Conditions: Nonsmall Cell Lung Cancer, Stage II Nonsmall Cell Lung Cancer Stage III
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
The purpose of this research study is to find out what effects (good or bad) may come from a new way of doing radiation therapy for lung cancer. This study is for patients who are not able to get surgery or chemotherapy with their radiation. The way of doing radiation therapy in this trial is called hypofractionated radiation therapy which is a standard approach, but this study allows the actual tumor to get an extra radiation dose while still protecting the organs that are near the tumor.

Detailed description:
Primary Objective:

• To determine the in-field control of hypofractionated radiotherapy consisting of 70 Gy in 25 fractions without concurrent chemotherapy measured at two years after the first post- radiotherapy scan.

Secondary Objective(s):

* To determine the toxicity profile of thoracic hypofractionated radiotherapy consisting of 70 Gy in 25 fractions as graded by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
* To determine proportion with local, regional, and distant progression at 1 and 2 years after the first post-radiotherapy scan, and compute progression-free and overall survival (progression-free survival and overall survival, respectively).

Arms:
arm 1: Hypofractionated radiation therapy will be delivered to all participants. The radiation will be planned in a special way to give the biggest parts of the tumors that are the most difficult to control a little more radiation every day than the lower risk areas.

Interventions: intervention 1: Hypofractionated Radiation Therapy intervention 2: Radiation Boost
Intervention descriptions: intervention 1: The prescribed dose will be 70 Gy in 25 fractions. Participants will radiation therapy once a day for 25 days, Monday through Friday (around 5 weeks). intervention 2: Undergo simultaneous integrated boost (SIB) to treat both planned target volumes with daily image guidance. This approach allows daily confirmation of target localization and simultaneous delivery of lower dose per fraction to low risk areas while maintaining a high dose per fraction to the highest risk areas.

Protocol document:
Prot_SAP_001.pdf: 
A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced 
NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
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WFBCCC # 62220 
 
Page 1 of 49 
 
Principal Investigator:                    
Michael Farris, M.D. 
Department of Radiation Oncology 
Wake Forest University School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
Radiation Oncology Co-Investigators: 
 
 
Corbin A. Helis, M.D. 
Department of Radiation Oncology 
Wake Forest School of Medicine 
Medical Center Blvd, Winston-Salem, NC 27157 
 
Heather Pacholke, M.D. 
Department of Radiation Oncology 
Radiation Oncology at Hayworth Cancer Center 
601 N Elm Street 
High Point, NC 27262 
 
Marc Leyrer, M.D. 
Department of Radiation Oncology 
J. Allen Knox Radiation Therapy Center 
557 Brookdale Dr 
Statesville, NC 28677 
 
Ryan T. Hughes, M.D. 
Department of Radiation Oncology 
Wake Forest School of Medicine 
 
William Blackstock, M.D. 
Department of Radiation Oncology Chair 
Wake Forest School of Medicine 
 
  
Medical Physics Co-Investigator: 
                   Biostatistician:    
 
Travis Jacobson, PhD 
Department of Radiation Oncology 
Wake Forest School of Medicine 
Medical Center Blvd, Winston-Salem, NC 27157 
 
 
Research Nurses: 
 
 
Sharon Averill 
 
Susan E. Wildman, BSN, RN, CCRC 
 
Laura Hayes RN 
 
Nikolas Soetermans 
 
Jeffrey Kettler 
 
 
 
 
Sheri Whittington RN 
 
 
  
 
Study Coordinator:                                                   Data Manager: 
 
 
Jeffrey Kettler 
 
 
 
 
 
 
 
 
Regulatory Contact: 
 
  
  
 
 
 
 
 
 
Participating Institution(s):     
 
  
          
  
 
 
Beverly Levine, Ph.D. 
Biostatistics Core 
Comprehensive Cancer Center 
Wake Forest University School of Medicine  
 
Amy Hughes 
 
Emily Teal  
 
Wake Forest University School of Medicine  
Winston Salem campus (Coordinating Center) 
Radiation Oncology at Hayworth Cancer Center 
J. Allen Knox Radiation Therapy Center 
Version Date:  04/22/21  
 
  
 
 
Confidential 
 


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Table of Contents 
1.0 
Introduction and Background 
4 
2.0 
Objectives 
9 
2.1 
Primary Objective(s) 
9 
2.2 
Secondary Objective(s) 
9 
3.0 
Patient Selection 
10 
3.1 
Inclusion Criteria 
10 
3.2 
Exclusion Criteria 
10 
3.3 
Inclusion of Women and Minorities 
10 
4.0 
Registration Procedures 
10 
5.0 
Study Outcomes and Study Measures 
11 
5.1 
Primary Outcome 
11 
5.2 
Secondary Outcomes 
11 
6.0 
Treatment Plan 
12 
6.1 
Study-Related Activities 
12 
6.1.1 
Radiation Therapy 
13 
6.2 
General Concomitant Medication and Supportive Care Guidelines 
16 
6.3 
Duration of Therapy/Study Follow-up 
16 
6.4 
Duration of Follow Up 
16 
6.5 
Criteria for Removal from Study 
16 
7.0 
Dosing Delays/Dose Modifications 
16 
8.0 
Measurement of Effect 
17 
8.1 
Antitumor Effect – Solid Tumors 
17 
8.1.1 
Survival Outcomes 
17 
9.0 
Adverse Events List and Reporting Requirements 
17 
9.1 
Adverse Event List for Hypofractionated Thoracic Radiotherapy 
17 
9.1.1      
 Cardiac and Pericardial Injury 
17 
9.2 
Adverse Event Characteristics 
18 
9.3 
STRC SAE Reporting Requirements 
19 
9.4 
WFUHS IRB AE Reporting Requirements 
19 
10.0 
Data Management 
20 
11.0 
Statistical Considerations 
20 
11.1 
Analysis of Primary Objective 
20 


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11.2 
Analysis of Secondary Objective 
21 
11.3 
Power and Sample Size 
21 
11.4 
Estimated Accrual Rate 
21 
11.5 
Estimated Study Length 
21 
11.6 
Interim Analysis Plan 
21 
References 
23 
Appendix A – Eligibility Checklist 
25 
Appendix B – Protocol Registration Form 
27 
Appendix C - Race & Ethnicity Verification Form 
28 
Appendix D Safety and Toxicity Review Committee (STRC) Serious Adverse Event (SAE) Notification 
SOP 
Error! Bookmark not defined. 
Appendix  E:  BED Calculations for Dose Levels and Constraints 
36 
Appendix F – Adverse Event Log 
37 
Appendix G – Follow-up Form 
38 
– 
38 
Appendix H – Off-Study Form 
39 
Appendix I – Treatment Response Evaluation 
40 
Appendix J Off Treatment Form 
41 
Appendix K-Withdrawal of consent for the intervention and medical record use 
42 
Appendix L-Vitals Form Only at pre treatment and at each followup 
43 
Appendix M-Con-med PRN Form 
44 
Appendix N:  Mandatory Target Coverage/Dose Constraint Compliance Confirmation. 
45 
Appendix O: Pre-Toxicity 
46 
Appendix P:  Pattern of Progression Collection 
47 
Appendix Q: RECIST 
48 
 
 


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STUDY SCHEMA 
 
 
 
1.0 
Introduction and Background 
 
Synopsis 
 
The selection of treatment modality for patients with non-small cell lung cancer is based on the stage, size, and 
distribution of disease. Patients with stage II-III NSCLC are routinely managed with surgery followed by adjuvant 
therapies or definitive chemoradiotherapy and consolidation immunotherapy. However, some patients may decline 
or be ineligible for surgery or systemic therapy due to surgically unresectable disease or medical comorbidity.  In 
patients with early stage NSCLC who are not operative candidates, stereotactic body radiotherapy (SBRT) is the 
standard of care.  However, there is a subset of patients with tumors in unfavorable locations who have a very high 
rate of high grade toxicity with SBRT.  In these patients, fractionated radiotherapy alone is often the only 
therapeutic option available.  No clear standard exists for the appropriate dose and fractionation of radiotherapy 
alone in this cohort.  However, local intrathoracic failure rates of up to 50% are a major source of morbidity and 
mortality in this population.  Published regimens have poor local control likely due to the lack of synergistic 
systemic therapy and inadequate biologically effective dose (BED) of radiation.  In the past, dose escalation in the 
mediastinum has been severely limited due to inability to adequately spare normal tissues.  With dramatic 
improvements in radiotherapy delivery and image guidance, it is now possible to achieve higher doses to tumor 
while simultaneously achieving reasonable normal tissue constraints.   
 
