LCI-LUN-NSC-SBRT-001: Phase II Prospective Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy Followed by Concurrent Mediastinal Chemoradiation and Adjuvant Immunotherapy for Locally-Advanced Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Lung Cancer Stage II, Lung Cancer Stage III, Non Small Cell Lung Cancer
Sponsor: Wake Forest University Health Sciences

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
1 
 
Protocol #:  LCI-LUN-NSC-SBRT-001 
TITLE: PHASE II PROSPECTIVE TRIAL OF PRIMARY LUNG TUMOR STEREOTACTIC BODY RADIATION 
THERAPY FOLLOWED BY CONCURRENT MEDIASTINAL CHEMORADIATION AND ADJUVANT 
IMMUNOTHERAPY FOR LOCALLY-ADVANCED NON-SMALL CELL LUNG CANCER 
LAY TITLE: USE OF HIGH DOSE RADIATION FOLLOWED BY CHEMOTHERAPY AND RADIATION AND 
ADJUVANT IMMUNOTHERAPY TO TREAT LOCALLY ADVANCED NON SMALL CELL LUNG CANCER 
Coordinating Center: 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
Sponsor-Investigator: 
John H. Heinzerling, MD 
Levine Cancer Institute  
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Phone: (704) 403-1577 
Email: John.Heinzerling@atriumhealth.org  
 
 
Statistician: 
James Symanowski, Ph.D. 
Levine Cancer Institute 
Department of Cancer Biostatistics 
1021 Morehead Medical Dr 
Charlotte, NC 28204 
Telephone: (980) 442-2371 
Email: James.Symanowski@atriumhealth.org   
 
Myra Robinson, MSPH 
Levine Cancer Institute 
Department of Cancer Biostatistics 
1021 Morehead Medical Dr 
Charlotte, NC 28204 
Telephone: (980) 442-2390 
Email: Myra.Robinson@atriumhealth.org 
  
 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
2 
 
 
          _________________________________________________________________________ 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable regulatory 
requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the guidance of 
the clinical investigation.  Reproduction or disclosure of this document whether in part or in full to parties not 
associated with the clinical investigation, or its use for any other purpose, without the prior written consent 
of the Sponsor-Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
 
 
 
 
 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
3 
 
Original Phase II / Version 7 / Date 03/16/2023 
PROTOCOL SUMMARY 
A. Study Title 
Phase II Prospective Trial of Primary Lung Stereotactic Body Radiation Therapy 
Followed by Concurrent Mediastinal Chemoradiation and Adjuvant Immunotherapy 
for Locally-advanced Non-small Cell Lung Cancer 
B. Indication 
Lung Cancer, first line treatment 
C. Clinical Phase 
II 
 
D. Summary of 
Rationale 
 
 
A challenge in the treatment of locally-advanced NSCLC is the synergistic toxicity of 
chemotherapy and radiation therapy when administered concurrently.  This is 
particularly true when treating a non-centrally located primary tumor and associated 
nodal metastasis, which often exposes the lung to considerable incidental 
radiotherapy doses. Our hypothesis is that initial treatment of the primary tumor with 
SBRT followed by concurrent chemotherapy and mediastinal radiation therapy will 
improve progression-free survival in subjects with locally-advanced NSCLC by 
improving the primary tumor control, which can allow also for an improvement in 
overall survival.     
We also hypothesize that this treatment regimen will be well-tolerated and associated 
with lower rates of radiation pneumonitis compared with conventional primary tumor 
and mediastinal concurrent chemoradiation. 
E. Study Objectives 
To determine the one-year progression-free survival rate, progression-free survival, 
overall survival, and toxicity of subjects with locally-advanced non-small cell lung 
cancer treated with stereotactic body radiation therapy followed by concurrent 
mediastinal chemoradiation.   
F. Sample Size 
60 PFS1 evaluable subjects (section 12.3) 
 
 
G. Inclusion/ 
Exclusion  
 
 
 
 
Newly diagnosed stage II or III non-small cell lung cancer 
 
Primary tumor ≤ 7cm that is peripheral or at least 2 cm away from involved 
nodal disease and amenable to SBRT 
 
Candidate for definitive chemoradiation based on clinical and laboratory 
evaluation 
 
H. Dosage/ Dosage 
Form, Route, 
And Dose 
Regimen 
SBRT 50-54 Gy in 3-5 fractions, Mediastinal Irradiation to 60 Gy in 2.0 Gy fractions 
with concurrent chemo radiation +adjuvant immunotherapy 
I. Statistical 
Analysis 
This study will enroll 60 PFS1 evaluable subjects and the frequency and proportion of 
subjects alive and progression free after 1-year will be calculated, along with a 95% 
Clopper-Pearson confidence interval. A one-sided test of proportions, with α = 0.10, 
will be carried out testing the null hypothesis that the 1-year progression free survival 
probability is less than 60%. 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
4 
 
SCHEMA 
                      
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
5 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computerized Tomography 
CTV 
Clinical Target Volume 
DLCO 
Diffusing Lung Capacity for Carbon Monoxide 
DSMC 
Data and Safety Monitoring Committee 
EC 
Ethics Committee 
EORTC QLQ-
C30 
European Organization for Research and Treatment of Cancer quality of life core 
questionnaire 
EORTC QLQ-
LC13 
European Organization for Research and Treatment of Cancer quality of life Lung 
cancer module 
FEV1 
Forced Expiratory Volume in 1 second 
Gy 
Gray 
GTV 
Gross Tumor Volume 
ICF 
Informed Consent Form 
IGTV 
Internal Gross Tumor Volume 
IRB 
Institutional Review Board 
MDASI-LC 
M.D. Anderson Symptom Inventory-Lung Cancer 
NSCLC 
Non-Small Cell Lung Cancer 
OAR 
Organ-At-Risk 
OS 
Overall Survival 
PD 
Progressive Disease 
PET/CT 
Positron Emission Tomography/Computed Tomography 
PFS 
Progression-Free Survival 
PHI 
Protected Health Information 
PI 
Principal Investigator 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
6 
 
PR 
Partial Response 
PTV 
Planning Target Volume 
QOL 
Quality of Life 
RBE 
Relative Biological Effectiveness 
RECIST 
Revised Reponse Evaluation Criteria in Solid Tumors 
SBRT 
Stereotactic Body Radiation Therapy 
SD 
Stable Disease 
S-I 
Sponsor-Investigator 
 
 
 
 
 
 
 
 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
7 
 
TABLE OF CONTENTS 
 
PROTOCOL SUMMARY........................................................................................................................3 
SCHEMA ............................................................................................................................................4 
LIST OF ABBREVIATIONS .................................................................................................................... 5 
TABLE OF CONTENTS .......................................................................................................................... 7 
1. 
OBJECTIVES ........................................................................................................................... 10 
1.1. 
Primary Objective ........................................................................................................................ 10 
1.2. 
Secondary Objectives .................................................................................................................. 10 
1.3. 
Safety Objectives ......................................................................................................................... 10 
1.4. 
Exploratory Objectives ................................................................................................................ 10 
2. 
BACKGROUND AND RATIONALE ............................................................................................. 11 
2.1. 
Study Disease .............................................................................................................................. 11 
2.2. 
SBRT in the treatment of lung cancer ......................................................................................... 11 
2.3. 
Background ................................................................................................................................. 11 
2.4. 
Study Rationale ........................................................................................................................... 12 
2.4.1. Rationale for Correlatives ............................................................................................................ 12 
3. 
SUBJECT SELECTION .............................................................................................................. 12 
3.1. 
Accrual ........................................................................................................................................ 12 
3.2. 
Inclusion Criteria ......................................................................................................................... 12 
3.3. 
Exclusion Criteria ......................................................................................................................... 14 
4. 
INVESTIGATIONAL PLAN ........................................................................................................ 14 
4.1. 
Study Milestones ......................................................................................................................... 14 
4.2. 
Overall Study Design ................................................................................................................... 14 
4.3. 
Registration and Enrollment ....................................................................................................... 14 
4.4. 
Pre-Treatment ............................................................................................................................. 15 
4.5. 
Study Treatment .......................................................................................................................... 15 
4.6 Quality of Life (QOL) Assessments: ................................................................................................... 15 
4.7 Biospecimen Collection ..................................................................................................................... 16 
4.8 End of Concurrent Mediastinal Chemoradiation .............................................................................. 17 
4.9 Adjuvant Immunotherapy ................................................................................................................. 17 
4.10 Post-Concurrent Mediastinal Chemoradiation Assessments .......................................................... 17 
4.11 Active Follow-up .............................................................................................................................. 18 
4.12 Long-term Follow-up ....................................................................................................................... 18 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
8 
 
4.13 Subject Withdrawal and Off-Study .................................................................................................. 18 
5. 
STUDY CALENDAR ................................................................................................................. 19 
6. 
TREATMENT PLAN ................................................................................................................. 22 
6.1 
Radiation Therapy ....................................................................................................................... 22 
6.2 
Concurrent Chemotherapy ......................................................................................................... 27 
6.3 
Durvalumab ................................................................................................................................. 28 
6.4 
Treatment Compliance ................................................................................................................ 31 
6.5 
Duration of Therapy .................................................................................................................... 31 
7 
STUDY ASSESSMENTS ............................................................................................................ 32 
7.1 
History and Physical: ................................................................................................................... 32 
7.2 
Positron emission tomography-computed tomography: ............................................................ 32 
7.3 
CT chest: ...................................................................................................................................... 32 
7.4 
Chest X-Ray:................................................................................................................................. 32 
7.5 
CT abdomen/pelvis: .................................................................................................................... 32 
7.6 
Neuroimaging: ............................................................................................................................. 32 
7.7 
Documentation of biopsy of primary tumor and/or nodes: ....................................................... 32 
7.8 
Laboratory assessments: ............................................................................................................. 32 
7.9 
Pulmonary Function Testing: ....................................................................................................... 32 
7.10 
Toxicity Assessment..................................................................................................................... 33 
7.11 
Quality of Life Assessment: ......................................................................................................... 33 
7.12 
Biospecimen collection: .............................................................................................................. 33 
8 
TREATMENT-RELATED ADVERSE EVENTS ................................................................................ 33 
8.1 
Adverse Events Related to Radiation .......................................................................................... 33 
8.2 
Adverse Events Related to Chemotherapy .................................................................................. 33 
8.3 
Adverse Events Related to Durvalumab ...................................................................................... 34 
9 
DATA AND SAFETY MONITORING PLAN .................................................................................. 35 
9.1 
Safety Monitoring ....................................................................................................................... 35 
9.2 
Data Quality Assurance ............................................................................................................... 35 
10 
SAFETY DATA COLLECTION, RECORDING AND REPORTING ...................................................... 35 
10.1 
Unanticipated Problem Definition .............................................................................................. 36 
10.2 
Adverse Event Definition ............................................................................................................. 36 
10.2.1 Abnormal Laboratory Values/Clinical Results Defined as AEs..................................................... 37 
10.3 
Adverse Events of Special Interest (AESI) Definition ................................................................... 37 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
9 
 
10.4 
Suspected Adverse Reaction Definition ...................................................................................... 37 
10.5 
“Unexpected” Definition ............................................................................................................. 37 
10.6 
Serious Adverse Event (SAE) Definition ....................................................................................... 37 
10.7 
AE and AESI Reporting................................................................................................................. 38 
10.8 
Expedited Safety Reporting to the Sponsor-Investigator ............................................................ 38 
10.9 
Expedited Safety Reporting to AstraZeneca ................................................................................ 39 
10.10 Expedited Safety Reporting to the IRB ........................................................................................ 39 
11 
MEASUREMENT OF EFFECT .................................................................................................... 39 
11.1 
Anti-tumor Effect – Solid Tumor .................................................................................................. 39 
12 
STATISTICAL CONSIDERATIONS .............................................................................................. 42 
12.1 
Sample Size ................................................................................................................................. 42 
12.2 
Endpoint Definitions ................................................................................................................... 43 
12.3 
Analysis Populations.................................................................................................................... 45 
12.4 
Analysis Methods ........................................................................................................................ 46 
13 
STUDY COMPLETION ............................................................................................................. 48 
13.1 
Completion .................................................................................................................................. 48 
13.2 
Termination ................................................................................................................................. 49 
14 
RETENTION OF RECORDS ....................................................................................................... 49 
15 
ETHICAL AND LEGAL ISSUES ................................................................................................... 49 
15.1 
Ethical and Legal Conduct of the Study....................................................................................... 49 
15.2 
Confidentiality ............................................................................................................................. 50 
16 
PUBLICATION POLICY ............................................................................................................ 50 
REFERENCES .................................................................................................................................... 51 
APPENDICES .................................................................................................................................... 52 
 
 
 
 
 
 
 
 
 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
10 
 
 
1. OBJECTIVES 
 
1.1. 
Primary Objective 
To assess the efficacy of a treatment regimen which involves Stereotactic Body Radiation Therapy 
(SBRT) delivered to the primary tumor followed by concurrent mediastinal chemoradiation by 
evaluating the proportion of subjects with locally-advanced non-small cell lung cancer (NSCLC) 
stage II/III who are alive and progression free at 12 months, and to compare to relevant historical 
controls. 
 
