in this table. 
Deviations Unacceptable occur when the stated Minor limits are exceeded. The table in Section 
5.3.3.1 lists dose volume limits for specific organs and structures. Exceeding these dose limits by 
more than 2.5% constitutes a Variation Acceptable. However, exceeding these dose limits by 
more than 5% (columns 2, 3 and 4 in the table) constitutes a Deviation Unacceptable, except 
for skin and rib which has dose constraints listed as suggested for planning. For centrally 
located tumor (see definition in Section 5.3.3.2.10), the constraints for “trachea & 
ipsilateral bronchus” is not required. 
 
5.3.3.5 Radiation therapy adverse events recording 
Some of the toxicities from consolidative RT using immunostimulating dose regimen might be 
challenge to be distinguished from the ones from immunotherapy, e.g., durvalumab therapy such 
as pneumonitis, pericarditis, etc.. However, there is concern about effects mainly if not only from 
consolidative RT on organs at risk, most notably central airway, esophagus and 
heart/pericardium, as these organs can be in immediate proximity to some centrally-located 
tumors, or chest wall/rib pain or focal skin rash in RT field treating some peripherally-located 
tumors. 
 

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Currently there is no clearly defined guideline to separate RT- vs. immunotherapy-related AE’s 
when both modalities are administered concurrently. For toxicities out of thorax and out of RT 
field, for the purpose of this study, we will define AE’s as durvalumab-related. For AE’s in 
tissues in thorax, i.e., chestwall/rib, esophagus, airway, great vessels and heart, or tissues 
adjacent to thorax such as liver and stomach, RT dose distributions in each organ will be 
reviewed from the sum plan combining RT plans of dCRT and hfRT. If TD5/5 dose constraint 
(the radiation dose that would result in 5% risk of severe complications within 5 years after 
irradiation based on QUANTEC, Marks et al 2010) is exceeded, we will define the SAE’s as RT-
related; otherwise as durvalumab-related. For the analyses on the incidence of treatment-related 
SAE’s for the stopping rule, all SAE’s will be summarized disregarding of whether it is RT- or 
durvalumab-related. Radiation pneumonitis is defined separately in section 5.3.3.5.4.  
 
5.3.3.5.1 Cardiac and pericardial injury 
Although cardiac and pericardial injury is uncommon in the conventionally fractionated course 
of RT, with large doses per fraction of hfRT or SBRT, a number of possible side-effects can be 
seen especially when given during immunotherapy. Hospitalization or outpatient referral to 
cardiology is recommended depending on symptoms and acuity. 
 
5.3.3.5.2 Gastrointestinal/esophageal injury 
The radiation effects on the esophagus can be acute: esophagitis (i.e., dysphagia, causing pain on 
swallowing, typically relatively soon after RT course is completed, and typically resolves on its 
own within days to a week or longer), or chronic, typically manifesting with dysphagia due to 
stenosis, or esophageal ulceration, with perforation in the extreme cases. Acute esophagitis will 
be managed according to severity with dietary modification, liquid analgesics, oral pain 
medications with IV fluid support if necessary. Management of diarrhea which is unlikely from 
RT alone, should follow Appendix I. 
 
5.3.3.5.3 Central airway/bronchial injury 
This bronchial injury with subsequent focal collapse of lung may impair overall pulmonary 
status. It also makes further assessment of tumor response more difficult as the collapsed lung 
approximates the treated tumor. Because atelectatic lung and tumor have similar imaging 
characteristics, radiology reports will often describe the overall process as progressive disease 
while the actual tumor may be stable or shrinking. Investigators are referred to the strict criteria 
for progressive disease in Section 6.0 of this protocol to avoid such mis-characterization. 
The consequences of bronchial toxicity, e.g., cough, dyspnea, hypoxia, impairment of pulmonary 
function test parameters, pleural effusion or pleuritic pain (associated with collapse), should all 
be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), v. 5.0. 
 
5.3.3.5.4 Lung injury  
Radiation pneumonitis is a subacute (weeks to months from treatment) inflammation of the end 
bronchioles and alveoli. Radiation fibrosis is a late manifestation of radiation injury to the 
irradiated lung. Given the small amount of lung that is typically included in the SBRT portals, 
lung toxicity has not been shown to increase significantly delivered after chemoradiation therapy 
as reported by Kumar et al 2017. However, again no data is available now when doing hfRT or 
SBRT boost with immunotherapy after chemoradiation therapy as in current trial design. The 
symptoms may be confused with other causes of respiratory deterioration, including infections, 
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as the clinical picture may be very similar to acute bacterial pneumonia, with fatigue, fever, 
shortness of breath, nonproductive cough, and a pulmonary infiltrate on chest x-ray. The 
infiltrate on chest x-ray should include the area treated to high dose, but may extend outside of 
these regions. The infiltrates may be characteristically “geometric” corresponding to the 
radiation portal, but may also be ill defined. 
 
Since both RT and immunotherapy alone can cause pneumonitis, we further defined radiation 
pneumonitis per convention as: 
 
The diagnosis of radiation pneumonitis is based on a combination of typical symptoms (eg, 
cough, dyspnea, and sometimes fever), compatible imaging findings per CXR and/or CT chest, 
dose distribution of radiation therapy, and exclusion of other causes, such as infection including 
the novel coronavirus SARS-CoV-2 (COVID-19), heart failure, pulmonary embolism, drug-
induced pneumonitis, bleeding, and progression of the primary tumor. The opacities on imaging 
should conform to or at least overlap with the high isodose lines (IDLs) of radiation port/field 
defined by 50% IDL or above in either the initial dCRT or the hfRT plan (modified from Olivier 
et al 2020). 
 
Accordingly, durvalumab-related pneumonitis is defined for those with typical symptoms, 
compatible imaging findings but with opacities showing no overlapping with high IDLs of 
radiation port/field defined by 50% IDL or above in either the initial dCRT or the hfRT plan, 
after clusion of other causes as defined above. 
 
We recognize that there is no commonly accepted definition of “radiation pneumonitis” in the 
era of immunotherapy. Based on the above definition, the diagnosis is to be made upon 
physicians’ clinical judgement based on factors listed, and commonly in a multi-disciplinary 
fashion.  
 
In current proposed study, all pneumonitis will be defined as “radiation pneumonitis” vs. 
“Durvalumab-related pneumonitis” at our best judgement, but will be combined in toxicity 
analyses as in the PACIFIC trial and medically treated the same. Accordingly, CTCAE 5.0 only 
categorize “pneumonitis” as in one condition and does not differentiate the cause.  
 
Subjects reporting symptoms as above will be promptly evaluated and treated. Mild pneumonitis 
may be treated with nonsteroidal anti-inflammatory agents or steroid inhalers. More significant 
pneumonitis will be treated with systemic steroids, bronchodilators, and pulmonary toilet. Supra- 
and concurrent infections should be treated with antibiotics. Consideration of prophylaxis of 
opportunistic infections should be considered in immunocompromised subjects. Details are 
provided in Section 5.3.3.5 and in Appendix I. 
 
5.3.3.5 Toxicity management guidelines 
Toxicities other than what are listed in Section 5.3.3.5 should be managed the same way as 
managing side effects from immunotherapy since it is likely contributed mostly from 
durvalumab which could be enhanced by the immunostimulating effects of consolidative RT. 
In the situation that subject develops significant side effects from the first fraction of 
consolidative RT such as acute worsening of dyspnea, cough (dry or productive), arrhythmia, 
etc., imaging study such as a chest X-ray and/or ECG should be ordered within 24 hours. 

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Hospitalization and/or steroid use will be determined per treating physician(s). If the subject 
develops grade 2 pneumonitis, postponing the second fraction to up to one week after the 
first one is allowed in the trial if subject’s condition returns to baseline within 3 days with 
maximum supportive care. If not, the second fraction of consolidative RT will be cancelled. 
Any grade 3 pneumonitis developed after the first fraction of consolidative RT but prior to the 
second fraction immediately warrant cancelling of the second fraction. For other acute symptoms 
developed after the first fraction, cancelling of the second fraction of consolidative RT will be 
based on the recommendation of treating physician(s). The subject will remain on the protocol 
for assessment and other related follow-ups per protocol unless he/she decides to withdrawal. 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab are provided in Appendix I 
 
Subjects should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis.. In the absence of a clear alternative etiology, events should be considered potentially 
immune related. 
 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see section 3.3. of this protocol and the Dosing Modification and Toxicity 
Management Guidelines in Appendix I). 
 
Following the first dose of IP, subsequent administration of durvalumab can be modified based 
on toxicities observed as described in the Dosing Modification and Toxicity Management 
Guidelines in Appendix I provided by Astra Zeneca. These guidelines apply to AEs considered 
causally related to durvalumab monotherapy by the reporting investigators previously. 
 
Dose reductions of durvalumab are not permitted.  
 
Subjects should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related. 
 
All toxicities will be graded according to NCI CTCAE, Version 5.0. 
 
5.4 Restrictions during the study and concomitant treatment(s) 
5.4.1 Restrictions during the study 
The following restrictions apply while the subject is receiving study treatment and for the 
specified times before and after: 
Female subject of child-bearing potential 
- 
Female subjects of childbearing potential who are not abstinent and intend to be sexually 
active with a non-sterilized male partner must use at least 1 highly effective method of 
contraception (table below) from the time of screening throughout the total duration of 
the drug treatment and the drug washout period (90 days after the last dose of 
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childbearing potential must use male condom plus spermicide throughout this period. 
Cessation of birth control after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control. Female subjects should also refrain from 
breastfeeding throughout this period. 
Male subjects with a female partner of childbearing potential 
- 
Non-sterilized male subjects who are not abstinent and intend to be sexually active with a 
female partner of childbearing potential must use a male condom plus spermicide from 
the time of screening throughout the total duration of the drug treatment and the drug 
washout period (90 days after the last dose of durvalumab). However, periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
contraception. Male subjects should refrain from sperm donation throughout this period. 
- 
Female partners (of childbearing potential) of male subjects must also use a highly 
effective method of contraception throughout this period (table below). 
 
Natural born females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral salpingectomy, 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.  
• 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. 
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 the table below. 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). 
 
Highly Effective Methods of Contraception (<1% Failure Rate) 
 
Barrier/Intrauterine methods 
Hormonal Methods 

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Copper T intrauterine device 
Levonorgestrel-releasing intrauterine system 
(e.g., Mirena®)a 
Implants: Etonogestrel-releasing implants: 
e.g. Implanon® or Norplant® Intravaginal: 
Ethinylestradiol/etonogestrel- releasing 
intravaginal devices: e.g. NuvaRing® 
Injection: Medroxyprogesterone injection: 
e.g. Depo-Provera® 
Combined Pill: Normal and low dose 
combined oral contraceptive pill 
Patch: Norelgestromin/ethinylestradiol- 
releasing transdermal system: e.g. Ortho 
Evra® 
Minipillc: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone-based 
a 
This is also considered a hormonal method 
 
Blood donation 
Subjects should not donate blood while participating in this study; or for at least 90 days 
following the last infusion of durvalumab or 90 days after receipt of the final dose of 
durvalumab, or at least six months after last dose of RT, whichever occurs longest. 
 
5.5 Concomitant treatment(s) 
5.5.1 Permitted concomitant medications 
 
Supportive Medications 
Supportive medication/class of drug: 
Usage: 
Concomitant    medications    or     treatments  (e.g., 
acetaminophen 
or 
diphenhydramine) 
deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above 
To be administered as prescribed by the 
Investigator 
Best 
supportive 
care 
(including 
antibiotics, 
nutritional support, correction of metabolic disorders, 
optimal symptom control, and pain management 
[including palliative radiotherapy to non-target 
lesions, etc]) 
Should be used, when necessary, for all 
subjects 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
 
5.5.2 Excluded concomitant medications 
 

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Prohibited Concomitant Medications 
Prohibited medication/class of drug: 
Usage: 
Any investigational anticancer therapy other 
than those under investigation in this study 
Should not be given concomitantly whilst the 
subject is on study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 
other than those under investigation in this 
study 
Should not be given concomitantly whilst the 
subject is on study treatment 
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study 
Should not be given concomitantly whilst the 
subject is on study treatment. (Concurrent use of 
hormones for non-cancer-related conditions [e.g., 
insulin for diabetes and hormone replacement 
therapy] is acceptable. Local treatment of isolated 
lesions, excluding target lesions, for palliative 
intent is acceptable [e.g., by local surgery or 
radiotherapy]) 
Immunosuppressive medications including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers 
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions: 
• 
Use of immunosuppressive medications 
for the management of IP-related AEs, 
• 
Use in subjects with contrast allergies. 
• 
In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted. 
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential 
for the management of non-immunotherapy related 
events experienced by the subject (e.g., chronic 
obstructive pulmonary disease, radiation, nausea, 
etc). 
Drugs with laxative properties and herbal or 
natural remedies for constipation 
Should be used with caution through to 90 days 
after the last dose of durvalumab during the study 
EGFR TKIs 
Should not be given concomitantly. 
Should be used with caution in the 90 days post last 
dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with 1st generation EGFR 
TKIs) has been reported when durvalumab has 
been given concomitantly. 
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP (including SoC) 
Herbal and natural remedies which may have 
immune-modulating effects 
Should not be given concomitantly unless agreed 
by the Principal investigator 

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Section 6.0 MEASUREMENT OF EFFECT 
6.1 Investigator RECIST 1.1-based assessments 
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013): 
• Response to immunotherapy may be delayed 
• Response to immunotherapy may occur after PD by conventional criteria 
• The appearance of new lesions may not represent PD with immunotherapy 
• SD while on immunotherapy may be durable and represent clinical benefit. 
Based on the above-described unique response to immunotherapy and based on guidelines 
from regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation 
of anticancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune 
modulating anticancer compounds, the study may wish to implement the following in 
addition to standard RECIST 1.1 criteria: 
• RECIST will be modified so that PD must be confirmed at the next scheduled visit, 
preferably, and no earlier than 4 weeks after the initial assessment of PD in the absence 
of clinically significant deterioration. Treatment with durvalumab would continue 
between the initial assessment of progression and confirmation for progression. 
• In addition, subjects may continue to receive durvalumab beyond confirmed PD in the 
absence of clinically significant deterioration and if investigators consider that subjects 
continue to receive benefit from treatment. 
Modification of RECIST as described may discourage the early discontinuation of 
durvalumab and provide a more complete evaluation of its antitumor activity than would be 
seen with conventional response criteria. Nonetheless, the efficacy analysis will be 
conducted by programmatically deriving each efficacy endpoint based on RECIST 1.1 
criteria. 
* Of note, clinically significant deterioration is considered to be a rapid tumor 
progression that necessitates treatment with anticancer therapy other than durvalumab 
or with symptomatic progression that requires urgent medical intervention (e.g., central 
nervous system metastasis, respiratory failure due to tumor compression, spinal cord 
compression). 
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a subject discontinues study drug or receives 
another anti-cancer therapy. 
At each visit, subjects will be programmatically assigned a RECIST 1.1 visit response of 
CR, PR, NED, SD, or PD depending on the status of their disease compared with baseline 
and previous assessments. Subjects with no evidence of disease at follow-up in the absence 
of new lesions will be assigned a response of NED. 
If a subject has had a tumor assessment which cannot be evaluated even after multi-
disciplinary evaluation among treating physician(s), radiologist(s), etc., then the subject 
will be assigned a visit response of not evaluable (NE) (unless there is evidence of 
progression in which case the response will be assigned as PD). 
Subjects who have disease control following completion of 12 months of treatment or 
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PD will continue to have objective tumor assessments (see Study assessment tables, Section 
7.0). 
Confirmation of progression guidelines are set for the following reasons: 
• for subject management and treatment decisions 
• in the absence of significant clinical deterioration, to promote the collection of 
additional scans after the first radiologic RECIST 1.1 assessment of progressive 
disease (PD) in order to distinguish pseudoprogression from true radiologic 
progression, also known as RECIST 1.1 modified for confirmation of progression 
• when scans are evaluated by Investigator and by BICR, to reduce informative 
censoring by Investigator assessments (Investigator assesses PD at a time-point 
earlier than does BICR). 
Confirmed objective disease progression refers to either of the following scenarios:  
1. clinical progression/deterioration followed by a radiologic verification scan (PD by 
RECIST 1.1); or  
2. in the absence of significant clinical deterioration, radiologic PD by RECIST 1.1 
followed by a second radiologic confirmation scan with PD assessed according to the 
specific confirmation of progression criteria listed below. RECIST 1.1 modified for 
confirmation of progression refers to the second scenario above. The confirmatory scan 
should occur preferably at the next scheduled imaging visit and no earlier than 4 weeks 
following the date of the immediate prior assessment of PD with RECIST 1.1. 
Immediate prior radiologic progression would be considered confirmed if any the following 
criteria are met in the confirmatory scan: 
• ≥20% increase in the sum diameters of target lesions (TLs) compared with the nadir 
at 2 consecutive visits, with an absolute increase of at least 5 mm in sum of 
diameters compared to nadir, 
 
• and/or significant progression (worsening) of non-target lesions (NTLs) and/or of 
pre- existing new lesions at the confirmatory scan time-point compared with the 
immediate prior time-point (Note: Pre-existing new lesions are evaluated as NTLs at 
the confirmatory scan time-point), 
 
• and/or additional new unequivocal lesions at the confirmatory scan time-point. 
 