We recently published a series on dose escalated hypofractionated radiation in patients with stage I - IIB NSCLC 
including patients with ultracentral tumors and N1 disease.  Our 2 year local control approximated 70% and the 
regimen was well tolerated, with no grade 3+ acute esophagitis or grade 4-5 toxicities.   We propose here a single-
arm phase 2 study to investigate the efficacy and safety of an established hypofractionated radiotherapy regimen for 
varying stages of NSCLC.13,21 We plan to improve on our prior delivery methods through utilization of  a planning 
technique known as simultaneous integrated boost (SIB) with daily image guidance. This approach allows daily 
confirmation of target localization and simultaneous delivery of lower dose per fraction to low risk areas while 
maintaining a high dose per fraction to the highest risk areas.  In our previous series all tissue was treated at the 
same high dose per fraction, including surrounding normal tissues.  This current planning approach will further 
facilitate sparing normal tissues while allowing for slightly higher doses to the tumor.     
Biologic Effective Dose and the Rationale for Hypofractionated Radiotherapy 
Current guidelines recommend concurrent chemoradiotherapy followed by consolidative immunotherapy 
for patients with stage II-III NSCLC who are not surgical candidates.  The rationale for the delivery of concurrent 


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chemoradiotherapy is based on a meta-analysis showing improved overall survival when compared to sequential 
chemoradiotherapy, primarily due to an increase in loco-regional control.2  However, various comorbidities, medical 
contraindications or patient preference sometimes preclude the delivery of concurrent chemotherapy. In these cases, 
radiotherapy alone is often utilized.  Local control with standard radiotherapy alone is poor.  This has led to the 
investigation of multiple different fractionation regimens.   
Multiple studies have employed various altered fractionation regimens in the management of NSCLC 
patients with radiotherapy alone and a benefit to survival outcomes has been suggested with the use of modified 
fractionation, typically accelerated hyperfractionation, compared to conventional fractionation.  However, the total 
doses in these studies were still limited, and local control remained poor, with 2 year rates in the 45-50% range.24 A 
pooled analysis of multiple RTOG studies, most of which included concurrent chemotherapy reported a loco-
regional failure rate of 46%.22  These regimens are often evaluated using biologic effective dose (BED), which 
converts different physical radiation doses to a standard model.  BED is a function of the dose per fraction (df) of 
radiation, the total number of fractions (nf) and the α/β ratio, which measures the radiosensitivity of a given tissue, 
and is generally assumed to be 10 for tumors and 3 for normal tissues (conventionally written as BED10 and BED3), 
and is calculated using the equation 𝑩𝑩𝑩𝑩𝑩𝑩 =  𝒅𝒅(𝒏𝒏)(𝟏𝟏+ 𝒅𝒅/(𝜶𝜶/𝜷𝜷) (see Appendix E).12,22  An important assumption 
of BED is that the radiation is given over the same total time period.  This is important as many tumors, including 
NSCLC, exhibit rapid repopulation during radiotherapy, and prolonged treatment courses or treatment breaks may 
allow for greater tumor repopulation, in effect decreasing the BED delivered.11 This has led to interest in 
hypofractionated radiotherapy (HRT) which would allow radiation to be completed prior to the onset of rapid 
repopulation. 
Efficacy and Toxicity of HRT in Prior Studies 
In patients with early stage NSCLC who are not operable candidates, SBRT is the current standard of care.  
Early experiences with SBRT identified a group of patients with centrally located lesions, defined as within 2 cm of 
the trachea, left and right mainstem bronchi and lobar bronchi, who were at an elevated risk of fatal toxicity.  
Slightly more fractionated regimens of SBRT, typically 5 to 8 fractions, have been reported as being well tolerated 
in these patients while maintaining local control rates over 90%.3  However, more recently, a further subgroup of 
patients with ultra-central lesions has been identified as being at even greater risk for fatal toxicity.  The definition 
of an ultra-central lesion is heterogenous, but generally includes patients with lesions within 1 cm of the proximal 
bronchial tree or esophagus, or with the planning target volume overlapping the proximal bronchial tree or the 
esophagus.19,20   
The recently reported Nordic HILUS study defined ultra-central as tumors within 1 cm of the proximal 
bronchial tree, with the notable exclusion of patients with tumor invading the bronchus.  Patients with these tumors 
were treated with dose de-escalated SBRT to 56 Gy in 8 fractions.  However, the radiation was prescribed to 
approximately the 67% isodose line, leading to maximal doses in the radiation plan of around 150% of the 
prescription dose (84 Gy physical dose).  The study found that even with dose de-escalated SBRT, rates of severe 
toxicity remained high, with 22 of 65 patients (33.8%) experiencing Grade 3-5 toxicity, including 10 with Grade 5 
toxicity (15.4%), mostly bronchopulmonary hemorrhage.  Notably, local control was also lower than with higher 
dose SBRT regimens, with 2 year local control of 83%.  Due to the high rates of severe and fatal toxicity, the 
authors felt that 56 Gy in 8 fractions could not be recommended for ultracentral lesions closely abutting the trachea 
and mainstem bronchi, and could only be recommended caution in other ultracentral lesions.19 
A treatment planning study reported that using 50 Gy in 5 fractions or 60 Gy in 8 fractions (both common 
dose-fractionation schemes for centrally located lung tumors) prioritized to maximize target coverage and tumor 
control yielded estimated tumor control rates over 90%, but with a predicted Grade 4 or higher toxicity rates of 44-
68%.  When the same tumors were planned to minimize toxicity, tumor control decreased to approximately 60%.  
This, combined with the results of the HILUS study, indicate that SBRT for ultracentral lung lesions may not be 
feasible without significantly compromising tumor control.25 


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In patients with stage II-III NSCLC who are medically inoperable and not candidates for chemotherapy, 45 
Gy delivered in 15 fractions (BED10 = 58.5) is a commonly utilized HRT schedule with a favorable toxicity profile. 
Unfortunately, locoregional control rates ranged between approximately 40-60%, similar to that of conventionally-
fractionated RT alone.1  A randomized study of elderly NSCLC patients treated with conventionally fractionated 
radiotherapy (60 Gy in 30 fractions, BED10 = 72) with or without concurrent carboplatin observed recurrence or 
progression in the treated volume in 60% of patients in both arms. Another study which retrospectively assessed 
outcomes after moderate HRT alone (66 Gy in 30 fractions, BED10 = 80.52) found a 2 year local control rate of 
57%  This study also reported a significant difference in cause-specific survival in patients with local control, with a 
2 year CSS of 56% in those with local control and only 32% in those who had local failure.15 By comparison, 
locoregional failure in an observational study from this institution using 70.2 Gy in 26 fractions (a HRT regimen) 
was 32% at 3 years and treatment was very well tolerated.13  Institutional review of a small number of patients 
treated with this regimen for Stage III NSCLC without concurrent chemotherapy showed excellent results and no 
high grade toxicity (unpublished data). 
A Phase I dose escalation trial conducted by Westover and colleagues investigated the outcomes of 15 
fraction hypofractionated radiation alone for patients with Stage II-IV NSCLC who were not candidates for other 
therapies.  They found that the maximum tolerated dose was 60 Gy in 15 fractions (BED10 = 84 Gy).  However, they 
were unable to provide estimates of local control due to poor OS (median 6 months), likely due at least in part to the 
inclusion of patients with metastatic disease (28% of patients).31 
The Alliance CALGB 31102 protocol was a phase 1 study of concurrent chemotherapy with a HRT, 
escalating dose by progressive hypofractionation (60 Gy delivered in 27, 24, 22, and 20 fractions, respectively). 
HRT was given with concurrent carboplatin/paclitaxel. Twenty-six percent of patients had Grade 3 or greater 
toxicity and 3 cases of Grade 5 toxicity were observed. As a result, the maximum tolerated dose was set at 60 Gy in 
24 fractions (BED10 = 75 Gy). Local progression occurred in only 24% of patients using this treatment paradigm 
suggesting an improvement in tumor control from RT alone as described previously. However, this regimen utilized 
concurrent chemotherapy, which was thought to have contributed to the significant toxicity rates. Additionally, the 
trial allowed patients with endobronchial tumors, tumors invading major cardiovascular structures, and did not 
constrain the doses delivered to the tracheobronchial tree.30  As a result, many radiation oncologists today 
extrapolate the results of this study to patients not eligible for concurrent chemotherapy and treat patients with HRT 
alone using this regimen. At this point, there is no prospective evidence to support this treatment regimen for 
radiation therapy alone in this specific cohort. 
Cannon and colleagues reported a Phase I trial that dose escalated radiotherapy for locally advanced 
NSCLC treated with 25 fractions of radiation without concurrent chemotherapy.  Dose escalation was done using a 
Bayesian dose-escalation scheme based on the predicted risk of pneumonitis.  They reported a MTD dose of 63.25 
Gy, but were unable to determine the safety of doses between this and 75 Gy in 25 fractions, as there were only 3 
patients treated between these dose levels.  The reported Grade 4-5 toxicities were mostly (67%) related to damage 
to the tracheobronchial tree.  Doses delivered to small volumes of the tracheobronchial tree were noted to be 
predictive of high grade toxicity, with EQD2 doses of 75 Gy to 3cm3 and 83 Gy maximal dose reported as 
correlating to a 5% toxicity rate at 2 years.6  Of note, patients with endobronchial disease and disease with invasion 
of major cardiovascular structures were eligible for the trial, and there were no reported attempts to minimize dose 
to bronchial structures reported, which may have contributed to severe bronchial toxicity seen. 
The SOCCAR trial was a Randomized Phase II trial investigating 55 Gy in 20 fractions of radiotherapy 
prescribed to the reference with concurrent or sequential cisplatin and vinorelbine (BED10 = 70.13 Gy, EQD210 = 
58.44 Gy).  Treatment was tolerated as expected, however, local control was only 45% at 2 years in the sequential 
arm.  However, as regular follow up scans were not mandated, this must be interpreted with caution.23   
A recent retrospective study reported a 5 year local relapse free survival of 55% and a 5 year overall 
survival of 40% in patients with Stage III NSCLC treated with hypofractionated radiation therapy of 66 Gy in 24 
fractions (BED10 = 84.15 Gy) with low dose daily concurrent cisplatin.  This treatment regimen was overall well 
tolerated, with 11% of patients with Grade 3-5 gastrointestinal toxicity, the majority of which was Grade 3 radiation 