1.2. 
Secondary Objectives 
Secondary objectives will be to evaluate the treatment regimen based on the following:  
a. Progression free survival 
b. Overall survival 
c. Radiologic clinical complete response rate following completion of therapy 
d. Objective response rate as defined by RECIST v 1.1 
e. Local and locoregional control 
f. Patterns of failure (primary, locoregional, or distant) 
g. Quality of life 
 
1.3. 
Safety Objectives 
The safety objectives are to assess complications and adverse events that occur throughout the 
treatment regimen. Specific adverse events of interest will be the following: 
a. Rate of grade 2+ radiation pneumonitis  
b. Rate of grade 3+ pulmonary events  
 
1.4. 
Exploratory Objectives 
Exploratory objectives include: 
 
Differential expression of cytokines and chemokines associated with the radiation therapy 
will be determined and associations with radiation-induced lung toxicity will be 
evaluated.  
 
Quantify and categorize lung texture changes using lung density analysis (LDA) and lung 
texture analysis (LTA) algorithms and quantify changes over time up to 24 months after 
radiation treatment.  
 
Evaluate dosimetric causes of lung texture changes and small airway collapse utilizing 
post treatment CT scans 
 
Correlate selected outcomes (including toxicity and PFT changes) with lung changes as 
quantified by lung texture analysis software. 
 
 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
11 
 
2. BACKGROUND AND RATIONALE 
 
2.1. 
Study Disease 
Outcomes for non-small cell lung cancer (NSCLC) patients who present with locally-advanced 
disease remain poor, with 5-year overall survival of 15%1 and primary tumor local control of only 
51%2 following concurrent chemoradiation when radiotherapy is delivered in conventional 
fractionation in 1.8-2.0 Gy per fraction. 
 
2.2. 
SBRT in the treatment of lung cancer 
A newer approach that has been extremely effective in controlling lung primary tumors is 
stereotactic body radiation therapy (SBRT).  SBRT delivers an ultra-high dose per fraction (typically 
>8-10 Gy per fraction) of radiation to a target.  By delivering ablative radiotherapy doses, SBRT 
allows for maximizing cell-killing effect of tumor, likely due to delivery of higher biological 
equivalent doses of radiotherapy than achievable with conventionally fractionated irradiation.  
SBRT also minimizes dose received by surrounding organs due to a rapid dose falloff gradient 
encompassing the tumor.3 In prospective phase II studies, SBRT has been associated with local 
control rates of over 90% for patients with medically inoperable stage I NSCLC.6  SBRT has also 
improved survival for medically inoperable patients with stage I NSCLC compared with 
conventionally fractionated radiotherapy.3 However, SBRT has not routinely been incorporated 
into the treatment paradigm for unresectable locally-advanced NSCLC due to concerns about the 
potential toxicity of high doses per radiotherapy fraction to central structures when treating 
mediastinal lymph node metastases.   
 
2.3. 
Background 
Studies have shown that the principle site of intrathoracic failure is at the primary tumor and 
isolated mediastinal nodal failures are extremely rare.7,2  Another challenge in the treatment of 
locally-advanced NSCLC is the synergistic toxicity of chemotherapy and radiation therapy when 
administered concurrently.  This is particularly true when treating a non-centrally located primary 
tumor and associated nodal metastasis, which often expose the lung to considerable incidental 
radiotherapy doses.  The risk of radiation pneumonitis is highest when a large volume of lung is 
being irradiated and when concurrent chemotherapy is administered, and this subacute toxicity 
can be fatal.8,7  In fact, the rates of radiation pneumonitis with conventionally fractionated 
concurrent chemoradiation for locally-advanced NSCLC are approximately 30%8 , compared with 
approximately 3% with SBRT for stage I NSCLC. 20   
Acute radiation pneumonitis is thought to be largely inflammatory and exudative in nature, with 
cytokine and inflammatory marker changes evident during and at the time of radiation therapy 
completion.  Additionally, acute radiation pneumonitis is highly correlated with the subsequent 
development of late pulmonary fibrosis4, which limits patient lung function and is the primary 
factor accounting for up to 47% of NSCLC patients reporting a decline in overall quality of life by 
12 months after radiation therapy.5  Although cytokine changes are evident during treatment, 
radiation-induced pulmonary fibrosis clinically occurs months to years after radiation therapy, 
when the lung tissue enters a fibrotic state in which inflammatory cell concentrations decrease 
and a marked thickening of alveolar walls occurs due to collagen deposition. 
Although it is well known that external beam radiation therapy induces both acute and late 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
12 
 
pulmonary changes in normal tissues, little is known regarding which cytokines and chemokines 
are important regulators in the development of acute pneumonitis or chronic pulmonary fibrosis.  
Even less data is available regarding the effects that radiation therapy has on such cytokines and 
chemokines. In a review of current literature, the over- or under- expression of a number of 
chemokines, cytokines, and inflammatory markers have been implicated in the pathogenesis of 
radiation pneumonitis and radiation-induced pulmonary fibrosis for both conventionally 
fractionated radiation therapy and SBRT.  These include IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-
13, IL-17, MCP-1α, IFN-γ, MIP-1α, TNF-α, TGF-β, Eotaxin, GM-CSF, and CXCL-1.  Adjuvant 
immunotherapy with durvalumab recently showed benefit after chemoradiation in stage III NSCLC 
and has become standard treatment after chemoradiation for unresectable stage III NSCLC.19  
Immunotherapy has known synergistic effects with radiation and immune cell killing often 
indicated by cytokine release.  Little data exists regarding which cytokines and chemokines may 
regulate this cell kill process in relation to timing with radiation and effects of high dose radiation 
on immune associated tumor response. 
 
2.4. 
Study Rationale 
Our hypothesis is that initial treatment of the primary tumor with SBRT followed by concurrent 
chemotherapy and mediastinal radiation therapy will improve progression-free survival in 
subjects with locally-advanced NSCLC by improving the primary tumor control, which can allow 
also for an improvement in overall survival.   
We also hypothesize that this treatment regimen will be well-tolerated and associated with 
lower rates of radiation pneumonitis compared with conventional primary tumor and 
mediastinal concurrent chemoradiation.   
 
2.4.1. Rationale for Correlatives 
We hypothesize that IL-1α and IL-6 will be overexpressed during radiation therapy, 
whereas TGF-β and IL-13 will be overexpressed following radiation therapy completion, 
and that cytokine and chemokine change will be more pronounced during conventionally 
fractionated radiation therapy.   
 
 
 
3. SUBJECT SELECTION 
 
3.1. Accrual 
A total of 60 PFS1 evaluable subjects (section 12.3) will be enrolled to this study over 
approximately 4 years. 
Subjects will be recruited from the Levine Cancer Institute (LCI) and possibly other participating 
sites. 
Both men and women of all races and ethnic groups are eligible for this trial.  We would expect 
about 50% of the subject accrual to include women and 20% of the subject accrual to be minority 
subjects based on our current studied population and patient demographics. 
3.2. 
Inclusion Criteria 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
13 
 
Subjects must meet all the following criteria:  
 
a. Histologic or cytologic documentation of NSCLC (all histologies allowed) 
b. Stage II or III disease (AJCC 7th Edition) based on imaging as required during 
screening:  
i.  Stage II disease includes only subjects with medically inoperable N1 disease 
otherwise meeting eligibility criteria 
ii. Primary tumor ≤ 7 cm  
c. Subjects with non-malignant pleural effusion identified on CT scan are eligible 
provided the effusion is not known or demonstrated to be an exudative effusion. 
i. If a pleural effusion is present, the following criteria must be met to exclude 
malignant involvement: 
1. A pleuracentesis is required if pleural fluid is present and visible on 
both CT scan and chest x-ray.  Pleural fluid cytology must be 
negative for malignancy. 
2. Effusions that are minimal and too small for pleuracentesis as 
determined by the investigator will be eligible for enrollment. 
d. FEV1 ≥ 1.0 Liter or ≥ 40% predicted with or without bronchodilator within six 
months prior to initiation of study treatment.  
i.  Subjects who meet the criterion above without O2, but who need acute 
(started within 10 days prior to enrollment) supplemental oxygen due to 
tumor-caused obstruction/hypoxia are eligible, provided the amount of the 
O2 needed has been stable. 
e. Age ≥18 years.   
f. ECOG performance status ≤ 2  
g. Subjects must have normal organ and marrow function as defined below: 
i. Leukocytes ≥4,000/mcL 
ii. Absolute neutrophil count ≥1,500/mcL 
iii. Platelets ≥100,000/mcL 
iv. Total bilirubin ≤1.5 times the upper limit of normal 
v. Creatinine clearance > 25 mL/min/1.73 m2  
h. Negative serum or urine pregnancy test prior to enrollment for women of 
childbearing age and potential 
i. 
The effects of radiation on the developing human fetus are not well described and 
animal studies have shown that durvalumab can cause fetal harm when 
administered to a pregnant woman.  For these reasons, women of child-bearing 
potential and non-sterilized men who are sexually active with a woman of child-
bearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry  and for the duration of 
study treatment.  Women of child-bearing potential must agree to use contraception 
for 3 months after the last dose of durvalumab. Should a woman become pregnant 
or suspect she is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately. 
j. 
Must be considered a candidate for durvalumab, per the treating  

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
14 
 
investigator   
k. Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.3. Exclusion Criteria 
Subjects must not meet any of the following criteria.  
 
a. Subjects who have had prior systemic therapy for lung cancer 
b. Subjects who have had prior radiation to the region of the chest that would result in 
overlap of radiation therapy fields and determined by the treating physician to 
impede the treatment of the study malignancy. 
c. Subjects who are actively being treated on any other interventional research study. 
d. Prior invasive malignancy unless disease free for a minimum of 3 years from 
enrollment. However, non-melanoma skin cancer, low risk prostate cancer, well 
differentiated thyroid cancers, in situ carcinomas of the breast, oral cavity, cervix, 
and other organs, and tumors (regardless of invasive or non-invasive) that are not 
thought to impact the life expectancy of the subject according to the treating 
investigator is permissible. 
e. Centrally located primary tumor < 2 cm from involved nodal disease which would 
result in significant overlap of radiation dose. Centrally located is  defined as within 
or touching the zone of the proximal bronchial tree, which is a volume 2 cm in all 
directions around the proximal bronchial tree (carina, right and left main bronchi, 
right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, 
lingular bronchus right and left lower lobe bronchi). 
   
4. INVESTIGATIONAL PLAN 
 
4.1. 
Study Milestones 
Enrollment date: the date of first SBRT dose 
Treatment Discontinuation date: the date the investigator decides to discontinue subject from all 
study treatment (defined as SBRT, concurrent mediastinal chemoradiation, or durvalumab) 
4.2. 
Overall Study Design 
This is a single-arm, single-stage Phase II study designed to evaluate the 1-year PFS rate in subjects 
with locally-advanced NSCLC (stage II/III) (Study Schema). A total of 60 PFS1 evaluable subjects 
(section 12.3) will be enrolled.  
Data from this study will be collected on electronic case report forms (eCRFs) and stored in the 
study database.  
 
4.3. 
Registration and Enrollment 
No protocol related assessments may be performed prior to obtaining informed consent. 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
15 
 
Following informed consent, subjects will be registered and assigned a Sequence Number. The 
Sequence Number will be a four-digit number sequentially assigned to the subject. 
A subject who, for any reason (i.e. failure to satisfy the eligibility criteria or withdraws consent), 
terminates their participation in the study before receiving first dose of SBRT is regarded as a 
“screen failure.” Screen failures will not be included as enrolled subjects or count towards sample 
size requirements. 
 
4.4. 
Pre-Treatment 
 
Visit 1: Subject undergoes history and physical per standard of care and is identified for study by 
the treating physician. Pathologic and radiologic review of available studies are performed per 
standard of care and at the discretion of the treating physician. Informed consent is obtained and 
necessary tests ordered. Please see Study Calendar, Section 5, for details regarding baseline 
condition, pretreatment scans, labs, smoking history and blood collection.  
 
Visit 2: Simulation/planning session for SBRT.  
  
 
 
4.5. 
Study Treatment 
 
Visit 3: Blood sample for research obtained prior to starting SBRT.  If not already completed, 
Quality of Life (QOL) Evaluation should be obtained prior to SBRT.  Subject begins SBRT. Treatment 
course is 3 to 5 total visits over 1-2 weeks.  Blood sample for research obtained during the course 
of SBRT. For acceptable time frame refer to Section 4.6 Biospecimen Collection. 
 
Visit 4: Subject undergoes simulation/planning session for mediastinal irradiation. 
 
Visit 5: Subject begins concurrent chemoradiation.  Treatment course is 30-37 visits over 6-8 
weeks. QOL Evaluation after completion of SBRT but prior to initiation of concurrent 
chemoradiation. See Section 4.4 for details regarding the QOL time-point. CBC with differential 
and chemistries checked as per standard of care.  Blood sample for research obtained during the 
course of concurrent chemoradiation. For acceptable time frame refer to Section 4.6 Biospecimen 
Collection. Toxicity assessment done weekly.  
 