NOTE: In order to have confirmed objective disease progression, there should be two 
consecutive assessments meeting the PD definition: the first PD by RECIST 1.1 and the second 
PD using the confirmation of progression criteria (above). If the first assessment fulfilling the PD 
definition by RECIST 1.1 is not confirmed, continue with assessments until the next PD by 
RECIST 1.1, which in turn will need its own immediate subsequent confirmation scan.  In the 
absence of significant clinical deterioration, treatment with study drug may continue between the 
initial assessment of progression and the scan to confirm progression. 
If the confirmation scan confirms progression, then the date of the prior scan with PD should be 
declared as the date of progression. 
If progression is not confirmed, in the absence of significant clinical deterioration, then the 
subject should continue study drug and on-treatment assessments until the next PD which will 
also require a follow-up confirmation scan. If the first PD is not confirmed by the immediate 
next scan, then the Investigator should not change the PD assessment of the first scan. 
6.1.1 Timing of Tumor Assessments 

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Tumor assessment must occur every 12 weeks (± 2 weeks) relative to Day 0 during the first 48 
weeks following the first administration of durvalumab, and thereafter until confirmed objective 
disease progression or death. 
 
Tumor assessment in subjects who achieve disease control following 12 months of durvalumab 
treatment will continue to be completed every 12 weeks (± 2 weeks) relative to Day 0 until 
confirmed disease progression, death, or until 2 years post-Day 0, whichever comes first. Tumor 
assessment following confirmed disease progression will be completed according to standard of 
care. Tumor assessment occurring beyond 2 years post-Day 0 will be completed according to 
standard of care.  
 
Tumor assessment in subjects who discontinue treatment with durvalumab for any reason other 
than confirmed disease progression will continue to be completed every 12 weeks (± 2 weeks) 
relative to Day 0 until confirmed disease progression, death, or until 2 years post-Day 0, 
whichever comes first. Tumor assessment following confirmed disease progression will be 
completed according to standard of care. Tumor assessment occurring beyond 2 years post-Day 0 
will be completed according to standard of care. 
 
Tumor assessment in subjects who continue to receive durvalumab post-confirmed disease 
progression must be completed every 12 weeks (± 2 week) relative to Day 0 until treatment with 
durvalumab is discontinued. Upon discontinuation of durvalumab, tumor assessment will be 
completed according to standard of care.  
 
Tumor assessment in subjects who discontinue durvalumab post-confirmed disease progression 
will be completed according to standard of care.  
 
6.1.2 Efficacy variable in primary and secondary endpoints 
6.1.2.1 Progression-free survival (PFS) 
PFS (assessed per RECIST 1.1) will be defined as the time from Day 0 until the date of objective 
disease progression or death (by any cause in the absence of progression) regardless of whether 
the subject withdraws from therapy or receives another anti-cancer therapy prior to progression. 
Subjects who have not progressed or died at the time of analysis will be censored at the time of 
the latest date of assessment from their last evaluable RECIST 1.1 assessment. However, if the 
subject progresses or dies after 2 or more missed visits, the subject will be censored at the time 
of the latest evaluable RECIST 1.1 assessment prior to the 2 missed visits. If the subject has no 
evaluable visits or does not have baseline data they will be censored at Day 1 unless they die 
within 2 visits of baseline. 
The PFS time will always be derived based on scan/assessment dates not visit dates. RECIST 1.1 
assessments/scans contributing towards a particular visit may be performed on different dates. 
The following rules will be applied: 
• The date of progression will be determined based on the earliest of the scan dates of the 
component that triggered the progression for the adjudicated reviewer selecting PD or of 
either reviewer where both select PD as a time point response. 
 
• For investigational assessments, the date of progression will be determined based on the 
earliest of the RECIST assessment/scan dates of the component that indicates progression 
 

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• When censoring a subject for PFS the subject will be censored at the latest of the dates 
contributing to a particular overall visit assessment. 
 
Note: For target lesions, only the latest scan date is recorded in the RECIST eCRF out of all scans performed at that 
assessment for the target lesions and similarly for non-target lesions only the latest scan date is recorded out of all 
scans performed at that assessment for the nontarget lesions. 
Additionally, PFS will be obtained using the algorithm described above by RECIST 1.1, but following a 
modification whereby any objective disease progression must be confirmed by the next scheduled scan. The 
confirmatory scan must be no sooner than 4 weeks after the initial suspected progression. If disease progression is 
confirmed (or disease progression occurs and no further scans are recorded) then the date of progression will be 
when it was originally observed. Subjects with a single disease progression and no further tumour assessment scans 
will be treated as PD in the analysis. 
In the absence of clinically significant deterioration the investigational site is advised to continue the subject on 
study drug until progression has been confirmed. 
 
6.1.2.2 Overall survival (OS) 
OS is defined as the time from Day 0 until death due to any cause. Any subject not known to 
have died at the time of analysis will be censored based on the last recorded date on which the 
subject was known to be alive. 
Note: Survival calls will be made in the week following the date of DCO for the analysis, and if 
subjects are confirmed to be alive or if the death date is post the DCO date these subjects will be 
censored at the date of DCO. Death dates may be found by checking publicly available death 
registries. 
 
6.1.2.3 Time to death or distant metastasis (TTDM)  
TTDM will be defined as the time from Day 0 until the first date of distant metastasis or death in 
the absence of distant metastasis. Distant metastasis is defined as any new lesion that is outside 
of the radiation field according to RECIST 1.1 or proven by biopsy. Subjects who have not 
developed distant metastasis or died at the time of analysis will be censored at the time of the 
latest date of assessment from their last evaluable RECIST 1.1 assessment. However, if the 
subject has distant metastasis or dies after 2 or more missed visits, the subject will be censored at 
the time of the latest evaluable RECIST 1.1 assessment prior to the 2 missed visits. If the subject 
has no evaluable visits or does not have baseline data they will be censored at Day 1 unless they 
die within 2 visits of baseline. 
 
 

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Section 7.0 STUDY PARAMETERS 
SCHEDULE OF STUDY ASSESSMENTS 
 
Baseline Evaluation assessments during standard care of definitive chemoradiation therapy 
( dCRT) (Only for patients consented prior to dCRT) 
definitive chemoradiation (dCRT) phase 
Week 1and 2 
Week 3 
+/-3 days 
Week 4 
+/-3 
days 
Week 5 
+/-3 
days 
Week 6 
+/-3 
days 
Week 7 
+/-3 
days 
Week 8 
+/-3 days 
Week 9 
+/-3 
days 
Procedure/Scale 
Screening  
 
 
Visit No. 
3 
Visit 
No. 4 
Visit 
No. 5 
Visit 
No. 6 
Visit 
No. 7 
Visit No. 
8 
Visit 
No. 9b 
Informed consent for preliminary 
enrollment  
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Exam (full)  
X 
 
 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
Targeted physical exam based 
on symptoms 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs & Weight & Heighta 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
 
Xc 
 
 
 
 
 
 
 
Laboratory Assessments 
 
Clinical Chemistry   
X 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
 
Creatinine Clearance 
X 
 
 
 
 
 
 
 
Hematology 
X 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
 
Coagulation (PT/INR) 
X 
--------------------------- As clinically indicated ----------------------- 
TSH, T4  (reflex free T3g) 
X 
--------------------------- As clinically indicated ----------------------- 
Pregnancy testf 
X 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
Monitoring 
 
 Adverse Event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
Review of prior/concomitant 
medications 
X 
 
 
 
 
 
 
 
Other assessments and assays 
 
 
 
 
 
 
 
 
 
 
Imaging by CT/MRI/PET 
X 
 
 
 
 
 
 
 
Tumor pathology review 
 
X 
 
 
 
 
 
 
 
CT simulation (for planning 
definitive CRT) 
 
 
X 
 
 
 
 
 
 
 
Definitive CRT (30-33 fractions 
RT, with two or 
more cycles of chemotherapy) 
 
X 

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definitive chemoradiation (dCRT) phase 
Week 1and 2 
Week 3 
+/-3 days 
Week 4 
+/-3 
days 
Week 5 
+/-3 
days 
Week 6 
+/-3 
days 
Week 7 
+/-3 
days 
Week 8 
+/-3 days 
Week 9 
+/-3 
days 
Procedure/Scale 
Screening  
 
 
Visit No. 
3 
Visit 
No. 4 
Visit 
No. 5 
Visit 
No. 6 
Visit 
No. 7 
Visit No. 
8 
Visit 
No. 9b 
PD-L1 (optional) testing from 
tissue 
X 
 
 
 
 
 
 
 
Collect archival biopsy tissue for 
Immunohistochemistry staining 
(optional) for immune cell 
markers including confocal 
microscopy 
X 
 
 
 
 
 
 
 
Blood draw for tumor marker 
research (exploratory endpoint)e 
 
X 
 
X 
 
X 
 
 
X 
 
a Height will only be taken at initial study visit;  
b Depending on the total number of fractions of RT, subjects may finish in week 8 or 9. For those finish in week 8, the No. 9 visit 
is not necessary;  
c 12-lead ECG (triplicate ECGs are done only if QTcF is ≥470 [triplicate ECGs done 2-5 minutes apart]), See section 5.2.1 
d Blood drawn per chemotherapy schedule and may vary per treating physician/standard care;  
e Blood draw for exploratory research. See section 5.2.3.2. for details.  
f For women of childbearing potential only. A serum pregnancy test is acceptable. Women of childbearing potential are required 
to have a pregnancy test within 7 days prior to the first dose of durvalumab and then every 4 weeks. Pregnancy test may occur on 
Day 1, but results must be available and reviewed by the treating physician or Investigator prior to commencing an infusion 
g Free T3 will only be measured if TSH, and/or T4 is abnormal or if there is clinical suspicion of an AE related to the endocrine 
system. 
 
 

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Schedule of new tumor baseline assessments, durvalumab + Consolidative hfRT after 
dCRT, treatment to progression 
Confirmation 
of Eligibility 
(Baseline 
Assessmentb) 
C1 
CT 
sim 
C2 
RT (1st 
boost) 
RT (2nd  
boost) 
 
C3 to C26 or PD 
Week 
 
Screening 
 
1 
 
2 
 
3 
4 
5 
6 - 52 
Day 
 
 
Screening 
 
 
1a 
 
 
8-14 
 
 
15-21 
 
 
22-35 
 
22-35 
Q14 ± 3 days unless 
dosing needs to be held 
for toxicity reasons 
Informed consentb 
(X) 
Review of Eligibility 
criteria 
X 
 
Demographics  
X 
 
Physical exam (full) 
X 
 
Targeted physical exam 
(based on 
symptoms)/Routine 
follow-ups 
Xr 
 
Xs 
 
Xt 
 
Xu 
Medical History 
X 
 
 
 
 
 
ECOG performance 
status 
X 
 
X 
 
X 
 
Xu 
Vital signs (including 
weight and height)c 
X 
X 
X 
X 
 
X 
ECGd 
X 
As clinically indicated 
For combinations with an agent with pro-arrhythmic potential or where effect 
of the combination on QT is not known more intense ECG monitoring than 
below may be required. 
Laboratory Assessments 
 
Clinical chemistrye 
X 
Xf 
X 
 
X 
Creatinine Clearance 
X 
Xf 
 
 
 
Hematologye 
X 
Xf 
X 
 
X 
Coagulation labs 
(PT/INR) 
X 
--------------------------- As clinically indicated ----------------------- 
TSH, T4g, (reflex free T3 
h) 
X 
Xf 
--------------------------- As clinically indicated ----------------------- 
Pregnancy testi 
X 
Xf 
X 
 
X 
Urinalysis 
X 
 
 
 
 
Monitoring 
Concomitant 
medications 
X 
<-------------------------------------------------------------------------------------------> 
AE/SAE assessment l 
    <------------------------------------------------------------------------------------> 
IP administration/ 
Therapy 
Durvalumabm 
X 
 
X 
 
 
X 

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Confirmation 
of Eligibility 
(Baseline 
Assessmentb) 
C1 
CT 
sim 
C2 
RT (1st 
boost) 
RT (2nd  
boost) 
 
C3 to C26 or PD 
Week 
 
Screening 
 
1 
 
2 
 
3 
4 
5 
6 - 52 
Day 
 
 
Screening 
 
 
1a 
 
 
8-14 
 
 
15-21 
 
 
22-35 
 
22-35 
Q14 ± 3 days unless 
dosing needs to be held 
for toxicity reasons 
 hfRT (QOD)k 
X  
X 
CT simulation (for 
planning hfRT) 
Xp 
Other assessments and 
assays 
EORTC QLQ-C30 v. 3 
and LC13 module 
X 
 
X 
 
 
 
Xu 
Tumor biopsy (archival 
or newly acquired)a 
X 
Tumor biopsy (archival, 
if available, for patients 
who submit a newly 
acquired biopsy at 
screening for PD-L1 
status) 
X 
Tumor biopsy (after 
hfRT)j (optional) 
 
X 
Blood draws for 
exploratory research 
endpointq 
X 
 
X 
X 
X 
X 
Efficacy evaluations 
 
Tumor assessment 
(CT/MRI/PET) (RECIST 
1.1) n,o 
X (Day 0) 
Q12w ± 2w for the first 48 weeks (relative to Day 0, and thereafter until 
confirmed objective disease progression/death (whichever comes first). The 
schedule of q12w ± 2 week for first 48 weeks and thereafter MUST be 
followed regardless of any delays in dosing. See Section 6.1.1 for details 
regarding the timing of scans. 
 
a 
Every effort should be made to minimize the time between screening and starting durvalumab treatment. (i.e. within 1 day 
of completion of screening, but allow the first infusion to start up to 28 days after initial phase of radiation therapy (with 
concurrent chemotherapy)) 
b 
Most subjects will be consented prior to start of standard clinical care of definitive chemo-radiation therapy (dCRT).  
However, informed consent of study procedures may occur within the screening period after dCRT and prior to 
consolidative hfRT. Tumor pathology review will be performed only on new consented subjects.  The collection of 
additional biopsies upon progression is strongly encouraged. If laboratory or imaging procedures were performed for 
alternate reasons prior to signing consent, these can be used for screening purposes with consent of the subject.  
c 
Body weight is recorded at each visit along with vital signs.  Height is only at screening.  For subjects that consented 
prior to dCRT, weight and height does not need to recorded for confirmation of eligibility again. 
d 
Patients who signed consent prior to starting dCRT do not need to complete an additional ECG at this timepoint if the 
ECG requirements were satisfied prior to starting dCRT. If the baseline/screening ECG shows a QTcF ≥ 470 ms, the 
QTcF can be recalculated by performing triplicate ECGs completed 2-5 minutes apart. The recalculated QTcF must be < 
470 ms to satisfy eligibility requirements. 
e 
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if 
clinically indicated. 
f 
If screening clinical chemistry and hematology assessments are performed within 3 days prior to Day 1 (first infusion 
day), they do not need to be repeated at Day 1. 
g 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at day 1. 
h 
Free T3 will only be measured if TSH and/or T4 is abnormal or if there is clinical suspicion of an AE related to the 
endocrine system. 
i 
For women of childbearing potential only. Women of childbearing potential are required to have a pregnancy test within 7 

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days prior to the first dose of durvalumab and then every 4 weeks. Pregnancy test may occur on Day 1, but results must be 
available and reviewed by the treating physician or Investigator prior to commencing an infusion 
j 
Tumor biopsy is scheduled two months after completing consolidative RT (±1 week), which is optional but strongly 
recommended. 
k 
Consolidative hfRT is scheduled in between the second and third cycle of durvalumab, to be delivered every other day 
(QOD) with exception that, if the first dose is on a Friday, the second dose is allowed to be delivered on the following 
Monday. 
l 
For AEs/SAEs reported, additional information such as medical history and concomitant medications may be needed 
m 
Results for LFTs, electrolytes and creatinine must be available before commencing an infusion (within 3 days) and 
reviewed by the treating physician or Investigator prior to dosing. 
n 
RECIST assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast of the 
chest, abdomen (including liver and adrenal glands) and pelvis. Pelvic imaging is recommended only when primary or 
metastatic disease in the pelvic region is likely. Additional anatomy should be imaged based on signs and symptoms of 
individual subjects at baseline and follow-up. Baseline assessments (CT or PET/CT) should be performed no more than 
28 days before the date of consent and, ideally, should be performed as close as possible to and prior to the start of IP. 
The confirmatory scans should be performed preferably at the next scheduled imaging visit and no less than 4 weeks after 
the prior assessment of PD (in the absence of clinically significant deterioration). If an unscheduled assessment was 
performed and the subject has not progressed, every attempt should be made to perform the subsequent assessments at 
their next scheduled visit. 
o 
See Section 6.1.1 for details regarding the timing of scans 
p 
A CT simulation at radiation oncology will be performed within one week before the second cycle of durvalumab to 
allow sufficient time planning of consolidative RT. 
q 
Blood drawn for exploratory research purpose, see section 5.2.3.2 for details.  
r 
This follow-up visit is optional if no need of delay of starting the first cycle of durvalumab after being finally enrolled 
due to recovery from the initial phase of radiation therapy (with concurrent chemotherapy). If significant delay is required 
(up to 42 days after the end of the chemoradiation therapy), this visit is required to determined the eligibility of the 
subject for this trial based on his/her recovery status.  
s 
Follow-up visit is within 24 hours before CT simulation. 
t 
A follow-up visit on the same day of but prior to each fraction of consolidative RT (two visits). 
u 
A follow-up visit will be scheduled q12 weeks within the first 48 weeks after study treatment start and thereafter until 
confirmed disease progression or death.  
 
