Clinical trial NCT04003246
Conditions: Non Small Cell Lung Cancer Lung Cancer Stage III
Keywords: Lung
Sponsor: University of Texas Southwestern Medical Center
Start date: 2020-04-03; Completion date: 2024-11-05
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Single arm, Phase II trial of concurrent Durvalumab (MEDI 4736) and radiotherapy followed by consolidative Durvalumb (MEDI 4736) for Stage III Non-Small Cell Lung Cancer (NSCLC)

Detailed description:
Immunotherapy has significantly improved the survival outcomes of patients with various cancer types including thoracic malignancies. In the PACIFIC study, patients with locally advanced NSCLC were randomized to the anti-PDL1 antibody durvalumab or placebo for up to 12 months after completion of concurrent chemoradiation. While NSCLC is typically considered relatively non-immunogenic, RT is thought to augment tumor immunogenicity(Iyengar \& Gerber, 2013). The abscopal effect refers to the observation that the benefit seen in PACIFIC, along with the growing role of immunotherapy for the treatment advanced (stage IV) NSCLC, suggests that earlier exposure to durvalumab may improve outcomes and be well tolerated, thereby permitting de-escalation of therapy through removal of conventional chemotherapy from these regimens to a local area results in an antitumor effect distant to the radiation site.

Durvalumab (Imfimzi; MEDI4736; AstraZeneca) is a human monoclonal antibody of the immunoglobulin (Ig) G1 kappa subclass that inhibits binding of PD-L1 (B7-H1, CD274) to PD-1 (CD279) and CD80 (B7-1). MEDI4736 is composed of 2 identical heavy chains and 2 identical light chains, with an overall molecular weight of approximately 149 kDa. MEDI4736 contains a triple mutation in the constant domain of the Ig G1 heavy chain that reduces binding to complement protein C1q and the Fcγ receptors involved in triggering effector function. Durvlumab binds with high affinity and specificity to human PD-L1 and blocks its interaction with PD-1 and CD80

Arms: arm 1: All subjects receive the same therapeutic intervention of 1500mg intravenous durvalumab once every 4 weeks while receiving a 60 Gy/30 Fraction course of thoracic radiotherapy. After radiotherapy is complete, subjects continue to receive 1500mg intravenous durvalumab once every 4 weeks for up to one year following the start of treatment.
Interventions: intervention 1: Thoracic RT and Durvalumab intervention 2: Consolidative Durvalumab
Intervention descriptions: intervention 1: 1500mg every 4 weeks \[Q4W\] intravenous \[IV\], first dose within 3 days of RT initiation intervention 2: 1500mg every 4 weeks \[Q4W\] intravenous \[IV\] up to one year

Protocol documents:
Prot_SAP_000.pdf: 
 
STU2019-1082, Zhang, FormA3-Protocol, Mod_19, 04-03-24 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
 
 
STU 2019-1082 
Phase II Concurrent Durvalumab (MEDI4736) and radiotherapy followed by consolidative 
Durvalumab (MEDI4736) for Stage III Non-Small Cell Lung Cancer (NSCLC) 
 
 
Principal Investigator:  
Yuanyuan Zhang, MD 
 
 
 
 
UT Southwestern Medical Center  
 
 
 
 
5323 Harry Hines Blvd, Dallas, TX, 75390 
 
 
 
 
(Phone) 214/648-6764 
 
 
 
 
Email: Yuayuan.Zhang@UTSouthwestern.edu 
 
 
 
 
 
 
 
 
 
Biostatistician: 
 
Chul Ahn, PhD 
 
 
 
 
UT Southwestern Medical Center  
 
 
 
 
5323 Harry Hines Blvd, Dallas, TX, 75390 
 
 
 
 
(Phone) 214/648-9418 
 
 
 
 
(Fax) 214/648-3934 
 
 
 
 
Chul.Ahn@UTSouthwestern.edu 
 
Study Drug/Treatment: 
Durvalumab (MEDI4736), IMFINZI 
 
Funding Source:  
AstraZeneca  
 
Initial version: 
1.0 
 
Amended: 
 
2.0 Date: 12/09/2019 
 
 
3.0 Date: 02/03/2020 
 
 
4.0 Date: 03/04/2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 


 
STU2019-1082, Zhang, FormA3-Protocol, Mod_19, 04-03-24 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable U.S. federal regulations and ICH guidelines. 
 
Amendment/Version #_____4________________________ 
 
STU-2019-1082 
Phase II Concurrent Durvalumab (MEDI 4736) and radiotherapy followed by consolidative 
Durvalumab (MEDI 4736) for Stage III Non-Small Cell Lung Cancer (NSCLC) 
 
 
Principal Investigator (PI) Name: Yuanyuan Zhang  
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 


 
STU2019-1082, Zhang, FormA3-Protocol, Mod_19, 04-03-24 
 
 
 
 
1 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS............................................................................................................. 4 
STUDY SCHEMA ............................................................................................................................ 5 
STUDY SUMMARY ......................................................................................................................... 6 
1.0 
BACKGROUND AND RATIONALE ...................................................................................... 7 
1.1 
Disease Background........................................................................................................ 7 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities ................. 8 
1.3 
Other Agents .................................................................................................................. 12 
1.4 
Rationale ........................................................................................................................ 13 
1.5 
Correlative Studies ........................................................................................................ 15 
2.0 
STUDY OBJECTIVES ......................................................................................................... 16 
2.1 
Primary Objectives ......................................................................................................... 16 
2.2 
Secondary Objectives .................................................................................................... 16 
2.3 
Exploratory Objectives ................................................................................................... 16 
2.4 
Endpoints ....................................................................................................................... 17 
3.0 
PATIENT ELIGIBILITY ........................................................................................................ 17 
3.1 
Inclusion Criteria ............................................................................................................ 17 
3.2 
Exclusion Criteria ........................................................................................................... 19 
4.0 
TREATMENT PLAN ............................................................................................................ 20 
4.1 
Treatment Dosage and Administration .......................................................................... 20 
4.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 20 
4.3 
Concomitant Medications/Treatments ........................................................................... 20 
4.4 
Other Modalities or Procedures ..................................................................................... 21 
4.5 
Duration of Therapy ....................................................................................................... 29 
4.6 
Duration of Follow Up .................................................................................................... 29 


 
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4.7 
Removal of Patients from Protocol Therapy .................................................................. 28 
4.8 
Patient Replacement ..................................................................................................... 29 
5.0 
STUDY PROCEDURES ....................................................................................................... 29 
5.1 
Screening/Baseline Procedures .................................................................................... 29 
5.2 
Procedures During Treatment ....................................................................................... 30 
5.3 
Follow-up Procedures .................................................................................................... 30 
5.4 
Time and Events Table .................................................................................................. 30 
5.5 
Removal of Subjects from Study ................................................................................... 34 
5.6 
Study Restrictions .......................................................................................................... 35 
6.0 
MEASUREMENT OF EFFECT ............................................................................................ 36 
6.1 
Antitumor Effect- Solid Tumors ...................................................................................... 37 
6.2 
Safety/Tolerability .......................................................................................................... 40 
7.0 
ADVERSE EVENTS ............................................................................................................. 40 
7.1 
Experimental Therapy.................................................................................................... 40 
7.2 
Adverse Event Monitoring ............................................................................................. 40 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 43 
8.0 
DRUG/TREATMENT INFORMATION ................................................................................. 47 
8.1 
Agent/Treatment (Durvalumab) ..................................................................................... 48 
9.0 
CORRELATIVES/SPECIAL STUDIES ................................................................................ 49 
9.1 
Sample Collection Guidelines ........................................................................................ 49 
9.2 
Assay Methodology ....................................................................................................... 49 
9.3 
Specimen Banking ......................................................................................................... 49 
10.0 
STATISTICAL CONSIDERATIONS .................................................................................. 50 
10.1 
Study Design/Study Endpoints ...................................................................................... 50 
10.2 
Sample Size and Accrual .............................................................................................. 50 
10.3 
Data Analyses Plans...................................................................................................... 51 


 
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11.0 
STUDY MANAGEMENT .................................................................................................... 51 
11.1 
Conflict of Interest .......................................................................................................... 51 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 51 
11.3 
Registration Procedures ................................................................................................ 52 
11.4 
Data Management and Monitoring/Auditing .................................................................. 52 
11.5 
Adherence to the Protocol ............................................................................................. 53 
11.6 
Amendments to the Protocol ......................................................................................... 54 
11.7 
Record Retention ........................................................................................................... 54 
11.8 
Obligations of Investigators ........................................................................................... 54 
12.0 
REFERENCES ................................................................................................................... 49 
13.0 
APPENDICES .................................................................................................................... 57 
 
 
 


 
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4 
LIST OF ABBREVIATIONS (EXAMPLES) 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IHC 
Immunohistochemistry 
IV (or iv) 
Intravenously 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PD-L1 
Programmed death-ligand 1 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PR 
Partial Response 
RCB 
Residual Cancer Burden 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
WBC 
White Blood Cells 
 
 
 
 
 
 
 
 


 
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5 
 
 
 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thoracic RT 60 Gy/30F 
Durvalumab/MEDI 4736 
1500mg every 4 weeks [Q4W] intravenous 
[IV], first dose within 3 days of RT initiation  
Patient registration 
Stage III non-small cell lung cancer 
Zubrod 0 or 1 
Consolidative Durvalumab/MEDI 4736 
1500mg every 4 weeks [Q4W] intravenous 
[IV] up to one year 
 


 
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STUDY SUMMARY 
Title 
Single arm, Phase II trial of concurrent Durvalumab (MEDI 4736) and 
radiotherapy followed by consolidative Durvalumab (MEDI 4736) for 
Stage III Non-Small Cell Lung Cancer (NSCLC) 
Short Title 
TBD 
Protocol Number 
STU-2019-1082 
Phase 
Phase 2 
Methodology 
Open label  
Study Duration 
4 years 
Study Center(s) 
Single-center  
Objectives 
12-month progression-free survival (PFS) rate based on an assessment 
by an investigators according to RECIST 1.1 criteria 
Number of Subjects 
50 
Diagnosis and Main 
Inclusion Criteria 
Stage III non-small cell lung cancer 
Zubrod 0 or 1 
Study Product(s), Dose, 
Route, Regimen 
Durvalumab/MEDI 4736 
1500mg every 4 weeks [Q4W] intravenous during concurrent 
radiotherapy, 1500mg every 4 weeks [Q4W] intravenous [IV] up to one 
year during consolidative phase.  
Thoracic RT 60 Gy/30F  
Duration of administration 
1 year 
Reference therapy 
Concurrent chemo-radiation  
Statistical Methodology 
Progression-free survival and overall survival will be estimated using the 
Kaplan-Meier approach and the corresponding confidence intervals will 
be estimated using Greenwood’s formula. Distant metastases-free 
survival, local and regional control will be estimated using the Kaplan-
Meier approach. 
 
 
 


 
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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Until the recent developments of immunotherapy, we have reached a plateau in outcomes for 
locally advanced non-small cell lung cancer (LA-NSCLC). Despite aggressive therapy with 
concurrent chemoradiation, fewer than 20-25% of patients with stage III NSCLC achieve 5-year 
survival and are presumably cured.  To date, modifications of chemotherapy or dose escalation of 
radiotherapy (RT) have not improved these outcomes.   
 
Immunotherapy has significantly improved the survival outcomes of patients with various cancer 
types including thoracic malignancies. In the PACIFIC study, patients with locally advanced NSCLC 
were randomized to the anti-PDL1 antibody durvalumab or placebo for up to 12 months after 
completion of concurrent chemoradiation.  Outcomes in the durvalumab arm were significantly 
better, regardless of tumor PDL1 status.  Median PFS was 17.2 months in the durvalumab group 
(95% CI, 13.1 to 23.9) vs. 5.6 months (95% CI, 4.6 to 7.7) in the placebo group. The 24-month 
overall survival rate was 66.3% (95% confidence interval [CI], 61.7 to 70.4) in the durvalumab group 
vs. 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P=0.005). (Antonia et al., 2018; 
Antonia et al., 2017). The time to death or distant metastasis was longer in the durvalumab group 
than in the placebo group (median, 28.3 months [95% CI, 24.0 to 34.9] vs. 16.2 months [95% CI, 
12.5 to 21.1]; stratified hazard ratio, 0.53; 95% CI, 0.41 to 0.68). Following this study, consolidation 
durvalumab after chemoradiation received FDA approval and is now considered standard of care.     
 
While NSCLC is typically considered relatively non-immunogenic, RT is thought to augment tumor 
immunogenicity(Iyengar & Gerber, 2013). The abscopal effect refers to the observation that RT to 
a local area results in an antitumor effect distant to the radiation site.  One proposed mechanism 
for this phenomenon is inducing the release of circulating tumor antigen or inflammatory factors 
that could then mediate an augmented immune response against distant malignant lesions 
expressing similar tumor antigens.  Supporting this hypothesis, local RT has been shown to 
increase the activity of natural killer cells (Uchida, Mizutani, Nagamuta, & Ikenaga, 1989).  
 