 
Visit 6: Subject begins durvalumab after completion of concurrent chemoradiation. Subjects will 
receive durvalumab per  Section 6.3.7. Study procedures to be performed per Section 5. 
 
4.6 Quality of Life (QOL) Assessments: 
 
QOL assessments utilizing the M.D. Anderson Symptom Inventory-Lung Cancer (MDASI-LC), 
European Organization for Research and Treatment of Cancer quality of life core questionnaire 
Version 3 (EORTC QLQ-C30) and European Organization for Research and Treatment of Cancer 
quality of life Lung cancer module (EORTC QLQ-LC13) lung surveys will be obtained at six time 
points: prior to the initiation of SBRT, after the completion of SBRT but prior to the initiation of 
concurrent mediastinal chemoradiation, one month after the completion of concurrent 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
16 
 
mediastinal chemoradiation, and at 3, 6, and 12 months after the last treatment of concurrent 
mediastinal chemoradiation.  Note: The “prior to the initiation of concurrent mediastinal 
chemoradiation” QOL time-point should ideally be done prior to initiation of concurrent 
mediastinal chemoradiation. However, it is acceptable to administer the QOL within the first 3 
days of initiation of concurrent mediastinal chemoradiation. In the event that radiation and 
chemotherapy are not started on the same day, the QOL should be administered ideally prior to 
the start of the first modality (i.e. radiation or chemotherapy) but it is acceptable to administer 
within 3 days of the start of the first modality initiated. QOL questionnaires may be administered 
in the clinic or over the phone. 
 
4.7 Biospecimen Collection 
 
Biospecimens will be collected as described below. The results of any analyses will not be 
included in subjects’ clinical medical record.  Samples will be labeled with a study specific 
Sequence Number without the use of personal health information (PHI).  Blood samples will be 
obtained at the time of clinical blood collection for standard of care labs whenever possible to 
minimize additional discomfort to subjects. 
 
4.7.1 Blood Samples for Correlatives  
Blood samples will be obtained exclusively for research purposes at the time points 
specified below. Analyses will include inflammatory marker analysis to determine which 
cytokines and chemokines are differentially expressed with radiation therapy and may 
be associated with radiation-induced lung toxicity. Additional blood samples will be 
collected and stored for potential future analysis. 
 
Inflammatory Marker Analysis: Blood samples (two 10-ml EDTA tubes) will be processed and 
stored at -80ºC for analyses.  
1. Prior to the initiation of SBRT 
2. During the course of SBRT (preferentially on the final day of SBRT but within the 
range of the day of the fraction before the final fraction of SBRT and 5 days after 
completing SBRT):  
3. During the course of concurrent mediastinal chemoradiation (preferentially in the 
final week of conventionally fractionated radiation therapy but within the range of 
two weeks before the final fraction of conventionally fractionated radiation therapy 
and one week after completing conventionally fractionated radiation therapy) 
4. Two–five weeks after the first dose of durvalumab (just prior to the 2nd dose of 
durvalumab). Sample not required for subjects who have already received the second 
dose of durvalumab at the time of the amendment approval or for subjects who do 
not ultimately initiate durvalumab for whatever reason. 
 
Additional blood for potential future analysis will be collected as follows: 
 
Two 10 ml EDTA tubes will be collected, processed and stored at -80ºC  
 
Two 8.5 ml CPT tubes will be collected for blood cell separation and storage 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
17 
 
1. Prior to the initiation of SBRT 
2. During the course of concurrent mediastinal chemoradiation (in the final week of 
conventionally fractionated radiation therapy but within the range of two weeks 
before the final fraction of conventionally fractionated radiation therapy and one 
week after completing conventionally fractionated radiation therapy) 
3. Two-five weeks after first dose of durvalumab (just prior to the 2nd dose of 
durvalumab). Sample not required for subjects who have already received the second 
dose of durvalumab at the time of the amendment approval or for subjects who do 
not ultimately initiate durvalumab for whatever reason. 
 
Blood samples stored for future use will be stored with a study-specific Sequence Number 
without the use of personal health information (PHI). 
 
4.7.2 Archived Tumor Tissue for Correlatives 
Archived tumor tissue samples for potential future analysis will be collected (if available) for 
each enrolled subject.  
The best available tissue block (preferably > 20% tumor content; equivalent of 4-6 14-gauge 
cores or ~ 5x5 mm of tissue) will be obtained and sent to the Atrium Health Biospecimen 
Repository. If a block is not able to be sent, the site may send 20 unstained slides (4 to 6 microns 
each). 
4.8 End of Concurrent Mediastinal Chemoradiation 
 
Subjects will have toxicity assessment and QOL evaluation approximately 30 days after the last 
treatment of concurrent mediastinal chemoradiation. Subjects will be followed for a minimum of 
12 months after the last treatment of concurrent mediastinal chemoradiation to determine safety 
and acute toxicity. SAEs will be reportable for up to 90 days after the last dose of durvalumab 
(subjects who receive durvalumab) per Section 10.8.  
 
4.9 Adjuvant Immunotherapy 
Subjects will receive adjuvant durvalumab per Section 6.3.7 after completion of concurrent 
mediastinal chemoradiation.  
 
4.10 Post-Concurrent Mediastinal Chemoradiation Assessments 
All subjects will be evaluated approximately 3 months from the last treatment of concurrent 
mediastinal chemoradiation by the treating radiation oncologist, referring physician, or physician 
extender. Thereafter, subjects will be evaluated approximately every 3 months for the remainder 
of Year 1 and for Year 2, approximately every 6 months for Year 3, and approximately annually for 
Years 4-5 from the last treatment of concurrent mediastinal chemoradiation per study procedures 
defined in Section 5 are met. Some of these assessments will occur concurrently with adjuvant 
durvalumab administration.  If subjects are no longer in the local area or otherwise not able to 
return for assessment, communications such as a telephone call or letter will be sent as follow up. 
Assessment of the disease by imaging for subjects who have not yet had documented disease 
progression will be performed at intervals as described in Section 7. Additionally, effort will be 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
18 
 
made to continue to collect imaging assessments done per standard of care after disease 
progression in order to inform local/regional/distant control endpoints (described in Sections 
12.2.6 – 12.2.9). Collection of imaging assessment data is not required after local/regional/distant 
progression, subsequent anti-cancer therapy is initiated or after the 60-month follow-up visit.  
 
4.11 Active Follow-up 
Subjects who discontinue study treatment for any reason, including progression, will move into 
Active Follow-up and continue completion of the Post-Concurrent Mediastinal Chemoradiation 
assessments as defined in the Study Calendar in Section 5 and the section above (4.10) up until 
completion of the 60-month follow-up visit. Post-Concurrent Mediastinal Chemoradiation 
assessments are required for all subjects at a minimum of through the 12-month follow-up visit. 
Subjects who have met endpoints for local/regional/distant control (e.g. disease progression 
locally, regionally and distally) or started subsequent anti-cancer therapy prior to the 60-month 
follow-up visit will move into Long-Term Follow-up per Section 4.12. 
 
4.12 Long-term Follow-up 
Subjects who have completed at a minimum of through the 12 month Active Follow-up visit with 
subsequent disease progression (locally, regionally and distally) or initiation of subsequent anti-
cancer therapy or completion of the 60-month follow-up visit will move into Long-Term Follow-
up.  
 
Subjects in Long-Term Follow-up will be contacted approximately every 12 months for survival 
until the criteria for the final analysis is met. Phone contact is acceptable. 
 
4.13 Subject Withdrawal and Off-Study 
 
Subjects may withdraw consent at any time for any reason or be removed from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the Sponsor if for safety reasons or other reasons per 
investigator discretion. 
In this trial, a subject may discontinue from study treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent for study 
participation. 
A subject will be discontinued from the trial for any of the following reasons: 
 
The subject withdraws consent for participation on the study 
 
The subject is lost to follow-up 
 
Investigator’s decision to withdraw the subject from study  
 
Noncompliance with study treatment or procedure requirements per investigator’s 
discretion 
 
Subject death 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
19 
 
In all cases, the reason for withdrawal and/or subject going Off Study must be documented in the 
subject’s medical record and/or research record and recorded in the CTMS.   
Subjects that are Off Study will not participate in any study related procedures, including data 
collection. 
 
5. STUDY CALENDAR 
 
Study 
Procedures 
 Screeningj  
During 
SBRT 
During Concurrent 
Mediastinal 
Chemoradiation 
One Month After 
Concurrent 
Mediastinal 
Chemoradiations 
Adjuvant 
Immunotherapy/ 
Post- Concurrent 
Mediastinal 
Chemoradiation 
Assessments 
Active  Follow-Upt,bb 
 
Long-term 
Follow-Up cc 
History and Physical 
Exam a,r,dd 
X 
Xn  
Xb 
X 
 
Xz,aa 
Xaa 
 
Performance Status 
Assessment r,dd 
X 
Xn 
Xb 
X 
 
Xz,aa 
Xaa 
 
PET/CT  
Xk 
 
 
 
 
X 
3 months after completion of concurrent mediastinal chemoradiation 
timepoint only 
 
CT Chest d,q 
Xk  
 
 
 
 
Xw 
 
Chest X-Ray 
Xo 
 
 
 
 
 
 
CT Abdomen/Pelvis c,d  
X k 
 
 
 
 
X 
Only if unable to obtain PET/CT at the 3 months after completion of 
concurrent mediastinal chemoradiation timepoint only 
 
Neuroimaging (MRI 
brain or CT head)d 
Xk 
 
 
 
 
 
 
Documentation of 
Biopsy of Primary 
Tumor and/or Nodes  
Xe 
 
 
 
 
 
 
CBC with differential 
X 
 
Xm 
 
Xz 
 
 
Electrolytes 
Xv 
 
Xm 
 
 
Xz 
 
 
LFTs 
Xv 
 
 
 
 
Xz 
 
 
TSH, free T4, amylase, 
lipase, LDH and UA 
 
 
 
 
 
Xz 
 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
20 
 
Study 
Procedures 
 Screeningj  
During 
SBRT 
During Concurrent 
Mediastinal 
Chemoradiation 
One Month After 
Concurrent 
Mediastinal 
Chemoradiations 
Adjuvant 
Immunotherapy/ 
Post- Concurrent 
Mediastinal 
Chemoradiation 
Assessments 
Active  Follow-Upt,bb 
 
Long-term 
Follow-Up cc 
Pulmonary Function 
Testing f 
Xl 
 
 
 
 
Xu 
Xu 
 
Pregnancy Test g  
X 
 
 
 
 
 
 
Toxicity Assessment p 
         
X 
Xn 
X b 
X 
 
X 
X 
 
Quality of Life 
Assessment h  
X 
X 
 
 
 
X  
 
X 
X 
 
Inflammatory Marker 
Analysis i 
X 
X 
X 
 
X 
2-5 weeks after first 
durvalumab only 
 
 
Blood Correlatives for 
Potential Future 
Research x 
X 
 
X 
 
X 
2-5 weeks after first 
durvalumab only 
 
 
Archived Tumor Tissuey 
X 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
X 
X 
 
a: Includes vital signs and weight. Smoking history at screening visit only. 
b: Weekly (treatment visits) 
c: only required if unable to obtain PET/CT 
d: should be performed with IV contrast unless approved by the Sponsor-Investigator 
e: documentation of prior pathology of primary tumor and/or nodes is required 
f: to include FEV1 and DLCO  
g: serum or urine; within 14 days of enrollment for women of child bearing potential 
h: QOL using the MDASI-LC, EORTC QLQ-C30 and EORTC QLQ-LC13 lung surveys will be obtained at six time points: 1) within 30 days 
prior to the initiation of SBRT, 2) after completion of SBRT but within 7 days prior to initiation of concurrent mediastinal chemoradiation 
(see Section 4.4 for details regarding the QOL time-point), 3) at One Month After Concurrent Mediastinal Chemoradiation Visit (± 7 
days), 4) at 3 month follow-up (±60 days), 5) at 6 month follow-up (±60 days), and 6) at 12 month follow-up (±60 days). QOL may be 
administered in the clinic or over the phone.  
i: Blood samples [(2) 10 ml EDTA tubes] for inflammatory marker analysis will be obtained at the following time-points: 1) prior to 
initiation of SBRT, 2) during SBRT (preferentially on the final day of SBRT but within the range of the day of the fraction before the final 
fraction of SBRT and 5 days after completing SBRT), and 3) during the course of concurrent mediastinal chemoradiation (preferentially in 
the final week of conventionally fractionated radiation therapy but within the range of two weeks before the final fraction of 
conventionally fractionated radiation therapy and one week after the last treatment of  conventionally fractionated radiation therapy), 4) 
2-5 weeks after the first dose of durvalumab (just prior to the 2nd dose of durvalumab); sample not required for subjects who have 
already received the second dose of durvalumab at the time of the amendment or for subjects who do not ultimately initiate 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
21 
 