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esophagitis, and a Grade 3-5 respiratory, thoracic, and mediastinal toxicity rate of 8.4%.  Grade 5 toxicity in this 
series was acceptable at 2.6%, with one Grade 5 esophageal ulcer, one respiratory failure, one heart failure, and only 
one mediastinal hemorrhage.9 
Simultaneous Integrated Boost for NSCLC 
Simultaneous integrated boost (SIB), also known as dose painting, is an advanced radiotherapy technique that uses 
inverse planning to deliver different dose levels to different areas during the same fraction.  This technique is 
commonly used is standard practice for many disease sites such as anal canal and head and neck malignancies.16,18  
The ability to use dose painting to deliver higher doses of radiation to selected volumes holds promise in NSCLC as 
it may allow dose escalation to gross disease while delivering lower doses to areas at risk for subclinical disease or 
in too close proximity to critical structures for ideal doses.  However, prospective evidence with this technique is 
limited in the setting of NSCLC. 
One of the first prospective experiences reporting a concomitant or integrated boost for locally advanced non-small 
cell lung cancer (LA-NSCLC) was a Phase II study conducted by the Korean Radiation Oncology Group. This study 
delivered 45 Gy in 25 fractions (BED10 = 53.1 Gy) to the planning target volume (PTV) with a boost to the gross 
tumor volume (GTV) to a total dose of 60 Gy in 25 fractions (BED10 = 74 Gy) with concurrent carboplatin and 
paclitaxel using 3D plans.  Treatment was well tolerated considering the limitations of the treatment techniques 
available at the time, with two cases (4.1%) of Grade 5 hemoptysis, both in patients with T4 disease involving the 
heart or main pulmonary artery, and 3 total cases of Grade 4 toxicity (2 pharynx/esophagus and 1 lung).  
Unfortunately, the local control was suboptimal, with a 2 year local progression free survival of 53%, and a crude 
local failure rate of 39%.7     
A more recent simultaneous integrated boost approach for Stage III NSCLC was reported in a Phase I study 
investigating 30 fraction radiotherapy with concurrent chemotherapy.  The investigators delivered 60 Gy in 30 
fractions to standard volumes with an escalating SIB to the iGTV plus a 5mm margin.  The MTD for the SIB was 
determined to be 72 Gy in 30 fractions, with dose limiting toxicity seen in acute esophagitis.  As these were 
preliminary results, late toxicity was not reported.  The local control of this regimen was very promising, with a 
loco-regional recurrence rate of 7% (1 of 15 patients).14  
Selection of HRT Dose 
Various hypofractionated radiotherapy (HRT) regimens have been reported for the management of patients 
with early-stage NSCLC not amenable to surgery or SBRT, HRT is commonly implemented, but the optimal dose 
schedule has not been established. Selection of HRT dose has been informed by studies of HRT/stereotactic body 
radiotherapy (SBRT) which have established a direct correlation between BED and tumor control.17,26 Generally 
speaking, RT doses with BED10 > 100 results in significantly improved disease control when compared to doses 
with BED10 < 100. For this reason, efforts to deliver various regimens of HRT that reach or approach a BED10 of 
100 Gy are of interest. A study conducted by the Cancer and Leukemia Group B (CALGB) 39904 protocol4 
evaluated various HRT regimens to a total dose of 70 Gy in 17-29 fractions without concurrent chemotherapy for 
early stage T1-T2N0 NSCLC.  In this Phase I study, disease control was favorable and no dose-limiting toxicity was 
observed.  
For patients with NSCLC not amenable to SBRT, surgery or concurrent chemoradiotherapy, a commonly 
utilized HRT fractionation at our institution is 70.2 Gy in 26 fractions. This regimen has a BED10 of 89.15 Gy. 
Recent data from our institution show that this fractionation results in favorable disease control and toxicity 
profiles.13  In our cohort, which included stage II patients and those with hilar (N1) nodal involvement, 96% were 
treated with 70.2 Gy in 26 fractions. The 3 year cumulative incidence of locoregional failure (including in untreated 
regional lymph nodes) was 32%, and only 2 (4%) of patients developed CTCAE version 4.0 Grade 3 radiation 
pneumonitis after treatment. No instances of Grade 3+ esophagitis occurred.  Based on these data, a similar dose 
fractionation scheme of 70 Gy in 25 fractions (BED10 = 89.6 Gy) is likely to have a 2 year local control rate of 
approximately 70%.  In cases where PBT dose constraints cannot be met, the dose to the PTV within 1 cm of the 


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PBT will be reduced slightly to 67.5 Gy in 25 fractions (BED10 = 85.73 Gy, BED3 = 128.25 Gy) to reduce the risk of 
serious toxicity. A similar dose (66 Gy in 24 fractions, BED10 = 84.15 Gy, BED3 = 126.5 Gy) has been previously 
reported to be well tolerated with concurrent low dose daily cisplatin.9 
Selection of Dose Constraints for the Proximal Bronchial Tree, Esophagus, and Heart 
 
Proximal Bronchial Tree 
 
Based on reports of severe bronchial toxicity with SBRT of centrally located NSCLC, determining proper 
dose constraints for high dose radiotherapy to mediastinal structures has been of increasing interest.29  The recently 
reported multi-institutional RTOG 0813 trial of SBRT for centrally located NSCLC found an MTD of 60 Gy in 5 
fractions while limiting the proximal bronchial tree and esophagus adjacent to the target to 105% of the prescription 
dose and avoiding circumferential irradiation of these structures.  Local control was also excellent, with in field 
control rates exceeding 90%.3   
 
Attempts to use hypofractionation for more advanced disease have been less successful, with one series 
reporting 38% Grade 3 or higher toxicity, including 21% Grade 5 toxicity, in patients with mostly Stage IIB-IIIA 
NSCLC treated with 60 Gy in 12 fractions.  However, this series made no attempt to constrain the proximal 
bronchial tree, and over 50% of patients had endobronchial tumors, and the BED3 of this regimen is 160 Gy.28
 