Note: All assessments on treatment days are to be performed prior to infusion of durvalumab or delivery of each fraction of 
consolidative RT, unless otherwise indicated. 
 
Abbreviations: C Cycle; ECG Electrocardiogram; IM Intramuscular; LFT Liver function test; q12w Every 12 weeks; QOD Every 
other day; T3  Triiodothyronine;  T4 Thyroxine; TSH Thyroid-stimulating hormone. 
 
 

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Follow-Up Assessments 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
12 Months and Every 6 
Months (±2 weeks) until 
confirmed PD 
30 
3 
6 
9 
Physical examinationa 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X  
X 
X 
AE/SAE assessmentd 
X 
----------------------------------------------X----------------------------------------------- 
Concomitant medications 
X 
 
 
Palliative radiotherapy 
--------------------------- As clinically indicated ----------------------- 
Subsequent anticancer therapy 
X 
X 
X 
X 
X 
Survival status: phone contact with subjects 
who refuse to return for evaluations and agree 
to be contacted 
 
 
X 
 
X 
 
X 
 
X (every 2 months) 
Hematology 
X 
X 
 
 
X 
Serum chemistry 
X 
X 
 
 
 
TSH, and fT4 (fT3 )b 
X 
 
 
 
 
Blood draws exploratory researchc  
X 
X 
X 
X 
X 
 Tumour assessment (CT or MRI) 
For subjects who achieve disease control following 12 months of treatment, tumor 
assessments should be performed every 12 weeks (±2 weeks) relative to Day 0   until 
confirmed PD by RECIST 1.1 by investigational site review. Please refer to Section 6.1 for 
timings of confirmatory scans. 
 
For subjects who discontinue durvalumab due to toxicity (or symptomatic deterioration), 
tumor assessments should be performed relative to the relative to Day 0 as follows: every 12 
weeks (±2 week)  until confirmed disease progression, death, or until 2 years post-Day 0, 
whichever comes first. . 
Upon confirmed PD, scans should be conducted according to local standard clinical practice 
. 
 
For subjects who continue on durvalumab post-confirmed progression at the 
investigator’s discretion, tumor assessments should be performed every 12 weeks (± 2 
weeks) relative to Day 0 until treatment with durvalumab is discontinued. Upon 
discontinuation of durvalumab, tumor assessment will be completed according to standard 
of care. 
 
For subjects who discontinue durvalumab following confirmed progression, scans 
should be conducted according to local clinical practice . 
a  Full physical exam 
b   Free T3 will only be measured if TSH and/or T4 is abnormal. They should also be measured if there is clinical suspicion of an 
adverse event related to the endocrine system. 
c Blood drawn for exploratory research purpose, see section 5.2.3.2 for details. Subjects that have had disease progression will not 
have the samples drawn for research. 
d Adverse events of special interest will be collected and reported through the duration of the follow-up phase. See section 9.0 for 
details.  
 

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Section 8.0 DRUG FORMULATION AND PROCUREMENT 
8.1 Durvalumab  
The Investigational Products Supply section of AstraZeneca will supply durvalumab to the 
investigator as a 500-mg vial solution for infusion after dilution. Although durvalumab now is 
FDA-approved for stage III NSCLC as standard consolidative/adjuvant therapy after definitive 
CRT, combined use with immunostimulating dose of consolidative hfRT has not been tested 
for safety or efficacy before. 
 
8.1.1 Formulation/packaging/storage 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-
hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it 
has a pH of 6.0 and a density of 1.054 g/mL. The nominal fill volume is 10.0 mL. 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Drug product should be kept in secondary original packaging until use to prevent prolonged 
light exposure. 
 
8.1.2 Durvalumab doses and treatment regimens 
Subjects enrolled will receive Durvalumab 10 mg/kg via a 60-minute iv infusion Q2W ± 3 days 
for up to 12 months (maximum of 26 doses, last dose at Week 50) or until confirmed disease 
progression, whichever comes first, unless there is unacceptable toxicity, withdrawal of 
consent, or another discontinuation criterion is met. 
 
8.1.3 Study drug preparation 
Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed: 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
Standard infusion time is 1 hour. In the event that there are interruptions during infusion, the 
total allowed infusion time should not exceed 8 hours at room temperature. 
 
Do not co-administer other drugs through the same infusion line. 
 
The IV line will be flushed with a volume of IV diluent 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. 
 
If either preparation time or infusion time exceeds the time limits a new dose must be prepared 
from new vials. Durvalumab does not contain preservatives, and any unused portion must be 
discarded. 
 
Preparation of durvalumab doses for administration with an iv bag 
 

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Doses of 10 mg/kg will be administered using an iv bag containing 0.9% (weight/volume) saline 
or 5% (w/v) dextrose, with a final durvalumab concentration of 15 mg/ml, and delivered through 
an iv administration set with a 0.2-μm or 0.22-μm in-line filter. 
 
Subject weight at baseline should be used for dosing calculations unless there is a ≥10% change 
in weight. Dosing day weight can be used for dosing calculations instead of baseline weight per 
institutional standard. An additional volume of 0.9% (weight/volume) saline equal to the 
calculated volume of durvalumab to be added to the iv bag must be removed from the bag prior 
to addition of durvalumab. The calculated volume of durvalumab is then added to the iv bag, and 
the bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag. Add the 
calculated volume of durvalumab to the IV bag. The IV bag size should be selected such that the 
final concentration is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. 
 
Dose calculation 
 
Per institutional standard protocol. Refer to Appendix II.  
 
8.1.4 Monitoring of dose administration 
Subjects will be monitored before, during and after the infusion as specified in the Schedule of 
Assessment. Subjects are monitored per institutional standards during the infusion period. 
 
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 subjects 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. The standard 
infusion time is one hour, however if there are interruptions during infusion, the total allowed 
time from infusion start to completion of infusion should not exceed 4 hours at room 
temperature, with maximum total time at room temperature not exceeding 4 hours (otherwise 
requires new infusion preparation). For management of subjects who experience an infusion 
reaction, please refer to the toxicity and management guidelines in Appendix I. 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit subjects to an intensive care unit if necessary. 
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Study Physician. 
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. 
 
8.1.5 Accountability and dispensation 
Per institutional standard protocol. 

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8.1.6 Disposition of unused investigational study drug  
Per institutional standard protocol.  
 
8.2 Investigational consolidative radiation therapy  
Consolidative hfRT will be tested for its safety and efficacy in this trial concurrently with 
durvalumab. For detailed treatment planning, see Section 8.0. 
 
Section 9.0 TOXICITY REPORTING GUIDELINES 
This protocol will comply with monitoring and adverse event reporting requirements of the 
UNMC Fred & Pamela Buffett Cancer Center Data Monitoring plan.  The protocol will adhere to 
the institutional and FDA guidelines for the toxicity reporting. 
 
All subjects will be closely followed for toxicity from the time of the first administration of study 
medication until 90 days after last administration of study medication.  For the subjects enrolled 
prior to dCRT, adverse events (AE’s) will not be captured during standard dCRTsince it is not 
relevant to the investigational therapy (consolidative hfRT with concurrent durvalumab). 
However, baseline information for this population in the form of internal or outside facility 
documentations will be captured by retrospective review of the medical records internally or to 
be requested from outside facilities. Subjects during dCRT routinely are evaluated by their 
radiation oncologists during weekly on-treatment visits (OTVs) with safety concerns 
documented. All AE reporting will begin on the date of the first administration of study 
medication through the entire follow-up period of each subject. For subjects enrolled prior to 
dCRT that are determined ineligible post-dCRT, AEs will not be reported or recorded since they 
received no study medication. We acknowledge that AE's/SAE's may not follow the more typical 
cytotoxic 30 day duration of occurrence, and that this requires ongoing vigilance by the 
investigators to report later AE's/SAE's as events of medical importance if there is any plausible 
likelihood of a relationship with study therapy because of the type/specificity of the AE/SAE 
relative to anti-PD-L1 therapy. 
 
Adverse events will be assessed by reports from subjects to their physician/Investigator and by 
physical examinations.  Per NCI guidelines, SAEs and AEs will be graded and toxicity assessed 
using the revised NCI CTCAE version 5.0. All adverse events (AE) and serious adverse events 
(SAEs) will be followed until resolution, a return to baseline or ≤ grade 1 levels, or until no 
reasonable improvement is expected.  During the course of the study, all AEs and SAEs should 
be proactively followed up for each subject for as long as the event is ongoing.  Every effort 
should be made to obtain a resolution for all events, even if the events continue after the subject 
has discontinued study drug or the study has completed. 
 
Deaths occurring within 30 days of study treatment regardless of relationship will be reported to 
the UNMC Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Committee 
(DSMC).  
 
Any AEs that are unresolved at the subject’s last visit in the study are followed by the 
Investigator for as long as medically indicated, but without further recording in the eCRF.  
AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 

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Cases where a subject shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to be 
reported as SAEs. Please refer to Appendix I for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s law. 
 
9.1 Definitions Adverse Events 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
 
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-
existing condition. An abnormal laboratory finding (including ECG finding) that requires an 
action or intervention by the investigator, or a finding judged by the investigator to represent a 
change beyond the range of normal physiologic fluctuation, should be reported as an AE. 
Adverse events may be treatment emergent (i.e., occurring after initial receipt of investigational 
product) or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received first cycle of durvalumab. 
 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the 
subject being enrolled into the study) for a documented pre-existing condition, that did not 
worsen from baseline, is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
 
Unexpected Adverse Event  
An AE in which the specificity, severity, or frequency is not consistent with (a) the IRB 
application and detailed protocol; (b) Risk information in the ICF; (c) the current investigator’s 
brochure; or (d) Investigational plan or protocol  
The term AE is used to include both serious and non-serious AEs. 
 
Serious Adverse Events 
A serious adverse event is one that at any dose (including overdose) and regardless of causality:  
• Results in death  
• Is a serious threat to life, health, safety or welfare-fare of subject 1  
• Requires inpatient hospitalization or prolongation of existing hospitalization  
• Requires intervention to prevent permanent impairment or damage 
• Results in persistent or significant disability or incapacity2  
• Is a congenital anomaly or birth defect  
• Is another serious important medical event3  
• Is any medical event in an investigational drug study that requires treatment to prevent 
one of the outcomes listed above 
• Seriously jeopardizes the rights, safety, or welfare of subjects  

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1Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse event; it 
does not refer to a serious adverse event that hypothetically might have caused death if it were more severe.  
2Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability to 
carry out normal life functions.  
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
situations where none of the outcomes listed above occurred.  Important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above should also usually be 
considered serious.  Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.  A new diagnosis of cancer during the course of a treatment 
should be considered as medically important.  
 
Adverse Events of Special Interest (AESI) 
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. AESI are defined 
as AEs that include, but are not limited to, events with a potential inflammatory or immune-
mediated mechanism that may require more frequent monitoring and/or interventions such as 
corticosteroids, immunosuppressants, and/or endocrine therapy. An AESI may be serious or non-
serious. Adverse events of special interest will be collected and reported through the duration of 
the follow-up phase. 
 
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician. 
 
AESIs observed with durvalumab include: 
• Diarrhea / Colitis  
• Intestinal perforations 
• Pneumonitis / ILD 
• Hepatic events 
• Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus) 
• Guillain-Barré syndromeMyasthenia gravis  
• Rash / Dermatitis 
• Renal events 
• Pancreatitis / serum lipase and amylase increases 
• Myocarditis 
• Myositis / Polymyositis 
• Other inflammatory responses that are rare / less frequent with a potential immune- 
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis 
and other events involving the eye, skin, haematological and rheumatological events. 
vasculitis, non-infectious meningitis and non-infectious encephalitis. 
 
It is possible that events with an inflammatory or immune-mediated mechanism could occur in 
nearly all organs. In addition, infusion-related reactions and hypersensitivity/anaphylactic 
reactions with a different underlying pharmacological etiology are also considered AESIs. 
 

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Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab Investigator’s Brochures. More specific guidelines for their evaluation and 
treatment are described in detail in the Dosing Modification and Toxicity Management 
Guidelines (please see Appendix I). These guidelines have been prepared by Astra-Zeneca to 
assist the Investigator in the exercise of his/her clinical judgment in treating these types of 
toxicities. These guidelines apply to AEs considered causally related to the study drug/study 
regimen by the reporting investigator. 
 
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality suggestive 
of pneumonitis/interstitial lung disease is observed, toxicity management as described in detail in 
the Dosing Modification and Toxicity Management Guidelines (see Appendix I) will be applied. 
The results of the full diagnostic workup (including high-resolution computed tomography 
(HRCT), blood and sputum culture, hematological parameters etc) will be captured in the eCRF. 
It is strongly recommended to perform a full diagnostic workup, to exclude alternative causes 
such as lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary 
hemorrhage. In the presence of confirmatory HRCT scans where other causes of respiratory 
symptoms have been excluded, a diagnosis of pneumonitis (ILD) should be considered and the 
Dosing Modification and Toxicity Management Guidelines should be followed. 
 
Pneumonitis (ILD) investigation 
The following assessments, and additional assessments if required, will be performed to enhance 
the investigation and diagnosis of potential cases of pneumonitis. The results of the assessment 
will be collected. 
• Physical examination 
− 
Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including 
auscultation for lung field will be assessed. 
 
• SpO2 
− 
Saturation of peripheral oxygen (SpO2) 
• Other items 
− 
When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible: 
 
(i) 
ILD Markers (KL-6, SP-D) and β-D-glucan 
 
(ii) 
Tumor markers: Particular tumor markers which are related to disease 
progression. 
 
9.2 Adverse Event Reporting Requirements Per University of Nebraska 
Medical Center, IRB and Fred & Pamela Buffett Cancer Center Data and 
Safety Monitoring Committee (DSMC) and Astra Zeneca Reporting 
9.2.1  IRB Reporting  
All internal adverse events (AEs) will be reported to the local IRB promptly per institutional 
human research protection program policies. 
 

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9.2.2 Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Committee 
(DSMC) Reporting 
 
  Reporting of the following will be done in accordance with DSMC guidelines: 
• 
All SAEs and toxicity will be reported to the DSMC. However, no SAEs will be 
reported prior to the start of study medication. 
 
• 
All AE grade 3 or higher (expected or unexpected, regardless of attribution) will 
be reported to the DSMC. In certain investigator-initiated institutional trials where 
virtually 100% of subjects are guaranteed to experience very specific known 
grade 3 or higher toxicities (e.g., hematologic toxicity in stem cell transplant 
studies), the requirement for reporting of those toxicities may be waived at the 
discretion of the DSMC based on initial protocol review and in conjunction with 
investigator input if required. For this trial, no AEs will be reported prior to the 
start of study medication. 
 
Attribution of AE: The likelihood of relationship of the AE to the study drugs will be determined 
by the investigator based on the following definitions:  
 
Not related:  The subject was not exposed to the study treatment or another cause that is 
obvious.  
Probably not related: The AE is most likely explained by another cause, and the time of 
occurrence of the AE is not reasonably related to the study treatment.  
Possibly related: Study treatment administration and AE occurrence reasonably related in time, 
and the AE is explained equally well by causes other than study treatment, or treatment 
administration and AE occurrence are not reasonably related in time, but the AE is not 
obviously a result of other causes.  
Probably related: Study treatment administration and AE occurrence are reasonably related in 
time, and the AE is more likely explained by study treatment than by other mechanisms.  
Definitely related: The occurrence and timing of the AE are clearly attributable to the study 
treatment.  
  
A guide to the interpretation of the causality question is found in Appendix I. 
AEs will be collected from the time the subject starts study medication and ending 90 days 
following the final dose of study medication. All AEs will be followed until resolution or until 
no further improvement is expected. AEs judged by the investigator as not related or probably 
not related to the treatment will NOT be followed beyond the 90 days after the final dose of 
study drug. 
All SAEs and AE reporting will be completed using DSMC approved forms.  Detailed policy 
and procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html  
 
9.2.3 Astra Zeneca Reporting 
The investigator and/or sponsor must inform the FDA, via the MedWatch form, of any serious or 
unexpected adverse events that occur in accordance with the reporting obligations of 21 CFR 
312.32, and will concurrently forward all such reports to AstraZeneca.  A copy of the MedWatch 
report must be emailed to AstraZeneca at the time the event is reported to the FDA. 