durvalumab for whatever reason.See Section 4.7.1. 
j: Screening assessments to be performed within 30 days of enrollment unless otherwise specified 
k: Within 90 days prior to enrollment 
l: Within 6 months prior to enrollment 
m: As clinically indicated as determined by the treating investigator 
n. Any time prior to and during any of the SBRT treatments including the day of the last treatment 
o. In subjects with a pleural effusion visible on CT scan, a chest x-ray is required to confirm that a pleuracentesis is not required, see 
Section 3.2 d 
p. Baseline pre-existing symptoms and conditions present at the time of informed consent and prior to the first dose of study treatment 
should be documented. Toxicity assessment  should start at study treatment initiation and continue up to 12 months after the last dose 
of concurrent mediastinal chemoradiation. Collection requirements are as follows: All AEs from initiation of study treatment until 90 
days after last dose of protocol-directed durvalumab. After this time period, if less than 12 months has elapsed since last dose of 
concurrent mediastinal chemoradiation, AESIs (as defined in Section 10.3) until 12 months after last dose of concurrent mediastinal 
chemoradiation. For subjects who do not initiate protocol-directed durvalumab, AESI’s starting on the date the decision is made that 
durvalumab will not be initiated through 12 months after last dose of concurrent mediastinal chemoradiation.  
q. Imaging required at the following time-points: 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 mos (+/- 60 days) from completion of 
concurrent mediastinal chemoradiation. Imaging schedule only required for subjects who have not yet had disease progression (local, 
regional and distant) or started subsequent anti-cancer therapy. Additionally, effort will be made to continue to collect imaging 
assessments done per standard of care after disease progression in order to inform local/regional/distant control endpoints (described 
in Sections 12.2.6 – 12.2.9). Collection of imaging assessment data is not required after subsequent anti-cancer therapy is initiated.   
r. Not required after 12 months of follow-up in subjects who have documented disease progression 
s. Required for all subjects; may occur during adjuvant immunotherapy   
t. All follow-up time points and procedures are timed from last treatment of concurrent mediastinal chemoradiation (+/- 60 days). If a 
current follow-up visit overlaps with the next follow-up time-point (within the 60 day window), one visit can be used for both time-
points. This is allowed as long as all required assessments for both time-points are completed (e.g. if the 9-month visit occurs at 10 ½ 
months from last concurrent chemoradiation, all procedures required at the 12 month visit are required at this visit)  
u 6- and 12-month follow-up visits only (+/- 60 days); additional time points as clinically indicated 
v. At screening, a comprehensive metabolic panel (CMP) will be acceptable to meet electrolytes and LFTs requirement  
w. Chest CT at 3 months not required if a post-mediastinal chemoradiation completion CT was performed prior to the 3-month follow-up 
time-point as part of standard of care 
x. Correlative blood samples will be obtained for potential future analysis [(2) 10 ml EDTA tubes] and (2) 8.5 ml CPT tubes] at the 
following time-points: 1) prior to initiation of SBRT 2) during the course of concurrent mediastinal chemoradiation (preferentially in the 
final week of conventionally fractionated radiation therapy but within the range of two weeks before the final fraction of conventionally 
fractionated radiation therapy and one week after the last treatment of  conventionally fractionated radiation therapy and 3) 2-5 weeks 
after the first dose of durvalumab (just prior to the 2nd dose of durvalumab); sample not required for subjects who have already received 
the second dose of durvalumab at the time of the amendment or for subjects who do not ultimately initiate durvalumab for whatever 
reason..  See Section 4.7.1. 
y. Submit archived tumor specimen of tumor, if available. See Section 4.7.2. Tissue should not be submitted until the subject has been 
enrolled into the study.  
z. All safety assessments for adjuvant durvalumab administration to be performed per treating investigator  
aa. History and physical exam and performance status should be performed at the following time-points after completion of concurrent 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
22 
 
mediastinal chemoradiation: 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 mos (±60 days).  Subjects who have disease progression will be 
required to have these assessments performed up through the 12-month time-point. SAEs will be reported in subjects who have 
initiated durvalumab per Section 10.8.  
bb. Subjects who discontinue study treatment for any reason, including progression, will move into Active Follow-up and continue 
completion of the Post-Concurrent Mediastinal Chemoradiation assessments until completion of the 60-month follow-up visit. Post-
Concurent Mediastinal Chemoradiation assessments are required for a minimum of 12 months after last treatment of conconcurrent 
mediastinal chemoradiation. Subjects who have met end-points for local/regional/distant control (i.e. disease progression locally, 
regionally and distally) or have started subsequent anti-cancer therapy after 12 months of Active Follow-up but prior to the 60-month 
follow-up visit will move into Long-Term Follow-up per Section 4.1.2  
cc. Subjects will move into Long-term Follow-up for either of the following: Completion of at minimum the 12-month Active Follow-up 
visit with subsequent disease progression (local, regional and distant) or initiation of subsequent anti-cancer therapy or completion of 
the 60 month Active Follow-up assessment (in absence of disease progression or initiation of subsequent anti-cancer therapy). Subjects 
will be contacted approximately every 12 months for survival until the criteria for the final analysis are met. Phone contact is acceptable. 
dd. Office visits after enrollment may be performed virtually during the COVID-19 pandemic, per investigator discretion 
 
 
6. TREATMENT PLAN 
6.1 Radiation Therapy 
6.1.1 
Treatment Planning, Imaging and Localization Requirements 
 
All subjects will be immobilized in a custom designed device in the appropriate 
position.   
 
Radiation treatment planning CT or PET/CT scans (contrast preferred) will be 
required to define gross target volume (GTV) and clinical target volume (CTV). The 
treatment planning CT or PET/CT scan should be acquired with the subject in the 
same position and using the same immobilization device as for treatment.  All 
tissues to be irradiated must be included in the CT scan. Planning CT scan will be 
done at ≤3 mm intervals from encompassing the region of interest with sufficient 
margin for treatment planning. Four dimensional CT is required for linac-based 
treatment with SBRT t account for tumor motion.  Additional treatment planning 
scans may be performed during the course of radiotherapy as necessary.  Imaging, 
including PET/CT, may be fused with the planning CT images to better visualize the 
anatomy when indicated. 
 
Primary tumors will be classified as either central or peripheral for the purposes of 
SBRT treatment planning.  Tumor within or touching the zone of the proximal 
bronchial tree, defined as a volume 2 cm in all directions around the proximal 
bronchial tree (carina, right and left main bronchi, right and left upper lobe 
bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right 
and left lower lobe bronchi) will be classified as central.  Central primary tumors 
must be at least 2 cm from involved nodal disease.  All other primary tumors will 
be classified as peripheral and do not have a specified distance from involved 
nodal disease.   
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
23 
 
6.1.2 
Target Contouring 
 
 
SBRT: 
 
Primary Gross Tumor Volume (GTV_Primary) is defined as gross primary disease 
determined from imaging, clinical information, and/or endoscopic findings. The 
GTV will consist of the primary parenchymal tumor as visualized on CT and PET.  
 
Primary Internal Gross Tumor Volume (IGTV_Primary): This will consist of the 
GTV_Primary plus an additional margin based on the 4D-CT image sets to account 
for tumor motion. 
 
Clinical Target Volume (CTV_Primary): A margin of up to 5 mm will be added to the 
IGTV_Primary to account for microscopic extension of tumor at the discretion of 
the treating radiation oncologist.  The addition of a CTV is encouraged for all 
primary tumors >3 cm.  For tumors greater than 3 cm up to 5 cm, a 3 mm 
expansion is encouraged.  For tumors greater than 5 cm, a 5 mm expansion is 
encouraged.  All CTV expansions can be asymmetric and should not extend into 
uninvolved organs. 
 
Primary Planning Target Volume (PTV_Primary): A 5 mm margin will be added to 
the CTV_Primary for setup error.  In cases where a CTV expansion is not used, a 5 
mm margin will be added directly to IGTV_Primary to create the PTV_Primary. 
 
 
Mediastinal Radiotherapy: 
 
Mediastinal Gross Tumor Volume (GTV_Med): This will consist of gross disease in 
the mediastinum, excluding the primary tumor, determined from imaging, clinical 
information, and/or endoscopic findings. The GTV will consist of the mediastinal 
disease as visualized on CT and PET scans, including any lymph node ≥ 1.5 cm in 
longest axis on CT scan or with an SUV of ≥ 3.0, consistent with abnormal on PET 
imaging. 
 
 
4DCT Planning 
 
Mediastinal Internal Gross Tumor Volume (IGTV_Med): This will consist of the 
GTV_Med plus an additional margin based on the 4D-CT image sets to account for 
tumor motion with respiration. 
 
Mediastinal Clinical Target Volume (CTV_Med): A 5 mm margin without extending 
into uninvolved organs will be added to the IGTV_Med to account for microscopic 
extension of tumor.  At the discretion of the treating radiation oncologist, the 
CTV_Med can be expanded beyond a 5 mm margin on the IGTV_Med to allow for 
the inclusion of regions of potential microscopic extension for the entire nodal 
level for any nodal station that has gross disease.  
 
Mediastinal Planning Target Volume (PTV_Med): A 5 mm margin will be added to 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
24 
 
the CTV_Med for setup error. 
 
3D Planning 
 
Mediastinal Clinical Target Volume (CTV_Med): A 5 mm margin without extending 
into uninvolved organs will be added to the GTV_Med to account for microscopic 
extension of tumor.  At the discretion of the treating radiation oncologist, the 
CTV_Med can be expanded beyond a 5 mm margin on the GTV_Med to allow for 
the inclusion of regions of potential microscopic extension for the entire nodal 
level for any nodal station that has gross disease.  
 
Mediastinal Planning Target Volume (PTV_Med): A 10 mm margin in the cranial-
caudal direction and 8 mm margin in the radial circumferential direction will be 
added to the CTV_Med for setup error and to account for tumor motion with 
respiration. 
 
6.1.3 
Normal Structures  
 
SBRT: 
 
The following normal structures will be contoured: lung (right and left to be 
contoured separately), spinal cord, esophagus, heart, brachial plexus, carina, great 
vessels, chest wall, ribs, trachea, skin, proximal bronchus, proximal bronchus + 2 
cm. 
 
Mediastinal Radiotherapy: 
 
The following normal structures will be contoured: lung (right and left to be 
contoured separately), spinal cord, esophagus, heart, brachial plexus, carina. 
 
6.1.4 
Dose fractionation and Specification  
 
SBRT: 
 
The prescription dose per fraction to the PTV_Primary will be 12.5 Gy/day to 50 Gy 
or 18 Gy/day to 54 Gy for peripheral tumors and 10 Gy/day to 50 Gy for central 
tumors.  Subjects will be treated daily or every other day without a planned 
treatment break.  
 
The primary tumor will be contoured for all subjects and the isocenter will be 
placed at the center of the primary tumor for all subjects.  
 
Mediastinal Radiotherapy:  
 
The prescription dose per fraction to the PTV_Med will be 2.0 Gy (RBE)/day to 60 
Gy. Subjects will be treated daily, 5 days/week, without a planned treatment 
break.  
The carina will be contoured for all subjects and the isocenter will be placed at 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
25 
 
mid-carina for all subjects.  
 
6.1.5 
Treatment Planning  
 
Dose specifications: 
Dose constraints for PTV_Primary: 
At least 95% of the PTV will be encompassed by 100% of the prescription dose. 
 
The prescription isodose surface will be chosen such that 95% of the target 
volume (PTV) is conformally covered by the prescription isodose surface (PTV V100RX 
= 95%) and 99% of the target volume (PTV) receives a minimum of 90% of the 
prescription dose (PTV V90%RX > 99%). 
 
Dose Constraints for PTV_Med:  
At least 95% of the PTV will be encompassed by 95% of the prescription dose. 
 
Normal tissue constraints:   
 
Table 1 SBRT Maximum Dose Constraints 
 
OAR 
3 Fractions 
4 Fractions 
5 fractions 
Spinal Cord 
18 Gy (6 Gy/fx) 
26 Gy (6.5 Gy/fx) 
28 Gy (5.6 
Gy/fx) 
Esophagus 
30 Gy (10 Gy/fx) 
30 Gy (7.5 Gy/fx) 
38 Gy (7.6 
Gy/fx) 
Brachial Plexus 
21 Gy (7 Gy/fx) 
27.2 Gy (6.8 Gy/fx) 
32.5Gy (6.5 
Gy/fx) 
Heart/Pericardium 
30 Gy (10 Gy/fx) 
34 Gy (8.5 Gy/fx) 
38 Gy (7.6 
Gy/fx) 
Great Vessels 
39 Gy (13 Gy/fx) 
49 Gy (12.25 Gy/fx) 
53 Gy (10.6 
Gy/fx) 
Trachea/Proximal 
Bronchi 
30 Gy (10 Gy/fx) 
34.8 Gy (8.7 Gy/fx) 
50 Gy (10 
Gy/fx) 
Rib 
30 Gy (10 Gy/fx) 
30 Gy (7.5 Gy/fx) 
57 Gy (11.4 
Gy/fx) 
Skin 
30 Gy (10 Gy/fx) 
36 Gy (9 Gy/fx) 
38.5 Gy (7.7 
Gy/fx 
Stomach 
27 Gy (9 Gy/fx) 
30 Gy (7.5 Gy/fx) 
35 Gy (7 
Gy/fx) 
 
 
*Rib dose in excess of the above constraints will be documented but is not a 
reason to necessitate subject withdrawal.  In cases where the rib dose constraint 
will be exceeded, attempts should be made to keep the dose as low as achievable.  
For central tumors, every effort should be made to spare the contralateral wall of 
the adjacent organ at risk including the proximal bronchial tree, esophagus, or 
heart.  Dose in excess of above constraints to those structures will be documented 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
26 
 
but is not a reason to necessitate subject withdrawal. 
 