Two Phase I studies, one with concurrent chemotherapy and one without, arrived at similar MTDs of 60 Gy 
in 24 fractions (with concurrent chemotherapy) and 63.25 Gy in 25 fractions (without concurrent chemotherapy).6,30  
The dose limiting toxicity seen in these trials was also largely driven by complications related to vascular and 
bronchial injury.  As with other experiences, patients with endobronchial disease and pulmonary vascular invasion 
were included and no attempt was made to constrain the bronchial tree.  Cannon and colleagues attempted to 
develop a normal tissue complication probability model for the tracheobronchial tree based their Phase I study.6  
They reported a 5% late Grade 5 toxicity risk with a bronchial dose of EQD2  of 75 Gy to 3cm3 of the 
tracheobronchial tree, assuming an α/β ratio of 3.  For 25 fractions, this is approximately 66.25 Gy (EQD23 = 74.86 
Gy, see Appendix E for BED and EQD2 calculations).  However, this model is limited by the number of patients 
enrolled on dose levels between the reported MTD and dose levels where toxicity was reported (total of 3 patients).  
Similarly, the Nordic HILUS study estimated that patients with ultracentral lesions could likely be treated safely 
with a bronchial dose constraint of 70-80 Gy EQD2.  However, this is limited by small numbers of patients and is 
particularly uncertain in patients with lesions abutting the trachea and mainstem bronchi.19 
 
We plan to decrease bronchial toxicity risk in multiple ways.  First, we will reduce the high dose level for 
the target area in close proximity to the PBT when dose constraints cannot be met.For these patients, a high dose 
level of 67.5 Gy in 25 fractions will be prescribed, which is nearly biologically equivalent to 66 Gy in 24 fractions, 
which has been reported to be safe when used in patients with Stage III NSCLC with daily cisplatin.9  Second, 
during construction of the RT plan, any overlapping proximal bronchial tree plus a 5mm uniform expansion 
(planning organ at risk volume or PRV) will be excluded from the high dose PTV.  Second, we will provide dose 
constraints to bronchial structures (mandatory for maximal dose, and ideal for volumetric constraints) in a similar 
fashion to RTOG 0813.  Finally, we will limit the maximum dose in the entire plan to no more than 115%, unlike 
the Nordic HILUS study, further reducing the risk of very high doses of radiation being delivered to the proximal 
bronchial tree due to intrafractional motion. 
Esophagus 
As with the proximal bronchial tree, late esophageal toxicity is of concern in high dose radiotherapy to the 
mediastinum and centrally located lung tumors.  In RTOG 0813, esophagus adjacent to the target was limited to 
105% of the prescription dose.  They noted minimal late esophageal toxicity with doses up to 60 Gy in 5 fractions3  
Additionally, in Alliance/CALGB 31102, the esophagus was limited to a maximal dose of 105% of the prescription, 
and a V55 Gy of under 30%, with no reported late Grade 3 or higher toxicity.30  Furthermore, a recent normal tissue 
complication model of the esophagus developed based on patients treated with hypofractionated radiotherapy 
reported a 5% late high grade esophageal complication rate with a maximal EQD23 dose of 113.3 Gy.10 Based on 
these data, we will plan for mandatory esophagus constraints of 73.5 Gy (105% of prescription, EQD23 = 87.3 Gy) 


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and a V55 Gy under 30%.  As with the bronchial tree, the esophagus plus a 5mm uniform expansion will be 
excluded from the high dose target volume.   
 
Heart 
Dose constraints to the heart have become increasingly important in radiotherapy for NSCLC.  RTOG 0617 has 
reported decreased overall survival for low doses of radiation to the heart.5  This may have accounted for the poorer 
overall survival seen in the high dose arm of the trial.  A recent analysis of this trial reported the heart V50 Gy as a 
significant stratification point, with a 1 year overall survival of 70.2% for patients with a heart V50 Gy under 25%, 
compared with 46.8% for those with a heart V50 Gy over 25%.27  An additional secondary analysis of the trial 
revealed decreased heart dose with the use of IMRT compared with 3D, despite larger target volumes in the intensity 
modulated radiation therapy (IMRT) patients.8  The same analysis reported that the heart V40Gy was significantly 
associated with overall survival on multivariable analysis.  We will plan to use more strict dose constraints on this 
protocol, as well as anticipated near universal use of IMRT, in order to minimize the risk of late cardiac toxicity. 
Clinical Summary 
The therapeutic options for patients with Stage II-III NSCLC and ultracentral early stage NSCLC who are not 
eligible for surgery or definitive chemoradiotherapy are controversial. Fractionated radiation therapy alone is often 
the only option for these patients. Radiation therapy alone can be given in several manners, using conventional 
fractionation or hypofractionated radiotherapy.  Conventional radiotherapy alone (without concurrent chemotherapy) 
results in inadequate disease control and survival. Multiple retrospective studies have evaluated the efficacy of HRT 
regimens with widely variable results.  Prospective data on the use of HRT using modern radiotherapy techniques is 
lacking, and the available evidence is limited by the potentially poor patient selection and inadequate dose 
constraints to the tracheobronchial tree.  In this proposed phase 2 study, we aim to assess prospectively, a regimen 
that our institution has shown to have efficacy and safety in patients with up to Stage IIB disease using an SIB 
technique to stay within the threshold of critical normal tissue tolerance, including major airway structures, the 
heart, and the esophagus. 
2.0 
Objectives 
 
2.1 
Primary Objective(s) 
 
2.1.1 
To determine the in-field control of hypofractionated radiotherapy consisting of 70 Gy in 
25 fractions without concurrent chemotherapy measured at two years after the first post- 
radiotherapy scan.  
2.2 
Secondary Objective(s) 
 
2.2.1 
To determine the toxicity profile of thoracic HRT consisting of 70 Gy in 25 fractions as 
graded by CTCAE version 5.0 
2.2.2 
To determine proportion with local, regional, and distant progression at 1 and 2 years 
after the first post-radiotherapy scan, and compute progression-free and overall survival 
(PFS and OS, respectively). 


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3.0 
Patient Selection 
 
3.1 
Inclusion Criteria  
 
3.1.1 
Histological confirmation of non-small cell lung cancer by either biopsy or cytology 
3.1.2 
AJCC 8th Edition Stage II-III or ultracentral Stage IB disease as determined by PET/CT 
and MRI Brain 
3.1.2.1 Ultracentral disease will be defined as edge of gross visible tumor within 1cm of 
the proximal bronchial tree 
3.1.3 
ECOG Performance Status of 0-3 
3.1.4 
Patient is not eligible for or has declined surgical resection or SBRT as determined by the 
treating physician 
3.1.5 
Patient is not eligible for or has declined concurrent chemotherapy as determined by the 
treating physician 
3.1.5.1 While we expect it to be an uncommon event, sequential use of systemic therapy 
after completion of RT is permissible if the patient’s status improves such that 
they become eligible for such therapies, per the discretion of a multidisciplinary 
tumor board. 
3.1.6 
Negative serum or urine pregnancy test within 2 weeks of the date of enrollment 
for women of child-bearing potential 
3.1.7 
Ability to understand and the willingness to sign an IRB-approved informed consent 
document (either directly or via a legally authorized representative). 
3.2 
Exclusion Criteria  
 
3.2.1 
History of previous thoracic radiotherapy with the exception of prior radiotherapy for 
breast cancer without overlap of the fields with the cancer to be treated 
3.2.2 
Prior systemic therapy or surgery for the study cancer 
3.2.3 
Prior malignancy within the past two years except for non-melanoma skin cancer, 
prostate cancer, or any in-situ malignancy 
3.2.4 
Receipt of anti-angiogenic therapy, such as bevacizumab, within 6 months of enrollment 
3.2.5 
Pregnant women are excluded from this study because radiation therapy has known 
potential for teratogenic or abortifacient effects.  
 
3.3 
Inclusion of Women and Minorities 
 
 
 
 
Men and women of all races and ethnicities who meet the above-described eligibility 
criteria are eligible to participate in this study. The study consent form will also be provided in 
Spanish for Spanish-speaking participants.  
 
 
 
 
Based on WFBCCC population estimates, we may expect approximately 44% of 
participants to be women. Translating this to our sample size estimate of 43, we may enroll 
approximately 19 women. We may enroll approximately 10-13% Black or African American. 
Based on our catchment area and hospital demographics we do not expect accruals of individuals 
of Hispanic/ Latino, American Indian/Alaska Native or Asian ancestry; however, no individual 
will be excluded from the study if they satisfy the above inclusion/exclusion criteria. Should we 
not meet or exceed these estimates, the PI will engage the Office of the Center for Health Equity to 
discuss strategies to enhance recruitment in these target populations. 
 