Conversely, the therapeutic effects of ablative RT on local tumors are dependent on anti-tumor 
immune responses (Iyengar & Gerber, 2013). Of note, Formenti and colleagues demonstrated that 
the abscopal effect of radiotherapy is in part immune-mediated and that T cells are required to 
mediate distant tumor effects of radiotherapy (Demaria et al., 2004). In a preclinical model, ablative 
RT dramatically increased T-cell priming in draining lymphoid tissues, leading to reduction of the 
primary tumor or distant metastases in a CD8+ T-cell-dependent fashion.  In the same model, these 
RT-initiated immune responses were greatly amplified by local immunotherapy (Lee et al., 2009). 
Particularly relevant to the current proposal, RT has been shown to increase tumor expression of 
PD-L1, and combined RT plus PD-1-pathway targeting results in synergistic suppression of tumor-
infiltrating myeloid-derived suppressor cells (MDSCs), thereby promoting anti-tumor immunity 
(Deng et al., 2014).  
 
In contrast to CTLA-4 (which exerts its regulatory effects in the priming phase of the immune 
response in regional lymph nodes), the negative regulatory effects of the PD-1/PD-L1 pathway 
occur in the effector phase of the immune response in peripheral tissues.  Following T-cell 
stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2, resulting in 
dephosphorylation of multiple effector molecules involved in the CD3 T-cell signaling cascade 
(Talmadge, Donkor, & Scholar, 2007). PD-1 is expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T-cells, B-cells, T regulatory cells (Tregs), and natural killer (NK) cells 
(Hodi et al., 2008; Hodi et al., 2010).  Although healthy organs express little (if any) PD-L1, 
numerous cancers are known to express abundant levels of PD-L1.  PD-1/PD-L1 has been 
suggested to regulate tumor-specific T-cell expansion in patients with melanoma, suggesting that 
the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and therefore represents an 
attractive target for therapeutic intervention.   


 
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8 
 
Blocking PD-L1 is a similar approach to that taken by CTLA4 inhibition with ipilimumab, but has 
some potential advantages.  First, the expression of CTLA-4 and its ligands is restricted to the 
hematopoietic system; thus, the site of action for molecules targeting CTLA-4 is solely the 
peripheral lymphoid organs.  In contrast, PD-L1 is expressed not only on cells of the hematopoietic 
system but also on a range of tumor types.  Targeting of PD-L1 could therefore have additional 
effects within the tumor microenvironment.  Secondly, CTLA-4 plays an early and critical role in 
controlling T-cell activation.  This is reflected in the phenotype of CTLA-4 knockout mice, which die 
at an age of between 3 weeks and 4 weeks due to lymphoproliferative disease and tissue 
destruction.  In contrast PD-L1, via binding to PD-1, acts later in the process of T-cell activation 
(Fife & Bluestone, 2008) and is considered more dispensable for the control of initial T-cell 
activation.  This distinction is reflected in the phenotype of PD-L1 knockout mice, which are viable 
and have normal T-cell numbers and activation levels, but have increased T-cell activation in 
response to antigen and increased susceptibility in certain autoimmunity models (Dong et al., 2004; 
Latchman et al., 2004).  Based on these data, inhibition of PD-L1 would be expected to have 
reduced toxicity relative to inhibition of CTLA-4.  In support of this supposition, monotherapy clinical 
studies testing the tolerability of agents targeting PD-1 have shown a more favorable toxicity profile 
than ipilimumab (Berger et al., 2008; Brahmer et al., 2010; Wolchok et al., 2010).   
 
The benefit seen in PACIFIC, along with the growing role of immunotherapy for the treatment 
advanced (stage IV) NSCLC, suggests that earlier exposure to durvalumab may improve outcomes 
and be well tolerated, thereby permitting de-escalation of therapy through removal of conventional 
chemotherapy from these regimens. 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
Durvalumab (Imfimzi; MEDI4736; AstraZeneca) is a human monoclonal antibody of the 
immunoglobulin (Ig) G1 kappa subclass that inhibits binding of PD-L1 (B7-H1, CD274) to PD-1 
(CD279) and CD80 (B7-1).  MEDI4736 is composed of 2 identical heavy chains and 2 identical light 
chains, with an overall molecular weight of approximately 149 kDa.  MEDI4736 contains a triple 
mutation in the constant domain of the Ig G1 heavy chain that reduces binding to complement 
protein C1q and the Fcγ receptors involved in triggering effector function. Durvlumab binds with 
high affinity and specificity to human PD-L1 and blocks its interaction with PD-1 and CD80.   
 
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, 
hypophysitis and adrenal insufficiency) hepatitis/increases in transaminases, nephritis/increases in 
creatinine, pancreatitis/increases in amylase and lipase, rash/pruritus/dermatitis, myocarditis, 
myositis/polymyositis, other rare or less frequent inflammatory events including neurotoxicities, 
infusion-related reactions, hypersensitivity reactions, vasculitis, non-infectious meningitis and non-
infectious encephalitis. and infections/serious infections.  
 
For information on all identified and potential risks with durvalumab please always refer to the 
current version of the durvalumab Investigator Brochure (IB). Further information on these risks 
can be found in the current version of the durvalumab IB. In monotherapy clinical studies AEs (all 
grades) reported very commonly (≥ 10% 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 4% of patients experienced an AE 
that resulted in permanent discontinuation of durvalumab and approximately 7% 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 II).  
 
 
A Phase I, multicentre, open label, dose-escalation, and dose-expansion study was conducted to 
determine the MTD or optimal biologic dose, safety, PK, immunogenicity, and anti-tumour activity 


 
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9 
of MEDI4736 in adult patients with advanced solid tumours, refractory to standard therapy (Study 
CD-ON-MEDI4736-1108). The safety profile of durvalumab in this population was consistent with 
that of other immunotherapies and with its known safety profile as monotherapy in patients with 
more advanced disease (stage IIIB or IV NSCLC)(Antonia SJ). Safety data are available for the 20 
patients in the Q2W dose-escalation cohorts.  Nineteen of the 20 patients treated at the Q2W 
schedule have reported at least 1 treatment-emergent AE.  No patient has had a DLT at doses up 
to 10 mg/kg.  The most frequent treatment-emergent AEs reported in 3 or more patients included 
fatigue (6 patients), constipation, decreased appetite, diarrhoea, dyspnoea and nausea (4 patients 
each), and cough, dehydration, hypertension, pyrexia and rash (3 patients each).  Seven patients 
have had an AE that has been considered by the reporting investigator to be related to treatment: 
diarrhoea, vomiting, fatigue, dizziness and rash (2 patients each), and anaemia, nausea, influenza-
like illness, infusion-related reaction, dehydration, and pruritus (1 patient each).  The majority of 
AEs (in 15 of the 20 patients) have been Common Terminology Criteria for Adverse Event (CTCAE) 
Grade 1 or 2.  There have been no Grade 3 or higher treatment-related AEs.  One patient (in the 
1.0 mg/kg cohort) had 2 events of Grade 3 hyponatremia, which occurred in the setting of 
dehydration.   Four patients (1 patient in each of the 0.1, 0.3, 3.0, and 10.0 mg/kg cohorts) died 
due to AEs.  None of the events were considered by the reporting investigator to be related to 
treatment.  Three of these deaths were due to progression of disease (PD) recorded as serious 
adverse events (SAEs); the fourth death was due to retroperitoneal haemorrhage. 
 
In addition to trials in advanced disease, durvalumab was investigated in stage III non-resectable 
NSCLC in the PACIFIC trial.  In this study, patients were randomized to durvalumab 1500 mg IV or 
placebo every 14 days for up to one year, following completion of concurrent chemoradiation.  The 
durvalumab arm demonstrated improved PFS and OS compared to the placebo arm (Figure 1). 
Tumor PD-L1 expression was tested retrospectively using archival tumor tissue obtained prior to 
chemoradiotherapy. Durvalumab improved overall survival for all but PD-L1 <1% group (Figure 
2A). Durvalumab also improved progression-free survival in each of the PD-L1 subgroups (Figure 
2 B). Limitations of PD-L1 subgroup analyses include the post-hoc nature with no pre-specified 
statistical adjustmetn, incomplete sample collection and small sample size of subgroups, the low 
number of events resulting in imbalances in baseline clinical characterisitics. The most common 
treatment-related adverse events included cough, pneumonitis, dyspnea, fatigue and  diarrhea. 
Apparent immune-related adverse events included pneumonitis, pruritis and rash.  Table 1 lists 
AEs by treatment arm and severity.  Pneumonitis, arguably the greatest concern in a trial combining 
sequential thoracic chemoradiation and immune checkpoint inhibition, was numerically increased 
in the durvalumab arm, but severe cases remained less than 5%:  33.9 (3.4% grade 3-4) in the 
durvalumab arm versus 24.8% (2.6% grade 3-4) in the placebo arm.  Toxicity event terms that 
could represent similar processes, such as dyspnea and pneumonia, occurred at comparable rates 
between durvalumab and placebo arms, and reached grade 3-4 in fewer than 5% of patients.  The 
use of combination therapies may contribute to the increased incidnece of penumonitis in the 
PACIFIC trial compared to the previously reported 3-5% (Suresh et al., 2018).  Additionally, most 
cases of pneumonitis were reversible with stopping treatment, initiating glucocorticoids, or both. 
 
 
Figure 1. Overall Survival (A) and Progression Free Survival (B) in PACIFIC study  
 
(A) 


 
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10 
 
 
 
(B) 
 
 
 
 


 
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11 
Figure 2.Exploratory, Post-hoc Subgroup Analyses of Overall Survival (A) and Progression 
Free Survival (B) by PD-L1 Status (ITT population in PACIFIC study) 
  
 
(A) 
 
 
 
(B) 
 
 
 


 
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12 
 
Table 1. Safety Summary of Pacific Trial  
 
 
 
1.3 
Other Agents 
As of January 2019, six monoclonal antibodies targeting the PD1/PDL1 pathway have received 
FDA approval for the treatment of various malignancies, including nivolumab (Opdivo), 
pembrolizumab (Keytruda), atezolizumab (Tencentriq), durvalumab (Imfimzi), avelumab 
(Bavencio), cepilimumab (Yervoy).  Nivolumab (Opdivo), pembrolizumab (Keytruda), and 
atezolizumab (Tecentriq) are approved for advanced (stage 4) NSCLC.  Durvalumab is approved 
for locally advanced (stage 3) NSCLC. 
Efficacy and toxicity among the various PD1- and PDL1-targeted agents in NSCLC are comparable.  
Single-agent response rates in previously treated patients range 15-20% (Reck et al., 2016; 
Rittmeyer et al., 2017; Rizvi et al., 2015; Tanvetyanon, Creelan, & Antonia, 2016; Zhou et al., 2016). 
Generally, biomarkers predicting benefit include tumor PDL1 expression, tumor mutational burden, 
and microsatellite instability (Dudley, Lin, Le, & Eshleman, 2016; Fabrizio et al., 2018; Patel & 
Kurzrock, 2015). Although immune checkpoint inhibitors are typically well tolerated, a minority of 
patients develop immune-related adverse events (irAEs). The overall incidence of irAEs has been 
low in clinical trials that evaluated monotherapy with anti-PD-1 and anti-PD-L1 therapies (typically 
<5%) (Suresh, Naidoo, Lin, & Danoff, 2018). These autoimmune toxicities occur when immune 
stimulation results in an immune-mediated attach on normal tissues and organs. In clinical studies 
enrolling 1889 patients with various cancers who received IMFINZI (AstraZeneca Safety 
information), pneumonitis occurred in 5% of patients, including Grade 3 (0.8%), Grade 4 (<0.1%), 
and Grade 5 (0.3%) pneumonitis; Hepatitis occurred in 12% of patients, including Grade 3 (4.4%), 