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It is the responsibility of the investigator of each study site to compile all necessary information 
and ensure that the FDA receives a report according to the FDA reporting requirement timelines 
and to ensure that these reports are also submitted to AstraZeneca at the same time. 
* A cover page should accompany the MedWatch form indicating the following: 
• 
“Notification from an Investigator Sponsored Study” 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-18-13876) 
* Site investigator must also indicate, either in the SAE report or the cover page, the causality of 
events in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox:  AEMailboxClinicalTrialTCS@astrazeneca.com  
 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the IP and have been identified after the 
patient’s inclusion in this study. 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca preferably using the MedDRA coding language for serious 
adverse events. This information should be reported on a monthly basis and under no 
circumstance less frequently than quarterly. 
 
The grading scales found in the revised NCI CTCAE version 5.0 will be utilized for all events 
with an assigned CTCAE grading.  For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used.  A copy of the CTCAE version 5.0 can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
 
9.2.3.1 Reporting of deaths to AstraZeneca 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
durvalumab safety follow-up period must be reported to AstraZeneca as follows: 
• Death that is clearly the result of disease progression should be documented but should 
not be reported as an SAE. 
• Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to AstraZeneca as a SAE within 24 hours 
(see Section 9.3.2 for further details). The report should contain a comment regarding 
the co-involvement of progression of disease, if appropriate, and should assign main 
and contributory causes of death. 
• Deaths with an unknown cause should always be reported as a SAE. 
 
9.2.3.2 Other events requiring reporting 
Overdose 

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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 AstraZeneca Patient 
Safety or designee using the designated Safety e-mailbox. If the overdose results in an AE, the 
AE must also be recorded as an AE (see Section 9.2). 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 
9.2). There is currently no specific treatment in the event of an overdose of durvalumab. 
The investigator will use clinical judgment to treat any overdose. 
 
Hepatic function abnormality  
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law case 
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 AstraZeneca 
Patient Safety using the designated Safety e-mailbox (see Section 9.2.3 for contact 
information), unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or 
bile duct obstruction) that is unrelated to investigational product has been confirmed. The 
criteria for a potential Hy’s Law case is Aspartate Aminotransferase (AST) or Alanine 
Aminotransferase (ALT) ≥3x Upper Limit of Normal (ULN) together with Total Bilirubin 
(TBL) ≥2xULN at any point during the study following the start of study medication (with or 
without consolidative RT) irrespective of an increase in Alkaline Phosphatase (ALP). 
• 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 AstraZeneca. 
 
Pregnancy 
 
No patients currently pregnant is eligible for the trial. 
 
Maternal exposure 
 
If a subject becomes pregnant during the course of the study, the durvalumab should be 
discontinued immediately, and planned consolidative hfRT should be cancelled. 
 
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 

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abnormality) should be followed up and documented even if the subject was discontinued from 
the study only if the subject agrees to such follow-up. 
 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, i.e., immediately, but no 
later than 24 hours of when he or she becomes aware of it. 
 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 5 
calendar days for SAEs and within 30 days for all other pregnancies. 
 
The same timelines apply when outcome information is available. 
 
Paternal exposure  
 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of durvalumab or 180 days after the last dose of consolidative RT, 
whichever is the longer time period. 
 
Pregnancy of the subject’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 180 days after the last dose 
of durvalumab monotherapy, whichever is the longer time period should, if possible, be followed 
up and documented. 
 
9.3 Monitoring  
Various methods will be implemented to exchange information with study personnel:  
• Site Initiation/Orientation  
• Investigator meetings as feasible  
• Email distributions/reports as needed  
 
9.3.1 Data Monitoring 
For this study, data monitoring is the act of overseeing the progress of a clinical trial, and of 
ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard 
operating procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory 
requirement(s).  Monitoring is a Quality Control, continuous process during the entire trial. 
 
9.4 Auditing   
 
Auditing is a systematic and independent examination of trial-related activities and documents to 
determine: 
• whether the evaluated trial-related activities were conducted 
•  the data were recorded, analyzed, and accurately reported, according to the protocol, to 
the sponsor's SOPs, GCP, and applicable regulatory requirement(s).  
 
Auditing is a Quality Assurance, one point process during the trial. 
 

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This study will undergo audit on at least a semi-annual basis by the UNMC Fred & Pamela 
Buffett Cancer Center Audit Committee.  
 
Detailed policy and procedures for this section may be reviewed at: 
https://www.unmc.edu/cancercenter/clinical/prms.html . 
 
Section 10.0 STATISTICAL CONSIDERATIONS 
 
 
10.1 Description of analysis sets  
A comprehensive statistical analysis plan (SAP) will be prepared and finalized before first 
subject in. The efficacy Analysis Set and the Safety Analysis Set described below will be applied 
to all subjects that start study treatment. 
 
10.1.1 Safety analysis set 
 
All subjects who received at least one dose of durvalumab and received or were planned to 
receive the selected hfRT dose level determined by the initial 3+3 dose escalation study after 
being enrolled will be included in the safety population. Throughout the safety results sections, 
subjects who develop severe adverse effects (SAEs) who would not be candidate for hfRT after 
final eligibility confirmation will be still counted in the set so that the rate of SAEs will not be 
underestimated in this study. 
 
When assessing safety and tolerability, summaries will be produced based on the safety analysis 
set. 
 
10.1.2 Efficacy analysis set 
 
All subjects who received at least one dose of durvalumab and received or were planned to 
receive the selected hfRT dose level determined by the initial 3+3 dose escalation study after 
being enrolled and for whom any post-dose data are available will be included in the efficacy 
analysis set. This intention-to-treat approach will provide the best comparison between data from 
the current trial to the historical data from the PACIFIC study. 
 
10.2 Methods of statistical analyses 
 
Descriptive statistics will be used for all variables. Continuous variables will be summarized by 
the number of observations, mean, standard deviation, median, minimum, and maximum. 
Categorical variables will be summarized by frequency counts and percentages for each 
category. Unless otherwise stated, percentages will be calculated out of the entire correlated 
analysis set. 
 
Baseline will be the last assessment of the variable under consideration prior to the intake of the 
first infusion of study drug, except for efficacy variables. For efficacy variables, baseline is 
defined as the last visit prior to day 0. 
 

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Time to event variables will be summarized using Kaplan-Meier Curves; this includes OS, time 
to onset of symptoms, PFS and TTDM. Chi-square or Fisher’s exact test (as appropriate) will be 
used to compare treatment response to steroids for subjects who develop aRP during or shortly 
after dCRT but prior to starting of durvalumab to those having aRP within six months after 
hfRT. Imaging features will be compared using two-sample or paired t-tests (or an appropriate 
non-parametric test) as appropriate to the hypothesis being tested. Unless otherwise stated, a 
significance level of 0.05 will be assumed for all tests. 
 
All data collected will be listed. 
 
Results of all statistical analysis will be presented using a 95% confidence interval (CI) and p- 
value, unless otherwise stated. 
 
10.2.1 Safety analyses 
 
Toxicities data will be analyzed as categorical variables which will be summarized by frequency 
counts and percentages for each category as one of the primary endpoints of the study to 
compare numerically with historical data. Percentages will be calculated out of the population 
total for the safety analysis set. Due to the unique biology of potential interaction between certain 
range of immunostimulating RT with immunotherapy drug such as PD-L1 inhibitor, this study is 
not designed with dose escalation for RT but rather use a fixed dose regimen that has been tested 
as being safe when applied alone in previous study. No statistical comparison will be performed 
on safety data obtained in this study. 
 
10.2.2 Efficacy analyses 
 
12-month PFS is one of the primary endpoints and the study has been sized to compare the 
results from current trial to historical results from PACIFIC study. 18-month PFS, 12-month OS 
and QoL/Function improvement rate using EORTC QLQ-C30 tests are secondary endpoints. 
Kaplan-Meier analysis will be used to compare PFS at 12 and 18 months and OS at 12 months 
between historical PACIFIC study data and combination therapy. 
 
Efficacy data will be summarized and analyzed on the efficacy analysis set. 
 
Survival data obtained from current study will be compared with historical data in PACIFIC trial 
with z-test based on the methods from Parkin and Haukulinen1991, with P value < 0.05 defined 
as being statistically significant. 
 
10.2.3 Exploratory analyses 
 
Expression levels of biomarkers including PD-L1 levels in tumor microenvironment from 
immunohistochemistry studies or peripheral sPD-L1 before and after hfRT will be analyzed as 
continuous or categorical variables which will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by frequency counts and percentages for each category. The relationship of these 
variables with disease progression will be studied by univariate analyses with log-rank tests. 
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Hazards regression if appropriate. 
 
10.2.4 Interim analyses 
 
An interim analyses is planned for current study for primarily estimating efficacy to facilitate 
trial completion. Interim analyses will be performed 6 months (± 15 days) after the 12th subject at 
the selected hfRT dose level determined by the initial 3+3 dose escalation study is enrolled 
counting from his/her first day of study treatment. When the 12th patient has completed 6 
months, then accrual will be held for interim analysis.  The design will allow reasonable long 
median follow-up for meaningful data analysis. Disease progression will be summarized and 
analyzed for the first 12 subjects enrolled. If 7 or more subjects have disease progression or died, 
the trial will be terminated or halted before further discussion with statistician and AstraZeneca. 
Otherwise the trial will proceed to finish enrollment.   
 
10.3 Determination of sample size 
 
To shorten the duration of the proposed study, we will evaluate the 12-month PFS data for the 
potential benefit of adding consolidative RT with hypofractionated fractionation (hfRT) to be 
compared with the historical data but incorporating an interim analysis after recruiting thirteen 
subjects. In our case, the historical data from PACIFIC trial will be used. An additional 20% PFS 
increase is expected when adding hfRT to durvalumab, i.e., a one- year PFS of 75.9% or higher 
is predicted for this study. The sample size was estimated with the assistance from our 
statistician to achieve 80% statistical power. 
 
Sample size justification: Simon’s optimal two-stage design to test the null hypothesis of the 
progression free survival proportion of P<=55.9% versus the alternative of P>=75.9% has an 
expected sample size of 18.2 and a probability of early termination of 0.675. If the treatment is 
actually not effective, there is a 0.096 probability of concluding that it is (the target for this value 
was 0.10). If the treatment is actually effective, there is a 0.19 probability of concluding that it is 
not (the target for this value was 0.20). After testing the treatment on 12 subjects at the selected 
hfRT dose level determined by the initial 3+3 dose escalation study in the first stage, the trial 
will be terminated or halted before further discussion with statistician and AstraZeneca if 7 or 
more subjects have disease progression, defined by locoregional or distal progression per 
RECIST criteria 1.1, or death. If the trial goes on to the second stage, a total of 32 subjects will 
be studied (12). If the total number responding is less than or equal to 20, the drug is rejected. If 
15% dropout rate, then total is subjects are 37, to achieve a power of 82% and alpha or 
significant level 0.10. 
 
Considering the initial 3+3 dose escalation step, an additional 6 patients may be enrolled and 
treated at hfRT dose level that will not be selected for the second step of efficacy study, a total of 
37+6=43 patients could be needed for this project.  
 
10.4 Stopping rule 
  
The trial will be stopped if, at any time, a total of two cases developed grade 5 toxicity after 
consolidative RT from side effects caused by immunotherapy and/or consolidative RT if other 
causes including tumor progression can be ruled out. With grade 5 toxicities only occurred in 

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4.4% of patients in the durvalumab arm in PACIFIC trial, having an increased mortality rate to 
above 6%, if happened in this trial, would most likely offset any potential survival benefit adding 
consolidative RT rendering continuing the trial be meaningless as well as raise concerns of 
safety. 
 
At the initial 3+3 dose escalation step of the trial, if the starting dose level of hfRT (6.5Gy x 2 
fractions) exceeds MTD, the trial will be terminated. 
 
An interim analysis will be conducted at six months after enrolling the 12th patient treated with 
the final selected dose of hfRT. The trial will be terminated if 7 or more have disease progression 
including death caused by disease progression. Of note, if patient(s) died of disease progression, 
the number of death caused by disease progression will be counted; If patient(s) died of toxicities 
caused by immunotherapy and/or consolidative RT, the number of death will not be counted. If, 
as stated above, a total of two cases developed grade 5 toxicity after consolidative RT from side 
effects caused by immunotherapy and/or consolidative RT if other causes including tumor 
progression can be ruled out, the trial will be terminated no matter how many cases with disease 
progression occur.  
  
 
Section 11.0 Records to be Kept 
 
Information regarding the actual treatments, adverse effects, radiographic and laboratory 
information will be recorded on appropriate forms in the Advarra electronic data capture system 
detailed below. Additionally, serious adverse events, when noted, will be recorded on site via the 
standard serious adverse event reporting as noted in Section 9 of this protocol.  
 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Patient data protection. 
 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Site investigator files shall be retained for a time as indicated 
by their individual institutional requirements or as outlined in the study agreement or required by 
regulatory authorities. 
 
11.1 Quality Assurance 
Complete records must be maintained in a research chart on each patient treated on the protocol. 
Research chart can be maintained either as an electronic record, paper chart or a combination or 
both. These records should include primary documentation (e.g., lab. report slips, physician 
notes, etc.) which confirm that:  
- The subject met the eligibility criteria.  
- Signed informed consent was obtained prior to treatment.  
- Treatment was given according to protocol (dated notes about doses given & reasons for 
any dose modifications).  
- Toxicity was assessed according to protocol (laboratory report slips, etc.).  

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- Response was assessed according to protocol (dated notes on clinical assessment, lab reports as 
appropriate). 
 
11.2 Responsibilities of the Principal Investigator  
The PI is responsible for ensuring that the protocol and its appendices are followed, particularly 
when other departments are involved in the trial.  The PI oversees the quality of the data 
collected in the electronic case report forms.  The data obtained during the trial are recorded 
directly, with all modifications of data signed, dated, and justified as stated above.  Modifications 
must conform to the procedures defined for paper and electronic records. 
For the entire group of persons involved in carrying out the trial (day, night and emergency 
personnel), the PI is responsible for the following: 
 
1. 
Ensuring that the personnel are informed of the protocol used and that they understand the 
part they are responsible for implementing. 
2. 
Training personnel if necessary. 
3. 
Designating individual(s) specifically responsible for the administrative management of 
the trial. 
Ensuring that other departments or services involved in this trial are informed of the trial and 
determining with them the specific operating procedures necessary to conduct the trial. 
 
11.3 Advarra Electronic Data Capturing (EDC) System 
Data will be stored electronically for this study in the Advarra EDC system contained on the 
company’s secure server. Data forms will not differ from the paper versions with the exception 
of an electronic format containing the UNMC Fred & Pamela Buffett Cancer Center and Advarra 
logo.  
 
Advarra EDC provides for remote data collection that meets FDA 21 CFR Part 11 requirements 
as well as HIPAA and other regulatory requirements designed to enhance data security and 
protect subject confidentiality. Authorized users log into Advarra through a secure connection 
and must provide a valid username, password, and database ID. This data may be made available 
to the public at large. 
 
SECTION 12.0 PATIENT CONSENT 
12.1 Human Subjects Research Protection Training 
All personnel involved in this research project will have completed the OHRP-approved 
computer based training course on the Protection of Human Research Subjects. All clinical and 
correlative research included in this application will have approval by the institutional review 
board. 
 
12.2 Study Population  
Subjects are from all socio-economic groups and will be entered into the study without bias with 
respect to gender or race. Attempts will be made to recruit minorities. No vulnerable subjects 
will be included in the study. 
 
12.3 Sources of Material 

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Pathology material (frozen tissue if available, if not then 5-6 unstained slides or a block) must be 
reviewed, and the diagnosis confirmed by University Nebraska Medical Center pathology 
department as outlined in the protocol.(retrospectively). 
 
12.4 Recruitment and Informed Consent 
Subjects with an initial diagnosis of stage III non-small cell lung cancer (NSCLC) seen and 
evaluated at Nebraska Medicine (NM) will be available for recruitment These subjects will be 
informed of the nature of this study, and will be asked to participate on a voluntary basis after 
informing them of the possible risks and benefits of the study. A number of public registries may 
be accessible to health care providers and prospective subjects as listed on the protocol title page. 
 
12.5 Subject Competency 
Subjects will be eligible to participate in the study only if they are competent to give informed 
consent. A subject that the investigators judges to be incompetent will not be enrolled. 
 
12.6 Process of Informed Consent 
If the patient chooses to be a participant in this study, informed consent will be obtained by the 
investigators. The study and procedures involved including the risks will be explained in detail to 
each subject. It will be clearly explained to the subject that this is a research study and that 
participation is entirely on a voluntary basis. Subjects will be given the option to discuss the 
study with a family member, friend, counselor or, another physician. The participating 
investigators will be available to discuss the study with them. 
 