4.0 
Registration Procedures 
 


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All patients entered on any WFBCCC trial, whether treatment, companion, or cancer control trial, must be linked to 
the study in EPIC within 24 hours of Informed Consent. Patients must be registered prior to the initiation of 
treatment.   
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu)            
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
You must perform the following steps in order to ensure prompt registration of your patient: 
 
1. Complete the Eligibility Checklist (Appendix A) 
2. Complete the Protocol Registration Form (Appendix B) 
3. Alert the Cancer Center registrar by phone, and then send the signed Informed Consent Form, 
Eligibility Checklist and Protocol Registration Form to the registrar, either by fax or e-mail. 
4. Fax/e-mail ALL eligibility source documents with registration. Patients will not be registered without 
all required supporting documents.  Note: If labs were performed at an outside institution, provide a 
printout of the results. Ensure that the most recent lab values are sent. 
To complete the registration process, the Registrar will:   
● 
Assign a patient study number 
● 
Register the patient on the study 
5.0 
Study Outcomes and Study Measures 
5.1 
Primary Outcome 
5.1.1 
The primary outcome measure will be presence/absence of any in-field progression by 2 
years.  In-field progression is defined as growth of the targeted lesions beyond the treated 
volume.  The treated volume will be defined as the 28.75 Gy isodose line (50% of 57.5 
Gy).  Pathologic confirmation of tumor progression is preferred, but can be determined 
radiographically by Multidisciplinary Thoracic Oncology Program consensus if biopsy of 
the lesion in question is not feasible or safe. 
5.2 
Secondary Outcomes 
5.2.1 
Toxicities will be evaluated per CTCAE Version 5.0 one month following completion of 
therapy and then every 3 months thereafter until 25 months from completion of radiation 
therapy. 
5.2.2 
Patterns of progression will be defined as follows: Local progression will be defined as in 
field progression (see Section 5.1.1); regional progression will be defined as any new 
regional lymphadenopathy in the hilum or mediastinum that was not included in the gross 
tumor volume (GTV); distant progression will be defined as any radiographic or 
pathologic evidence of disease outside the primary tumor and regional lymph nodes, 
including subsequent pulmonary parenchymal lesions. Progression-free survival will be 
evaluated by considering the time from registration to progression of disease or death; 
those who do not experience either outcome will be censored at date of last visit. Overall 
survival will be evaluated by considering the time from registration to death from any 
cause; those who do not die will be censored at date of last visit. Progression will be 
assessed through CT scans administered immediately following treatment and then every 
3 months after that, out to 25 months.  
 


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6.0 
Treatment Plan 
6.1 
Study-Related Activities  
 
 
 
Activity 
 
Pre- 
Studya 
Prior to 
First 
Fraction of 
RT 
 
At Each 
Weekly 
Treatment 
Visit on 
RT 
 
1 month after 
RT completion 
 
Every 3 months 
after 1 month 
post-RT scan 
until 25 months 
after RTl 
 
Informed consent 
 
X 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
X 
X 
 
Concurrent meds 
 
X 
 
 
 
 
 
Physical exam 
 
X 
 
 
X 
X 
 
Vital signsg 
 
X 
 
 
X 
X 
 
Heightd, Weight,g 
 
X 
 
 
X 
X 
 
Performance Statusg 
 
X 
 
X 
X 
X 
 
Tumor measurementse 
 
X 
 
 
X 
X 
 
B-HCGb 
 
X 
 
 
 
 
FDG PET/CT Skull Base 
to Mid Thighj 
X 
 
 
 
 
MRI Brain with contrasti 
X 
 
 
 
 
 
CT Chest/Abdomenc 
 
 
 
 
X 
X 
 
Adverse event evaluationf 
 
X 
 
X 
X 
X 
Mandatory target 
coverage/dose constraint 
compliancek 
 
 
X 
 
 
 
a Pre-study requirements listed in table must be completed within 12 weeks prior to registration. 
b Serum or urine pregnancy test (women of childbearing potential).  This must be completed within one week 
prior to initiation of radiotherapy for women of childbearing potential. For our purposes postmenopausal women 
are defined as women over the age of 45 years old with at least 12 months from their date of last menstruation. 
c CT Chest/Abdomen will be with contrast unless the patient has a documented contraindication to IV CT contrast 
(ie inadequate renal function or anaphylaxis).  The scan must include the entire bilateral lungs, liver, and bilateral 
adrenal glands.  CT Chest/Abdomen/Pelvis is also acceptable. 
d Height measured at pre-study only 
e See Appendix Q 
f See Appendices F and G 
g See Appendix L 
h See Appendix C 
i If MRI is contraindicated, CT Head with contrast is also acceptable. 
j  National guidelines indicates a PET scan is good for 3 months (12 weeks). 
k See Appendix N 
l For all follow-up imaging and clinic follow-up time points above, a flexibility window of +/- 8 weeks is allowed.  


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6.1.1 
Radiation Therapy 
 
Hypofractionated radiation therapy will be delivered to all patients.  The prescribed dose will be 
70 Gy in 25 fractions 
 
1. Technical Factors and Radiation Planning 
a. 
Radiation Dose Selection 
i. 
The radiation dose for the high dose PTV was selected based on previous clinical 
experience with 70.2 Gy in 26 fractions, and decreasing the treatment course by one 
fraction, leading to a high dose of 70 Gy in 25 fractions.  As this dose is likely not 
necessary for control of microscopic disease treated in the clinical target volume (CTV), 
a lower dose CTV will be treated to 57.5 Gy in 25 fractions.  This lower dose was 
selected based on BED and EQ2D calculations, which can be used to compare doses 
using non-standard (ie non 1.8-2 Gy) fraction sizes (see Table 1).   
ii. 
 
Table 1.  COMPARISON BED and EQD2 for Dose Fractionation Schemes 
Dose / Fractions 
BED10 Gy 
(Tumor) 
BED3 Gy 
(Normal 
Tissue) 
EQD210 
Gy 
(Tumor) 
EQD23 Gy 2 
(Normal 
Tissue) 
60 Gy / 30 fx (SoC) 
72 
100 
60 
60 
66 Gy / 30 fx 
80.52 
114.4 
67.1 
68.84 
70.2 Gy / 26 fx 
89.15 
133.38 
74.3 
80.03 
58.5 Gy / 26 fx 
71.66 
102.38 
59.72 
61.43 
66 Gy / 24 fx 
84.15 
126.5 
70.13 
75.9 
70 Gy / 25 fx 
89.6 
135.33 
74.67 
81.2 
67.5 Gy / 25 fx 
85.73 
128.25 
71.44 
76.95 
57.5 Gy / 25 fx 
70.72 
101.58 
58.94 
60.95 
 
b. CT Simulation 
i. 
All patients will undergo CT simulation of the chest.  The use of intravenous contrast 
with the CT simulation is not mandatory.   
ii. 
4D-CT will be obtained for motion management.  The use of abdominal compression or 
respiratory gating is encouraged. 
iii. 
Immobilization will be done with a customized vacuum sealed bag.  
 
 
c. 
Target Volume Definitions: 