 
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13 
Grade 4 (0.4%), and Grade 5 (0.2%) hepatitis; colitis or diarrhea occurred in 18% of patients, 
including Grade 3 (1.0%) and Grade 4 (0.1%) colitis.; hypothyroidism occurred in 11% of patients, 
while hyperthyroidism occurred in 7% of patients; adrenal insufficiency occurred in 0.7% of patients, 
including Grade 3 (<0.1%) adrenal insufficiency; Hypopituitarism leading to adrenal insufficiency 
and diabetes insipidus occurred in <0.1%; nephritis occurred in 6.3% of the patients including 
Grade 3 (1.1%), Grade 4 (0.2%), and Grade 5 (0.1%) nephritis; 26% of patients developed rash or 
dermatitis and 0.4% of the patients developed vitiligo.  In rare cases (<<1%), autoimmune 
encephalitis (Burke, Hardesty, & Downs, 2018) and myocarditis (Semper, Muehlberg, Schulz-
Menger, Allewelt, & Grohe, 2016) have been reported.  Grade 3 irAEs are quite rare, occuring in 
fewer than 5% of patients (Antonia et al., 2018; Hellmann et al., 2017; Rizvi et al., 2015). Depending 
on severity, irAEs may be managed with treatment withholding and immunosuppression, most 
commonly corticosteroids. 
1.4 
Rationale 
This study is designed to determine if adding durvalumab both during and after thoracic radiation 
for locally advanced NSCLC provides comparable outcomes to concurrent chemoradiation followed 
by consolidation durvalumab. Additionally, we hypothesize that the regimen under study will be 
better tolerated. 
The benefit seen in PACIFIC, along with the growing role of immunotherapy for the treatment 
advanced (stage IV) NSCLC, suggests that earlier exposure to durvalumab may improve outcomes 
and be well tolerated, thereby permitting de-escalation of therapy through removal of conventional 
chemotherapy from these regimens. Indeed, the resulting improved outcomes from adding 
durvalumab to chemoradiation in the PACIFIC trial represent a greater magnitude of benefit from 
immunotherapy than was achieved from adding chemotherapy to thoracic radiation therapy. 
EORTC08844 compared radiotherapy alone, concurrent radiotherapy plus weekly low dose 
cisplatin and concurrent radiotherapy plus daily cisplatin (Schaake-Koning et al., 1992) showed 
improved overall survival rate of 12% with radiotherapy alone, 19% with weekly cisplatin and 26% 
with daily cisplatin. Another study showed similar improvement with the addition of carboplatin and 
VP16 (Jeremic, Shibamoto, Acimovic, & Djuric, 1995). They also represent a greater degree of 
benefit than has been observed from the addition of immunotherapy to chemotherapy in advanced 
NSCLC. Recently, IMpower131 trial enrolled 1,021 patients with stage IV squamous NSCLC 
randomly assigned to either atezolizumab plus carboplatin and nab-paclitaxel or carboplatin and 
paclitaxel alone. The median progression free survival is 6.3 months for atezolizumab plus 
chemotherapy compared to 5.6 months for chemotherapy alone (P=0.001) (Robert M. Jotte, 2018). 
Together, these observations suggest that thoracic radiation therapy and durvalumab represent a 
particularly favorable combination, supporting years of preclinical studies and case reports 
demonstrating synergy between radiation therapy and immunotherapy. PACIFIC2 and other 
ongoing trials provide evidence that concurrent thoracic radiation therapy and immune checkpoint 
inhibitor therapy is likely to be well tolerated. For example, concurrent palliative radiotherapy with 
durvalumab was well-tolerated in a cohort of patients included in a phase ½ trial in France (Levy, 
Massard, Soria, & Deutsch, 2016). 
 
In this trial, enrollment is not restricted to patients with PD-L1-positive tumors for numerous 
reasons.  In preclinical models, RT has been shown to increase tumor expression of PD-L1 (Deng 
et al., 2014) which would limit the correlation of outcomes with pre-RT tissue biomarkers.  The 
observation that tumor PD-L1 expression may be prognostic in general lung cancer populations—
but not among cases treated with radiation or chemotherapy (Sun J-M, 2014)—further suggests 
that baseline assessment of this biomarker may not adequately define the target population most 
likely to benefit.  Despite early reports suggesting that PD-L1-positive patients appear to derive 
particular benefit from PD-1- and PD-L1-targeted therapies, the definition of PD-L1-positivity 
remains unclear.  Finally, in the PACIFIC study, durvalumab was associated with improved PFS 
and OS in an unselected population. Durvalumab improved overall survival for all but PD-L1 <1% 
group and progression-free survival in each of the PD-L1 subgroups.   


 
STU2019-1082, Zhang, FormA3-Protocol, Mod_19, 04-03-24 
 
 
 
 
14 
 
Compared to anti-CTLA-4 antibodies (eg, ipilimumab, tremelimumab), it has become clear that anti-
PD-L1/anti-PD1 antibodies have greater anti-tumor efficacy in NSCLC, as evidenced by the 
unprecedented overall survival results in previously treated advanced NSCLC.  Although drugs in 
these classes tend to have quite similar efficacy and safety profiles, by far the greatest experience 
in the locally advanced NSCLC and chemoradiation settings is with durvalumab, where it was U.S. 
FDA approved in February 2018.  Furthermore, anti-PD-L1 antibodies may have hypothetical safety 
advantage over anti-PD1 antibodies.  Anti-PD-L1 antibodies inhibit only PD-L1, while anti-PD1 
antibodies inhibit PD-L1 and PD-L2.  Durvalumab is highly selective for PD-L1 and does not bind 
to PD-L2, which plays a role in controlling inflammation in normal tissue, and which might potentially 
decrease the immune-related toxicity associated with the PD-L2 interaction (Mezquita & Planchard, 
2018).  
    
There is preclinical evidence supporting the administration of immunotherapy before, during, and 
after RT.  However, administration of immunotherapy before radiation could delay potentially 
curative treatment for this aggressive disease.  The benefit seen in PACIFIC, along with the growing 
role of immunotherapy for the treatment advanced (stage IV) NSCLC, suggests that earlier and 
greater exposure to durvalumab may improve outcomes and allow removal of conventional 
chemotherapy from these regimens. As no chemotherapy will be given with durvalumab in this 
study, no steroid premedication will be administered, thereby theoretically optimizing immune 
stimulation. The continuation of durvalumab after completion of thoracic radiotherapy is supported 
by the PACIFIC trial and several clinical and laboratory observations. For example, administration 
of the immunotherapeutic L-BLP25 vaccine after completion of concurrent chemoradiation was well 
tolerated and had efficacy in stage III NSCLC (Butts et al., 2014). Clinical observations of anti-
CTLA-4 antibodies suggest that immunotherapy administration following RT may provide 
synergistic effects (Postow et al., 2012).  
 
The administration of durvalumab for up to 1 year is based on apparent clinical benefit shown in 
the PACIFIC study, experience in advanced NSCLC, and available tolerability data. This duration 
covers the time-period when patients are at greatest risk of recurrence or progression.  
Furthermore, preclinical studies have demonstrated that continued stimulation of the immune 
system contributes to the anticancer effects of CTLA-4 blockade (Maker, Attia, & Rosenberg, 2005; 
Tarhini & Iqbal, 2010). The potential value of repeated dosing also has been seen in human studies 
of the anti-CTLA-4 antibody ipilimumab.  In one dramatic and illustrative case, a heavily pretreated 
patient with ovarian cancer and increasing CA-125 (GVAX vaccine refractory) was enrolled onto a 
monotherapy ipilimumab (MDX-010) study (Hodi et al., 2008). After the first dose of ipilimumab 
(MDX-010), her CA-125 decreased dramatically. Re-dosing at the time of CA-125 increase resulted 
in an even more rapid decline in her CA-125. Repeated dosing following CA-125 increases 
occurred 4 times to date and with clear and dramatic reductions in CA-125.    
 
Finally, disease-related considerations suggest that a one-year duration of durvalumab is optimal.  
Among patients with stage 3 NSCLC who achieve disease control after chemoradiation, 
approximately 75% of cases that eventually progress will do so within the first 12 months after 
completion of chemoradiation, indicating that this represents the highest risk period (Butts et al., 
2014).  Post-treatment fluorodeoxyglucose (FDG) uptake not representing disease recurrence or 
progression has occurred up to 15 months after completion of chemoradiation (Larici et al., 2011).  
If such radiographic findings correspond to physiologic effects related to tumor antigenic 
stimulation, then this period might represent the optimal period to capitalize on the abscopal effect.   
 
In this trial, patients will receive a fixed dose of 1500mg IV infusion every four weeks with concurrent 
chemotherapy and then every 4 weeks in the consolidative phase. Although the PACIFIC trial 
administered durvalumab every 2 weeks for up to one year, monthly administration improves 
convenience, has been shown not to compromise safety or efficacy and is the dosing regimen 
employed in the PACIFIC2 trial.  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 only minor impact of body weight (WT) 


 
STU2019-1082, Zhang, FormA3-Protocol, Mod_19, 04-03-24 
 
 
 
 
15 
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 
1,000 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). Wang and colleagues investigated 12 monoclonal antibodies and found that 
fixed and body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 
antibodies (Wang et al 2009)]. In addition, they investigated 18 therapeutic proteins and peptides 
and showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-patient 
variability in pharmacokinetic/pharmacodynamics parameters (Zhang et al 2012).  
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Given expectation of similar pharmacokinetic exposure and 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) is included in the current 
study. 
 
 
1.5 
 Correlative Studies 
1.5.1  
Tumor PD-L1 Expression 
 
The effect of tumor PD-L1 expression on treatment response to anti-PD-L1 targeted 
immunotherapy is a key focus of ongoing investigation. Identification of predictive biomarkers of 
response to therapy protects patients from exposure to risks of ineffective therapies and improves 
cost-effectiveness. Submission of formalin-fixed and paraffin embedded tumor samples (blocks) 
from core or excisional biopsy is recommended for all patients at the time of study enrollment.  
Although PD-L1 expression has been associated with improved outcomes from anti-PD1/PD-L1 
therapy in advanced NSCLC, the benefit has been less apparent in trials combining these agents 
with other therapies, including cytotoxic chemotherapy for stage 4 disease (Herbst et al., 2016; 
Langer et al., 2016; Socinski et al., 2018) or chemoradiation (Antonia et al., 2018). Based on the 
results of KEYNOTE-021 cohort G, a randomized phase II trial, the U.S. Food and Drug 
Administration has approved the triple combination of carboplatin, pemetrexed, and 
pembrolizumab in all patients with non–squamous cell NSCLC, regardless of PD-L1 expression 
levels (Langer et al., 2016). Previously reported results from the IMpower150 study showed that 
the combination of TECENTRIQ and Avastin plus carboplatin and paclitaxel has longer 
progression-free survival compared to Avastin plus carboplatin and paclitaxel in the first-line 
treatment of people with advanced non-squamous NSCLC (Socinski et al., 2018). This PFS benefit 
was observed across key subgroups, including those with varying levels of PD-L1 expression. 
Finally, as noted above, PDL1 levels may change after administration of radiation therapy.  We 
therefore hypothesize that any association between tumor PD-L1 expression and clinical outcomes 
will be modest in this trial. Analysis of PD-L1 expression and other biomarkers may be evaluated 
as determined by additional data associated with disease progression or response to durvalumab. 
 
1.5.2 
 Optional tumor tissue collection and studies 
If a standard-of-care diagnostic biopsy to confirm recurrence is obtained, at least two core biopsies, 
minimum, should be obtained as part of this recurrence biopsy. Paraffin embedded tissue from this 
biopsy will be used for confirmation of recurrence and for additional research.  Any remaining tumor 
tissue will be stored for additional research. Patients may consent to have tissue and/or blood 
submitted at recurrence.  
 
The remaining tumor samples may be used to analyze the expression and spatial distribution of 
immune-related or response-related markers by multiplex immunohistochemistry, which may 
include but are not limited to PD-L1, CTLA-4, CD3, CD4, CD8, CD45RO, FOXP3, granzyme B, 


 
STU2019-1082, Zhang, FormA3-Protocol, Mod_19, 04-03-24 
 
 
 
 
16 
OX40, PD1, cleaved caspase 3, and Ki67. Archived material (or biopsies if available) may also be 
analyzed for the presence of key genomic features such as EGFR, KRAS, and ALK alterations to 
evaluate their potential relevance and correlations with response to durvalumab.  
 
1.5.3 
Optional blood collection for blood born biomarkers 
Blood samples will be analyzed to evaluate protein, nucleic acid, and cellular biomarkers that relate 
to durvalumab. PBMC will also be isolated from whole blood and will be preserved, and may be 
used for subsequent flow cytometry or assessment of the diversity of the immune cell repertoire 
based on VDJ coding region analysis, the relationship to clinical responses, and changes in 
response to treatment with durvalumab. Blood collected for analysis of immune cell gene 
expression profiles within the peripheral compartments will be evaluated for any relationship with 
efficacy endpoints. Serum samples may also be anlayzed for analysis of circulating soluble factors 
in relation to immune status at baseline and in response to treatment. Factors to be analyzed may 
include but are not limited to IFN-γ, tumour necrosis factor-α, interleukin (IL)-2, IL-6, IL-10, IL-8, IL-
12, and levels of soluble PD-L1.  
 
Recent studies have found that more than 25% of healthy individuals have strong IgG humoral 
immune responses to a variety of self-antigens, indicating that a “benign” form autoimmunity is 
much more common than autoimmune disease (Wandstrat et al., 2006). This autoimmunity is 
directed against a variety of self-antigens. These findings indicate that many healthy individuals 
exhibit significant autoimmunity that is regulated in the peripheral immune system by pathways 
such as those triggered by CTLA-4 and PD1. Consistent with this, CTLA-4 and PD1 are both known 
to potentiate autoimmune disease, suggesting that the inhibition of these regulatory pathways 
aggravates pre-existing autoimmunity.  Based on this, we hypothesize that checkpoint therapy 
immune-related adverse events often result from the activation of pre-existing autoimmunity.  
 
We have the capacity to this hypothesis by utilizing a variety of novel technologies to quantify 
autoimmune responses.  Specifically, we have the ability to measure IgG autoantibody reactivity 
against more than 120 systemic and organ-specific antigens simultaneously.  
 