12.7 Subject/Representative Comprehension 
When the process of informed consent is completed, the subject will be asked to state in his/her 
own words, the purpose of the study, the procedures that will be carried out, potential risk, 
potential benefits to the subject, the alternatives and the right to withdraw from the study. If there 
is any indication that a given subject's comprehension is anything less than accurate, the points 
of confusion will be discussed and clarified. 
 
12.8 Information Purposely Withheld 
The results of the tests done solely for research purposes will not be disclosed to the subject. No 
other information will be purposely withheld from the subject. 
 
12.9 Potential Benefits of the Proposed Research to the Subjects 
It is anticipated that the combination of hfRT and durvalumab would result in prolonged survival 
in this subject population.  
 
12.10 Potential Benefits to Society 
Information obtained from this study may help other subjects by contributing to the knowledge 
of NSCLC and whether this treatment offers potential advantages over other treatments currently 
available. 
 
12.11 Potential Risks 
The use of Durvalumab and hfRT are associated with numerous potential risks. Combined 
immunotherapy/radiation is considered a valid treatment option for patients with NSCLC. It is 

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believed the treatment option outlined in the study will not pose significant additional risks 
compared to conventional treatment.  
 
12.12 Therapeutic Alternatives 
If  patients choose not to participate in this study they may elect to receive standard therapy as 
per their primary oncologist, which may include surgery, chemotherapy, or radiation, or a 
combination of these approaches. The treatment recommendations may or may not be similar to 
treatment as described in this protocol. As yet, there is no proven benefit to the use of 
Durvalumab and hfRT in this patient population as outlined in this protocol document is 
considered investigational. 
 
12.13 Risk/Benefit Relationship 
Although there are inherent risks involved because of the use of chemotherapy and radiotherapy 
we anticipate that subjects who receive the treatment phase of the protocol will do no worse than 
expected with standard therapy, and may experience an improved outcome. The risk is 
considered to be acceptable in the setting of cancer. 
 
12.14 Consent Form Documents 
No information will be purposely withheld from the subjects.  The consent document used in this 
study will include the adult consent document. See attached consent form. 
 
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Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after 
Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017; 377:1919-29. 
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Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of 
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Brahmer JR, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Nivolumab (anti-PD-1, 
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Butte MJ, Keir ME, Phamduy TB, Freeman GJ, Sharpe AH. PD-L1 interacts specifically with 
B7- 1 to inhibit T cell proliferation. Immunity. 2007;27:111-22. 
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L. Deng et al., Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity 
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Drake et al. 2013 
Drake CG, McDermott DF, Sznol M, Choueiri TK, Kluger HM, Powderly JD et al. Survival, 
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Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 
2004;22:329-60. 
Ellis et al. 2008 
Ellis S, Carroll KJ, Pemberton K. Analysis of duration of response in oncology trials. Contemp 
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Fairman et al. 2014 
Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C, et al. Pharmacokinetics of 
durvalumab, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid 
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Fife and Bluestone 2008 
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 
and PD-1 pathways. Immunol Rev. 2008;224:166-82. 
Gandhi et al. 2015 
Gandhi SJ, Minn AJ, Vonderheide RH, Wherry EJ, Hahn SM, Maity A. Awakening the immune 
system with radiation: optimal dose and fractionation. Cancer Lett 2015;368:185–90. 
Hegde et al. 2018 
Hegde AM, Cherry RC, Stroud CRG, Pinnamaneni R, Cherukuri SD, Sharma N, et al. Outcomes 
of immunomodulatory radiation strategies in combination with nivolumab compared with single 
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Herbst et al. 2013 
Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria JC, Hamid O, et al. A study of 
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Hodi et al. 2014 
Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP et al. Long-term 
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Keir et al. 2008 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol. 2008;26:677-704. 
Kumar et al. 2017 

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S. Kumar et al., Update of a Prospective Study of Stereotactic Body Radiation Therapy for Post- 
Chemoradiation Residual Disease in Stage II/III Non-Small Cell Lung Cancer. Int J Radiat 
Oncol Biol Phys 99, 652-659 (2017). 
Lan and DeMets 1983 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
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Luke et al. 2018 
Luke JJ, Lemons JM, Karrison TG, Pitroda SP, Melotek JM, et al Safety and Clinical Activity of 
Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid 
Tumors. J Clin Oncol. 2018 Jun 1; 36(16):1611-1618. 
Marks et al. 2010 
Marks LB et al. Guest editor’s introduction to QUANTEC: a users guide. Int. J. Radiation 
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Monjazeb and Schoenfeld 2016 
Monjazeb AM, Schoenfeld JD. Radiation dose and checkpoint blockade immunotherapy: 
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Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of B7-H1 
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Sep;35(4):741-9. 
Olivier et al. 2020 
Olivier, KR, Peikert, T, Owen, D Radiation-induced lung injury. Uptodate 2020. 
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Section 14.0  
Data Collection Forms  
A data collection plan for electronic data capture forms (eCRF) is submitted as part of this 
protocol for the scientific review committee review.   
 

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Page 82 of 128 
 
In addition, the study team has the following items provided, at the time of site activation, as an 
accompaniment to the protocol.  These items are provided electronically as a study site manual 
and Manual of Operations (MOP) to guide the study operations.

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Toxicity Management Guidelines (TMGs) 
Drug Substance 
Durvalumab and 
Tremelimumab 
 
 
TMG Version 
21 September 2023 
 
 
 
ANNEX TO PROTOCOL 
 
Dosing Modification and Toxicity Management Guidelines (TMGs) for 
Durvalumab Monotherapy, Durvalumab in Combination with other Products, or 
Tremelimumab Monotherapy 
 
 
Note: Annex is to be used in any clinical trial protocol within which patients 
are treated with Durvalumab Monotherapy, Durvalumab in Combination 
with other Products, or Tremelimumab Monotherapy 
Appendix I - Dosing Modification and Toxicity Management Guidelines 

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Table of Contents 
Dosing Modification and Toxicity Management Guidelines (TMGs) for Durvalumab Monotherapy, Durvalumab in 
Combination with other Products, or Tremelimumab Monotherapy –September 2023 ................................................................. 4 
Relevant Society Guidelines for Management of imAEs ............................................................................................................... 5 
Pediatric Considerations Regarding Immune-Mediated Reactions ................................................................................................ 6 
Specific Immune-Mediated Reactions ........................................................................................................................................... 7 
Pneumonitis/Interstitial Lung Disease (ILD) ................................................................................................................................. 7 
Diarrhea/Colitis ............................................................................................................................................................................. 9 
Hepatitis ...................................................................................................................................................................................... 12 
Hepatitis ...................................................................................................................................................................................... 14 
Nephritis and/or renal dysfunction ............................................................................................................................................... 17 
Dermatologic Adverse Events 
(Including Pemphigoid) .......................................................................................................... 18 
Endocrinopathy ............................................................................................................................................................................ 20 
Amylase/Lipase increased ........................................................................................................................................................... 21 
Acute Pancreatitis ........................................................................................................................................................................ 22 
Aseptic Meningitis ....................................................................................................................................................................... 23 
Encephalitis ................................................................................................................................................................................. 24 
Demyelinating Disease (optic neuritis, transverse myelitis, acute demyelinating encephalomyelitis (ADEM)) ......................... 24 
Peripheral neuropathy .................................................................................................................................................................. 25 
Guillain-Barré Syndrome (GBS) ................................................................................................................................................. 26 
Myasthenia gravis ........................................................................................................................................................................ 26 
Myocarditis .................................................................................................................................................................................. 27 
Myositis/ Polymyositis ................................................................................................................................................................ 28 
Other–Immune-Mediated Reactions ............................................................................................................................................ 33 
Infusion-Related Reactions .......................................................................................................................................................... 34 
Non-Immune-Mediated Reactions ............................................................................................................................................... 35 
List of Abbreviations ................................................................................................................................................................... 36 

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VERSION HISTORY 
 
 
The Toxicity Management Guidelines (TMGs) have been developed to assist investigators with 
the recognition and management of toxicities associated with use of the immune-checkpoint 
inhibitors durvalumab [MEDI4736] (PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor). Given 
the similar underlying mechanism of toxicities observed with these two compounds, these TMGs 
are applicable to the management of patients receiving either drug as monotherapy or both drugs 
in combination. Additionally, these guidelines are applicable when either durvalumab or 
tremelimumab or a combination of these two immune checkpoint inhibitors (ICI) is used in 
combination with other anti-cancer drugs (e.g., antineoplastic chemotherapy, targeted agents). 
These other anticancer drugs can be administered concurrently or sequentially as part of a 
protocol- specific treatment regimen. The TMGs provide information for the management of 
immune- mediated reactions, infusion-related reactions, and non-immune-mediated reactions 
that may be observed with monotherapy or combination ICI regimens, with specific instructions 
for ICI dose modifications (including discontinuation) and treatment interventions. Investigators 
are advised however to use local practice guidelines and consult local references for the 
management of toxicities observed with other anti-cancer treatment. 
Dosing modification and toxicity management for immune-mediated, infusion-related, and non- 
immune–mediated reactions associated with the use of a checkpoint inhibitor or checkpoint 
inhibitors in clinical study protocol (CSP) – whether that is durvalumab alone, tremelimumab 
alone, or durvalumab + tremelimumab in combination, or durvalumab +/- tremelimumab in 
combination with other anti-cancer drugs (i.e., antineoplastic chemotherapy, targeted agents) 
administered concurrently or sequentially – should therefore be performed in accordance with 
this Annex to CSP, which for the purposes of submission and approval of substantial updates is 
maintained as a standalone document. TMG updates are iterated by date, and should be used in 
accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version specified 
in the CSP. 
Although the TMG versioning is independent of the protocol, the TMG Annex to Protocol should 
be read in conjunction with the Clinical Study Protocol, where if applicable additional references 
for the management of toxicities observed with other anti-cancer treatment are included in the 
specific section of the Clinical Study Protocol. 
September 2023 

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Dosing Modification and Toxicity Management Guidelines (TMGs) for Durvalumab Monotherapy, 
Durvalumab in Combination with other Products, or Tremelimumab Monotherapy –September 2023 
 
General Considerations Regarding Immune-Mediated Reactions 
 
These guidelines are provided as a recommendation to support investigators in the management of potential immune-mediated adverse events (imAEs). 
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible 
immune-mediated reactions. Investigators are advised to take into consideration the appropriate practice guidelines and other society 
guidelines (e.g., National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO)) in the 
management of these events. Refer to the section of the table titled “Other -Immune-Mediated Reactions” for general guidance on 
imAEs not noted in the “Specific Immune-Mediated Reactions” section. 
Early identification and management of imAEs is essential to ensure safe use of the study drug. Monitor patients closely for 
symptoms and signs that may be clinical manifestations of underlying imAEs. Patients with suspected imAEs should be thoroughly 
evaluated to rule out any alternative etiologies (e.g., disease progression, concomitant medications, infections). In the absence of a 
clear alternative etiology, all such events should be managed as if they were immune-mediated. Institute medical management 
promptly, including specialty consultation as appropriate. In general, withhold study drug/study regimen for severe (Grade 3) 
imAEs. Permanently discontinue study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs 
that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks of initiating corticosteroids. 
Based on the severity of the imAE, durvalumab and/or tremelimumab should be withheld and corticosteroids administered. Upon 
improvement to Grade ≤ 1, corticosteroid should be tapered over ≥ 28 days. More potent immunosuppressive agents should be 
considered for events not responding to systemic steroids. Alternative immunosuppressive agents not listed in this guideline may be 
considered at the discretion of the investigator based on clinical practice and relevant guidelines. With long-term steroid and other 
immunosuppressive use, consider the need for glucose monitoring. 
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities graded per NCI CTCAE 
version in the applicable study protocol. 
Considerations for Prophylaxis for Long Term use of Steroids for Patients Receiving Immune Checkpoint Inhibitor Immunotherapy 
• 
Infection Prophylaxis: Pneumocystis jirovecii pneumonia (PJP), antifungal and Herpes Zoster reactivation 
• 
Gastritis: Consider prophylaxis for patients at high risk of gastritis (e.g. NSAID use, anticoagulation) when the patient is taking steroid therapy 
• 
Osteoporosis: Consider measures for prevention and mitigation of osteoporosis . 
 
 

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Relevant Society Guidelines for Management of imAEs 
 
These society guidelines are provided as references to serve in support of best clinical practice and the TMGs. Please note, these were the current versions of these 
guidelines at the time of updating TMGs. Please refer to the most up to date version of these guidelines. 
 
1. 
Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother 
Cancer 2021;9:e002435 
2. 
Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of 
Clinical Oncology (ASCO) Guideline Update. J Clin Oncol 2022;39(36):4073-4126. 
3. 
Haanen J, et al. Management of toxicities from immunotherapy: European Society for Medical Oncology (ESMO) clinical practice guideline for diagnosis, 
treatment, and follow-up. Annals Oncol 2022;33(12):1217-1238. 
4. 
Sangro B, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol 2020;72(2):320-341. 
5. 
Thompson JA, et al. National Comprehensive Cancer Network Guidelines: Management of immunotherapy-related toxicities version 2.2023. Published 
February 28, 2022. 
 

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4. 
 
 
Pediatric Considerations Regarding Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study drug/study 
regimen based on CTCAE grade/severity is the same for 
pediatric patients as it is for adult patients, as well as to 
permanently discontinue study drug/study regimen if unable to 
reduce corticosteroid ≤ a dose equivalent to that required for 
corticosteroid replacement therapy within 12 weeks of 
initiating corticosteroids. 
− All recommendations for specialist consultation should 
occur with a pediatric specialist in the specialty 
recommended. 
− The recommendations for steroid dosing (i.e., mg/kg/day) 
provided for adult patients should also be used for 
pediatric patients. 
− The recommendations for intravenous immunoglobulin 
(IVIG) and plasmapheresis use provided for adult patients 
may be considered for pediatric patients. 
−  The infliximab 5 mg/kg IV one time dose recommended 
for adults is the same as recommended for pediatric 
patients ≥ 6 years old. For subsequent dosing and dosing 
in children < 6 years old, consult a pediatric specialist. 
−  For pediatric dosing of mycophenolate mofetil, consult a 
pediatric specialist. 
− With long-term steroid and other immunosuppressive use, 
consider need for PJP prophylaxis, gastrointestinal 
protection, and glucose monitoring. 
 

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Specific Immune-Mediated Reactions 
 
Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial Lung Disease 
(ILD) 
Any Grade 
General Guidance 
For Any Grade 
(Refer to NCI CTCAE 
applicable version in 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology with similar clinical 
presentation (e.g. infection, progressive disease). 
study protocol for 
defining the CTCAE 
grade/severity) 
− Monitor patients for signs (e.g. tachypnoea) and 
symptoms of pneumonitis or ILD (new onset or 
worsening shortness of breath or cough). Evaluate 
patients with imaging and pulmonary function tests, 
including other diagnostic procedures as described 
below. 
− Suspected pneumonitis should be confirmed with 
radiographic imaging and other infectious and 
disease-related etiologies excluded, and managed as 
described below. 
− Initial work-up may include clinical evaluation, 
monitoring of oxygenation via pulse oximetry 
(resting and exertion), laboratory work-up (including 
clinically relevant culture specimens to rule out 
infection), 
and 
high- 
resolution 
computed 
tomography (CT) scan. 
− 
Consider Pulmonary and Infectious Diseases 
consults. 
Grade 1 
No dose modifications required. However, 
For Grade 1 
consider holding study drug/study regimen 
dose as clinically appropriate and during 
diagnostic work-up for other etiologies. 
− 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. 
Grade 2 
Hold study drug/study regimen dose until 
For Grade 2 
Grade 2 resolution to Grade ≤1. 
− 
Monitor 
symptoms 
daily 
and 

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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 (<10 mg 
prednisone or equivalent). 
consider hospitalization, as clinically 
indicated. 
− 
Consider Pulmonary and Infectious Diseases 
Consults; 
− 
Promptly start systemic steroids (e.g., prednisone 1 
to 2 mg/kg/day PO or IV equivalent). 
Consider HRCT or chest CT with contrast, Repeat 
imaging study as clinically indicated 
− If no improvement within 2 to 3 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− If no improvement within 2 to 3 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly 
start immunosuppressive therapy. such as tumor 
necrosis factor (TNF) inhibitors (e.g., infliximab at 
5 mg/kg IV once, may be repeated at 2 and 6 weeks 
after initial dose at the discretion of the treating 
provider or relevant practice guidelines). Caution: It 
is important to rule out sepsis and refer to infliximab 
label for general guidance before using infliximab. 
− Consider discussing with Clinical Study Lead. 