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i. 
GTV = gross tumor (both primary and lymph nodes) on CT simulation.  Lymph nodes > 
1 cm in short axis diameter or with an SUV > 3 are considered to be involved unless 
proven negative by biopsy.   
ii. 
iGTV = GTV accounting for tumor motion on all phases of 4D CT 
iii. 
CTV_7000 = iGTV with no expansion 
iv. 
CTV_5750 = iGTV uniformly expanded by 5mm 
1. CTV_5750 can be excluded from normal structures without radiographic 
evidence of invasion (for example≤ vertebral bodies, chest wall, or ribs) 
2. CTV_5750 should not be excluded from the trachea, esophagus, proximal 
bronchial tree, or intrathoracic cardiovascular structures 
v. 
PTV_7000 = CTV_7000 uniformly expanded 5mm minus Esophagus_PRV, PBT_PRV, 
and Brachial_Plexus_PRV (if applicable) 
vi. 
PTV_5750 = CTV_5750 uniformly expanded by 5mm 
vii. 
PTV_6750 = PTV_7000 minus PBT_1cm 
1. PTV_6750 will only be delineated in cases where dose constraints for the PBT 
cannot be met 
 
d. Organs at Risk to be contoured 
i. 
For all patients 
1. Bilateral lungs 
2. Spinal cord (5 cm above and below the PTV) 
3. Aorta (5 cm above and below the PTV) 
4. Esophagus (entire length) 
5. Esophagus_PRV = Esophagus plus 5mm uniform expansion 
6. Heart (including the pericardial sac) 
7. Trachea/proximal bronchial tree 
a. 
5 cm superior to the PTV to the end of all main lobar bronchi 
8. PBT_PRV = trachea and proximal bronchial tree plus 5mm uniform expansion 
ii. 
For patients with the PTV within 2 cm of the organ at risk* 
1. Brachial plexus  
a. 
Only the major trunks of the brachial plexus need to be contoured 
b. Left and right brachial plexuses should be contoured separately with 
generation of separate Brachial_Plexus_PRVs if the PTV is within 2 
cm of both brachial plexuses 
2. Brachial_Plexus_PRV = Brachial plexus plus 5mm uniform expansion 
3. Chest wall (3 cm superior and inferior to the PTV) 
4. Ribs 
5. Stomach 
6. Liver 
 
 
 
 
* if non-coplanar beams or arcs are used then all organs at risk must be contoured 
iii. 
For patients who cannot meet PBT dose constraints 
1. PBT_1cm = trachea and proximal bronchial tree plus 1 cm uniform expansion 
iv. 
 
e. 
Target Coverage Requirements 
i. 
Mandatory 
1. 95% of PTV_5750 to at least 95% of prescription (54.63 Gy) 
2. 99% of PTV_5750 to at least 90% of prescription (51.75 Gy) 
ii. 
Ideal 
1. 95% of PTV_7000/6750 to at least 95% of prescription (66.5 Gy/64.13 Gy) 
2. 100% of PTV_7000/6750 to at least 95% of prescription (66.5 Gy/64.13 Gy) 
3. 95% of PTV_7000/6750 to at least 100% of prescription (70 Gy/67.5 Gy) 
4. 99% of PTV_7000/6750 to at least 90% of prescription (63 Gy/60/75 Gy) 
5. 100% of PTV_5750 to at least 95% of prescription (54.63 Gy) 


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f. 
Organ at Risk Constraints 
i. 
Mandatory 
1. Spinal Cord: D0.03 cm3 < 45 Gy 
2. Esophagus: D0.03 cm3 < 73.5 Gy;  
3. Lungs-GTV: V20 Gy ≤ 35%;  
4. Proximal Bronchial Tree: D0.03 cm3 < 73.5 Gy; D3 cm3 < 66.25   
5. Heart D100% < 30 Gy 
6. Stomach: D0.03cm3 < 60 Gy 
7. Liver: Mean dose < 30 Gy; at least 700 cm3 of normal liver to < 15 Gy 
8. Maximum physical dose < 115% of high dose prescription 
a. 
PTV_7000: maximum physical dose < 80.50 Gy 
b. PTV_6750: maximum physical dose < 77.63 Gy 
ii. 
Ideal 
 
1. Lungs-GTV: V40 Gy < 10%; V30 Gy < 15%; V20 Gy < 30%; V10 Gy < 60%; 
mean dose < 20 Gy 
2. Proximal bronchial tree: Gy; D15% < 60 Gy 
3. Esophagus: Mean dose < 34 Gy; D10 cm3 < 60 Gy; D30% < 55 Gy 
4. Aorta: D0.03 cm3 < 76 Gy; D10 cm3 < 60 Gy 
5. Heart: Mean dose < 30 Gy; D25% < 50Gy; V45Gy < 30%;D0.03cm3 <73.5Gy 
6. Brachial plexus:  D0.03cm3 < 60 Gy 
7. Stomach: D0.03cm3 < 58 Gy; V50 Gy < 5 cm3; V45Gy < 75 cm3 
8. Liver:  Mean dose < 28 Gy 
9. Chest Wall: V30 Gy < 70 cm3 
10. Ribs: D0.03 cm3 < 57 Gy 
11. Maximum dose < 108% of high dose prescription 
a. 
PTV_7000: maximum physical dose < 75.6 Gy 
b. PTV_6750: maximum physical dose < 72.9 Gy 
g. Radiation Therapy prescription and planning 
i. 
Radiation prescription 
1. A simultaneous integrated boost will be used to treat all PTVs 
2. PTV_7000 = 70.00 Gy in 25 fractions (2.80 Gy per fraction) 
a. 
PTV_6750 = 67.5 Gy in 25 fractions (2.70 Gy per fraction) 
3. PTV_5750 = 57.50 Gy in 25 fractions (2.30 Gy per fraction) 
ii. 
3D-CRT, static IMRT, or VMAT plans are acceptable 
1. IMRT or VMAT are strongly preferred 
iii. 
Heterogeneity corrections will be used for all dose calculations 
iv. 
At least 95% of PTV_5750 must be covered by at least 95% of the prescription dose for 
that PTV.  If mandatory dose constraints to organs at risk are unable to be met, ideal 
target coverage requirements may be compromised at the discretion of the treating 
physician.  
v. 
Ideally no more than 1cm3 of normal tissue outside the PTV_5750 may receive > 62.1Gy 
vi. 
Circumferential high dose irradiation (70 Gy or higher) of the trachea, bronchus, and 
esophagus should be avoided 
h. Radiation Therapy Delivery 
i. 
Radiation therapy will be delivered once daily, 5 days per week, Monday-Friday.   
1. In cases where Radiation Oncology clinic is closed, the patient may receive only 
4 fractions per week at the discretion of the treating radiation oncologist. 
2. Treatment breaks are allowable per the discretion of the treating radiation 
oncologist. 
ii. 
Daily image guidance with cone beam CT is recommended. 
 
 


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6.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients should receive full supportive care, including transfusions of blood and blood products, 
erythropoietin, antibiotics, antiemetics, etc., as clinically indicated. Anti-inflammatory or narcotic 
analgesics may be offered as needed. Medications considered necessary for the patient's well-being may be 
given at the discretion of the investigator, i.e., chronic treatments for concomitant medical conditions, as 
well as agents required for life-threatening medical problems, etc. The reason(s) for treatment, dosage, and 
dates of treatment should be recorded on the flow sheets. 
 
6.3 
Duration of Therapy/Study Follow-up 
 
Treatment may continue until the completion of radiotherapy or until one of the following criteria applies: 
 
● 
Disease progression 
● 
Intercurrent illness that prevents further administration of treatment 
or ability to present for follow-up visits (i.e. hospitalized) 
● 
Unacceptable adverse event(s) 
● 
Patient decides to withdraw from the study, or further follow-up on study 
● 
General or specific changes in the patient's condition that render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
• 
If patients have disease progression or require further radiation treatment outside the protocol, they will be 
treated at the discretion of their treating physician.  They will be followed for local control and survival for 
25 months after they have completed their initial radiation. 
 
 
6.4 
Duration of Follow Up 
 
Patients will be followed for a minimum of 30 days after the last radiation therapy fraction is administered 
for adverse events monitoring, unless otherwise specified in this section of the protocol. A different time 
frame may be longer but not shorter than 30 days unless a specific scientific rationale is presented to 
suggest that a shorter window can be used to identify events. Follow-up for serious adverse events and 
mortality after the last study dose is administered will take place during the routine clinic visits that the 
patient will have during the 30 day follow-up window (Also referenced in Appendix D).  If no visit occurs 
during this window, a phone call confirmation should be made to the patient to determine vital status and 
whether any adverse events and in particular, Grade 4 unexpected adverse events occurred during that 
window of time and recorded on Appendix F.   
 
Patients will be followed 25 months or until death after the last study radiation treatment for monitoring 
survival study endpoints. 
 