The protein array system that we have developed for autoantibody screening can also be used to 
assess antibodies against any antigen. Consequently, a panel of tumor-type-specific antigens may 
be incorporated into these arrays so that we can follow the level and specificity of anti-tumor 
humoral immunity elicited by checkpoint therapy in individual patients and correlate this with 
disease progression. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 
To determine the 12-month progression-free survival (PFS) rate for Stage III non-
small lung cancer patients treated with concurrent durvalumab and radiotherapy 
followed by consolidative durvalumab; 
2.2 
Secondary Objectives 
2.2.1 
To assess the safety and tolerability of concurrent durvalumab and radiotherapy 
compared to historical data from patients treated with standard of care chemo-
radiation; 
2.2.2 
To determine the overall survival (OS) defined as the time from study enrollment 
to death due to any cause; 
2.2.3 
To determine the distant metastases-free survival defined as the time from the 
study enrollment to any new distant lesion; 
2.2.4 
To determine the local and regional control defined as the time from the study 
enrollment to any local and regional lesion;  


 
STU2019-1082, Zhang, FormA3-Protocol, Mod_19, 04-03-24 
 
 
 
 
17 
2.3 
Exploratory Objectives 
2.3.1  
Biomarker and biomarker correlatives: To determine the OS and PFS in patients 
with (1) PD-L1-positive, (2) PD-L1-negative tumors and (3) PD-L1 not 
evaluable/undetermined tumors. 
2.3.2 
Proportion of patients alive at 12 and 24 months; 
2.4 
Endpoints 
2.4.1 
Primary endpoint of 12-month progression-free survival (PFS) rate is based on 
an assessment by an investigators according to RECIST 1.1 criteria; PFS is defined as 
the time from the study enrollment to documented progressive disease or death due to 
any cause, whichever occurs first; 
2.4.2 
Secondary endpoint of safety and tolerability will be assessed by adverse event 
according to CTCAE V.5; 
2.4.3 
Secondary endpoint of overall survival is defined as the time from study 
enrollment to death due to any cause; 
2.4.4 
Secondary endpoint of distant metastases free survival is defined as the time 
from the study enrollment to any new distant lesion; 
2.4.5 
Secondary endpoint of local and regional control defined as the time from the 
study enrollment to any local and regional lesion;  
2.4.6  
Exploratory endpoint of biomarker and biomarker correlatives; 
2.4.7 
Exploratory endpoint of proportion of patients alive at 12 and 24 months.  
 
3.0 
Subject ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
 
3.1.1 
Pathologically (histologically or cytologically) proven diagnosis of NSCLC with, 
medically inoperable (or patients who refuse resection) stage IIIA or stage IIIB disease 
(AJCC 8th edition); 
3.1.1.1 Inoperable Stage IIIA disease is defined by multiple and/or bulky N2 mediastinal 
lymph nodes on computed tomography (CT) scan such that, in the opinion of the 
treating investigator, the patient was not a candidate for surgical resection.  
3.1.1.2 N2 disease must have been documented by biopsy, or at a minimum by 
fluorodeoxyglucose positron emission tomography (PET) or CT if nodes were 
more than 2 cm in short axis diameter. 
3.1.1.3 T4 disease is often considered resectable at the discretion of a thoracic surgeon.  
Patients with T4N0 or T4N1 disease can be enrolled if their case is reviewed by a 
thoracic surgeon and felt to be unresectable or if they are either medically 
inoperable or refuse surgery. 
3.1.1.4 Stage IIIB patients have N3 or T4N2 status. N3 status must have been 
documented by the presence of a contralateral (to the primary tumor) mediastinal 
lymph node or supraclavicular or scalene lymph node proven by biopsy, or at a 
minimum by fluorodeoxyglucose uptake on PET or more than 2 cm in short axis 
diameter on CT scan. Patients with disease extending into the cervical region 
(defined as disease extending above cricoid cartilage) are not eligible.  
3.1.2 
Appropriate stage for study entry based on the following diagnostic workup: 
3.1.2.1 History/physical examination, including documentation of height, weight and vital 
signs, within 30 days prior to registration; 
3.1.2.2 CT scan with IV contrast (CT scan without contrast acceptable if IV contrast is 
medically contraindicated) of the lung and upper abdomen through the adrenal 
glands within 60 days prior to registration (recommended within 30 days prior to 
registration); 


 
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18 
3.1.2.3 MRI of the brain with contrast (or CT with contrast if MRI is medically 
contraindicated) within 60 days prior to registration; note: the use of intravenous 
contrast is required for the MRI or CT (unless medically contra-indicated). 
3.1.2.4 Whole-body FDG-PET/CT within 60 days prior to registration; 
3.1.3 
Age ≥ 18 years; 
3.1.4 
Life expectancy ≥ 12 weeks 
3.1.5 
Zubrod Performance Status of 0-1 within 30 days prior to registration; 
3.1.6 
Adequate respiratory function within 180 days prior to registration defined as follows: 
FEV1 > 1.2 liters; DLCO ≥ 50% predicted; 
3.1.7 
Patients with post-obstructive pneumonia are eligible provided they no longer require                          
intravenous antibiotics at registration; 
3.1.8 
Patients with a pleural effusion that is transudative, cytologically negative and non-
bloody, are eligible if the radiation oncologist feels the tumor can be encompassed 
within a reasonable field of radiotherapy; if pleural fluid is too small a volume to 
effectively sample by thoracentesis and does not show increased metabolic activity on 
CT/PET imaging, the patient will be remain eligible. 
3.1.9 
Adequate organ and marrow function as defined below 
3.1.9.1 Absolute neutrophil count >1.5 × 109/L  
3.1.9.2 Platelet count >100 × 109/L  
3.1.9.3 Baseline or post-transfusion Hemoglobin ≥9.0 g/dL 
3.1.9.4 Serum bilirubin≤ 1.5x upper limit of normal (ULN). This will not apply to patients 
with confirmed Gilbert’s syndrome, who will be allowed in consultation with their 
physician.  
3.1.9.5 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x 
ULN.  
3.1.9.6 Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 
mL/min as determined by Cockcroft-Gault (using actual body weight); 
 
Males:  
Creatinine CL = Weight (kg) × (140 - Age)  
(mL/min)  72 × serum creatinine (mg/dL) 
 
Females:  
Creatinine CL = Weight (kg) × (140 - Age) × 0.85  
(mL/min)  72 × serum creatinine (mg/dL) 
 
3.1.10 Negative serum pregnancy test within three days prior to registration for women of 
childbearing potential. 
3.1.11 Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the 
duration of study participation, and for 90 days following completion of therapy. Should 
a woman become pregnant or suspect she is pregnant while participating in this study, 
she should inform her treating physician immediately. 
 
3.1.12.1 
A female of child-bearing potential is any woman (regardless of 
sexual orientation, having undergone a tubal ligation, or remaining 
celibate by choice) who meets the following criteria: 
 
 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
3.1.12.2 
Evidence of post-menopausal status or negative urinary or 
serum pregnancy test for female pre-menopausal patients. Women will be 
considered post-menopausal if they have been amenorrheic for 12 months 


 
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19 
without an alternative medical cause. The following age-specific requirements 
apply:  
 
Women <50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of 
exogenous hormonal treatments and if they have luteinizing hormone 
and follicle-stimulating hormone levels in the post-menopausal range for 
the institution or underwent surgical sterilization (bilateral oophorectomy 
or hysterectomy).  
 
Women ≥50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments, had radiation-induced menopause with 
last menses >1 year ago, had chemotherapy-induced menopause with 
last menses >1 year ago, or underwent surgical sterilization (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy). 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent. 
3.2 
Exclusion Criteria 
 
3.2.1 
Definitive clinical or radiologic evidence of metastatic disease; 
3.2.2 
Subjects may not be receiving any other investigational agents for the treatment of the 
cancer under study. 
3.2.3 
Current invasive malignancy (except non-melanoma skin cancer, localized, non-muscle 
invasive bladder and prostate cancer not requiring ongoing active therapy).  Carcinoma in 
situ of the breast, oral cavity, or cervix are permissible regardless of timing;  
3.2.4 
Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields. For example, patients with prior breast radiotherapy treatments 
would likely be excluded;  
3.2.5 
Prior systemic treatment with chemotherapy, targeted therapy or an anti-PD-1, anti-PD-
L1 including durvalumab, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug 
specifically targeting T-cell costimulation or immune checkpoint pathways for locally 
advanced NSCLC. Prior chemotherapy and/or targeted therapy as adjuvant or 
neoadjuvant therapy for earlier-stage lung cancer is permitted as long as it was 
completed ≥6 months prior to enrollment. No prior anti-PD-1, anti-PD-L1 including 
durvalumab, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T-cell costimulation or immune checkpoint pathways is permitted; 
3.2.6 
A condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalents) or other immunosuppressive medications within 7 days of study 
drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg 
daily prednisone equivalents are permitted in the absence of active autoimmune disease;   
3.2.7 
Severe, active co-morbidity defined as follows: 
3.2.7.1 Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is 
acceptable. 
3.2.7.2 Active or prior documented autoimmune or inflammatory disorders (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: 
 
Patients with vitiligo or alopecia 


 
STU2019-1082, Zhang, FormA3-Protocol, Mod_19, 04-03-24 
 
 
 
 
20 
 
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable 
on hormone replacement  
 
Any chronic skin condition that does not require systemic therapy 
 
Patients without active disease in the last 5 years may be included but only 
after consultation with the study physician 
 
Patients with celiac disease controlled by diet alone 
 
3.2.7.3 Active infection including tuberculosis, hepatitis B, hepatitis C.   
3.2.7.4 History of allogenic organ transplantation. 
3.2.7.5 History of symptomatic or previously established interstitial lung disease; 
3.2.7.6 History of severe hypersensitivity reaction to any monoclonal antibody or allergy to 
study drug components; 
3.2.7.7 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 
days after the last dose of IP. 
3.2.8 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that, in the opinion of the investigator, would limit 
compliance with study requirements. 
3.2.9 
Pregnancy, nursing females, or women of childbearing potential and men who are 
sexually active and not willing/able to use medically acceptable forms of contraception; 
this exclusion is necessary because the treatment involved in this study may be 
significantly teratogenic. 
3.2.10 Patients whose radiation treatment plans are likely to encompass a volume of whole lung 
receiving ≥ 35% of lung volume. V20s up to 37% will be permitted and viewed as a minor 
deviation, provided that the treating radiation oncologist believes this level of exposure is 
within patient tolerance. 
3.2.11 Planned radiation cardiac dose V50 >25%. 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage, Preparation and Administration 
 
4.1.1 
Durvalumab/MEDI 4736 is administered 1500mg every 4 weeks (28±3 days) 
[Q4W] intravenous during concurrent radiotherapy, 1500mg every 4 weeks (28±3 
days) [Q4W] intravenous [iv] up to one year during consolidative phase. 
Durvalumab/MEDI 4736 will be started within ± 3 days of the start date of 
radiation therapy. 
 
4.1.2 
A dose of 1500 mg (for patients >30kg in weight ) will be administered using an 
IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV 
administration set with a 0.2- or 0.22-μm filter.  Add 30.0 mL of durvalumab (i.e., 
1500 mg 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.  
 
 
If patient weight falls to ≤ 30 kg, weight-based dosing at 20 mg/kg will be 
administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, 
with a final durvalumab concentration ranging from 1 to 15 mg/mL, and delivered 
through an IV administration set with a 0.2- or 0.22-μm filter.    
   


 
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21 
 
Standard infusion time is one hour, however if 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. 
 
 
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.   
4.1.3 
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 (MEDI4736) 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 
 
4.2        Toxicities and Dosing Delays 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table (section 5.4) Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 5.0. There are no durvalumab dose 
modifications. However, durvalumab doses may be delayed or omitted.  Dosing decisions 
and toxicity management should be made according to the system showing the greatest 
degree of toxicity as indicated in the toxicities and management algorithms (Appendix I).  
 
4.3 
Concomitant Medications/Treatments 
 
4.3.1  
Permitted Supportive/Ancillary Care and Concomitant Medications 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication.  
 
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 
10 mg daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids 
for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions 
(e.g., delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
 
Other permitted supportive/ancillary medications include but are not limited to the following:  
 
Anticonvulsants 
 
Antiemetics 
 
Anticoagulants 
 
Antidiarrheals 
 
Analgesics 
 
Hematopoietic Growth Factors 
 
Nutritional supplementation 
 
Highly active antiretroviral therapy (HAART) 
 


 
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22 
 
4.3.2 
Prohibited Therapies 
The following medications are prohibited during the study (unless utilized to treat a drug 
related adverse event): 
 
Immunosuppressive agents 
 
Immunosuppressive doses of systemic corticosteroids (except as stated in above) 
 
Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents for treatment of NSCLC) 
 
4.3.3 
Participation in Other Trials 
Patients may not participate in other clinical trials that are intended to treat the diagnosed 
lung cancer or intended to reduce toxicity of therapy.  
4.4 
Other Modalities or Procedures 
4.4.1  
Radiotherapy Treatment Technology 
This protocol requires the use of photons delivered either using 3D-CRT or IMRT 
techniques. The use of IGRT is highly encouraged but not required. No margin reduction 
will be allowed whether IGRT is used or not, and separate IGRT credentialing will not 
be required. 
4.4.2 
Radiotherapy Immobilization and Simulation 
Immobilization 
Proper immobilization is critical for this protocol. Patient setup reproducibility must be 
achieved using appropriate clinical devices. 
Simulation Imaging 
Contiguous CT slices of maximum 3 mm slice thickness should be obtained starting from 
the level of the cricoid cartilage and extending inferiorly through the entire liver volume. 
I.V. contrast-enhanced CT- simulation is recommended but not required in this study.  
CTs and PET/CTs should be used to guide tumor and normal organ volume definition. In 
the event that contrast-enhanced datasets are used for treatment planning, the density 
of the contrast should be overridden to a representative background electron density. 
Motion Management Technique 
Motion management is highly recommended for this protocol. In instances in which 
motion management is not possible, larger expansion volumes will be used to 
adequately cover the motion-related uncertainties. The types of motion management 
allowed on this study are 4DCT with ITV, active breath-hold, gated treatment, and 
abdominal compression. IMRT will be restricted to patients with less than 1cm of tumor 
motion on 4D imaging or utilizing of gating, ABC, or breath hold methods.  Abdominal 
compression as a method of minimizing respiratory motion is allowed.   
 