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Grade 3 or 4 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 
−  Hospitalize the patient 
− Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− Obtain Pulmonary and Infectious Diseases Consults; 
consider discussing with Clinical Study Lead, as 
needed. 
− Consider starting anti-infective therapy if infection is 
still a consideration on the basis of other diagnostic 
testing despite negative culture results 
−  Supportive care (e.g., oxygen). 
− If no improvement within 2 days, additional workup 
should be considered and prompt treatment with 
additional immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg IV, may be 
repeated at 2 and 6 weeks after initial dose at the 
discretion of the treating provider or relevant practice 
guidelines). Caution: rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab. 
Diarrhea/Colitis 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 

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study protocol for 
defining the CTCAE 
grade/severity) 
other medications, or infections), including testing 
for Clostridium difficile toxin, etc. 
− 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). 
− Consider further evaluation with imaging study with 
contrast. 
− 
Consult 
a 
gastrointestinal 
(GI) 
specialist 
for 
consideration of further workup. 
− 
WHEN 
SYMPTOMS 
OR 
EVALUATION 
INDICATE AN INTESTINAL PERFORATION 
IS SUSPECTED, CONSULT A SURGEON 
EXPERIENCED IN ABDOMINAL SURGERY 
IMMEDIATELY WITHOUT ANY DELAY. 
− PERMANENTLY DISCONTINUE STUDY DRUG 
FOR 
ANY 
GRADE 
OF 
INTESTINAL 
PERFORATION. 
− 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 
events, including intestinal perforation. 
− Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary changes 
(e.g., American Dietetic Association colitis diet), 
loperamide, and other supportive care measures. 
− 
If symptoms persist, consider checking lactoferrin 
and/or calprotectin; if positive, treat as Grade 2 
below. If negative and no infection, continue 
Grade 1 management. 
Grade 2 
Hold study drug/study regimen until 
resolution to Grade ≤1 
− 
If toxicity improves to Grade ≤1, then 
study drug/study regimen can be 
For Grade 2 
− 
Consider 
symptomatic 
treatment, 
including 
hydration, electrolyte replacement, dietary changes 

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resumed after completion of steroid 
taper 
(<10 
mg 
prednisone, 
or 
equivalent). 
(e.g., American Dietetic Association colitis diet), and 
loperamide and/or budesonide. 
− 
Consider further evaluation with imaging study with 
contrast. 
− 
Consider consult of a gastrointestinal (GI) specialist 
for consideration of further workup. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− If no improvement within 3 days despite therapy 
with 1 to 2 mg/kg IV methylprednisolone, reconsult 
GI specialist and, if indicated, promptly start 
additional 
immunosuppressant 
agent 
such 
as 
infliximab at 5 mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion of the 
treating provider or relevant practice guidelines. 
Caution: it is important to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab. 
− If perforation is suspected, consult a surgeon 
experienced in abdominal surgery immediately 
without any delay. 
− Consider, as necessary, discussing with Clinical 
Study Lead if no resolution to Grade ≤1 in 3 to 
4 days. 
Grade 3 or 4 
Grade 3 
− 
 For patients treated with durvalumab 
monotherapy, hold study drug/study 
regimen until resolution to Grade ≤1; 
study drug/study regimen can be 
resumed after completion of steroid 
taper (<10 mg prednisone per day, or 
equivalent). 
− 
 For patients treated with durvalumab 
in combination with other products 
(not tremelimumab), decision to be 
made at the discretion of the study 
For Grade 3 or 4 
− 
Urgent GI consult and imaging and/or colonoscopy 
as appropriate. 
− Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− Monitor stool frequency and volume and maintain 
hydration. 
− If still no improvement within 2 days, continue steroids 
and promptly add further immunosuppressants. (e.g., 
infliximab at 5 mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion of the treating 
provider or relevant practice guidelines). Caution: 
Ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before 
using infliximab. 

 
FIDENTIAL AND PROPRIETARY 
 
 
 
 
investigator, in discussion with 
AstraZeneca Clinical Study Lead. 
For patients treated with 
durvalumab in combination with 
tremelimumab or tremelimumab 
monotherapy: 
A. Permanently discontinue 
tremelimumab for Grade 3 
diarrhea/colitis. HOLD 
durvalumab until resolution to 
Grade  1; durvalumab alone 
can be resumed after completion 
of steroid taper (<10 mg 
prednisone per day or 
equivalent) 
B. Permanently discontinue both 
durvalumab and tremelimumab for 
1) Grade 4 diarrhea/colitis or 2) 
Any grade of intestinal perforation 
Grade 4 
Permanently discontinue 
study drug/study regimen. 
− 
If perforation is suspected, consult a surgeon 
experienced in abdominal surgery immediately 
without any delay. 
Hepatitis 
Any Grade 
General Guidance 
For Any Grade 
Infliximab should not be used for 
management of immune-related hepatitis. 
(Refer to NCI CTCAE 
applicable version in 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., viral hepatitis, disease 
progression, concomitant medications). 
study protocol for 
defining the CTCAE 
grade/severity) 
− 
Monitor and evaluate transaminases (aspartate 
aminotransferase [AST], alanine aminotransferase 
[ALT], alkaline phosphatase [ALP]) and total 
bilirubin . 
PLEASE SEE shaded area 
immediately below this 
section to find guidance for 
− 
No dose modifications. 
− 
If it worsens, then consider holding 
therapy. 
− 
Continue transaminase and total bilirubin monitoring 
per protocol. 
management of “Hepatitis 
ALT or AST ≤ 3 x 
(elevated LFTS)” in 
ULN or total bilirubin 
hepatocellular carcinoma 
≤ 1.5 x ULN 
CON 
TMG 
12 (36) 

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secondary tumour 
involvement of the liver with 
abnormal baseline values 
[BLV]) 
ALT or AST > 3 ≤ 5 x 
ULN or total bilirubin 
> 1.5 ≤ 3 x ULN 
− Hold study drug/study regimen dose 
until ALT or AST ≤ 3 x ULN or total 
bilirubin ≤ 1.5 x ULN. Resume study 
drug/study regimen after completion 
of steroid taper (<10 mg prednisone or 
equivalent). 
− Regular and frequent checking of transaminases and 
total bilirubin (e.g., every 1 to 2 days) until 
transaminases and total bilirubin elevations improve 
or resolve. 
- Consider checking creatinine phosphokinase (CPK) and 
aldolase (to rule out myositis) 
− 
Permanently 
discontinue 
study 
drug/study regimen for any case 
meeting Hy’s law laboratory criteria 
(AST or ALT >3 × ULN  AND 
− If no resolution to ALT or AST ≤ 3 x ULN or total 
bilirubin ≤ 1.5 x ULN in 1 to 2 days, consider 
discussing with Clinical Study Lead, as needed. 

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bilirubin >2 × ULN without initial 
findings of cholestasis (i.e., elevated 
ALP) and in the absence of any 
alternative cause. 
− 
If event is persistent (>2 to 3 days) or worsens, 
promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
ALT or AST > 5- 
≤ 10 x ULN 
− 
− 
Hold 
study 
drug/study 
regimen. 
Resume study drug/study regimen if 
elevations downgrade to ALT or AST 
≤ 3 x ULN or total bilirubin ≤ 1.5 x 
ULN after completion of steroid taper 
(<10 mg prednisone, or equivalent). 
If in combination with 
tremelimumab, do not restart 
tremelimumab. 
− Promptly initiate empiric IV methylprednisolone at 1 
to 2 mg/kg/day or equivalent. 
-  Check CPK and aldolase (to rule out myositis) 
− Perform Hepatology Consult, abdominal workup, and 
imaging as appropriate. 
−  If still no improvement within 2 to 3 days despite 1 
to 2 mg/kg/day methylprednisolone IV or equivalent, 
promptly 
start 
treatment 
with 
an 
additional 
immunosuppressant.(e.g., mycophenolate mofetil 
0.5 – 1 g every 12 hours then taper in consultation 
with hepatology consult or relevant practice 
guidelines). Discuss with Clinical Study Lead if 
mycophenolate is not available. Infliximab should 
NOT be used. 
Concurrent ALT or 
AST > 3 x ULN and 
Permanently discontinue study 
drug/study regimen. 
− Promptly initiate empiric IV methylprednisolone at 1 
to 2 mg/kg/day or equivalent. 
−  If still no improvement within 2 to 3 days despite 1 
to 2 mg/kg/day methylprednisolone IV or equivalent, 
promptly 
start 
treatment 
with 
an 
additional 
immunosuppressant.(e.g., mycophenolate mofetil 
0.5 – 1 g every 12 hours then taper in consultation 
with hepatology consult or relevant practice 
guidelines). Discuss with Clinical Study Lead if 
mycophenolate is not available. Infliximab should 
NOT be used. 
− Perform Hepatology Consult, abdominal workup, and 
imaging as appropriate. 
total bilirubin 
> 2 x ULN 
ALT or AST 
> 10 x ULN OR total 
bilirubin > 3 x ULN 
Hepatitis 
Any Elevations of 
General Guidance 
For Any Elevations Described 
(elevated transaminases and total 
bilirubin) 
Infliximab should not be used for 
AST, ALT, or T. Bili 
as Described Below 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., viral hepatitis, disease 
progression, concomitant medications, worsening of 
liver cirrhosis [e.g., portal vein thrombosis]). 
management of immune-related hepatitis. 
− 
Monitor and evaluate AST, ALT, ALP, and T. Bili. 
− For hepatitis B (HBV) + patients: evaluate 
quantitative HBV viral load, quantitative Hepatitis B 
surface antigen (HBsAg), or Hepatitis B envelope 
antigen (HBeAg). 

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− 
For hepatitis C (HCV) + patients: evaluate 
quantitative HCV viral load. 
THIS shaded area is guidance 
only for management of “Hepatitis 
(elevated LFTs)” in HCC patients 
− 
Consider consulting Hepatology or Infectious 
Diseases specialists regarding changing or starting 
antiviral HBV medications if HBV viral load is 
>2000 IU/ml. 
(or secondary tumour 
involvement of the liver with 
abnormal baseline values [BLV]) 
− 
Consider consulting Hepatology or Infectious 
Diseases specialists regarding changing or starting 
antiviral HCV medications if HCV viral load has 
increased by ≥2-fold. 
− 
For HCV+ with Hepatitis B core antibody (HBcAb)+: 
Evaluate for both HBV and HCV as above. 
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any time) occurs in 
setting 
of either increasing bilirubin or signs of 
Isolated AST or ALT 
>ULN and ≤2.5×BLV, 
− 
No dose modifications. 
− 
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat as 
described for elevations in the row 
below. 
DILI/liver decompensation 
− 
For all transaminase elevations , see 
instructions at bottom of shaded area 
if transaminase rise is not isolated but 
(at any time) occurs in setting of 
either increasing bilirubin or signs 
of DILI/liver decompensation 
ALT or AST > 2.5- 
≤ 5X BLV and ≤ 
− 
Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤2.5×BLV . 
− 
If toxicity worsens, then treat as 
described for elevations in the rows 
below. If toxicity improves to AST 
or ALT ≤2.5×BLV , resume study 
drug/study regimen after completion 
− Regular and frequent checking of Transaminases and 
total bilirubin (e.g., every 1 to 3 days) until elevations 
of these are improving or resolved. 
20xULN 
- 
Consider checking creatinine phosphokinase (CPK) 
and aldolase (to rule out myositis) 
− Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver 
perfusion. 
− 
Consider, as necessary, discussing with Clinical 
Study Lead. 

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of steroid taper (<10 mg prednisone, 
or equivalent). 
− 
If event is persistent (>2 to 3 days) or worsens, and 
investigator suspects toxicity to be an imAE, start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 2 to 3 days despite 1 
to 2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional workup. If still no improvement 
within 2 to 3 days despite 2mg/kg/day of IV 
methylprednisolone, consider additional abdominal 
workup (including liver biopsy) and imaging (i.e., 
liver ultrasound), and consider starting additional 
immunosuppressants. (e.g., mycophenolate mofetil 
0.5 – 1 g every 12 hours then taper in consultation 
with hepatology consult or relevant practice 
guidelines). Discuss Clinical Study Lead if 
mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
ALT or AST >5-7X 
BLV and ≤ 20X ULN 
− 
Withhold durvalumab and 
permanently discontinue 
tremelimumab 
− 
Resume study drug/study regimen if 
elevations downgrade to AST or ALT 
≤2.5×BLV and after completion of 
steroid taper (<10 mg prednisone, or 
equivalent). 
− 
Permanently 
discontinue 
study 
drug/study regimen if the elevations 
do not downgrade to  AST or ALT 
≤2.5×BLV within 14 days 
−  Regular and frequent checking of LFTs (e.g., every 
1-2 days) until elevations of these are improving or 
resolved. 
- 
Check CPK and aldolase (to rule out myositis) 
OR concurrent 2.5-5X 
BLV and ≤ 20XULN 
AND total bilirubin 
> 1.5 - < 2 x ULN 
− 
Consult 
hepatologist 
(unless 
investigator 
is 
hepatologist); 
obtain 
abdominal 
ultrasound, 
including Doppler assessment of liver perfusion; and 
consider liver biopsy. 
− Consider discussing with Clinical Study Lead, as 
needed. 
− 
If investigator suspects toxicity to be immune- 
mediated, 
promptly 
initiate 
empiric 
IV 
methylprednisolone at 1 to 2 mg/kg/day or 
equivalent. 
−  If no improvement within 2 to 3 days despite 1 to 
2 mg/kg/day methylprednisolone IV or equivalent, 
obtain liver biopsy (if it has not been done already) 
and promptly start treatment with an additional 
immunosuppressant. (e.g.,., mycophenolate mofetil 
0.5 – 1 g every 12 hours then taper in consultation 
with a hepatologist or relevant practice guidelines). 
Discuss with Study Clinical Lead if mycophenolate 
is not available. 
Infliximab should NOT be used. 

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ALT or AST > 7 X 
BLV OR > 20 ULN 
whichever occurs 
first OR bilirubin > 
3ULN 
Permanently discontinue study drug/study 
regimen. 
Same as above 
(except recommend obtaining liver biopsy early) 
Nephritis and/or renal dysfunction 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, 
infections, recent IV contrast, medications, fluid 
status). 
−  Consider Consulting a nephrologist. 
− Consider imaging studies to rule out any alternative 
etiology 
− 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, 
decreased urine output, or proteinuria). Follow urine 
protein/creatinine ratio every 3-7 days 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Monitor 
serum 
creatinine 
weekly 
and 
any 
accompanying symptoms. 
• 
If creatinine returns to baseline, resume regular 
monitoring per study protocol. 
• 
If creatinine worsens, depending on the 
severity, treat as Grade 2, 3, or 4. 
− 
Consider hydration, electrolyte replacement, and 
diuretics, as clinically indicated. 
− 
Consider nephrologist consult if not resolved within 
14 days, or earlier as clinically indicated 
Grade 2 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
For Grade 2 
− 
Consider 
including 
hydration, 
electrolyte 
replacement, and diuretics as clinically indicated 
− 
Follow urine protein/creatinine ratio every 3-7 days 
− 
Carefully monitor serum creatinine as clinically 
warranted. 

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of steroid taper (<10 mg prednisone, 
or equivalent). 
− 
Consult nephrologist and consider renal biopsy if 
clinically indicated. 
− 
Start prednisone 0.5 – 1 mg/kg/day if other causes are 
ruled out 
− If event is persistent beyond 5 days or worsens, increase 
to prednisone up to 2 mg/kg/day PO or IV equivalent. 
− If event is not responsive within 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, consider additional workup. When event 
returns to baseline, resume study drug/study regimen 
and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
Permanently discontinue study drug/study 
For Grade 3 or 4 
−  Carefully monitor serum creatinine daily. 
−  Follow urine protein/creatinine ratio every 3-7 days 
− 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 of steroids 
or worsens despite prednisone at 1 to 2 mg/kg/day PO 
or IV equivalent, consider additional workup and 
prompt treatment with an immunosuppressant 
regimen. 
Dermatologic Adverse Events 
(Including Pemphigoid) 
Any Grade 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology. 
− 
Monitor for signs and symptoms of dermatitis (rash 
and pruritus). 
HOLD STUDY DRUG IF GRADE 3 
PEMPHIGOID OR SEVERE CUTANEOUS 
ADVERSE REACTION (SCAR)1 IS 
SUSPECTED. 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
definition of 
severity/grade 
depending on type of 
skin rash) 
 
 

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− 
PERMANENTLY DISCONTINUE STUDY 
DRUG IF SCAR OR GRADE 3 PEMPIGOID IS 
CONFIRMED. 
Grade 1 
No dose modifications. 
For Grade 1 
− Consider symptomatic treatment, including oral 
antipruritics (e.g., diphenhydramine or hydroxyzine) 
and topical therapy (e.g., emollient, lotion, or 
institutional standard). 
Grade 2 
For persistent (>1 week) Grade 2 events, 
hold scheduled study drug/study regimen 
until resolution to Grade ≤1 or baseline. 
− 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper (<10 mg prednisone, or 
equivalent). 
For Grade 2 
− Consider dermatology consult and skin biopsy, as 
indicated. 
− Consider symptomatic treatment, including oral 
antipruritics (e.g., diphenhydramine or hydroxyzine) 
and topical therapy 
−  Consider moderate-strength topical steroid. 
−  If no improvement of rash/skin lesions occurs within 
1 week or is worsening despite symptomatic 
treatment and/or use of moderate strength topical 
steroid, consider discussing with Clinical Study 
Lead, as needed, and promptly start systemic steroids 
such as prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
Grade 3 
For Grade 3 
− Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
− If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper  (<10  mg  prednisone,  or 
equivalent). 
For Grade 
− 
Reconsult a dermatologist. Consider skin biopsy 
(preferably more than 1) as clinically feasible. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor the extent of rash [Rule of Nines]. 
− 
Consider, as necessary, discussing with Clinical 
Study Lead. 
Grade 4 
For Grade 4 
Permanently discontinue study drug/study 
regimen. 
For Grade 4 
− 
Reconsult a dermatologist. Consider skin biopsy 
(preferably more than 1) as clinically feasible. 
− 
Promptly initiate empiric IV methylprednisolone 1 
to 2 mg/kg/day or equivalent. 