Dose-volume histograms from the sum SBRT-Mediastinum plan should be 
performed for spinal cord, lungs, heart, and esophagus. 
 
When assessing the composite plan of the primary tumor and of the mediastinum, 
the maximal spinal cord dose should not exceed 50 Gy (RBE) in 2 Gy/fraction 
equivalents.  No more than 37% of the total lung volume minus GTV should 
receive greater than 20 Gy (RBE).  The mean dose of the total lung volume minus 
GTV should be no greater than 20 Gy.  No more than 50% of the total cardiac 
volume should receive greater than 40 Gy (RBE).  The mean dose of the esophagus 
should be no greater than 34 Gy.  All attempts should be made to minimize dose 
overlap of the SBRT course and the mediastinal course, particularly overlap of 
dose in the spinal cord, esophagus, brachial plexus, heart, great vessels, trachea, 
and proximal bronchus.  
 
6.1.6 
Treatment Duration 
 
SBRT: 
 
SBRT will be completed in 1-2 weeks. 
 
Mediastinal Radiotherapy: 
 
Concurrent mediastinal chemoradiation will in most instances be completed in 
under 8 weeks from the start of the course of chemoradiation. This may be 
extended if subjects require a break from treatment. Criteria for break would 
include any Grade 3 non-hematologic toxicity at Investigator discretion, Grade 4 
hematologic toxicity at PI discretion, or Grade 4 non-hematologic toxicity.     
 
6.1.7 
Equipment and Beam Delivery  
 
SBRT and Photons: A ≥ 6 MV photon beam will be used. 6 MV is preferred.  IMRT 
is allowed and encouraged for mediastinal radiotherapy. 
 
All treatments will be given with the subject in the appropriate immobilization 
device. Film or digital images will be taken prior to the initial treatment to verify 
the position of the subject and the aperture and as appropriate. A radiation 
oncologist will check the first film on all fields. A radiation therapist or radiation 
oncologist will check subsequent films taken before treatment. All set-up films will 
be permanently filed for all subjects.  
 
6.1.8 
IGRT and Quality Assurance  
 
Daily portal films, and/or daily online radiographic imaging is required to be 
performed prior to each fraction of treatment. Volumetric imaging or continuous 
intermittent kV imaging and volume or fiducial match is required prior to each 
fraction of SBRT.   

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
27 
 
 
The first 3 cases from participating sites will have pretreatment review by the 
participating site PI or a participating site radiation oncology designee.  The first 3 
cases from Atrium Health will have pretreatment review by the coordinating 
center S-I or a coordinating center radiation oncology designee.  Additionally, the 
first 3 cases from each treatment center within the coordinating center will have 
pretreatment review by the coordinating center S-I or a coordinating center 
radiation oncologist designee, and first 3 cases from each treatment center within 
the participating site will have pretreatment review by the participating site PI or a 
participating site radiation oncologist designee. Additional pretreatment reviews 
may be requested at the discretion of the coordinating center S-I. Central review 
will be supervised by the coordinating center S-I.   
  
6.2 Concurrent Chemotherapy 
  
A single platinum-based doublet chemotherapy regimen is to be administered 
during radiotherapy. The choice of the chemotherapy regimen is at the discretion 
of the treating physician. One of the following recognized standard-of-care, 
protocol-allowed regimens must be given with radiation therapy: 
 
Paclitaxel (50 mg/m2) intravenous over approximately 1 hour followed by 
Carboplatin AUC = 2 mg/mL/min intravenous weekly (every 7 days) during 
radiotherapy 
  
(Belani 2005) (NCCN 2014) 
For 1 treatment cycle (approximately 6 weeks in duration)  
Standard premedications with steroids, diphenhydramine, H2 receptor 
antagonist, and 5-HT3 receptor antagonist antiemetics must be 
administered per individual institutional guidelines.  
 
OR 
 
Etoposide (50 mg/m2/d) intravenous on days 1 to 5 and days 29 to 33 
Cisplatin (50 mg/m2/d) intravenous on days 1, 8, 29, and 36 
  
(Albain KS, et al. J Clin Oncol 2002; 20:3454-60) (NCCN 2014) 
For 2 treatment cycles (each cycle is 4 weeks in duration) 
Standard premedication with steroids and 5-HT3 receptor antagonist 
antiemetics must be administered per individual institutional guidelines. 
Standard intravenous hydration (≥ 1.5 liters) must be administered in 
conjunction with cisplatin.  
 
Chemotherapy regimens should not be switched after initiation unless approval is 
granted by the Sponsor-Investigator. 
 
Filgrastim and pegfilgrastim may not be used during concurrent 
chemoradiotherapy.  
 
Erythropoiesis-stimulating agents (epoetin alfa, darbepoetin alfa) may not be used 
during concurrent chemoradiotherapy. 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
28 
 
 
Chemotherapy dosing for all subjects will be based on actual body weight prior to 
each cycle, in accordance with ASCO guidelines (Griggs JJ, et al. J Clin Oncol 
2012;30:1553-61). 
 
Chemotherapy scheduling modifications of +/- 48 hours are allowed. 
Concurrent chemotherapy treatment must begin within 48 hours of mediastinal 
radiation therapy initiation.  
 
6.2.1 
Chemotherapy Drug Information 
 
All chemotherapy received on the protocol during the study treatment period will 
be commercially supplied. 
 
Refer to package insert(s) for detailed pharmacologic, safety information and 
preparation/administration instructions for chemotherapy drugs.  Chemotherapy 
will be administered per institutional guidelines. Please note that 1 treatment 
cycle (6 weeks in duration) is an example of a schedule, a 6-week duration is not 
required. Standard dose reductions will be used as required for drops in subject 
blood counts and other chemotherapy related toxicities, and will be performed 
under the direction of the treating investigator according to individual institutional 
guidelines. All dose modifications to study treatment will be done per treating 
physician discretion. 
 
6.2.2 
Permitted Supportive Therapy 
 
All supportive therapy for optimal medical care will be given during SBRT and 
concurrent chemoradiation 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. 
 
6.2.3 
Non-Permitted Supportive Therapy 
 
Filgrastim, pegfilgrastim and erythropoiesis-stimulating agents (epoetin alfa, 
darbepoetin alfa) may not be used during concurrent chemoradiotherapy. 
 
No other systemic or immunologic tumor-directed therapy may be administered 
while the subject is receiving protocol-directed therapy. 
 
 
6.3 Durvalumab 
All subjects will receive adjuvant immunotherapy with durvalumab until disease progression, 
unacceptable toxicity, or until a maximum of 12 cycles  of durvalumab therapy has been 
administered. In the event of treatment delays, a full 12 months cycles of durvalumab should 
be admininstered.  
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
29 
 
6.3.1 
Supplier/How Supplied 
Durvalumab will be provided by AstraZeneca as a 500 mg vial concentrate for 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 
label-claim volume is 10.0 mL. Durvalumab is a sterile, clear to opalescent, colorless to 
slightly yellow solution, free from visible particles. The investigational product will 
arrive with commercial labeling. The investigational product must be relabled with 
supplied investigational labels immediately upon receipt. 
 
6.3.2 
Preparation 
The dose of durvalumab (MEDI4736) for administration must be prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique.  Please refer to 
local prescribing information for in-use storage conditions and times.  Durvalumab will 
be prepared according to the most current version of the package insert.   
 
6.3.3 
Storage and Stability 
Durvalumab does not contain  preservatives, any unused portion must be discarded. 
Durvalumab vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Investigational product must be kept in original packaging until use to prevent 
prolonged light exposure. Administer infusion solution immediately once prepared. 
Please refer to most current package insert for information on prepared infusion 
stability.  
 
6.3.4 
Accountability 
An adequate record of receipt, distribution, destruction, or return of this agent must be 
kept in the form of a Drug Accountability Form. The investigator, or responsible party 
designated by the investigator, will maintain a careful record of the inventory using the 
Drug Accountability Form. The investigational drug for this clinical trial shall only be 
dispensed by authorized personnel to subjects enrolled in this clinical trial. 
 
6.3.5 
Destruction 
The investigator or designee is responsible for keeping accurate records of the clinical 
supplies received from AstraZeneca, including the amount remaining at the conclusion 
of the trial. Upon completion or termination of the study, all unused product will be 
destroyed at the site according to site pharmacy policies or as dictated by the 
manufacturer. Used vials can be destroyed immediately after preparation. It is the 
investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, 
state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
30 
 
 
 
 
6.3.6 
Administration 
Durvalumab may be administered after concurrent mediastinal chemoradiation per 
physician discretion. Durvalumab should be administered through an IV line containing 
a sterile, low-protein binding 0.2 or 0.22 micron in-line filter. Durvalumab should be 
administered as soon as possible after preparation, within the timeframes defined in 
Section 6.3.3.  Do not co-administer other drugs through the same infusion line.  
 
Do not co-administer other drugs through the same infusion line. The IV line will be 
flushed according to local practices to ensure the full dose is administered. Infusion 
time does not include the final flush time. If either preparation time or infusion time 
exceeds the time limits a new dose must be prepared from new vials.  
 
There are (2) different dosing schedules that may be administered, per investigator 
discretion. Dosing schedule may be switched after initiation of durvluamb, per 
investigator discretion. 
 
Table 2: Q 2 Week Dosing 
Drug 
Dose 
Route 
Schedule2 
Cycle Length 
Durvalumab 
10 mg/kg1  
 
Intravenously (IV) over 
approximately 60 
minutes3 
D1 and D15 
4 weeks (28 days) 
 
1 Calculated from most recent weight prior to durvalumab (baseline) during screening. Do not 
recalculate unless weight changes >10% from baseline weight. 
2 A +/- 3 day window is allowed 
3If there are interruptions during the infusion, the total allowed time must not exceed 8 hours at 
room temperature 
 
Table 3: Q 4 week Dosing1 
Drug 
Dose 
Route 
Schedule2 
Cycle Length 
Durvalumab 
1500 mg (flat dose) 
 
Intravenously (IV) over 
approximately 60 
minutes3 
D1  
4 weeks (28 days) 
 
1 Schedule only allowed in subjects weighing 30 kg or more, if weight is less than 30 kg, subject should 
receive durvalumab per Table 2. 
2 A +/- 3 day window is allowed 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
31 
 
3If there are interruptions during the infusion, the total allowed time must not exceed 8 hours at room 
temperature 
 
6.3.7 
Dose Modifications 
All durvalumab dose modifications should be per the most current durvalumab 
package insert and Investigator’s Brochure. Please also refer to the most current 
Toxicity Management Guidelines for guidance on durvalumab-related symptom 
management.  
 
6.3.8 
Reproductive Risks 
Durvalumab can cause fetal harm when administered to a pregnant woman. Females of 
child-bearing potential should be advised to use effective contraception during 
treatment with durvalumab and for at least 3 months after the last dose of durvalumab. 
Women should not breastfeed during treatment with durvalumab and for at least 3 
months after the last dose of durvalumab. If a subject becomes pregnant while on 
durvalumab, study treatment should be discontinued immediately. 
 
6.3.9 
Supportive Care 
Subjects should be monitored for immune-mediated adverse reactions, signs and 
symptoms of infection, and infusion-related reactions. Supportive care for any 
durvalumab-related toxicities should implemented per the most current version of the 
durvalumab package insert. Please also refer to the Toxicity Management Guidelines 
for guidance on durvalumab-related symptom management.  
 
 
6.4 Treatment Compliance 
 
Subject compliance with the treatment and protocol includes willingness to comply with all 
aspects of the protocol. At the discretion of the Sponsor-Investigator, a subject may be 
discontinued from the protocol for non-compliance with follow-up visits or treatment.  
 
6.5 
Duration of Therapy 
 
Study treatment will continue until the subject completes protocol-directed therapy (protocol 
therapy includes SBRT, concurrent mediastinal chemoradiation and protocol—directed 
durvalumab). Reasons why study treatment may be discontinued early may include: 
 
 
Disease progression 
 
Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Subject decides to withdraw from the protocol 
 
General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the Investigator. 
 