4.4.3 
Imaging for Structure Definition, Image Registration/Fusion and Follow up 
A whole-body FDG-PET/CT and an IV contrast enhanced CT scan or MRI exam (if CT 
scan with contrast is medically contraindicated, when MR of the chest is submitted, a non-
contrast chest CT should also be submitted) of the lung and upper abdomen through the 
adrenal glands are required within 60 days prior to registration. These exams will be used 
for disease staging and to assist in volume delineation in all eligible patients. 
 
4.4.4 
Accounting for Tumor Motion Approaches and Internal and Setup Margins 
Internal margin (IM): The IM used will be dictated by the motion management decision 
made at time of simulation. It is required for all cases, with the exception of instances in 
which simulation is done with 4DCT to develop a MIP of tumor volume (see number 4 
below). 
 
If the simulation is done with a free-breathing CT only, the IM will be 1 cm in the 


 
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23 
superior- inferior direction and 0.5 cm in the axial direction. 
 
If simulation is done with abdominal compression, the IM will be 0.7 cm in the 
superior-inferior direction and 0.5 cm in the axial direction. 
 
If simulation is done using an active breath-hold or gated breathing technique, the 
IM will be 0.5 cm in all directions. 
 
If simulation is done using a 4DCT to develop a maximum intensity projection of the 
tumor volume based on the entire tumor motion, no IM is needed.   
 
Setup Margin (SM): The SM will be 0.5 cm in all directions. No margin reduction will 
be allowed, even when using IGRT. The final PTV is constructed by expanding the 
just ITV or sum of the CTV + IM by the SM based on the definitions from Table A or 
B in section 5.2.5.  
 
4.4.5 
Definition of Target Volumes and Margins 
All structures must be labeled for digital RT data submission as listed in the table below. 
Capital letters, spacing and use of underscores must be applied exactly as indicated. 
Resubmission of data may be required if labeling of structures does not conform to the 
DICOM standard name listed. 
The structures marked as “Required” in the table must be contoured and submitted with 
the treatment plan.  
There are two tables below.  The first table applies to patients being treated using method 1, 
2, or 3 from section 5.2.4.   The second table applies only to patients being treated with 
method 4 of section 5.2.4 (4DCT with maximum intensity projection of the tumor volume 
based on the entire tumor motion) 
Contouring of the ITV_6000 is necessary only when the ITV approach is used. 
 
 
 


 
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24 
TABLE 2: FREE BREATHING / ABDOMINAL COMPRESSION / ACTIVE BREATH HOLD / 
GATING MOTION MANAGEMENT TECHNIQUES 
DICOM Standard 
Name
Description 
Detailed Specification 
GTV_6000 
GTV to receive 60 Gy 
 
Required for free 
breathing, active breath 
hold or gating motion 
management 
techniques 
The primary tumor and clinically positive lymph 
nodes seen on the planning CT 
(> 1cm short axis diameter) and pre-treatment PET 
scan (SUV > 3) will constitute the GTV. This 
volume(s) may be disjointed. In the event of a 
collapsed lobe or lung segment, the use of PET to 
distinguish tumor from fluid/atelectasis is 
encouraged. An ITV is defined at this point as the 
enveloping GTV motion over the course of a 
respiratory cycle. 
CTV_6000 
CTV to receive 60 Gy 
 
Required 
The CTV is defined to be the GTV plus a 0.5 cm 
margin to account for microscopic tumor extension. 
If an ITV is used, then a 0.5 cm margin is added to 
the ITV to form a CTV.  The CTV should be 
adjusted to not expand into other organs such as 
esophagus, major blood vessels, or bone. 
PTV_6000 
PTV to receive 60 Gy 
 
Required 
The PTV will be equal to the CTV+IM+SM.  IM and 
SM are defined in Section 5.2.4 above. In cases in 
which the PTV expansion extends outside of the 
skin, towards the spinal cord or into the spinal 
canal, it can be assumed that tumor motion will not 
occur in this direction, and the PTV margin in this 
direction can be limited. PTV margin can be 
limited up to 0.5 cm towards this particular 
dimension (skin or spinal cord). 
 
TABLE 3: 4D CT WITH MAXIMAL INTENSITY TUMOR VOLUME TECHNIQUE (PREFERRED 
METHOD) 
DICOM Standard 
Name
Description 
Detailed Specification 
iGTV_6000 
Defined as the 
enveloping GTV motion 
over the course of the 
entire respiratory cycle 
 
 
Required when a 4DCT 
is used to encapsulate 
entire breathing cycle 
volume   
The primary tumor and clinically positive lymph 
nodes seen on the planning CT (> 1 cm short axis 
diameter) and pre-treatment PET scan (SUV > 3) 
over the course of a respiratory cycle. This 
volume(s) may be disjointed. In the event of a 
collapsed lobe or lung segment, the use of PET to 
distinguish tumor from fluid/atelectasis is 
encouraged. 


 
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25 
ITV_6000 
ITV to receive 60 Gy 
 
Required when iGTV is 
drawn 
The ITV will be equal to the iGTV plus a 0.5 cm 
clinical margin as appropriate to account for 
microscopic tumor extension.  
PTV_6000 
PTV to receive 60 Gy 
 
Required 
The PTV will be equal to the ITV+SM.  SM is 
defined in Section 5.2.4 above. In cases in which 
the PTV expansion extends outside of the skin, 
towards the spinal cord or into the spinal canal, it 
can be assumed that tumor motion will not occur in 
this direction, and the PTV margin in this direction 
can be limited. PTV margin can be limited up to 
0.5 cm towards this particular dimension (skin or 
spinal cord). 
 
4.4.6 
Definition of Critical Structures and Margins 
Note: All required structures must be labeled for digital RT data submission 
exactly as listed in the first column of the table below. Capital letters and spacing 
must be used exactly as indicated. Resubmission of data may be required if 
labeling of structures does not conform to the DICOM Standard Name listed. 
DICOM Standard 
Name
Description 
Detailed Specification 
Spine Canal 
Spinal Canal 
 
Required
Boundaries: The bony limits of the spinal canal 
Cranial 
Top of C1 (or first CT slice) 
Caudal 
Bottom of L2 (or last slice of CT) 
Lungs 
Both Lungs minus 
GTV_6000 (or 
iGTV_6000) 
 
 
Required 
Boundaries: Use Lung OAR Atlas* 
Other notes: Both lungs merged into 1 structure 
and excluding the overlap with 
GTV_6000/iGTV_6000 
Esophagus 
Required 
Boundaries: The esophagus contour should include 
the mucosa, submucosa, and all muscular layers out 
to the fatty adventitia. 
Cranial:  Bottom of cricoid cartilage 
Caudal: GE junction 
Brachial Plexus 
Required for upper 
lobe tumors 
The ipsilateral brachial plexus should be contoured 
for upper lobe tumors 
Heart 
Required 
Cranial: Ascending Aorta 
Caudal: Apex 
External 
Required 
External contour of patient encompassing all internal 
organs on each slice 
Non PTV 
Required 
External (as described above) minus PTV 


 
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26 
*Investigators can access the Lung OAR Atlas at 
http://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx 
 
4.4.7 
Dose Prescription 
Note: The information provided in this section can be used for adjusting the dose 
constraints for treatment planning purposes. This table together with the planning 
priorities in Section 5.2.9 should be used during dose optimization. It is important 
to remember that ideal plans might not be achievable in all cases.  Thus, the 
Compliance Criteria table could be different than the information given here. Cases 
will be scored using the Compliance Criteria table. 
 
Target Standard 
Name 
Dose (Gy) 
Fraction 
Size (Gy) 
# of 
fractions 
Dose 
specification 
technique
PTV_6000 
60 
2.0 
30 
Covering 
exactly 95% of 
PTV
 
4.4.8 
Compliance Criteria 
The compliance criteria listed below will be used to score each case. Given 
the limitations inherent in the treatment planning process, the numbers given in this 
section can be different than the prescription table. The Per Protocol and Variation 
Acceptable categories are both considered to be acceptable. The Per Protocol 
cases can be viewed as ideal plans, and the Variation Acceptable category can 
include more challenging plans that do not fall at or near the ideal results. A final 
category, called Deviation Unacceptable, results when cases do not meet the 
requirements for either Per Protocol or Variation Acceptable. Plans falling in this 
category are considered to be suboptimal and additional treatment planning 
optimization is recommended. 
 
Target Volume Constraints and Compliance Criteria 
Name of 
Structure
Dosimetric 
parameter
Per Protocol 
Variation 
Acceptable
PTV_6000 
D95%(Gy) 
60 
58.8 to 61.2Gy 
(excluding 60 Gy) 
*Dmin(Gy) 
≥ 57 
≥54 Gy 
*Dmax(Gy) 
≤ 72 
≤75 Gy 
* Dmin and Dmax values are for a volume of 0.03 cc. 
 
 


 
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27 
Normal Structure Constraints and Compliance Criteria 
Name of 
Structure
Dosimetric 
parameter
Per Protocol 
Variation 
Acceptable*
Spine Canal 
D0.03cc(Gy) (max) 
≤ 50 
none 
Lungs 
V5Gy(%) 
≤ 65 
≤ 70 
V20Gy(%) 
≤ 35 
≤ 37 
Dmean(Gy) 
≤ 20 
≤ 22 
Esophagus 
V35Gy(%) 
≤ 50 
≤ 55 
V70Gy(%) 
≤ 20 
≤ 25 
Dmean(Gy) 
≤ 34 
≤ 37 
Brachial Plexus 
Dmax(Gy) 
≤63 
≤ 66 
Heart 
V30Gy(%) 
≤ 50 
≤ 55 
V45Gy(%) 
≤ 35 
≤ 40 
D0.03cc(Gy) (max) 
≤ 70 Gy 
≤ 75 Gy ** 
*The Variation Acceptable category extends the Per Protocol category numbers to allow for more 
challenging treatment planning problems.  The Variation Acceptable range does not include the Per 
Protocol values.  Plans will be scored as Deviation Unacceptable when Per Protocol and Variation 
Acceptable constraints are not met. 
** When this value cannot be achieved, treatment plans must be modified to move dose distribution 
hotspots away from the heart to avoid having the case scored as a Deviation Unacceptable. 
Delivery Compliance Criteria 
 
Per Protocol 
Variation 
Acceptable
Start date (days after 
step 1 registration) 
14 days 
15-30 days 
RT Elapsed Days 
< 45 days 
46-51 days 
Interruptions (other than 
holidays or weekends)
0-2 days 
3-7 days 
Note: Cases will be scored as Deviation Unacceptable when the time limits given above are 
not met. 
 
4.4.9 
Treatment Planning Priorities and Instructions 
 
Critical Structure and Target priorities are listed in order of decreasing importance: 
 
 
Spine Canal 
   
PTV  
 
 
Lungs 
 
 
Esophagus 
 
 
Heart 
 
 
Brachial Plexus 
 
  
If lung dose constraints are exceeded, several solutions can be entertained: 
 
For 3D-CRT: Increase the weighting of AP/PA treatments by 1, and reduce the obliques. 
This can be done as long as the cord dose, which takes precedence, is not exceeded. 
 
For 3D-CRT or IMRT: Reduce the CTV to the minimum range suggested above and/or 
reduce the PTV by choosing another motion management option with smaller internal 
margins. 
It is recommended that the esophagus not be circumferentially irradiated with > 60 Gy (i.e. 


 
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28 
the 60 Gy isodose line should not encompass the entire axial cross-section of the 
esophagus at any level). 
 