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− 
Consider hospitalization. 
− 
Monitor the extent of rash [Rule of Nines]. 
Consider, as necessary, discussing with Clinical Study 
Lead. 
Endocrinopathy 
Any Grade 
General Guidance 
For Any Grade 
(e.g., hyperthyroidism, thyroiditis, 
hypothyroidism, type 1 diabetes mellitus, 
(Depending on the 
type of 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression 
including brain metastases, or infections). 
hypophysitis, hypopituitarism, and adrenal 
insufficiency) 
endocrinopathy, refer 
to NCI CTCAE 
− 
Consider consulting an endocrinologist for endocrine 
events. 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity) 
− Consider discussing with Clinical Study Lead, as 
needed. 
− Monitor patients for signs and symptoms of 
endocrinopathies. (Non-specific symptoms include 
headache, fatigue, behaviour changes, mental status 
changes, photophobia, visual field cuts, vertigo, 
abdominal pain, unusual bowel habits, polydipsia, 
polyuria, hypotension, and weakness.) 
− Depending on the suspected endocrinopathy, monitor 
and evaluate thyroid function tests: thyroid 
stimulating hormone (TSH), free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood 
glucose and ketone levels, hemoglobin A1c 
(HgA1c)). If a patient experiences an AE that is 
thought to be possibly of autoimmune nature (e.g., 
thyroiditis, pancreatitis, hypophysitis, or diabetes 
insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody testing. 
− 
Investigators should ask subjects with 
endocrinopathies who may require prolonged or 
continued hormonal replacement, to consult their 
primary care physicians or endocrinologists about 
further monitoring and treatment after completion of 
the study. 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Monitor patient with appropriate endocrine function 
tests. 
− 
For 
suspected 
hypophysitis/hypopituitarism, 
consider consulting an endocrinologist to guide 

CONFIDENTIAL AND PROPRIETARY 
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assessment of early morning adrenocorticotropin 
hormone (ACTH), cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin 
levels, as well as cosyntropin stimulation test (though 
it may not be useful in diagnosing early secondary 
adrenal insufficiency). 
− 
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 consultation of 
an endocrinologist. 
Grade 2, 3, or 4 
− 
For Grade 2-4 endocrinopathies other 
For Grade 2, 3, or 4 
− Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider 
pituitary scan. 
− For all patients with abnormal endocrine work up, 
except those with isolated hypothyroidism or T1DM, 
and as guided by an endocrinologist, consider short- 
term corticosteroids (e.g., 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone 
replacement. 
− Isolated hypothyroidism may be treated with 
replacement therapy, without study drug/study 
regimen 
interruption, 
and 
without 
corticosteroids. 
− Isolated T1DM may be treated with appropriate 
diabetic therapy, and without corticosteroids. 
Only hold study drug/study regimen in setting of 
hyperglycemia when diagnostic workup is positive 
for diabetic ketoacidosis. 
− For patients with normal endocrine workup (laboratory 
assessment or magnetic resonance imaging (MRI) 
scans), repeat laboratory assessments/MRI as 
clinically indicated. 
than hypothyroidism and  type  1 
diabetes mellitus (T1DM), consider 
holding study drug/study regimen 
dose until acute symptoms resolve. 
− 
Study drug/study regimen can be 
resumed once patient stabilizes and 
after completion of steroid taper (<10 
mg prednisone, or equivalent). 
− 
Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement  (e.g., adrenal 
insufficiency) can be retreated with 
study  drug/study  regimen  if  the 
patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
Amylase/Lipase increased 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g. disease progression, 

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study protocol for 
defining the CTCAE 
grade/severity) 
viral infection, concomitant medications, substance 
abuse). 
− For modest asymptomatic elevations in serum 
amylase and lipase, corticosteroid treatment is not 
indicated as long as there are no other signs or 
symptoms of pancreatic inflammation. 
−  Assess for signs/symptoms of pancreatitis 
− Consider appropriate diagnostic testing (e.g., abdominal 
CT with contrast, MRCP if clinical suspicion of 
pancreatitis and no radiologic evidence on CT) 
− If isolated elevation of enzymes without evidence of 
pancreatitis, continue immunotherapy. Consider 
other causes of elevated amylase/lipase 
− If evidence of pancreatitis, manage according to 
pancreatitis recommendations 
Grade 1 
No dose modifications. 
Grade 2, 3, or 4 
For Grade 2, 3, or 4 
In consultation with relevant 
gastroenterology specialist consider 
continuing study drug/study regimen if no 
clinical/radiologic evidence of pancreatitis 
± improvement in amylase/lipase. 
Acute Pancreatitis 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology. 
− 
Consider Gastroenterology referral 
Grade 2 
Consider holding study drug/regimen 
Grade 2 
− 
Consider IV hydration 
− 
Consider Gastroenterology referral 

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Grade 3, or 4 
For Grade 3 
Hold study drug/study regimen until 
resolution of elevated enzymes and no 
radiologic findings 
If no elevation in enzymes or return to 
baseline values, then resume study 
drug/study regimen after completion of 
steroid taper (<10 mg prednisone, or 
equivalent). 
For Grade 4 
Permanently discontinue study drug/study 
regimen. 
For Grade 3, or 4 
− 
Promptly start systemic steroids prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
− 
IV hydration 
Nervous System Disorders 
Aseptic Meningitis 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
− Symptoms may include headache, 
photophobia, and neck stiffness, 
nausea/ vomiting which may resemble 
an infectious meningitis. 
−  Patients may be febrile. 
−  Mental status should be normal 
For Any Grade 
−  Consider neurology consult 
− Consider MRI brain with and without contrast with 
pituitary protocol and a lumbar puncture for 
diagnosis. 
−  Exclude bacterial and viral infections. (ie HSV) 
- 
Consider antibiotic for bacterial coverage until
cultures/panel results are back 
− Consider IV acyclovir until polymerase chain reactions 
are available 
Any Grade 
Permanently discontinue study drug/study 
regimen 
For Any Grade 
−  Consider neurology consult 
− Consider MRI brain with and without contrast with 
pituitary protocol and a lumbar puncture for 
diagnosis. 
−  Exclude bacterial and viral infections. (ie HSV) 
− 
Consider IV acyclovir until polymerase chain 
reactions are available 
− 
Consider, as necessary, discussing with Clinical 
Study Lead. 
− 
Consider hospitalization. 

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− Once infection has been ruled out promptly initiate 
empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
Encephalitis 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
− Symptoms may include Confusion, 
altered 
behaviour, 
headaches, 
seizures, short-term memory loss, 
depressed level of consciousness, 
focal 
weakness, 
and 
speech 
abnormality. 
− 
For Any Grade 
− 
Consider neurology consult 
− 
Consider testing including MRI of the brain with 
and without contrast, lumbar puncture, 
electroencephalogram (EEG) to evaluate for 
subclinical seizures, ESR, CRP, antineutrophil 
cytoplasmic antibody (ANCA) (if vasculitic process 
suspected), thyroid panel including TPO and 
thyroglobulin and additional autoantibodies to rule 
out paraneoplastic disorders. 
− 
Exclude bacterial and viral infections. (i.e. 
HSV)Consider IV acyclovir until polymerase chain 
reactions are available. 
Grade 2 
For Grade 2 
Permanently discontinue study drug/study 
regimen. 
For Grade 2 
− Consider, as necessary, discussing with the Clinical 
Study Lead. 
− Once infection has been ruled out methylprednisolone 
1–2 mg/kg/day 
− For progressive symptoms or if oligoclonal bands are 
present consider methylprednisolone 1 g IV daily for 
3–5 days plus IVIG or plasmapheresis 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 
− Consider, as necessary, discussing with Clinical 
Study Lead. 
−  Consider hospitalization. 
−  Once infection is ruled out, start methylprednisolone 
1 g IV daily for 3–5 days for progressive symptoms 
consider adding IVIG or plasmapheresis 
Demyelinating Disease (optic neuritis, 
transverse myelitis, acute demyelinating 
encephalomyelitis (ADEM)) 
Any Grade 
General Guidance 
− 
Permanently discontinue 
immunotherapy 
− 
Consider MRI of the spine and brain 
For Any Grade 
− 
Consider neurology consult 
− 
Inpatient care 
− 
Consider prompt initiation of high 
methylprednisolone pulse dosing 
− 
Strongly consider IVIG or plasmapheresis 

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− Once imaging is complete, consider 
lumbar puncture 
Consider testing to rule out additional 
aetiologies: B12, copper, HIV, rapid 
plasma reagin (RPR), ANA, anti- 
Ro/La antibodies, aquaporin-4 IgG, 
myelin oligodendrocyte glycoprotein 
(MOG) IgG, paraneoplastic panel 
Peripheral neuropathy 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− Patients should be evaluated to rule out any 
alternative etiology for neuropathy (e.g., 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 
(e.g., 
electromyogram 
and 
nerve 
conduction 
investigations are routinely indicated upon suspicion 
of such conditions and may be best facilitated by 
means of a neurology consultation. 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Consider discussing with the Clinical Study Lead, as 
needed. 
− 
Monitor symptoms for interference with ADLS, gait 
difficulties, imbalance, or autonomic dysfunction 
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
For Grade 2 
− 
Consult a neurologist. 
− 
Consider EMG/NCS 

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− Consider discussing with the Clinical Study Lead, as 
needed. 
− Observation for additional symptoms or consider 
initiating prednisone 0.5–1 mg/kg orally 
− If progression, initiate methylprednisolone 2–4 
mg/kg/day and treat as GBS 
− 
Sensory 
neuropathy/neuropathic 
pain 
may 
be 
managed 
by 
appropriate 
medications 
(e.g., 
gabapentin or duloxetine). 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 
− 
Consider discussing with Clinical Study Lead, as 
needed. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and consult a neurologist. 
− 
Treat per Guillain-Barré Syndrome 
recommendations 
Guillain-Barré Syndrome (GBS) 
General Guidance 
− 
Recommend hospitalization 
− 
Obtain neurology consult 
− 
Obtain MRI of spine to rule out compression lesion 
− 
Obtain lumbar puncture 
− 
Antibody tests for GBS variants 
− 
Pulmonary function tests 
− 
Obtain electromyography (EMG) and nerve 
conduction studies 
− 
Frequently monitor pulmonary function tests and 
neurologic evaluations 
− 
Monitor for concurrent autonomic dysfunction 
− 
Initiate medication as needed for neuropathic pain 
Grade 2-4 
Grade 2-4 
Permanently discontinue 
Start IVIG or plasmapheresis in addition to 
methylprednisolone 1 gram daily for 5 days, then 
taper over 4 weeks. 
Myasthenia gravis 
General Guidance 
− 
Obtain neurology consult 
− 
Recommend hospitalization 
− 
Obtain pulmonary function tests 

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− Obtain labs: ESR, CRP, creatine phosphokinase (CPK), 
aldolase and anti-striational antibodies 
− Consider cardiac exam, ECG, troponin, transthoracic 
echocardiogram 
for 
possible 
concomitant 
myocarditis 
− Obtain electromyography (EMG) and nerve conduction 
studies 
− Consider MRI of brain/spine to rule out CNS 
involvement by disease 
− Avoid medications that might exacerbate MG (e.g. beta 
blockers, some antibiotics, IV magnesium) 
Grade 2 
Permanently discontinue 
− Consider pyridostigmine 30mg three times daily and 
gradually increase based on symptoms (max dose 
120mg four times daily) 
− Consider starting low dose prednisone 20mg daily and 
increase every 3-5 days. (Target dose 1mg/kg/day. 
Max dose 100mg daily) 
Grade 3-4 
Permanently discontinue 
− 
Start methylprednisolone 1-2mg/kg/day. Taper 
steroids based on symptom improvement 
− 
Start plasmapheresis or IVIG 
− 
Consider rituximab if refractory to plasmapheresis 
or IVIG 
− 
Frequent PFT assessments 
− 
Daily neurologic evaluations 
Myocarditis 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
Discontinue drug permanently if biopsy- 
proven immune-mediated myocarditis. 
For Any Grade 
− Initial work-up should include clinical evaluation, B- 
type natriuretic peptide (BNP), cardiac enzymes, 
electrocardiogram (ECG), echocardiogram (ECHO), 
monitoring of oxygenation via pulse oximetry 
(resting and exertion), and additional laboratory 
work-up as indicated. Spiral CT or cardiac MRI can 
complement 
ECHO 
to 
assess 
wall 
motion 
abnormalities when needed. 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections) 
− The prompt diagnosis of immune-mediated myocarditis 
is important, particularly in patients with 

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baseline cardiopulmonary disease and reduced 
cardiac function. 
− Consider discussing with the Clinical Study Lead, as 
needed. 
− Monitor patients for signs and symptoms of myocarditis 
(new onset or worsening chest pain, arrhythmia, 
shortness of breath, peripheral edema). As some 
symptoms can overlap with lung toxicities, 
simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary 
embolism, congestive heart failure, malignant 
pericardial effusion). Consult a cardiologist early, to 
promptly assess whether and when to complete a 
cardiac biopsy, including any other diagnostic 
procedures. 
− as indicated. Spiral CT or cardiac MRI can complement 
ECHO to assess wall motion abnormalities when 
needed. 
Grade 2, 3 or 4 
− 
If Grade 2-4, permanently discontinue 
study drug/study regimen. 
For Grade 2-4 
− 
Monitor symptoms daily, hospitalize. 
− 
Consider cardiology consultation and a prompt start 
of high-dose/pulse corticosteroid therapy 
− 
Supportive care (e.g., oxygen). 
− 
If 
no 
improvement 
consider 
additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab), IVIG or plasmapheresis or other 
therapies depending on the clinical condition of the 
patient, based on the discretion of the treating 
specialist consultant r or relevant practice guidelines. 
Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance 
before 
using 
infliximab. 
Infliximab 
is 
contraindicated for patients who have heart 
failure. 
Myositis/ Polymyositis 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
General Guidance 
For Any Grade 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections). 

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defining the CTCAE 
grade/severity) 
− Monitor patients for signs and symptoms of 
poly/myositis. Typically, muscle weakness/pain 
occurs in proximal muscles including upper arms, 
thighs, shoulders, hips, neck and back, and; also 
difficulty breathing and/or trouble swallowing can 
occur and progress rapidly. Increased general 
feelings of tiredness and fatigue may occur, and there 
can be new-onset falling, difficulty getting up from a 
fall, and trouble climbing stairs, standing up from a 
seated position, and/or reaching up. 
− If poly/myositis is suspected, a Neurology consultation 
should be obtained early, with prompt guidance on 
diagnostic procedures. Myocarditis may co-occur 
with poly/myositis; refer to guidance under 
Myocarditis. Given breathing complications, refer to 
guidance 
under 
Pneumonitis/ILD. 
Given possibility of an existent (but previously 
unknown) 
autoimmune 
disorder, 
consider 
Rheumatology consultation. 
− Consider, as necessary, discussing with the Clinical 
Study Lead. 
- Consider that patients may present with or progress 
to rhabdomyolysis. Treat signs and symptoms as 
per institutional protocol or local clinical practice. 
− Initial work-up should include clinical evaluation, 
creatine kinase, aldolase, lactate dehydrogenase 
(LDH), blood urea nitrogen (BUN)/creatinine, 
erythrocyte sedimentation rate or C-reactive protein 
(CRP) level, urine myoglobin, and additional 
laboratory work-up as indicated, including a number 
of possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist consultation is 
indicated and could guide need for rheumatoid factor, 
antinuclear 
antibody, 
anti-smooth 
muscle, 
antisynthetase [such as anti-Jo-1], and/or signal- 
recognition particle antibodies). Confirmatory testing 
may include electromyography, nerve conduction 
studies, MRI of the muscles, and/or a 
muscle biopsy. Consider Barium swallow for 
evaluation of dysphagia or dysphonia. 

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Grade 1 
− 
No dose modifications. 
For Grade 1 
− Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically 
indicated. 
−  Consider Neurology consult. 