Study subject becomes pregnant 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
32 
 
 
In all cases, the reason for study treatment discontinuation must be documented in the subject’s 
medical record and/or research record and collected in the eCRF.   
NOTE: In the event the criteria for the final analysis are met, and there are subjects who have not 
yet been discontinued from study treatment, they will continue to receive therapy until one of 
the above criteria applies. 
7 
STUDY ASSESSMENTS 
7.1 History and Physical:  
Subject undergoes history and physical per standard of care and is identified for study by the 
treating physician. Pathologic and radiologic review of available studies are performed per 
standard of care and at the discretion of the treating physician.  Performance status is 
assessed per ECOG criteria.  Vital signs including weight, temperature, blood pressure, heart 
rate, respiratory rate.  These assessments are repeated after initiation of study treatment per 
the time-points indicated in Section 5. 
7.2 Positron emission tomography-computed tomography:  
Every effort will be made to obtain standard PET/CT at the timepoints indicated in Section 5. If 
PET/CT is not able to be performed, CT abdomen/pelvis  may be performed instead as 
referenced below.   
7.3 CT chest:  
This will be performed utilizing standard imaging procedures at the timepoints indicated in 
Section 5. Imaging should be performed with IV contrast unless approved by the Sponsor-
Investigator.  
7.4 Chest X-Ray:  
Chest x-ray will be performed at screening in subjects with a pleural effusion visible on CT scan 
to confirm that a pleuracentesis is not required. 
7.5 CT abdomen/pelvis:  
This will be performed utilizing standard imaging procedures at the time-points indicated in 
Section 5 if PET/CT is not performed.  Imaging should be performed with IV contrast unless 
approved by the Sponsor-Investigator. 
7.6 Neuroimaging:  
MRI of the brain with contrast (preferred) or CT of the head with contrast should be 
performed utilizing standard imaging procedures at the time-point as indicated in Section 5.  
Imaging should be performed with IV contrast unless approved by the Sponsor-Investigator. 
7.7 Documentation of biopsy of primary tumor and/or nodes:  
All techniques that may have been used for biopsy to obtain tissue confirmation of non-small 
cell histology are allowed including bronchoscopy, percutaneous, and surgical biopsy.  Repeat 
biopsy is not required but is permitted to document recurrence or failure.  
7.8 Laboratory assessments:   
Including CBC with differential, electrolytes, and LFTs. CBC with differential and electrolytes 
will be repeated after initiation of study treatment at the time-points identified in Section 5. 
7.9 Pulmonary Function Testing:  
Standard pulmonary function testing to include FEV1 and DLCO will be performed at the time-
points as indicated in Section 5. 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
33 
 
7.10 Toxicity Assessment 
Baseline pre-existing symptoms and conditions present at the time of informed consent and 
prior to the first dose of study treatment should be documented. Toxicity assessment  should 
start at study treatment initiation and continue at a minimum of up to 12 months after the last 
treatment of concurrent mediastinal chemoradiation. Collection requirements are as follows: 
All AEs from initiation of study treatment until 90 days after last dose of protocol-directed 
durvalumab. After this time period, if less than 12 months has elapsed since last dose of 
concurrent mediastinal chemoradiation, AESIs (as defined in Section 10.3) until 12 months 
after last dose of concurrent mediastinal chemoradiation. For subjects who do not initiate 
protocol-directed durvalumab, AESI’s starting on the date the decision is made that 
durvalumab will not be initiated through 12 months after last dose of concurrent mediastinal 
chemoradiation. 
7.11 Quality of Life Assessment:  
Quality of life will be reported during the study by each subject using the MDASI-lung and 
EORTC QLQ-LC13 lung surveys at the time-points as indicated in Section 5. 
7.12 Biospecimen collection:  
Blood samples and archived tissue for correlatives will be collected at the time-points as 
indicated in Section 5. 
 
8 
TREATMENT-RELATED ADVERSE EVENTS 
 
8.1 
Adverse Events Related to Radiation 
           Possible early side effects: 
 
Skin changes which may include dryness, redness, burning, swelling, or peeling of 
the skin 
 
Decrease in weight, low blood counts, loss of appetite, nausea, diarrhea, and 
fatigue.   
 
Irritation of the esophagus causing pain when swallowing 
 
Swelling/inflammation of the lung causing pain, fever, cough, or shortness of breath 
or difficulty breathing 
 
Rare: Ulcerations of the skin in the irradiated area.   
          Possible late side effects, although rare: 
 
Changes in the color or texture of the skin or hair in the treated area 
 
Ulcers or scars on the skin in the treated area 
 
Scars or shrinking of the lung that could cause shortness of breath 
 
Narrowing of the esophagus that could cause swallowing problems 
 
Bone damage that may lead to small cracks (fracture) in the bone 
 
Damage to the heart muscle, heart sac, or arteries that may lead to heart attack or 
heart disease or the need for surgical correction 
 
8.2 
Adverse Events Related to Chemotherapy 
 
Hematologic: Myelosuppression  
 
Gastrointestinal: Nausea and vomiting, electrolyte imbalance, diarrhea, stomatitis, 
mucositis, pharyngitis, typhlitis, ischemic colitis, neutropenic enterocolitis, increased 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
34 
 
liver function tests (SGOT, SGPT, bilirubin, alkaline phosphatase); hepatic failure, 
hepatic necrosis  
 
Heart: Arrhythmias, heart block, ventricular tachycardia, myocardial infarction (MI), 
bradycardia, atrial arrhythmia, hypotension, hypertension, lightheadedness  
 
Neurological: Sensory (taste), peripheral neuropathy, seizures, mood swings, hepatic 
encephalopathy, encephalopathy, sensation of flashing lights; blurred vision, 
scintillating scotoma  
 
Allergy: Anaphylactoid and urticarial reactions (acute); Stevens-Johnson Syndrome; 
flushing, rash, pruritus  
Other: Alopecia, fatigue, arthralgia, myopathy, myalgia, infiltration (erythema, 
induration, tenderness, rarely ulceration); radiation recall reaction. 
 
8.3 
Adverse Events Related to Durvalumab 
For complete information on safety, please refer to the latest version of the prescribing 
information for durvalumab, which can be found at www.imfinzihcp.com. Please also refer to 
the current version of the IB for a detailed summary of the monotherapy data including AEs, 
serious adverse events (SAEs), and Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 3 to 5 events reported across the durvalumab program.  
 
 
Immune-related reactions include, not limited to: 
o Pneumonitis/interstitial lung disease (ILD) 
o Hepatitis/increases in transaminases 
o Colitis 
o Endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal 
insufficiency, hyper- and hypothyroidism, type I diabetes mellitus and 
diabetes insipidus, and pancreatitis) 
o Nephritis/increases in creatinine 
o Dermatologic reactions including rash/dermatitis (including pemphigoid) 
o Uveitis 
o Myocarditis 
o Myositis/polymyositis 
o Thrombocytopenia 
o Other rare or less frequent inflammatory events including neuromuscular 
toxicities (e.g., Guillain-Barrè, myasthenia gravis) 
 
 
Serious infections 
 
Infusion-related reactions, including hypersensitivity 
 
Embryo-fetal toxicities 
 
Cough/productive cough 
 
Dyspnea 
 
Diarrhea 
 
Abdominal pain 
 
Pruritis 
 
Fatigue 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
35 
 
 
Pyrexia 
 
Pneumonia 
 
Intestinal perforation 
 
In monotherapy clinical studies, AEs at an incidence of ≥ 20% include events such as fatigue and 
decreased appetiate. Approximately 10% of participants discontinued the drug due to an AE. 
 
9 
DATA AND SAFETY MONITORING PLAN 
 
9.1 
Safety Monitoring 
 
This protocol will be monitored according to the processes in effect for all Levine Cancer 
Institute investigator-initiated studies and the protocol-specific monitoring plan and will 
abide by institutional standard operating procedures.  It is the responsibility of the Sponsor-
Investigator to monitor the safety data for this study.  The Sponsor-Investigator, Statistician, 
and other team members as needed will meet regularly to monitor subject consents, 
enrollment and retention, safety data for all subjects [including adverse events, Adverse 
Events of Special Interest (AESI’s), serious adverse events (SAE’s)], and validity/integrity of 
the data. Documentation of these meetings will be kept with study records. The Sponsor-
Investigator will submit data to the LCI Data and Safety Monitoring Committee according to 
the overarching LCI Data and Safety Monitoring Plan. 
 
9.2 Data Quality Assurance 
 
This study will be organized, performed, and reported in compliance with the study protocol, 
institutional standard operating procedures (SOPs), and other applicable regulations and 
guidelines (e.g. GCP).  
 
Subjects will be monitored by Levine Cancer Institute Research Monitors routinely for data 
quality. This monitoring will be done by comparing source documentation to the eCRFs. Any 
variation between the source documentation and the database will be discussed with the 
Sponsor-Investigator or appropriate research personnel. 
 
The study database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures. Data queries 
requiring clarification will be generated and addressed by Sponsor- Investigator or 
appropriate research personnel. Only authorized personnel will make corrections to the 
study database and all corrections will be documented in an electronic audit trail. 
 
 
10 
SAFETY DATA COLLECTION, RECORDING AND REPORTING 
 
Safety and tolerability, relationship to treatment and intensity will be assessed according to 
the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. AE and AESIs as 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
36 
 
defined in Sections 10.2 and 10.3 will be determined by the Investigator, documented in 
subject study charts and/or the medical record, and collected in the eCRF per Section 10.7. 
 
10.1 
Unanticipated Problem Definition 
 
An UAP is any incidence, experience or outcome that is unexpected, given the information 
provided in research-related documentation (e.g. Investigator’s brochure, informed consent) 
and the study population characteristics that is related or possibly related to participation in 
the research study and places the participant at an increased risk.   
 
10.2 
Adverse Event Definition 
 
An adverse event or adverse experience is any untoward medical occurrence in a study 
subject who is treated on study that does not necessarily have a causal relationship with this 
treatment.  An adverse event can therefore be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of the study treatment, whether or 
not considered related to it.  Pre-existing conditions that increase in frequency or severity or 
change in nature during or as a consequence of use of a study drug in human clinical trials 
are also considered adverse events.   
 
Pregnancy and/or elective abortions are not regarded as AEs unless there is a suspicion that 
the IP under study may have interfered with the effectiveness of a contraceptive medication. 
 
Any continuing medical condition or clinically significant laboratory abnormality with an 
onset date before the first date of study treatment should be considered pre-existing and 
should be documented in the subject’s medical records and/or in the study chart.  
 
The relationship to study intervention should be assessed using the following definitions: 
 
“Not Related:  Evidence exists that the AE has an etiology other than the study treatment 
(e.g., pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication).  This includes events that are considered remotely or unlikely related to study 
treatment. 
 
Related:  A temporal relationship exists between the event onset and administration of 
treatment.  It cannot be readily explained by the subject’s clinical state, intercurrent illness, 
or concomitant therapies.  In the case of cessation or reduction of the dose, the event 
abates or resolves and reappears upon re-challenge.  It should be emphasized that 
ineffective study treatment should not be considered as causally related in the context of AE 
reporting.  This includes events that are considered possibly, probably, or definitely related 
to study treatment.” 
 
The Investigator is responsible for verifying and providing source documentation for all 
collected adverse events and assigning the attribution for each event for all subjects enrolled 
on the trial. 
 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
37 
 
10.2.1 Abnormal Laboratory Values/Clinical Results Defined as AEs 
An abnormal laboratory value or clincal result is considered to be an AE if the abnormality is 
characterized by any of the following: 
 
Results in discontinuation from the study 
 
Requires treatment, delay or modification of study drug dose, or any other 
therapeutic intervention 
 
Grade 3 or higher, regardless of clinical significance 
 
If a laboratory/clinical result abnormality is one component of a diagnosis or syndrome, then 
only the diagnosis or syndrome should be collected as an AE.  If the laboratory 
abnormality/clinical result was not a part of a diagnosis or syndrome, then the abnormality 
should be collected as the AE. 
 
10.3 
Adverse Events of Special Interest (AESI) Definition 
Adverse Events of Special Interest for this protocol are defined as non-hematologic adverse 
events Grade 2 or higher related to SBRT or concurrent mediastinal chemoradiation. 
 
 
10.4 
Suspected Adverse Reaction Definition 
 
A SAR is an adverse event in which there is reasonable possibility that the study intervention 
caused the adverse event.  The Investigator is responsible for judging whether it is a 
reasonable possibility that the study treatment caused the adverse event. 
10.5 
“Unexpected” Definition  
An AE or SAR is to be considered unexpected if the event is not listed in the current 
Investigator Brochure and/or package insert or is not listed in the severity or specificity 
observed.  
10.6 
Serious Adverse Event (SAE) Definition 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening but are 
clearly of major clinical significance.   They may jeopardize the subject and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of 
bronchospasm in an emergency department would typically be considered serious.  

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
38 
 
 
The following do not meet the criteria for seriousness per ICH definition but must be 
reported in the same manner as SAEs:  
 
New primary cancer 
 
Overdose (dose of durvalumab in excess of the protocol directed dose) of 
durvalumab 
 
Pregnancy exposure: 
o Pregnancies of a subject or pregnant partner that occur within 90 days after 
the last dose of durvalumab. Signed authorization from the pregnant 
partner must be obtained prior to reporting any pregnancy information.  
 