4.4.10  Dose Calculations 
Primary dataset for dose calculation 
The primary dataset for dose calculation must be a free-breathing CT that was 
acquired along with 4DCT, an average intensity pixel CT (AveIP) generated from the 
4DCT, the breath- hold/gated CT, or the free-breathing CT acquired with no other 
motion management. Maximum Intensity Pixel (MIP) generated images from 4DCTs 
may not be used as the primary dose calculation dataset. 
Dose matrix resolution 
Dose grid size should be ≤ 3 mm in all directions. 
4.4.11    Daily Treatment Localization/IGRT 
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate 
accuracy and precision throughout its entire process from target and normal tissue 
delineation, to radiation delivery, to adaptation of therapy to anatomic and biological 
changes over time in individual patients. In this section we use the terminology IGRT to 
focus on image-guidance at the time of radiation delivery to ensure its adherence to the 
planned treatment. 
A reliable method of daily image guidance will be utilized.  This can include but is not limited 
to daily cone beam imaging, fiducial marker tracking systems, kV – kV matching.  Daily cone 
beam imaging aligned to the tumor and soft-tissue anatomy is considered the preferred 
approach. 
4.4.12    Radiation Therapy Adverse Events 
Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and 
esophagitis are expected side effects of radiation therapy.  
Cardiac Toxicity 
Radiation-induced myocarditis rarely occurs at doses lower than 50 Gy.  
Neurologic Toxicity 
Radiation-induced transverse myelitis rarely occurs at doses lower than 50 Gy. 
Esophagitis 
Esophageal complaints are common with combined modality therapy. Esophagitis does 
not constitute a reason to interrupt or delay radiotherapy or chemotherapy provided oral 
intake is sufficient to maintain hydration. Patients should be advised to avoid alcoholic, 
acidic, or spicy foods or beverages. Viscous Xylocaine, Carafate, or other medications 
should be used for symptomatic relief. Occasionally, narcotics may be required. 
It is not necessary to biopsy acute esophagitis in the first 2 weeks of combined therapy 
since it is rarely due to underlying viral or fungal disease. Acute esophagitis may persist 
for 4-6 weeks. If Grade 4 (CTCAE, v. 5) esophagitis occurs, and a treatment interruption 
is being considered, every effort should be made to limit it to ≤ 3 treatment days. Patients 
requiring hospitalization because of esophagitis may have their treatment interrupted.  
Pulmonary Toxicity 
Pneumonitis is possible in the later weeks of chemoradiotherapy and during the weeks 
that follow.  In general, pneumonitis is a diagnosis of exclusion and is treated with a 
combination of corticosteroids and supportive care at the discretion of the treating 
physician.   
Radiographic evidence of radiation change and subsequent fibrosis of the lung will occur 
within lung volume receiving ≥ 20 Gy, usually within the first 6 months after initiation of 
treatment. It is essential to spare as much normal lung as possible in order to avoid 
symptomatic lung injury. 
 


 
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29 
4.5 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 
one year or until 
 
Disease progression 
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Subject decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator”. 
4.6 
Duration of Follow Up 
Subjects will be followed every 3 months until 2 years post concurrent durvalumab/RT then 
every 6mos during year 3-5, then yearly or until death, whichever occurs first.  
 
Subjects who discontinue for reasons other than progressive disease will have post-
treatment follow-up for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent or becoming lost to follow-up. After documented 
disease progression each subject will be followed for overall survival until death, withdrawal 
of consent, or the end of the study (whichever occurs first).  Subjects removed from 
treatment for unacceptable adverse events will be followed until resolution or stabilization 
of the adverse event. 
4.7 
Removal of Patients from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator, and document the reason for treatment discontinuation 
and the date of discontinuation. The subject should be followed-up per protocol.  
4.8 
Subject Replacement 
Subjects missing 7 or more doses due to toxicity will not be replaced since these subjects 
will be considered to have experienced a dose limiting toxicity. 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 90 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical and surgical history, history of infections 
5.1.3 Demographics 
Age, gender, race, ethnicity 


 
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30 
5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 Performance status 
Performance status evaluated prior to study entry according to Appendix II. 
5.1.8 Adverse event assessment 
Baseline adverse events will be assessed. See section 7 for Adverse Event 
monitoring and reporting. 
5.1.9 Hematology 
5.1.10 Blood draw for correlative studies 
See Section 9.0 for details. 
5.1.11 
Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, amylase, lipase, ALT/SGPT, AST/SGOT, BUN, creatinine, 
electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and 
total bilirubin. 
5.1.12 
Pregnancy test (for females of child bearing potential) 
See section 3.1.12 for definition.  
5.1.13 
Tumor assessment 
5.2 
Procedures During Treatment 
5.2.1 
Concurrent phase  
 Physical exam including vital signs  
 Performance status  
 Adverse event assessment  
 Serum chemistries (amylase and lipase do not need to be resulted prior to 
treatment administration in the absence of clinical symptoms) 
 Adrenal function test and thyroid function test  
 Optional blood collection  
5.2.2 
Consolidative phase  
 Physical exam including vital signs  
 Performance status  
 Adverse event assessment  
 Serum chemistries (amylase and lipase do not need to be resulted prior to 
treatment administration in the absence of clinical symptoms) 
 Adrenal function tests and thyroid function tests 
 Chest CT include adrenals  
 Pulmonary function testing (PFT/DLCO) 
 Optional blood collection  


 
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31 
5.3 
Follow-up Procedures 
 
Follow up visit every 3 months for 2 years; every 6 months for years 3-5; then yearly 
Procedure 
 
Physical exam including vital signs  
 
Performance status  
 
Adverse event assessment  
 
Complete blood count and serum chemistries  
 
Adrenal function tests and thyroid function tests 
 
Chest CT include adrenals  
 
5.4 
Time and Events Table  
 
 
 
 


 
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32 
PRE-TREATMENT ASSESSMENTS  
Assessments
Prior to Registration 
(calendar days) 
Prior to Treatment
(calendar days) 
History and physical 
exam 
30 
 
Zubrod performance 
status 
30 
 
Tumor measurements 
30 
 
Rad Onc exam 
30 
 
Med Onc exam 
30 
 
CBC 
30 
 
CMP 
30 
 
Thyroid function test  
30 
 
AM cortisol, ACTH 
30 
 
Urinalysis  
30 
 
Serum pregnancy test if 
applicable  
3 
 
Baseline Chest X-Ray 
30 
 
Baseline EKG 
30 
 
Cytology/Pathology 
Report confirming 
NSCLC 
90 
 
Whole body FDG-
PET/CT (base of skull to 
mid-thigh) 
60 
 
CT chest with contrast 
and include adrenals* 
60 
 
MRI of brain (CT if MRI 
contraindicated) 
60 
 
Pulmonary function 
testing (PFTs/DLCO) 
90 
 
Informed consent 
Within 30 days including 
Day of registration 
 
Specimen collection for 
banking 
 
If patient consents:  See 
Section 9. 
 
* Patients do not need to have a separate CT of chest and upper abdomen with contrast if FDG-
PET/CT imaging includes a high quality CT chest with contrast 
 
 
 
 
 


 
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33 
ASSESSMENTS DURING CONCURRENT TREATMENT 
Assessments
Weekly (+/- 3 days)
At week 1 and 5 only 
(+/- 7 days) 
Performance status 
X 
 
CMP 
X1 
 
Thyroid function test 
 
X 
Adrenal function test  
 
X 
Rad Onc Evaluation 
X 
 
Med Onc evaluation 
 
X2 
Adverse event 
evaluation 
X 
 
Specimen collection for 
banking 
 
X3 
1 Biweekly 
2 Testing does not need to be repeated if performed within 7 days of starting protocol therapy. 
3Day 1 and Day 42  
 
 


 
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34 
ASSESSMENTS DURING CONSOLIDATIVE DURVALUMAB TREATMENT  
Assessments
Every month at 
infusion 
Every 3 months
Physical examination 
including vital signs 
(blood pressure, 
weight) 
X 
 
Zubrod performance 
status 
X 
 
CMP 
X 
 
Thyroid function (TSH, 
T3 and T4);  
 
Every 2 months 
AM cortisol, ACTH 
 
Every 2 months 
Serum or urine 
Pregnancy test 
X1 
 
AE evaluation 
X 
 
CT of chest with  
contrast and include 
adrenals 
 
X2 
Pulmonary function 
testing (PFTs/DLCO) 
 
X3 
Blood collection for 
banking 
 
X4 
1 Every 6 weeks 
2After completion of concurrent durvalumab/radiotherapy, radiographic assessment with CT chest 
with contrast including adrenals will occur within 2 weeks. Further radiographic assessment will 
occur every 3 months for 2 years. After 2 years, radiographic disease assessment should be 
performed every 6 months during year 3-5 then annually thereafter. FDG-PET/CT should be done 
to confirm clinically uncertain progression or treatment related effects at the discretion of the 
treating investigator. This imaging may be done locally. 
3At 6 months only.  
4At 12 weeks and end of the study.  
 
  
 
 
 


 
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35 
ASSESSMENTS IN FOLLOW UP  
Assessments
Every 3 mos  until 2 
years post 
concurrent 
durvalumab/RT 
then every 6mos 
during year 3-5, 
then yearly 
History and physical exam 
X 
Zubrod performance status 
X 
Tumor Measurement 
X 
Med Onc exam 
X 
AE Evaluation 
X 
CBC, BMP 
X 
 CT Chest with contrast and 
include adrenals 
X1 
1After completion of concurrent durvalumab/radiotherapy, radiographic assessment with 
CT chest with contrast including adrenals will occur within 2 weeks. Further radiographic 
assessment will occur every 3 months for 2 years. After 2 years, radiographic disease 
assessment should be performed every 6 months during year 3-5 then annually 
thereafter. FDG-PET/CT should be done to confirm clinically uncertain progression or 
treatment related effects at the discretion of the treating investigator. This imaging may 
be done locally. 
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; 
5.5.4 
Subject demonstrates disease progression (unless continued treatment with 
study drug/treatment is deemed appropriate at the discretion of the investigator); 
5.5.5 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.5.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.9 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the two years must be documented and 
approved by the Data Monitoring Committee. 


 
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36 
5.6 
Study Restrictions  
Female patient of child-bearing potential 
Female patients 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 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 monotherapy). 
Non-sterilized male partners of a female patient of 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 
patients should also refrain from breastfeeding throughout this period.  
Male patients with a female partner of childbearing potential 
 
Non-sterilized male patients 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 monotherapy). However, periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
contraception.  Male patients should refrain from sperm donation throughout this period. 
 
Female partners (of childbearing potential) of male patients must also use a highly effective 
method of contraception throughout this period.   
 
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 Table 2.  
Note that some contraception methods are not considered highly effective (e.g. male or 
female condom with or without spermicide; female cap, diaphragm, or sponge with or 
without spermicide; non-copper containing intrauterine device; progestogen-only oral 
hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action 
[excluding Cerazette/desogestrel which is considered highly effective]; and triphasic 
combined oral contraceptive pills). 
 


 
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37 
Table 1. Highly Effective Methods of Contraception (<1% Failure Rate) 
 Barrier/Intrauterine methods 
 Hormonal Methods 
 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 
Patients should not donate blood while participating in this study or for at least 90 days 
following the last infusion of durvalumab. 
6.0 
Measurement of Effect 
 
Antitumor Effect 
 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) 
Committee [Eur J Cancer. 2009;45(2):228-247]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 
6.1.1 
Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of 
their first treatment with study therapy. 
 
Evaluable for objective response.  Only those subjects who have measurable 
disease present at baseline, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for response. 
These subjects will have their response classified according to the definitions 
stated below. (Note: Subjects who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 


 
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38 
6.1.2 
Disease Parameters 
 
Measurable Disease: Tumor lesions: Must be accurately measured in at least 
one dimension (longest diameter in the plane of measurement is to be recorded) 
with a minimum size of: 
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
2. 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable) 
3. 20 mm by chest x-ray. 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). 
Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological 
nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the 
node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for 
MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of 
these measures is the short axis. For example, an abdominal node which is 
reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or 
followed. 
 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation therapy. 
 
Non-measurable disease.  
All other lesions are considered non-measurable, including small lesions (longest 
diameter < 10mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) 
as well as truly non-measurable lesions. Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
Target lesions.  
All measurable lesions up to a maximum of five lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified 
as target lesions 
 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the five target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  


 
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39 
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and not more than 60 days before the beginning of 
the treatment. 
 
Conventional CT should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
6.1.4 
Response Criteria 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.   
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 
mm (the sum may not be “0” if there are target nodes).  Determined by 
two separate observations conducted not less than 4 weeks apart. There 
can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): > 20% increase in the SLD taking as 
reference the smallest SLD recorded since the treatment started (nadir) 
and minimum 5 mm increase over the nadir.   
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. There can be no unequivocal new 
lesions. 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 
 
Incomplete Response/Stable Disease (Non-CR/Non-PD): Persistence of 
one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions 
6.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 


 
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40 
treatment started). The subject’s best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Time point response: patients with target (+/– non-target) disease. 
Target lesions 
Non-target lesions 
New 
lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, NE = not evaluable, PD = progressive disease, PR = 
partial response, SD = stable disease. 
 
Time point response: patients with non-target disease only. 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, NE = not evaluable, PD = progressive 
disease 
A ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can 
be measured is not advised. 
 