6.5 
Criteria for Removal from Study 
 
Patients may be removed from study when any of the criteria listed in section 6.3 applies.  
7.0 
Dosing Delays/Dose Modifications 
 
7.1 
Any Grade 3 or higher acute toxicity with the exception of hematologic and laboratory toxicity may  
result in a treatment break at the discretion of the treating investigator until it resolves to Grade 2 or 
less. Duration of treatment break is at the discretion of the treating radiation oncologist.  All labs will 


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be assessed by the treating physician to determine whether they are considered clinically significant 
or not clinically significant and treatment will be held at their discretion.  
8.0 
Measurement of Effect 
 
8.1 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the Response Evaluation Criteria in 
Solid Tumors (RECIST) criteria 1.1.1 Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria. 
8.1.1 
Survival Outcomes 
 
Progression-Free Survival is defined as the duration of time from the start of treatment to the time 
of progression, death, or date of last contact; those lost to follow-up will be censored. 
 
Overall Survival is defined as the duration of time from the start of treatment to date of death or 
date of last contact; those lost to follow-up will be censored. 
 
9.0 
Adverse Events List and Reporting Requirements 
9.1 
Adverse Event List for Hypofractionated Thoracic Radiotherapy 
9.1.1      
 Cardiac and Pericardial Injury 
9.1.1.1 
 
Although acute cardiac and pericardial injury is uncommon in the conventionally 
fractionated course of RT, with larger doses per fraction of this study, a number of 
possible side-effects can be seen.  
 
9.1.1.2 
 
Dose to the heart has been shown to impact long term overall survival.  All attempts 
to minimize dose to the heart will be made in accordance with the dose constraints in 
Section 6.2.1 
 
9.1.2 
Gastrointestinal/Esophageal Injury  
9.1.2.1 
 
The radiation effects on the esophagus can be acute: esophagitis (i.e., dysphagia, 
causing pain on swallowing, typically relatively soon after RT course is completed, 
and typically resolves on its own within days to a week or longer), or chronic, 
typically manifesting with dysphagia due to stenosis, or esophageal ulceration, with 
perforation in the extreme cases. The stomach and small bowel are also susceptible 
to radiation injury that manifests as nausea, anorexia, and vomiting (acute) or 
stenosis, ulceration, or rarely perforation (late).  The liver is exquisitely sensitive to 
radiation therapy.  Acute manifestation of liver toxicity is usually reflected by 
increasing hepatic enzymes (AST and ALT), as well as nausea.  Late radiation 
hepatotoxicity is extraordinarily rare when treating intrathoracic malignancies, as 
large amounts of the liver can be irradiated to high doses as long as an adequate 
volume of liver is spared and the mean dose is kept below 30 Gy (see Section 6.2.1). 


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9.1.3 
Central Airway/Bronchial Injury  
9.1.3.1 
 
Severe injury to the proximal tracheobronchial tree, resulting in fistula formation or 
hemoptysis, which may be fatal, is possible but rare (<5%).  This bronchial injury 
with subsequent focal collapse of lung may impair overall pulmonary status. It also 
makes further assessment of tumor response more difficult as the collapsed lung 
approximates the treated tumor. Because atelectatic lung and tumor have similar 
imaging characteristics, radiology reports will often describe the overall process as 
progressive disease while the actual tumor may be stable or shrinking.  The 
consequences of bronchial toxicity, e.g., cough, dyspnea, hypoxia, impairment of 
pulmonary function test parameters, pleural effusion or pleuritic pain (associated 
with collapse), should all be graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE), v. 5.0;  
9.1.4 
Lung Injury  
9.1.4.1 
 
Radiation pneumonitis is a subacute (weeks to months from treatment) inflammation 
of the end bronchioles and alveoli. Radiation fibrosis is a late manifestation of 
radiation injury to the irradiated lung. It is very important that a Radiation 
Oncologist participate in the care of the patient, as the clinical picture may be very 
similar to acute bacterial pneumonia, with fatigue, fever, shortness of breath, 
nonproductive cough, and a pulmonary infiltrate on chest x-ray. The infiltrate on 
chest x-ray should include the area treated to high dose, but may extend outside of 
these regions. The infiltrates may be characteristically “geometric” corresponding to 
the radiation portal, but may also be ill defined. Patients reporting symptoms as 
above will be promptly evaluated and treated. Mild radiation pneumonitis may be 
treated with nonsteroidal anti-inflammatory agents or steroid inhalers. More 
significant pneumonitis will be treated with systemic steroids, bronchodilators, and 
pulmonary toilet. Supra- and concurrent infections should be treated with antibiotics. 
Consideration of prophylaxis of opportunistic infections should be considered in 
immunocompromised patients. 
 
9.1.5 
Spinal Cord or Brachial Plexus Injury 
9.1.5.1 
 
Radiation myelitis and brachial plexopathy are rare late effects of radiation therapy 
(<1%).  In the extremely rare cases where radiation myelitis occurs, common 
symptoms include neuropathic pain, progressive weakness, and sensory changes.  
Radiation-induced brachial plexopathy presents in a similar fashion to radiation 
myelitis, with symptoms being limited to areas innervated by the affected brachial 
plexus.   
 
9.1.6 
Chest wall pain/rib fractures 
9.1.6.1 
 
Chest wall pain and/or pathologic rib fractures are uncommon complications of 
radical radiotherapy that are most frequently seen in the setting of SBRT to very 
peripheral lung lesions.  The most common symptom of the syndrome is pain in an 
area of the chest wall in very close proximity to high dose areas which typically 
responds to NSAIDs. 
9.2 
Adverse Event Characteristics 
 
● 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will 
be utilized for AE reporting. All appropriate treatment areas should have access to a copy of 


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the CTCAE version 5.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). 
 
● 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for 
expedited reporting purposes only.   
 
● 
Attribution of the AE: 
 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
9.3 
STRC SAE Reporting Requirements 
 
The Data Safety Monitoring Committee (DSMC) is responsible for reviewing SAEs for WFBCCC 
Institutional studies as outlined in Appendix D. All Adverse Events that occur during protocol intervention 
and are coded as either 1) unexpected grade 4, 2) unplanned inpatient hospitalization ≥ 24 hours (regardless 
of grade), or grade 5 (death) must be reported to the DSMC using the using the SAE console in WISER.  
 
All WFBCCC Clinical Protocol and Data Management (CPDM) staff members assisting a Principal 
Investigator in investigating, documenting and reporting an SAE qualifying for DSMC reporting are 
responsible for informing a clinical member of the DSMC as well as the entire committee via the email 
notification procedure of the occurrence of an SAE.  
9.4 
WFUHS IRB AE Reporting Requirements 
 
 
Any unanticipated problems involving risks to subjects or others and adverse events shall be promptly 
reported to the IRB, according to institutional policy. Reporting to the IRB is required regardless of the 
funding source, study sponsor, or whether the event involves an investigational or marketed drug, biologic 
or device. Reportable events are not limited to physical injury, but include psychological, economic and 
social harm. Reportable events may arise as a result of drugs, biological agents, devices, procedures or 
other interventions, or as a result of questionnaires, surveys, observations or other interactions with 
research subjects. 
 
 
All members of the research team are responsible for the appropriate reporting to the IRB and other 
applicable parties of unanticipated problems involving risk to subjects or others. The Principal Investigator, 
however, is ultimately responsible for ensuring the prompt reporting of unanticipated problems involving 
risk to subjects or others to the IRB. The Principal Investigator is also responsible for ensuring that all 
reported unanticipated risks to subjects and others which they receive are reviewed to determine whether 
the report represents a change in the risks and/or benefits to study participants, and whether any changes in 
the informed consent, protocol or other study-related documents are required. 
 
 
Any unanticipated problems involving risks to subjects or others occurring at a site where the study has 
been approved by the WFUHS IRB (internal events) must be reported to the WFUHS IRB within 7 
calendar days of the investigator or other members of the study team becoming aware of the event. 
 


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Any unanticipated problems involving risks to subjects or others occurring at another site conducting the 
same study that has been approved by the WFUHS IRB (external events) must be reported to the WFUHS 
IRB within 7 calendar days of the investigator or other members of the study team becoming aware of the 
event. 
 