Hepatic function abnormality is associated with liver injury and impaired liver 
function defined as (possible Hy’s Law case): 
o ALT ≥3 x ULN and total bilirubin ≥2 xULN (if fractionated and direct bilirubin 
>35%)  
or  
o ALT ≥3 x ULN and INR >1.5.  
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
10.7 
AE and AESI Reporting 
Toxicity reporting requirements are as follows: 
All AEs from initiation of study treatment until 90 days after last dose of protocol-directed 
durvalumab. After this time period, if less than 12 months has elapsed since last dose of 
concurrent mediastinal chemoradiation, AESIs (as defined in Section 10.3) until 12 months 
after last dose of concurrent mediastinal chemoradiation. For subjects who do not initiate 
protocol-directed durvalumab, AESI’s starting on the date the decision is made that 
durvalumab will not be initiated through 12 months after last dose of concurrent mediastinal 
chemoradiation.  
 
10.8 
Expedited Safety Reporting to the Sponsor-Investigator 
 
SAEs, pregnancies including pregnant partners and AEs requiring expedited reporting as 
defined in Section 10.6 must be reported to the Sponsor-Investigator within 1 business day of 
awareness. SAEs will be captured from the time of study treatment initiation through 90 days 
(30 days for subjects who have not yet initiated protocol-directed durvalumab) after the date 
of the last study treatment administration or until the initiation of subsequent anti-cancer 
therapy (minimum reporting period of 30 days after last dose of study treatment). SAEs that 
are determined to be related to study treatment or a research procedure are reportable for 
the subject’s duration of study participation. SAEs will be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, until progression has been stabilized, 
or until there has been acceptable resolution of the event. This may at times cause the follow-
up period for SAEs to be greater than 90 (or 30 for subjects who have not yet received 
protocol-directed durvalumab) days. The Sponsor-Investigator is responsible for following the 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
39 
 
subject during the required follow-up period even if the subject lives elsewhere or has been 
released from his or her care and is being treated under another service. 
 
The outcome of all pregnancies (including pregnant partners) should be followed up and 
documented. Written authorization must be obtained from a pregnant partner before any 
obtaining and reporting any information about the pregnancy to the sponsor. 
 
10.9 
Expedited Safety Reporting to AstraZeneca 
Note: SAEs will only be reported to AstraZeneca on subjects who have initiated protocol-
directed durvalumab. The following does not apply to subjects who have not yet initiated 
protocol-directed durvalumab. 
 
SAEs determined to be related to protocol-directed durvalumab per the Sponsor-Investigator 
and all pregnancies as defined in Section 10.6 will be reported to AstraZeneca within 1 
business day of Sponsor-Investigator awareness (both initial reports and follow-up reports). 
 
All other SAEs (determined to be unrelated to protocol-directed durvalumab) including initial 
and follow-up information will be provided to AstraZeneca by the Sponsor-Investigator or 
designee in a quarterly line listing. 
 
Death clearly resulting from disease progression should not reported to AstraZeneca as an 
SAE (but will be collected in the eCRF as an AE). 
 
The SAE report and accompanying cover page should be sent via 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. 
 
10.10 Expedited Safety Reporting to the IRB 
All events occurring during the conduct of a protocol and meeting the definition of an UAP or 
SAE will be reported to the IRB per IRB reporting requirements.  
 
Protocol deviations will be reported promptly to the IRB per IRB reporting requirements. 
 
11 
MEASUREMENT OF EFFECT 
 
11.1 
Anti-tumor Effect – Solid Tumor 
Response and progression will be evaluated in this study using a modification of the revised 
response evaluation criteria in solid tumors (RECIST) guideline version 1.1, allowing baseline 
scans to have occurred no more than 90 days prior to enrollment. 
 
11.1.1 Definitions 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
40 
 
Subjects will be evaluated for response based on pretreatment disease parameters below 
and follow up imaging at 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, and 60 months after the last 
treatment of concurrent mediastinal chemoradiation. Protocol-directed follow-up imaging 
will be discontinued for subjects who have documented disease progression. After PD, only 
imaging data from standard of care imaging will be collected until initiation of subsequent 
anti-cancer therapy. 
 
11.1.2 Disease Parameters 
 
Target lesions include the primary disease in the lung, mediastinum, and hilum.  The sum of 
longest diameters of the primary lung tumor and other solid tumor lesions and shortest axis 
for involved lymph nodes that are PET avid in subjects who have PET/CT (and have a long 
axis ≥1 cm (lymph nodes must have short axis ≥ 1.5 cm) will be measured prior to treatment 
and on follow up imaging. 
 
11.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation.  All baseline evaluations 
should be performed as closely as possible to the beginning of treatment and no more than 
90 days before the beginning of study treatment (enrollment). 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  The tumor 
measurements will be recorded on the eCRF. 
11.1.4 Response Criteria 
 
Response will be evaluated using RECIST 1.1 Criteria. 
 Complete Response: 
 
Target lesion: Disappearance of all target lesions. Any pathological lymph  
 
 
nodes (whether target or non-target) must have reduction in short axis to  
 
 
<10 mm. 
 
Non-target lesion: Disappearance of all non-target lesions. All lymph nodes   
 
must be non-pathological in size (<10 mm short axis). 
 
Partial Response: 
 
Target lesion: At least a 30% decrease in the sum of diameters of target, 
 
taking as reference the baseline sum diameters. 
 
Non-target lesion: Not applicable 
 
Stable Disease: 
 
Target lesion: Neither sufficient shrinkage to qualify for a partial response,   
 
nor sufficient increase to qualify for progressive disease, taking as reference   
 
the smallest sum diameters while on study. 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
41 
 
 
Non-target lesion: Not applicable. 
 
Progressive Disease: 
 
Target lesion: At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
one or more new lesions is also considered progression). 
 
Non-target lesion: Unequivocal progression (as described in RECIST version 1.1) of 
existing non-target lesions. (Note: the appearance of one or more new lesions is also 
considered progression). 
 
Non-Complete Response / Non-Progressive Disease: 
 
Target lesion: Not applicable 
 
Non-target lesion: Persistence of one or more non-target lesion(s) 
 
Table 4 Summary of RECIST 1.1 
 
 
Table 5 Time Point Response: Patients with Non-Target Disease Only 
Target 
Lesions 
Non-target Lesions 
New Lesions 
Overall 
Response 
Best Response for this 
Category also requires 
CR 
CR 
No 
CR 
Documented at least once 
 4 weeks from baseline 
CR 
Non-CR/Non-PD 
No 
PR 
Documented at least once 
 4 weeks from baseline 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Documented at least once 
 4 weeks from baseline 
Not all 
evaluated 
Non-PD 
No 
NE 
NA 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, and  
NE = inevaluable. 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
42 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 
STATISTICAL CONSIDERATIONS 
 
12.1 
Sample Size  
A total of 60 PFS1 evaluable subjects (section 12.3) will be enrolled to this study. The primary 
objective is to evaluate the 12-month progression free survival rate. The PACIFIC study19 reported 
a lower limit of the 95% confidence interval for median PFS of 13 months for subjects on the arm 
receiving durvalumab; however, PFS was measured from end of chemoradiotherapy in the 
PACIFIC study while we derive PFS from enrollment to the study (start of SBRT treatment). As such 
we are assuming a 15-month median PFS (allowing two months for SBRT and chemoradiation) 
which corresponds to a 12-month PFS rate of approximately 60.0%. Therefore, a single-stage 
design will be used to test the hypothesis that the 12-month PFS rate is less than or equal to 0.60. 
If at least 42 of the 60 subjects are alive and progression free at 12 months, the null hypothesis 
will be rejected (based on an exact binomial test) and the study treatment regimen may be 
considered for further evaluation in this subject population. Assuming a one-sided alpha = 0.10 
significance level, this sample size will provide at approximately 98% power to reject the null 
hypothesis, assuming the true 12-month PFS rate is 0.80. An increase in the PFS-12 rate of 0.20 in 
the context of this Phase II study is considered clinically relevant.  
Note, since not all enrolled subjects will have received adjuvant durvalumab due to both 
initiation of enrollment to the study prior to regulatory approval of durvalumab and previous 
investigator discretion for decision to administer durvalumab was allowed,, we must also consider 
the inclusion of subjects who do not receive durvalumab. The CALGB 30105 study (Socinski MA, 
et al. J Clin Oncol. 2008;26(15):2457-63) reported a 12-month PFS of 54.8% for Arm A 
(carboplatin + paclitaxel). The lower bound of the 95% confidence interval for one year PFS was 
38.7%. Therefore, we assume the null hypothesis for the subjects not receiving durvalumab to be 
0.40 and the alternative is assumed to be 0.60. Therefore, including subjects who did not receive 
durvalumab will reduce the power from 98%. Table 6 shows the conditional power of the study 
design given the sample size of enrolled subjects who do not receive adjuvant durvalumab (N1). 
Table 6 
N1 
Conditional Power 
5 
0.95472 
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 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
43 
 
6 
0.94832 
7 
0.94124 
8 
0.93344 
9 
0.92489 
10 
0.91555 
11 
0.90539 
12 
0.89439 
13 
0.88254 
14 
0.86982 
15 
0.85622 
16 
0.84175 
17 
0.82641 
18 
0.81021 
19 
0.79319 
20 
0.77536 
 
 
12.2 
Endpoint Definitions 
 
12.2.1 1-Year Progression-Free Survival 
 
The primary endpoint is 1-year progression-free survival, which will be calculated from a 
recorded binary variable determined for each subject indicating whether or not the subject 
experienced disease progression or death from any cause within 1 year from study enrollment. 
Disease progression will be classified according to Section 11.1.4.   
 
12.2.2 Progression Free Survival 
Progression free survival (PFS) is defined as the duration of time from enrollment to the study 
to first occurrence of either progressive disease or death. Disease progression must be 
objectively determined as per Section 11.1.4, where the date of PD is the date of the radiologic 
assessment that identified RECIST-defined progressive disease. If the subject died without 
documented disease progression, the date of progression will be the date of death. For 
surviving subjects who do not have documented disease progression, PFS will be censored at 
the date of last radiologic assessment. For subjects who receive subsequent anti-cancer 
therapy prior to documented disease progression, PFS will be censored at the date of last 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
44 
 
radiologic assessment prior to the commencement of subsequent therapy. Subjects who have 
an initial PFS event immediately following 2 or more consecutive missed assessments will be 
censored at the date of the last assessment prior to those missed assessments. For participants 
with only one missed assessment, the documented progressive disease status and assessment 
date will be used. 
12.2.3 Overall Survival 
Overall survival (OS) is defined as the duration of time from the date of enrollment to the study 
to the date of death from any cause. Subjects who are alive or lost to follow-up at the time of 
the analysis will be censored at the last known date they were alive. 
 
12.2.4 Radiologic Clinical Complete Response  
Radiologic clinical complete response will be recorded for each subject as a binary variable 
indicating whether or not the subject had no evidence of disease on PET/CT or CT scan 
approximately 3 months after the last treatment of concurrent mediastinal chemoradiation. 
 
12.2.5 Objective Response 
Objective response will be determined for each subject as a binary variable indicating whether 
or not the subject achieved a best overall response of CR or PR as determined per criteria 
described in Section 11.1.4.  
12.2.6 Local Control at 12 and 24 Months 
Local control (LC) is defined as the duration of time from enrollment to the study to first 
progression of the subject’s primary lesions(s). If a subject dies prior to local progression, local 
control will be censored at the date of death. For surviving subjects with no documented local 
progression, local control will be censored at the date of the last radiologic assessment that 
evaluated the local tumor(s). For subjects who receive subsequent anti-cancer therapy prior to 
documented local progression, local control will be censored at the date of last radiologic 
assessment that evaluated the local tumor(s) prior to the commencement of subsequent 
therapy. Local control will be estimated at 12 and 24 months. 
 
12.2.7 Regional Control at 12 and 24 months 
 
Regional control (RC) is defined as the duration of time from enrollment to the study to first 
progression of the subject’s regional lesion(s). If a subject dies prior to regional progression, 
regional control will be censored at the date of death. For surviving subjects with no 
documented regional progression, regional control will be censored at the date of the last 
radiologic assessment that evaluated the regional lesion(s). For subjects who receive 
subsequent anti-cancer therapy prior to documented regional progression, regional control will 
be censored at the date of last radiologic assessment that evaluated the regional lesion(s) prior 
to the commencement of subsequent therapy. Regional control will be estimated at 12 and 24 
months. 
 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
45 
 
12.2.8 Locoregional Control at 12 and 24 months 
Locoregional control is defined as the duration of time from enrollment to the study to first 
progression of the subject’s local and/or regional lesion(s), whichever occurs first. If a subject 
dies prior to locoregional progression, locoregional control will be censored at the date of 
death. For surviving subjects with no documented local and/or regional progression, 
locoregional control will be censored at the date of the last radiologic assessment that 
evaluated the locoregional lesion(s). For subjects who receive subsequent anti-cancer therapy 
prior to documented locoregional progression, locoregional control will be censored at the 
date of last radiologic assessment that evaluated the local and regional lesion(s) prior to the 
commencement of subsequent therapy. Locoregional control will be estimated at 12 and 24 
months. 
 
12.2.9  Distant Control at 12 and 24 months 
 
Distant control defined as the duration of time from enrollment to the study to first metastatic 
progression. If a subject dies prior to metastatic progression, distant control will be censored at 
the date of death. For surviving subjects with no documented mestastic progression, distant 
control will be censored at the date of the last radiologic assessment. For subjects who receive 
subsequent anti-cancer therapy prior to documented metastatic progression, distant control 
will be censored at the date of last radiologic assessment prior to the commencement of 
subsequent therapy. Distant control will be estimated at 12 and 24 months. 
 