6.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  


 
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41 
6.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from study 
enrollment to time of progression. 
6.2 
Safety/tolerability 
 
Analyses will be performed for all subjects having received at least one dose of study 
therapy. The study will use the CTCAE version 5.0 for reporting of adverse events.  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
7.0 
ADVERSE EVENTS 
7.1 
Experimental Therapy 
For the most recent safety update (in drug studies), please refer to the current 
Investigator’s Brochure or Study Agent Prescribing Information. 
7.1.1 
Contraindications 
 
 
There are no contraindications for IMFINZI® (durvalumab). 
7.1.2 
Special Warnings and Precautions for Use 
IMFINZI can cause serious, potentially fatal adverse reactions including immune-
mediated pneumonitis, hepatitis, colitis or diarrhea, endocrinopathies, nephritis, 
rash or dermatitis, other immune-mediated adverse reactions, infection, and 
infusion-related reactions. 
7.1.3 
Adverse Reactions 
In patients with Stage III NSCLC in the PACIFIC study (IMFINZI n=475), the most 
common adverse reactions (≥20% of patients) were cough (40%), fatigue (34%), 
pneumonitis or radiation pneumonitis (34%), upper respiratory tract infections 
(26%), dyspnea (25%), and rash (23%). The most common Grade 3 or 4 adverse 
reaction (≥3%) was pneumonia (7%). 
 
In patients with Stage III NSCLC in the PACIFIC study (IMFINZI n=475), 
discontinuation due to adverse reactions occurred in 15% of patients in the 
IMFINZI arm. Serious adverse reactions occurred in 29% of patients receiving 
IMFINZI. The most frequent serious adverse reactions (≥2% of patients) were 
pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal 
pneumonitis or radiation pneumonitis and fatal pneumonia occurred in <2% of 
patients and were similar across arms. 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of subject safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study 
therapy, will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline or is stable in the opinion of the investigator;  
 there is a satisfactory explanation other than the study therapy for the changes 


 
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42 
observed; or 
 death. 
 
7.2.1 
Definitions  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam, imaging finding or clinically significant laboratory finding), symptom, 
clinical event, or disease, temporarily associated with the subject’s participation in the 
research, whether or not it is considered related to the subject’s participation in the 
research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Adverse event of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest 
specific to understanding of the Investigational Product and may require close monitoring. 
An AESI may be serious or non-serious.  
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 and intestinal perforation 
 
Pneumonitis / ILD 
 
hepatitis / transaminase increases 
 
Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal 
insufficiency, hyper- and hypothyroidism and type I diabetes mellitus) 
 
Rash / Dermatitis 
 
Nephritis / Blood creatinine increases 
 
Pancreatitis  / serum lipase and amylase increases   
 
Myocarditis 
 
Myositis / Polymyositis Neuropathy / neuromuscular toxicity (e.g. 
Guillain-Barré, and myasthenia gravis) 
 
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 eyeskin, 
haematological and rheumatological events, vasculitis, non infectious 
meningitis and non-infectious encephalitis. 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs. 
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab Investigator’s Brochure. 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 the Sponsor to assist the Investigator in the exercise of his/her clinical judgment in 


 
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43 
treating these types of toxicities.  These guidelines apply to AEs considered causally 
related to the study drug/study regimen by the reporting investigator.  
Acute Adverse Events  
Adverse events occurring in the time period from the signing of the informed consent, 
through 90 days post treatment will be considered acute adverse events.   
Late Adverse Events (as applicable) 
Adverse events occurring in the time period from the end of acute monitoring, to 5 years 
post treatment, will be defined as late adverse events. Immune-mediated adverse events 
such as adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, 
diabetes mellitus, nephritis and renal dysfunction will be monitored by medical oncology 
and other specialists during follow up visit whereas radiation side effects will be monitored 
by radiation oncology.   
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Adverse 
events not specifically defined in the NCI CTCAE will be scored on the Adverse Event log 
according to the general guidelines provided by the NCI CTCAE and as outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
 
Results in death   
 
Immediately life-threatening  
 
Results in inpatient hospitalization1,2 or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and events 
that are expected in the context of the condition under study may be serious adverse 
events, independent of relatedness to the study itself. As examples, a car accident 
requiring >24 hour inpatient admission to the hospital would be a serious adverse event 
for any research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death which occurs during the protocol-specified period of monitoring for 
adverse and serious adverse events would be a serious adverse event, even if the event 
observed is a primary clinical endpoint of the study. 


 
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44 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital 
stay equal to or greater than 24 hours. Hospitalization is used as an indicator of the 
seriousness of the adverse event and should only be used for situations where the AE truly 
fits this definition and NOT for hospitalizations associated with less serious events. For 
example: a hospital visit where a patient is admitted for observation or minor treatment 
(e.g. hydration) and released in less than 24 hours. Furthermore, hospitalization for 
pharmacokinetic sampling is not an AE and therefore is not to be reported either as a 
routine AE or in an expedited report. 
7.2.2 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term unanticipated 
adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from the regulatory 
agencies considers unanticipated problems to include any incident, experience, or 
outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
 
 
 
 
AND 
• 
Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.3 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the 
SCCC DSMC and/or HRPP 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 


 
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45 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported as 
indicated in the sections below. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the treatment. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
 
the current known adverse events listed in the Agent Information Section of this 
protocol (if applicable); 
 
the drug package insert (if applicable); 
 
the current Investigator’s Brochure (if applicable) 
 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
 
7.3.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. All SAEs/UPIRSOs occurring during the protocol-specified 
monitoring period should be submitted to the SCCC DSMC within 5 business days of the 
PI or delegated study team members awareness of the event(s). In addition, for 
participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events. 
 
The UTSW Radiation Oncology research office is responsible for submitting 
SAEs/UPIRSOs to the SCCC DSMC Coordinator and AstraZeneca.  Hardcopies or 
electronic versions of the eIRB Reportable Event report; FDA Form #3500A forms, or 
other sponsor forms, if applicable; and/or any other supporting documentation available 
should be submitted to the DSMC Coordinator.  The DSMC Coordinator forwards the 
information onto the DSMC Chairman who determines if immediate action is required.  
Follow-up eIRB reports, and all subsequent SAE/UPIRSO documentation that is available 
are also submitted to the DSMC Chair who determines if further action is required.  
 
Written reports to: 
 
Department of Radiation Oncology  
Clinical Research Office  
The University of Texas Southwestern Medical Center  
FAX #: 214-645-8913 
  
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit a Reportable Event via eIRB with a copy of the final sponsor report as attached 
supporting documentation 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP/IRB 
 


 
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46 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
 
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences, outcomes, 
etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a 
subject’s underlying condition or not expected as a risk of the study; therefore, not 
included in the investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  Note: According to OHRP, if the adverse event is serious, it 
would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects 
(UADEs) and death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW IRB within 5 working days of 
PI awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of PI awareness. Investigators must report to 
their relying IRB according to the relying IRB’s policy. In addition, the external IRB’s 
responses or determinations on these local events must be submitted to the UT 
Southwestern IRB within 10 working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, 
and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/research-administration/irb/assets/policies-
combined.pdf. 
 
7.3.2 
 
Reporting SAEs and UPIRSOs to AstraZeneca  
 
 
Reporting of serious adverse events 
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period 
immediately following the time that written informed consent is obtained through 90 days 
after the last dose of durvalumab or until the initiation of alternative anticancer therapy. The 
investigator and/or Sponsor are responsible for informing the Ethics Committee and/or the 
Regulatory Authority of the SAE as per local requirements. 
 
The investigator and/or sponsor must inform the FDA, via a MedWatch/AdEERs 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/AdEERs report must be emailed to AstraZeneca at 
the time the event is reported to the FDA. It is the responsibility of the sponsor to compile 


 
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47 
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/AdEERs 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-##-#####) 
* Sponsor 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 
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. In the case of blinded trials, AstraZeneca will 
request that the Sponsor either provide a copy of the randomization code/ code break 
information or unblind those SAEs which require expedited reporting. 
 
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. 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.  
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab 
safety follow-up period will be documented <<as events for survival analysis>>, but will not 
be reported as an SAE. However, if an investigator learns of any SAEs, including death, at 
any time after the patient has been permanently withdrawn from study, and he/she 
considers there is a reasonable possibility that the event is related to study treatment, the 
investigator should notify the study sponsor and AstraZeneca/MedImmune Drug Safety. 
 
Medication errors  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. If a medication error occurs in the course of the study, then the 
Investigator or other site personnel informs Sponsor within 1 day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it. The Sponsor works with the 
Investigator to ensure that all relevant information is completed within 1 or 5 calendar days. 
The Sponsor must report to AstraZeneca Patient Safety using the designated Safety e-
mailbox 
 
Overdose 
An overdose is defined as a patient 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 patient with durvalumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-
mailbox within 7 calendar days or sooner when required. If the overdose results in an AE, 


 
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48 
the AE must also be recorded as an AE. 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. There 
is currently no specific treatment in the event of an overdose of durvalumab. The 
investigator will use clinical judgment to treat any overdose. 
 
Other events requiring reporting 
Hepatic function abnormality 
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law 
case in a study patient, with or without associated clinical manifestations, is required to be 
reported as “hepatic function abnormal” within 24 hours of knowledge of the event to the 
sponsor and AstraZeneca Patient Safety using the designated Safety e-mailbox (see 
Section 10.3.2 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 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 patient 
will be based on the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of 
the study patient must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  
 
Pregnancy 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be 
discontinued immediately.  
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under 
study may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented 
even if the patient was discontinued from the study.  
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel should inform 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 patients should refrain from fathering a child or donating sperm during the study and 
for 180 days after the last dose of durvalumab + any drug combination therapy or 90 days 
after the last dose of durvalumab monotherapy, whichever is the longer time period. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) occurring from the date of the first dose until 180 
days after the last dose of durvalumab + any drug combination therapy or 90 days after the 
last dose of durvalumab monotherapy, whichever is the longer time period should, if 
possible, be followed up and documented.  


 
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49 
 
Where a report of pregnancy is received, prior to obtaining information about the 
pregnancy, the Investigator must obtain the consent of the patient’s partner. Therefore, the 
local study team should adopt the generic ICF template in line with local procedures and 
submit it to the relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior 
to use. 
8.0 
DRUG/TREATMENT INFORMATION 
8.1 
Durvalumab 
 
Other names for the drug(s): MEDI 4736, IMFINZI 
 
 
Classification - type of agent: Immunotherapy  
 
 
Mode of action: PD-L1 blockage 
 
 
Protocol dose: Durvalumab/MEDI 4736 is administered 1500mg every 4 weeks (28±3 
days) [Q4W] intravenous during concurrent radiotherapy, 1500mg every 4 weeks 
[Q4W] (28±3 days) intravenous [iv] up to one year during consolidative phase. 
Durvalumab/MEDI 4736 will be started within ± 3 days of the start date of radiation 
therapy.   
 
 
Formulation/packaging/storage: Durvalumab (MEDI4736) will be supplied by 
AstraZeneca as a 500-mg vial solution for infusion after dilution.  The solution 
contains 50 mg/mL durvalumab (MEDI4736), 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 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 original packaging until use to prevent 
prolonged light exposure.  
 
 
Preparation of durvalumab doses for administration with an IV bag: The dose of 
durvalumab (MEDI4736) 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 (MEDI4736) 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 
 
A dose of 1500mg (for patients >30kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration 
set with a 0.2- or 0.22-μm filter.  Add 30.0 mL of durvalumab (ie, 1500mg 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. 
 
If weight falls to ≤ 30 kg, weight-based dosing at 20 mg/kg will be a administered using 
an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 
concentration ranging from 1 to 15mg/mL, and delivered through an IV administration 
set with a 0.2- or 0.22-μm filter. 
 
Standard infusion time 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.  If 


 
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50 
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.  
 
Side effects: Durvalumab can cause serious, potentially fatal adverse reactions 
including 
immune-mediated 
pneumonitis, 
hepatitis, 
colitis 
or 
diarrhea, 
endocrinopathies, nephritis, rash or dermatitis, other immune-mediated adverse 
reactions, infection, and infusion-related reactions. Refer the reader to the agent’s 
package insert for a comprehensive list of adverse events. 
 
Monitoring of dose administration: Patients will be monitored during and after the 
infusion with assessment of vital signs at the times specified in the Study Protocol.  
 
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 and re-initiated at 50% 
of the initial rate until completion of the infusion. For patients with a ≤Grade 2 infusion-
related reaction, subsequent infusions may be administered at 50% of the initial rate. 
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the 
investigator. If the infusion-related reaction is ≥Grade 3 or higher in severity, study drug 
will be discontinued. For management of patients who experience an infusion reaction, 
please refer to the toxicity and management guidelines in Appendix 1.  
 
As with any antibody, allergic reactions to dose administration are possible. 
Appropriate drugs and medical equipment to treat acute anaphylactic reactions must 
be immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. The study site must have immediate access to emergency resuscitation 
teams and equipment in addition to the ability to admit patients to an intensive care 
unit if necessary  
8.1.1 
Return and Retention of Study Drug 
Remaining drug will be destroyed according to institutional pharmacy 
instructions. 
9.0 
CORRELATIVES/SPECIAL STUDIES 
 
The goal of the planned laboratory correlative studies is to understand the effect of tumor PD-L1 
expression on treatment response to anti-PD-L1 targeted immunotherapy 
9.1 
Sample Collection Guidelines 
In this study, it is recommended that tissue be submitted to pathology department at UT 
Southwestern for PD-L1 expression analysis for all patients. It is highly recommended (but 
optional for the patient) that if any tissue remains after analysis, it will be stored at the 
Tissue Bank at UT Southwestern for future research. In addition, it is highly recommended 
(but optional for the patient) that fresh-frozen tumor biopsy, serum and peripheral blood 
specimens be submitted for the additional tests, 
 
Optional Samples will be collected at the following time points (+/- 7 days): 
 
Tissue submission to pathology department at UT Southwestern for PD-L1 
expression analysis for all patients (within 28 days) prior to study treatment. 
 