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− 
Consider, as necessary, discussing with the Clinical 
Study Lead. 
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. 
For Grade 2 
− 
Monitor symptoms daily and consider 
hospitalization. 
− 
Consider Rheumatology or Neurology consult, and 
initiate evaluation. 
− 
Consider, as necessary, discussing with the Clinical 
Study Lead. 
− 
If clinical course is rapidly progressive (particularly 
if difficulty breathing and/or trouble swallowing), 
promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with receiving 
input from Neurology consultant 
− 
If clinical course is not rapidly progressive, start 
systemic steroids (e.g., prednisone 1 to 2 mg/kg/day 
PO or IV equivalent); if no improvement within 2 to 
3 days, continue additional work up and start 
treatment with IV methylprednisolone 2 to 
4 mg/kg/day 
−  If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 
3 days, consider additional 
− 
 immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab), IVIG or plasmapheresis, or other 
therapies based on the discretion of the treating 
specialist consultant or relevant practice guideline 
Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance 
before using infliximab. 
Grade 3 
For Grade 3 
− Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
− 
Permanently 
discontinue 
study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
For Grade 3 
− 
Monitor symptoms closely; recommend 
hospitalization. 
− 
Consider Rheumatology and/or Neurology consult 
− 
Consider discussing with the Clinical Study Lead, 
as needed. 
− 
Promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with receiving 
input from Neurology consultant. 

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days or if there are signs of respiratory 
insufficiency. 
− 
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 2 to 3 
days, consider starting another immunosuppressive 
therapy such as a TNF inhibitor (e.g., infliximab at 
5 mg/kg IV, may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating provider 
or relevant practice guidelines). Caution: It is 
important to rule out sepsis and refer to 
infliximab label for general guidance before 
using infliximab. 
− 
Consider whether patient may require IV IG, 
plasmapheresis. 
Grade 4 
For Grade 4 
Permanently discontinue study drug/study 
regimen. 
Grade 4 
− 
Monitor symptoms closely; recommend 
hospitalization. 
− 
Consider Rheumatology and/or Neurology consult 
− 
Consider discussing with the Clinical Study Lead, 
as needed. 
− 
Promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with receiving 
input from Neurology consultant. 
− 
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 2 to 3 
days, consider starting another immunosuppressive 
therapy such as a TNF inhibitor (e.g., infliximab at 
5 mg/kg IV, may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating provider 
or relevant practice guidelines). Caution: It is 
important to rule out sepsis and refer to 
infliximab label for general guidance before 
using infliximab. 
 
1 SCAR terms include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Erythema Multiforme, Acute Generalized 
Exanthematous Pustulosis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Drug-induced hypersensitivity syndrome. 

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Other–Immune-Mediated Reactions 
 
Severity Grade of the Event 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTCAE 
grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: It is possible that events with an 
inflammatory or 
immune mediated mechanism could occur 
in nearly all organs, some of them are not 
noted specifically in these guidelines (e.g. 
immune thrombocytopenia, haemolytic 
anaemia, uveitis, vasculitis). 
− Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression, other medications, or infections). 
− The Clinical Study Lead may be contacted for 
immune-mediated reactions not listed in the 
“specific immune-mediated reactions” section 
−  Consultation with relevant specialist 
−  Treat accordingly, as per institutional standard. 
 
 
Grade 1 
No dose modifications. 
Monitor as clinically indicated 
Grade 2 
−  Hold study drug/study regimen until 
resolution to 
≤Grade 1 or baseline. 
−  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. 
− 
Consider whether study drug/study 
regimen 
should 
be 
permanently 
discontinued in Grade 2 events with high 
likelihood for morbidity and/or mortality 
when they do 
not 
rapidly 
improve 
to 
Grade 
<1 
upon 
treatment 
with systemic 
steroids 
and 
following full 
taper 
Grade 3 
Hold 
study 

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drug/study regimen until resolution to Grade 1 
 
or baseline 
 
Grade 4 
Permanently discontinue study drug/study 
regimen 
For Grade 2, 3, or 4 
Treat accordingly, as per institutional 
standard, appropriate clinical practice 
guidelines, and society guidelines. (See 
page 4). 
 
 
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 Clinical Study Lead.” 

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Infusion-Related Reactions 
 
Severity Grade of the Event 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTCAE grade/severity) 
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 (e.g., 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 (e.g., 
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. 

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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 or 
study protocol prior to subsequent doses. 
− Consider steroids for patients who have 
previously experienced infusion reaction; use of 
steroid premedication may be permitted in these 
situations 
 
 
 
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 standard, appropriate clinical practice 
guidelines, and society guidelines. 
 
 

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Non-Immune-Mediated Reactions 
 
Severity Grade of the Event 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTCAE grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for 
AEs not deemed to be related to study treatment 
(i.e., 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 2-3 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
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. 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 Clinical Study Lead.” 

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List of Abbreviations 
 
AChE 
Acetylcholinesterase 
ILD 
Interstitial lung disease 
ACTH 
Adrenocorticotropic hormone 
imAE(s) 
Immune-mediated adverse event(s) 
ALT 
Alanine aminotransferase 
INR 
International normalized ratio 
ASCO 
American Society of Clinical Oncology 
IU 
International units 
AST 
Aspartate aminotransferase 
IV 
Intravenous 
(T) Bili 
(Total) Bilirubin 
IVIG 
Intravenous immunoglobulin 
BNP 
B-type natriuretic peptide 
LDH 
Lactate dehydrogenase 
BUN 
Blood urea nitrogen 
LFTs 
Liver function tests 
CRP 
C-reactive protein 
LLN 
Lower limit of normal 
CSP 
Clinical Study Protocol 
MRCP 
Magnetic resonance cholangiopancreatography 
CT 
Computed tomography 
MRI 
Magnetic resonance imaging 
CTCAE 
Common Terminology Criteria for Adverse Events 
NCCN 
National Comprehensive Cancer Network 
CTLA-4 
Cytotoxic T-lymphocyte antigen-4 
NCI 
National Cancer Institute 
DILI 
Drug-induced liver injury 
PD-L1 
Programmed cell death ligand-1 
ECG 
Electrocardiogram 
PJP 
Pneumocystis jirovecii pneumonia 
ECHO 
Echocardiogram 
PO 
By mouth 
ESMO 
European Society of Medical Oncology 
SCAR 
Severe cutaneous adverse reaction 
GI 
Gastrointestinal 
SITC 
Society for Immunotherapy of Cancer 
HBcAb 
Hepatitis B core antibody 
SJS 
Stephen Johnson Syndrome 
HBeAg 
Hepatitis B envelope antigen 
T1DM 
Type 1 diabetes mellitus 
HBsAg 
Hepatitis B surface antigen 
T3 
Triiodothyronine 
HBV 
Hepatitis B virus 
T4 
Thyroxine 
HCC 
Hepatocellular cancer 
TEN 
Toxic Epidermal Necrolysis 
HCV 
Hepatitis C virus 
TMG(s) 
Toxicity management guideline(s) 
HgA1c 
Hemoglobin A1C 
TSH 
Thyroid stimulating hormone 

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ICI(s) 
Immune checkpoint inhibitor(s) 
ULN 
Upper limit of normal 
 

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APPENDIX II. Durvalumab Weight-based Dose Calculations 
Durvalumab Dosing 
For subjects weighing >30 kg, durvalumab should be dosed at 10 mg/kg Q2W in the protocol of 
this trial 
Example: 
1. 
Cohort dose: 10 mg/kg 
2. 
Subject weight: 30 kg 
3. 
Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg) 
4. 
Dose to be added into infusion bag: [rounded to the nearest tenth mL (0.1 mL)]: Dose 
(mL) = 300 mg / 50 (mg/mL) = 6.0 mL 
5. 
The number of vials required for dose preparation: Number of vials = 6.0 (mL) / 10.0 
(mL/vial) = 1 vial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX III 
Eligibility Checklist 
 
Site #  
Subject ID: 
 
 
IRB# 004-21    
Title: Phase I/II study to assess the immunostimulatory 
effects of consolidative hypofractionated radiation therapy 
(hfRT) for boosting the residual primary lung cancer in 
combiniation 
with 
Durvalumab 
 
after 
definitive 
chemoradiation therapy for stage III non-small cell lung 
cancer (NSCLC) 
 
Waiver #:  
Astra Zeneca Ref #: ESR-18-
13876 
 
 
Investigator:  Dr. Chi Zhang 
Inclusion Criteria:  Response should be YES 
Yes    No      N/A 
1. Pathologically diagnosed NSCLC (squamous cell carcinoma, 
adenocarcinoma, large-cell carcinoma, or non-small-cell lung cancer 
not otherwise specified), clinical stage III (AJCC 8th Ed.) 
[  ]     [  ]    [  ] 
2. At time of consent, subjects must be a candidate for dCRT. OR Must 
have received dCRT with at least 2 cycles of platinum-based 
chemotherapy concurrent with conventional fractionated radiation 
therapy with a total dose of 5700 – 6300 cGy. 
 
[  ]     [  ]    [  ] 
3. Patients must be aware of the nature of his/her disease and willingly 
provide written, informed consent. Including compliance with the 
requirements and restrictions listed in the informed consent form (ICF) 
and in this protocol. Written informed consent and any locally required 
authorization (e.g., Health Insurance Portability and Accountability Act 
in the US) obtained from the patient/legal representative prior to 
performing any protocol-related procedures, including screening 
evaluations. 
[  ]     [  ]    [  ] 
4. Age ≥ 19 years at time of study entry 
[  ]     [  ]    [  ] 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1 at enrollment. 
[  ]     [  ]    [  ] 
6. Life expectancy of > 12 weeks. 
[  ]     [  ]    [  ] 

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7. Adequate normal organ and marrow function as defined below: 
a.Hemoglobin ≥ 9.0 g/dL (5.59 mmol/Lb.ANC 1.5 (≥ 1500 per mm3)  
c. Platelet count ≥ 100 x 109/L (≥ 100,000 per mm3) 
 Hemaglobin: ________   ANC: ______    Platelet count: ________ 
 d. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). 
This will not apply to subjects with confirmed Gilbert’s syndrome 
(persistent or recurrent hyperbilirubinemia that is predominantly 
unconjugated in the absence of hemolysis or hepatic pathology), who 
will be allowed only in consultation with their physician.    
Bilirubin____________ 
e. AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal 
(ULN). 
AST_______ALT________  
f. Measured creatinine clearance (CL) > 40 mL/min or calculated 
creatinine CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft 
and Gault 1976).  
 
Creatinine:________  Calculated creatinine clearance:__________ 
[  ]     [  ]    [  ] 
 
8. Evidence of post-menopausal status or negative serum pregnancy test 
for female pre-menopausal patients. 
Status: _______________     Pregnancy test date: _________________ 
 
[  ]     [  ]   [  ] 
9. Patient is willing and able to comply with the protocol for the 
duration of the study including undergoing treatment and scheduled 
visits and examinations including follow up 
[  ]     [  ]   [  ] 
 
Exclusion Criteria: Response should be NO 
 
Yes No N/A 
1. Involvement in the planning and/or conduct of the study (applies to 
both AstraZeneca staff and/or staff at the study site)   
[  ] [  ] [  ] 
 
2. Patients who have received prior anti–PD-1, anti PD-L1 or anti 
CTLA-4 
[  ] [  ] [  ] 
3. Participation in another clinical study with an investigational 
product during the last 4 weeks. 
[  ] [  ] [  ] 
4. Concurrent enrollment in another clinical study, unless it is an 
observational (non-interventional) clinical study or during the follow-
up period of an interventional study. 
[  ] [  ] [  ] 
5. Mixed small cell and non-small cell lung cancer histology 
[  ] [  ] [  ] 
6. Subjects who receive sequential chemoradiation therapy for locally 
advanced NSCLC.  
[  ] [  ] [  ] 
7. Subjects with locally advanced NSCLC who have progressed  
during definitive  platinumbased, concurrent chemoradiation therapy. 
[  ] [  ] [  ] 

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8.  Any unresolved toxicity (NCI CTCAE Grade >2) from previous 
anticancer therapy with the exception of alopecia, vitiligo, and the 
laboratory values defined in the inclusion criteria 
a. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-
case basis after consultation with the Study Physician. 
b. Patients with irreversible toxicity not reasonably expected to be 
exacerbated by treatment with durvalumab may be included only 
after consultation with the Study Physician. For example, post-
operative neurological deficits for previous benign brain tumors, 
urinary incontinence from radical prostatectomy for prostate 
cancer, peripheral neuropathy from chemotherapy for breast cancer 
[  ] [  ] [  ] 
9. Any concurrent chemotherapy, immunotherapy, biologic, or 
hormonal therapy for cancer treatment. Concurrent use of hormonal 
therapy for non-cancer-related conditions (e.g., hormone replacement 
therapy) is acceptable.  
[  ] [  ] [  ] 
10. Major surgical procedure (as defined by the investigator) within 28 
days prior to the first dose of immunotherapy (excluding the placement 
of vascular access) that would prevent administration of study drug or 
radiation therapy. 
[  ] [  ] [  ] 
11. History of allogenic organ transplantation. 
[  ] [  ] [  ] 
12. Active or prior documented autoimmune or inflammatory disorders 
within the past 2 years (including inflammatory bowel disease [e.g., 
colitis or Crohn’s disease], diverticulitis [with the exception of 
diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, 
rheumatoid arthritis hypophysitis, uveitis, etc]). The following are 
exceptions to this criterion: 
a. Patients with vitiligo or alopecia 
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome 
stable on hormone replacement or Graves’ disease). 
c. Any chronic skin condition including psoriasis that does not require 
systemic therapy (within the past 2 years). 
d. Patients without active disease in the last 5 years may be included but 
only after consultation with the study physician. 
e. Patients with celiac disease controlled by diet alone.  
[  ] [  ] [  ] 
13. Known allergy or hypersensitivity to Durvalumab or any excipient. 
[  ] [  ] [  ] 
14. Any uncontrolled intercurrent illness, including but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, 
uncontrolled hypertension, unstable angina pectoris, cardiac 
arrhythmia, interstitial lung disease, serious chronic gastrointestinal 
conditions associated with diarrhea, or psychiatric illness/social 
situations that would limit compliance with study requirements, 
substantially increase risk of incurring AEs or compromise the ability 
of the subject to give written informed consent.  
[  ] [  ] [  ] 

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15. History of another primary malignancy except for:  
a. Malignancy treated with curative intent and with no known active 
disease ≥5 years before the informed consent and of low potential risk 
for recurrence 
b. Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease 
c. Adequately treated carcinoma in situ without evidence of disease 
[  ] [  ] [  ] 
16. History of primary immunodeficiency.  
[  ] [  ] [  ] 
17. Known history or active infection of tuberculosis, hepatitis B 
(known positive HBV surface antigen (HBsAg) result), hepatitis C, or 
human immunodeficiency virus (positive HIV 1/2 antibodies). 
[  ] [  ] [  ] 
18. Current or prior use of immunosuppressive medication within 14 
days before the first dose of durvalumab.  The following are 
exceptions to this criterion: 
a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., 
intra articular injection) 
b. Systemic corticosteroids at doses ≤10 mg/day of prednisone or its 
equivalent 
c.  Steroids as premedication for hypersensitivity reactions (e.g., CT 
scan premedication) 
d. Systemic steroid administration required to manage toxicities 
arising from radiation therapy delivered as part of the 
chemoradiation therapy for locally advanced NSCLC is allowed. 
[  ] [  ] [  ] 
19. Receipt of live attenuated vaccine within 30 days prior to the first 
dose of IP. Note: Patients , if enrolled, should not receive live vaccines 
whilst receiving IP and up to 30 days after the last dose of IP.  
[  ] [  ] [  ] 
20. Female subjects who are pregnant or breastfeeding or male or 
female subjects of reproductive potential who are not willing to 
employ effective birth control from screening to 90 days after the last 
dose of durvalumab therapy.  
[  ] [  ] [  ] 
21. Prior randomization or treatment in a previous durvalumab and/or 
tremilimumab clinical study regardless of treatment arm assignment. 
[  ] [  ] [  ] 
22.  Any prior Grade ≥3 immune-related adverse event (irAE) while 
receiving any previous immunotherapy agent, or unresolved irAE 
>Grade 1 
[  ] [  ] [  ] 
23. Previous history of RT (other than RT as part of the dCRT for the 
current course of NSCLC) involving any part of the lungs, chest wall, 
thoracic spine or breast(s).  
[  ] [  ] [  ] 
24. Judgment by the investigator that the subject is unsuitable to 
participate in the study for any condition and the subject is unlikely to 
comply with study procedures, restrictions and requirements.  
[  ] [  ] [  ] 
 25. Mean QT interval corrected for heart rate using Fredericia’s 
formula (QTcF) ≥470 ms. Only one ECG is required at screening if the 
QTcF < 470 ms. Triplicate ECGs performed 2-5 minutes apart should 
only be performed if screening ECG shows QTcF ≥470 ms 
[  ] [  ] [  ] 

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Eligibility: [  ] Subject satisfies all criteria 
                    [  ] Subject not formally eligible, but admitted to this study because 
(state reason): 
 
_____________________________________________________________________________ 
                    [  ] Subject DID NOT Meet Eligibility Criteria 
 
 
Subject Initials: ______________         DOB:_________________ 
 
ELIGIBILITY reviewed and confirmed by:  
 
Investigator Signature _______________________Date_____________     
 
Printed Name of Investigator:  __________________________