12.2.10  Quality of Life 
 
QOL will be assessed utilizing the MDASI-lung cancer and EORTC QLQ-C30, EORTC QLQ-LC13 
lung surveys. Surveys will be obtained at the time points as indicated in Section 5. 
 
12.2.11 Safety Endpoints 
Safety endpoints will include radiation dosing administration (including dose of radiation 
received for both SBRT and mediastinal radiation, and other dosimetry parameters), incidence 
of AESIs, incidence of SAEs and deaths while on study. Toxicities will be assessed using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 
Toxicities will be tabulated by type and grade separately for each phase of treatment. Selected 
adverse events for this objective will include the following: 
 
Grade 2 or higher radiation pneumonitis 
 
Grade 3 or higher pulmonary events 
 
12.3 
Analysis Populations 
 
All subjects who receive at least one fraction of SBRT will be included in all efficacy and safety 
populations. The population evaluable for the primary endpoint (PFS1 evaluable population) will 
include all subjects in the efficacy population who have experienced a PFS event within one year 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
46 
 
of enrollment or have at least one year of follow-up time from enrollment. Evaluation of the 
secondary endpoints will be conducted on the efficacy population. Analysis of objective response 
will be conducted on those subjects in the efficacy population with measurable disease present at 
baseline. For the exploratory analysis, the immune marker population will contain all subjects 
who received at least one fraction of SBRT and who had at least one blood sample drawn. The 
exploratory analysis of lung texture data will be conducted on the population of subjects who 
receive at least one fraction of SBRT and who also have available data from the lung texture 
analysis software. 
 
12.4 
Analysis Methods 
12.4.1 Timing of Analysis 
 
The primary analysis will occur when all subjects in the study have experienced a 
progression or when they have been on study for 1 year. Baseline characteristics and 
secondary endpoints will also be assessed at the time of the primary analyses.  Updated 
analyses will be conducted after all subjects have been on study for at least 2 years or are 
off study otherwise. A final analysis will be conducted after the overall survival censoring 
rate reaches 30%, or after all surviving subjects have been followed for at least 5 years after 
last treatment of mediastinal chemoradiation or are off study otherwise, whichever occurs 
first. 
 
 
12.4.2 Subject Disposition 
An accounting of all consenting subjects will be provided at the end of the study. This will 
include a breakdown of subjects who consented, received study treatment, discontinued 
treatment early, died, and were lost to follow-up or withdrew consent. 
12.4.3 Baseline Subject and Disease Characteristics 
 
A summary of subject and disease-related characteristics will be completed. 
 
12.4.4 Efficacy Analyses 
 
12.4.4.1 
Primary Analysis 
The primary analysis will be to compare the progression free survival rate at one 
year in PFS1 evaluable subjects receiving the study treatment regimen to a 
relevant historical control rate. The frequency and proportion of subjects alive and 
progression free at 1 year will be calculated, along with a 95% Clopper Pearson 
confidence interval. A one-sided exact binomial test of proportions, with alpha = 
0.05, will be carried out, testing the null hypothesis that the 1-year progression 
free survival probability is less than 40%. Based on the sample size calculations 
described in Section 12.1, if at least 42 subjects are alive and progression free at 
1-year, the null hypothesis can be rejected. 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
47 
 
 
12.4.4.2 
Secondary Analyses 
 
OS and PFS will be analyzed using Kaplan Meier techniques. Medians, 25th, and 
75th percentiles will be estimated. Selected landmarks for OS and PFS at 1-year, 2-
years, and 3-years will be obtained from the Kaplan Meier curves.. Clinical 
complete response and objective response rates will be estimated with 
proportions and associated 95% Clopper Pearson confidence intervals will be 
calculated. 
 
    Landmark local control, regional control, locoregional control, and distant control 
will be estimated along with 95% confidence intervals at 12 and 24 months using 
Kaplan Meier methods. Additionally, patterns of primary, locoregional, and distant 
failure will be derived from the local, locoregional, and distant control, 
respectively, and reported. 
 
   Total scores and subscales from the QOL surveys (MDASI-LC, EORTC QLQ-C30, 
EORTC QLQ-LC13 lung) will be summarized for each subject and evaluated over 
time (six time points). Change from baseline will be described for each post-
baseline timepoint and individual trajectories will be examined graphically and 
with linear mixed models. The models will include subject as a random factor in 
order to account for within-subject correlation. 
 
   Note, secondary analyses may involve subsets of subjects based on the delivered 
dose of therapy. 
 
12.4.5 Safety Analysis 
Incidence rates for adverse events, treatment-emergent adverse events, SAEs, 
deaths, and complications recorded from the time of initiation of SBRT until the 
end of the collection period (defined in Sections 10.7 and 10.8) will be 
summarized as counts and proportions. For selected events, 95% Clopper Pearson 
confidence intervals will be calculated. Treatment-emergent adverse events are 
defined as follows:  
 
 
An adverse event that occurs after treatment start that was not present at 
the time of treatment start; or 
 
An adverse event that increases in severity after treatment start if the 
event was present at the time of treatment start. 
 
The frequency and proportion of subjects with clinical symptoms of and receiving 
treatment with steroids for radiation pneumonitis (grade ≥ 2) within 6 months of 
the last treatment of concurrent mediastinal chemoradiation will be reported. 
Grade 3 or higher pulmonary events will also be summarized with frequencies and 
proportions. Additionally, radiation dosimetry parameters will be correlated with 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
48 
 
the incidence of select adverse events. The continuous dosimetry data will be 
summarized with medians and ranges among those who did and did not 
experience the select adverse events. 
 
12.4.6  Exploratory Analyses 
The impact of baseline subject and disease characteristics on outcomes will be 
evaluated. Univariate models will be used to identify individual prognostic factors 
and multivariate models will be used to identify independent prognostic factors. 
Additionally, in an effort to determine inflammatory markers, changes in 
expression levels of chemokines and cytokines will be evaluated over time (prior 
to SBRT, during SBRT, and during mediastinal chemoradiation. Differentially 
expressed chemokines and cytokines will be correlated with toxicity endpoints, 
specifically to explore associations with radiation-induced lung toxicity.   
 
Radiation fibrosis is a common radiologic observation after SBRT in the lung that 
often appears as partial lung atelectasis.  This is a scarring effect usually in the 
lung tissue that surrounds the primary tumor and can change over time.  Some 
patients have more fibrosis than others, and there are likely multiple factors that 
affect the level of fibrosis that occurs in patients.  Fibrosis is likely a mechanism of 
small airway collapse from small airway radiation injury.  Quantifying the amount 
of fibrosis and resulting effects on lung function has not been studied.  Newer 
software is available to analyze CT scans and quantify as well as categorize lung 
texture.  Provided sufficient sample sizes are available, post treatment CT scans 
will be evaluated utilizing lung texture analysis and lung density analysis software 
to quantify and categorize lung changes pre-SBRT versus post-SBRT, at CT scan 
time points, up to 24 months after SBRT treatment completion.  The shift in 
distribution of the lung texture data over those time points will be calculated and 
will also be correlated with dose information from the treatment plan to evaluate 
if there are dosimetric causes of lung texture changes and small airway collapse.  
In addition, the effect of lung texture changes over time on selected outcomes, 
such as toxicity and PFT changes, will be evaluated. Further discovery-type 
evaluations of the predictive nature of lung texture changes as may also be 
carried out on an ad hoc basic. 
13 
STUDY COMPLETION 
 
13.1 Completion 
 
The study will be considered complete when one or more of the following conditions is 
met: 
 
All subjects have completed all study visits. 
 
All subjects have discontinued from the study. 
 
The IRB, LCI DSMC, Sponsor-Investigator discontinues the study because of safety 
considerations. 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
49 
 
13.2 Termination 
 
The study will be terminated when one or more of the following conditions occur: 
If risk-benefit ratio becomes unacceptable owing to, for example: 
 
Safety findings from this study (e.g. SAEs) 
 
Results of parallel clinical studies 
 
If the study conduct (e.g. recruitment rate; drop-out rate; data quality; 
protocol compliance) does not suggest a proper completion of the trial 
within a reasonable time frame. 
The Sponsor-Investigator has the right to close the trial at any site and at any time. 
For any of the above closures, the following applies: 
   Closures should occur only after consultation between involved parties. 
 
All affected institutions must be informed as applicable according to local law.   
 
In case of a partial study closure, ongoing subjects, including those in follow- up, 
must be taken care of in an ethical manner. 
 
Details for individual subject's withdrawal can be found in Section 5.9. 
 
14 
RETENTION OF RECORDS 
 
Essential documentation (e.g. adverse events, records of study treatment receipt and 
dispensation), including all IRB correspondence, will be retained for at least 2 years after the 
investigation is completed.  Documentation will be readily available upon request. 
 
15 
ETHICAL AND LEGAL ISSUES 
 
15.1 Ethical and Legal Conduct of the Study 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and  
documentation of this study, are designed to ensure that the Investigator abide by Good Clinical 
Practice (GCP) guidelines and under the guiding principles detailed in the Declaration of Helsinki.  
The study will also be carried out in keeping with applicable local law(s) and regulation(s). 
 
Documented approval from appropriate agencies (e.g. DSMC, IRB) will be obtained for all 
participating centers before start of the study, according to GCP, local laws, regulations and 
organizations.   
 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the Investigators may not modify or alter the procedures described in this protocol.   
 
Modifications to the study protocol will not be implemented by the investigator without 
discussion with the Sponsor- -Investigator at Levine Cancer Institute.  However, the Investigators 
may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to the trial subjects without prior approval from applicable agencies.  As soon as 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
50 
 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the appropriate agencies.  Any deviations 
from the protocol must be explained and documented by the Investigator. 
 
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  
The Sponsor-Investigator is responsible for overseeing the treatment of all study subjects.  The 
Sponsor-Investigator must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all applicable regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Sponsor-Investigator will be responsible for assuring that all the required data will be 
collected and properly documented. 
 
15.2 Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
 
16 
PUBLICATION POLICY 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the coordinating center Sponsor-Investigator for the purposes 
of performing the study, will be published or passed on to any third party without the consent of 
the coordinating center study Sponsor- Investigator from Levine Cancer Institute.  Any 
investigator involved with this study is obligated to provide the Sponsor- Investigator with all data 
derived from the study. 
The Sponsor-Investigator will ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov.  
 
 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
51 
 
REFERENCES 
1. Aupérin A, et al. J Clin Oncol. 2010;28(13):2181-90. 
2. Rosenzweig KE, et al. J Clin Oncol. 2007;25(35):5557-61. 
3. Simone CB 2nd, et al. Chest. 2013;143(6):1784-90. 
4. Mazeron R, et al. Int J Radiat Oncol Biol Phys. 2010;77(1):38-43. 
5. Movsas B, et al. Int J Radiat Oncol Biol Phys. 2013;87(2):S1-S2. 
6. Timmerman R, et al. JAMA. 2010;303(11):1070-6. 
7. Bradley JD, et al. Int J Rad Oncol Biol Phys. 2003;56(2):342-7. 
8. Palma DA, et al. Int J Radiat Oncol Biol Phys. 2013;85(2):444-50. 
9. Bradley JD, et al. Int J Radiat Oncol Biol Phys. 2007;69(4):985-92. 
10. AJCC 7th Edition. 
11. Belani CP, et al. J Clin Oncol. 2005;23(25):5883-91.  
12. NCCN, 2016. 
13. Albain KS, et al. J Clin Oncol 2002;20:3454-60. 
14. Griggs JJ, et al. J Clin Oncol. 2012;30:1553-61. 
15. Smith TJ, et al. J Clin Oncol. 2006;24:3187-205 
16. Rizzo JD, et al. J Oncol Pract. 2010;6:317–20. 
17. Socinski MA, et al. J Clin Oncol. 2008;26(15):2457-63. 
18. Curran WJ Jr, et al. J Natl Cancer Inst. 2011;103(19):1452-60).   
19. Antonia, SJ, et al.  N Engl J Med. 2017; Sep 8. doi: 10.1056/NEJMoa1709937 
20. Simone CB 2nd. American Society for Radiation Oncology 56th Annual Meeting, 2014. 
 
 
 
 
 
 
 
 
 

Protocol Number: LCI-LUN-NSC-SBRT-001  
Version 7:  03/16/2023 
52 
 
APPENDICES 
 
Appendix A. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Radiation 
Pneumonitis Grading 
 
Grade 1 – asymptomatic; clinical or diagnostic observations only; intervention not indicated 
Grade 2 – symptomatic; medical intervention indicated; limiting instrumental ADL 
Grade 3 – severe symptoms; limiting self care ADL; oxygen indicated 
Grade 4 – life-threatening respiratory compromise; urgent intervention indicated (e.g. tracheotomy or 
intubation) 
Grade 5 – death 
 
Appendix B. Quality of Life Questionnaires 
 
MDASI-lung  
 
EORTC QLQ-LC13