Collection of 8cc plasma at study enrollment, at week 6, week 12 and end of the 
study. 
9.2 
Assay Methodology 
PDL-1 testing will utilize the Ventana SP263 assay and should be performed in accordance 
with the package insert on the Ventana Benchmark platform (Ultra or XT).  The remaining 
tumor samples may be used to analyze the expression and spatial distribution of immune-
related or response-related markers by multiplex immunohistochemistry, which may 


 
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51 
include but are not limited to PD-L1, CTLA-4, CD3, CD4, CD8, CD45RO, FOXP3, 
granzyme B, OX40, PD1, cleaved caspase 3, and Ki67. Archived material (or biopsies if 
available) may also be analyzed for the presence of key genomic features such as EGFR, 
KRAS, and ALK alterations to evaluate their potential relevance and correlations with 
response to durvalumab. Blood samples will be analyzed to evaluate protein, nucleic acid, 
and cellular biomarkers that relate to durvalumab. PBMC will also be isolated from whole 
blood and will be preserved, and may be used for subsequent flow cytometry or 
assessment of the diversity of the immune cell repertoire based on VDJ coding region 
analysis, the relationship to clinical responses, and changes in response to treatment with 
durvalumab. Blood collected for analysis of immune cell gene expression profiles within 
the peripheral compartments will be evaluated for any relationship with efficacy endpoints. 
Serum samples may also be analyzed for analysis of circulating soluble factors in relation 
to immune status at baseline and in response to treatment. Factors to be analyzed may 
include but are not limited to IFN-γ, tumor necrosis factor-α, interleukin (IL)-2, IL-6, IL-10, 
IL-8, IL-12, and levels of soluble PD-L1.  
 
 
9.3 
Specimen Banking 
If any tissue remains after analysis, it will be stored at the Tissue Bank at UT Southwestern 
for future research. Collaborators will be required to complete an agreement (a Material 
Transfer Agreement or recharge agreement) that states specimens will only be released 
for use in disclosed research. Any data obtained from the use of clinical specimen will be 
the property of UT Southwestern for publication and any licensing agreement will be strictly 
adhered to.  
 
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value. The Informed Consent form contains this information and informs the subject that 
there is the potential for financial gain by UT Southwestern, the investigator or a 
collaborating researcher or entity.  
 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available: 
 
Diagnosis  
 
Collection time in relation to study treatment 
 
Clinical outcome – if available 
 
Demographic data 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
10.1.1 Study design: The study is a single armed, phase II trial to evaluate concurrent 
Durvalumab and radiotherapy followed by consolidative Durvalumab for Stage III Non-
Small Cell Lung Cancer (NSCLC). 
10.1.2 Primary endpoint of 12-month progression-free survival (PFS) rate is based on 
an assessment by an investigators according to RECIST 1.1 criteria; PFS is defined as 
the time from the study enrollment to documented progressive disease or death due to 
any cause, whichever occurs first; 
10.1.3 Secondary endpoint of safety and tolerability will be assessed by adverse event 
according to CTCAE V.5; 
10.1.4 Secondary endpoint of overall survival is defined as the time from study 
enrollment to death due to any cause; 
10.1.5 Secondary endpoint of distant metastases free survival is defined as the time 
from the study enrollment to any new distant lesion; 


 
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52 
10.1.6 Secondary endpoint of local and regional control defined as the time from the 
study enrollment to any local and regional lesion;  
10.1.7  Exploratory endpoint of biomarker and biomarker correlatives; 
10.1.8 Exploratory endpoint of proportion of patients alive at 12 and 24 months.  
10.2 
Accrual 
In the PACIFIC trial, patients who received consolidative durvalumab after chemoradiation 
had a 12-month PFS rate of 55%.  PFS was measured starting after completion of 
chemoradiation, when anti-PDL1 treatment was started.  This represents the assumed 
performance of the experimental arm in this study. We recognize that all patients who were 
randomized in the PACIFIC trial had tolerated and not progressed on chemoradiation, 
which represents some degree of selection bias.  The possibility of early progression or 
treatment intolerance were taken into account when selecting the margins for the non-
inferiority design of this study.  A sample size of 47 achieves 80% power to detect a non-
inferiority against an upper hazard ratio of 1.4 using a log-rank test at a 0.1 significance 
level when the actual hazard ratio is 1.0 and the standard of care group hazard rate is 
0.5978 (which is equal to 1-year PFS rate of 55% using an exponential model). Three 
additional patients will be enrolled (total N=50) to account for 5% loss to follow-up. Patients 
will be accrued for a period of 3 years with 1-year follow-up.  
10.3 
Data Analyses 
10.3.1  Survival outcome 
Progression-free survival and overall survival will be estimated using the Kaplan-Meier 
approach and the corresponding confidence intervals will be estimated using Greenwood’s 
formula. Distant metastases-free survival, local and regional control will be estimated using 
the Kaplan-Meier approach. 
 
10.3.2 Toxicities: 
Only adverse events assessed to be definitely, probably, or possibly related to protocol 
treatment will be considered. Toxicity rate and it confidence interval will be estimated using 
an exact binomial approach. 
 
10.3.3 Exploratory Endpoints: 
Exploratory data analysis will be conducted for the exploratory endpoints. Generalized 
estimating equation (GEE) approach will be used to investigate if there are significant 
changes in biomarkers over time. Proportion of patients alive at 12 and 24 months will be 
estimated using the Kaplan-Meier method. 
 
10.3.4 Interim Reports to Monitor the Study Progress   
Interim reports with descriptive statistics will be prepared twice a year until the initial 
manuscript reporting the treatment results has been accepted for publication. In general, 
the interim reports will contain information about the patient accrual rate with a projected 
completion date for the accrual phase; data quality; compliance rate of treatment delivery 
with the distributions of important prognostic baseline variables; and the frequencies and 
severity of adverse events.  
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy 


 
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53 
on Conflicts of Interest.  All investigators will follow the University conflict of interest 
policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the informed 
consent discussion. 
11.3 
Registration Procedures 
All subjects must be registered with the Radiation Oncology Research Office before 
enrollment to study. Prior to registration, eligibility criteria must be confirmed with the 
Radiation Oncology Study Coordinator. To register a subject, call 214-546-1477 Monday 
through Friday, 9:00AM-5:00PM.  
 
New subjects will receive a number beginning with 001 upon study consent such that the 
first subject consented is numbered 001, the second subject consented receives the 
number 002, etc.  
 
Upon confirmation of eligibility and enrollment as per the afore-mentioned instructions, the 
subject will be assigned a secondary number in the order of enrollment. For example, 
subject 001 will become 001-01 upon enrollment. If subject 002 screen fails, and subject 
003 is the next subject enrolled, subject 003 will become 003-02 and so-on.  
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration code according to the 
numbering schema outlined above, which should then be entered as the patient study id 
in Velos upon updating the status to enrolled. 
 
The numbering schema should clearly identify the site number; the sequential number of 
the subject enrolled as well as the status of the subjects enrolled so that the number of 
subjects consented versus the number of subjects actually enrolled may be easily 
identified.   
 
11.4 
Data Management and Monitoring/Auditing 
 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic case 
report forms in accordance with Simmons Comprehensive Cancer Center requirements, 
as appropriate for the project 


 
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54 
 
The Medical Oncologist investigators and delegates, will perform an Immunotherapy 
Assurance Review of all patients in this trial.  The Radiation Oncologist investigators and 
delegates, will perform an RT Quality Assurance Review after the first 20 cases enrolled.  
Subsequent reviews will continue in a periodic and timely fashion.  The final cases will be 
reviewed within 3 months after this study has reached the target accrual. The goal of the 
review is to evaluate protocol compliance.  The scoring mechanism is: Per Protocol, 
Variation 
Acceptable, 
and 
Deviation 
Unacceptable. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all local 
serious adverse events and UPIRSOs in real time as they are reported and reviews 
adverse events on a quarterly basis.  The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to ensure 
data integrity and regulatory compliance.  A copy of the DSMC plan is available upon 
request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The QAC works as part 
of the DSMC to conduct regular audits based on the level of risk. Audit findings are 
reviewed at the next available DSMC meeting.  In this way, frequency of DSMC monitoring 
is dependent upon the level of risk.  Risk level is determined by the DSMC Chairman and 
a number of factors such as the phase of the study; the type of investigational agent, device 
or intervention being studied; and monitoring required to ensure the safety of study subjects 
based on the associated risks of the study. Protocol-specific DSMC plans must be 
consistent with these principles.  
11.5 
Adherence to the Protocol 
Except for an emergency situation, in which proper care for the protection, safety, and well-
being of the study subject requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
11.5.1 Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an emergency 
and is: 
 intentional on part of the investigator; or 
 in the investigator’s control; or 
 not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
 Reporting requirement: Exceptions are non-emergency deviations that require prospective 
IRB approval before being implemented. Call the IRB if your request is urgent. 
If IRB approval is not obtained beforehand, this constitutes a major deviation. 
11.5.2 Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
 avoid immediate apparent harm, or 
 protect the life or physical well-being of subjects or others 
 Reporting requirement: Emergency deviations must be promptly reported 
to the IRB within 5 working days of occurrence. 
 


 
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55 
11.5.3 Major Deviations (also called violations): include any departure from IRB-
approved research that: 
 
Harmed or placed subject(s) or others at risk of harm (i.e., did or has the 
potential to negatively affect the safety, rights, or welfare of subjects or others), 
or 
 
Affect data quality (e.g., the completeness, accuracy, reliability, or validity of the 
data) or the science of the research (e.g., the primary outcome/endpoint of the 
study) 
 Reporting requirement: Major deviations must be promptly reported to  
the IRB within 5 working days of PI awareness. 
 
11.5.4 Minor Deviations: include any departure from IRB-approved research that: 
 
Did not harm or place subject(s) or others at risk of harm (i.e., did not or did not 
have the potential to negatively affect the safety, rights, or welfare of subjects 
or others), or 
 
Did not affect data quality (e.g., the completeness, accuracy, reliability, or 
validity of the data) or the science of the research (e.g., the primary 
outcome/endpoint of the study) 
 Reporting requirement: Minor deviations should be tracked and 
summarized in the progress report at the next IRB continuing review. 
 
11.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with 
a drug seeking regulatory approval and marketing, these documents shall be retained for 
at least two years after the last approval of marketing application in an International 
Conference on Harmonization (ICH) region. In all other cases, study documents should be 
kept on file until three years after the completion and final study report of this investigational 
study. 
11.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 


 
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56 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will require 
his/her final signature to verify the accuracy of the data. 
 
 
12.0 
REFERENCES 
 
Antonia SJ, B. J., Khleif S, et al. Phase 1/2 study of the safety and clinical activity of durvalumab in 
patients with non-small cell lung cancer (NSCLC). . Presented at the 41st European Society for 
Medical Oncology Annual Meeting, Copenhagen, October 7–11, 2016. (Poster.).  
Antonia, S. J., Villegas, A., Daniel, D., Vicente, D., Murakami, S., Hui, R., . . . Investigators, P. (2018). 
Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med, 
379(24), 2342-2350. doi:10.1056/NEJMoa1809697 
Antonia, S. J., Villegas, A., Daniel, D., Vicente, D., Murakami, S., Hui, R., . . . Investigators, P. (2017). 
Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med, 
377(20), 1919-1929. doi:10.1056/NEJMoa1709937 
Berger, R., Rotem-Yehudar, R., Slama, G., Landes, S., Kneller, A., Leiba, M., . . . Nagler, A. (2008). 
Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-
1, in patients with advanced hematologic malignancies. Clin Cancer Res, 14(10), 3044-3051. 
doi:10.1158/1078-0432.CCR-07-4079 
Brahmer, J. R., Drake, C. G., Wollner, I., Powderly, J. D., Picus, J., Sharfman, W. H., . . . Topalian, S. L. 
(2010). Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid 
tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol, 
28(19), 3167-3175. doi:10.1200/JCO.2009.26.7609 
Burke, M., Hardesty, M., & Downs, W. (2018). A case of severe encephalitis while on PD-1 
immunotherapy for recurrent clear cell ovarian cancer. Gynecol Oncol Rep, 24, 51-53. 
doi:10.1016/j.gore.2018.03.007 
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13.0 
APPENDICES 
APPENDIX I. Dosing Modification and Toxicity Management Guidelines for Immune-
Mediated, Infusion-Related, and Non-immune-mediated reaction. 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version History 
September 2023 
 
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 protocolspecific 
treatment regimen. The TMGs provide information for the management of immunemediated 
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 nonimmune– 
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.   
 


 
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APPENDIX II ECOG Performance Status