 
Any event, incident, experience, or outcome that alters the risk versus potential benefit of the research and 
as a result warrants a substantive change in the research protocol or informed consent process/document in 
order to insure the safety, rights or welfare of research subjects.  
10.0 Data Management 
 
Informed consent document 
EPIC 
Protocol registration form 
WISER/OnCore 
Pre-Toxicity 
WISER/OnCore 
Off study, Off treatment, Withdrawal 
WISER/OnCore 
Vitals Form 
REDCap 
Con-med PRN Form 
WISER/OnCore 
Follow up Post Washout 
REDCap 
Treatment Response Evaluation 
REDCap 
Pattern of Progression 
REDCap 
Adverse Events Log 
WISER/OnCore 
Mandatory Target Coverage/Dose Constraint 
Compliance Confirmation 
REDCap 
 
This project will utilize REDCap Clinical Data Interoperability Services. This is a special 
feature for importing data into REDCap from WakeOne. It provides an adjudication process 
whereby REDCap users can approve all incoming data from WakeOne before it is officially 
saved in their REDCap project. REDCap Clinical Data Interoperability Services can only be 
enabled by a REDCap administrator who serves as an honest broker to PHI. REDCap’s Clinical 
Data Interoperability Services can only be accessed by users with valid WakeOne credentials. 
Using the Clinical Data Interoperability Service requires using the Medical Record Number 
(MRN) as a key to automatically gather demographics and laboratory data and reduces data 
entry errors. 
 
11.0 Statistical Considerations 
 
With the exception of our primary aim, which is comparative and hypothesis-testing (relative to a historical control), 
the rest of our analysis plan is largely descriptive in nature. 
 
11.1 
Analysis of Primary Objective 
 
 
11.1.1 We will compare the proportion of the sample with any in-field progression at 2 years to the 
historical control proportion of 0.5, using a one-sample z-test. We expect that a proportion 


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(around 10-15%) of our initial baseline sample will be missing data on this primary outcome at 
2 years, and therefore we have correspondingly increased our target recruitment by this 
percentage (see section 11.3 below).    
11.2 
Analysis of Secondary Objective 
 
11.2.1 We will compute the proportion of the sample developing any toxicity of grade 2 or higher over 
the 25 months, and construct a corresponding 95% confidence interval. 
11.2.2 
We will compute proportions of patients who have experienced local progression by 13 
months (1 year following first post-radiotherapy scan) and by 25 months (2 years following 
first post-radiotherapy scan), and will also compute the same two proportions considering 
regional progression, distant progression, and any (of the 3 categories) progression.  We will  
construct 95% confidence intervals around these proportions. Those patients for whom we are 
unable to determine progression status at 1 and 2 years (e.g., because they do not return for 
the necessary scans, or because they die without evidence of progression) will be left out of 
these analyses.  We will evaluate PFS and OS first using the Kaplan-Meier lifetable method, 
and will estimate median survival and corresponding 95% CIs; we will also explore simple 
Cox proportional hazards models of each of these survival outcomes, to examine the 
predictive influence of variables such as age, gender, ECOG performance status, stage at 
diagnosis, PTV 7000+6750 volume, and PTV 5750 volume. Patients who are lost to follow-
up will be censored at that time in these analyses.  
11.3 Power and Sample Size 
11.3.1 
Prior studies suggest an average proportion of 0.50 of patients who are free from in-field  
progression at 2 years following standard radiotherapy alone.4,9  Based on prior reports of dose 
escalated hypofractionated radiotherapy and our institutional experience using a similar dose 
fractionation scheme, we hypothesize that HRT will improve 2 year freedom from in-field 
progression from this 50% to 75%.1,2,22  With a sample size of n=25, we will have 80% power to 
detect this increase, assuming a one-tailed  α of 0.05. We anticipate that approximately 10% -15% 
of patients recruited will not provide data on our primary outcome at 2 years, so we anticipate 
recruiting n=30 patients total to allow us to have a total n of 25 for our primary analysis. 
 
  11.4 Estimated Accrual Rate 
11.4.1 Based on review of recent case volume at WFBMC, we estimate one accrual per 
month across all sites, or 12 patients per year. 
 
11.5 Estimated Study Length 
11.5.1 Based on the estimated accrual rate, we anticipate a 2.5 year (29-31 months) duration 
of accrual. 
 
11.6 Interim Analysis Plan 
 
 
 
No formal interim analysis is planned; however, if 5 patients develop Grade 4 or 5 bronchial fistula, 
bronchopulmonary hemorrhage, esophageal fistula, hemorrhage or perforation as defined by CTCAE 
version 5.0, the study will be halted.  Patients who have known in-field progression of disease or new or 


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progressive disease involving the structure that develops the Grade 4 or 5 toxicity prior to toxicity 
development will not be counted. 


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Page 23 of 49 
 
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Jeter MD, Gomez D, Nguyen Q-N, Komaki R, Zhang X, Zhu X, et al: Simultaneous Integrated Boost for 
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Kachnic LA, Winter K, Myerson RJ, Goodyear MD, Willins J, Esthappan J, et al: RTOG 0529: a phase 2 
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mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol 
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50:2939–2949, 2014 
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ultra-central lung tumors: prioritize target coverage or organs at risk? Radiat Oncol 13:57, 2018 
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Senthi S, Haasbeek CJA, Slotman BJ, Senan S: Outcomes of stereotactic ablative radiotherapy for central 
lung tumours: a systematic review. Radiother Oncol 106:276–282, 2013 
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Speirs CK, DeWees TA, Rehman S, Molotievschi A, Velez MA, Mullen D, et al: Heart Dose Is an 
Independent Dosimetric Predictor of Overall Survival in Locally Advanced Non-Small Cell Lung Cancer. J 
Thorac Oncol 12:293–301, 2017 
28.  
Tekatli H, Haasbeek N, Dahele M, De Haan P, Verbakel W, Bongers E, et al: Outcomes of 
Hypofractionated High-Dose Radiotherapy in Poor-Risk Patients with “Ultracentral” Non–Small Cell Lung 
Cancer. J Thorac Oncol 11:1081–1089, 2016 
29.  
Timmerman R, McGarry R, Yiannoutsos C, Papiez L, Tudor K, DeLuca J, et al: Excessive toxicity when 
treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable 
early-stage lung cancer. J Clin Oncol 24:4833–4839, 2006 
30.  
Urbanic JJ, Wang X, Bogart JA, Stinchcombe TE, Hodgson L, Schild SE, et al: Phase 1 Study of 
Accelerated Hypofractionated Radiation Therapy With Concurrent Chemotherapy for Stage III Non-Small 
Cell Lung Cancer: CALGB 31102 (Alliance). Int J Radiat Oncol Biol Phys 101:177–185, 2018 
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Westover KD, Loo BW Jr, Gerber DE, Iyengar P, Choy H, Diehn M, et al: Precision Hypofractionated 
Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation 
Trial. Int J Radiat Oncol Biol Phys 93:72–81, 2015 


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Appendix A – Eligibility Checklist 
 
IRB Protocol No.  
WFBCCC Protocol No.62220  
Study Title: A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced NSCLC Patients 
who Decline or are Ineligible for Surgery or Chemotherapy 
 
Principal Investigator Dr. Farris 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria is 
met 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab results) 
Histological confirmation of non-small cell lung 
cancer by either biopsy or cytology 
□ 
□ 
 
AJCC 8th Edition Stage II-III or ultracentral 
Stage IB NSCLC as determined by PET/CT and 
MRI Brain 
□ 
□ 
 
ECOG Performance Status of 0-3 
□ 
□ 
 
Patient is not eligible for or has declined 
surgical resection or SBRT as determined by the 
treating physician 
□ 
□ 
 
Patient is not eligible for or has declined 
concurrent chemotherapy as determined by the 
treating physician 
□ 
□ 
 
While we expect it to be an uncommon event, 
sequential use of systemic therapy after 
completion of RT is permissible if the patient’s 
status improves such that they become eligible 
for such therapies, per the discretion of a 
multidisciplinary tumor board. 
□ 
□ 
 
Negative serum or urine pregnancy test within 2 
weeks of the date of enrollment 
for women of child-bearing potential 
□ 
□ 
 
Ability to understand and the willingness to sign 
an IRB-approved informed consent document 
(either directly or via a legally authorized 
representative) 
□ 
□ 
 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to Confirm * 
(Please document dates and lab results) 
History of previous thoracic radiotherapy with 
the exception of prior radiotherapy for breast 
cancer without overlap of the fields with the 
cancer to be treated 
□ 
□ 
 
Prior systemic therapy or surgery for the study 
cancer 
□ 
□ 
 
Prior malignancy within the past two years 
except for non-melanoma skin cancer, prostate 
cancer, or any in-situ malignancy 
□ 
□ 
 
Receipt of anti-angiogenic therapy within 6 
months of enrollment 
□ 
□ 
 
Pregnant women are excluded from this study 
because radiation therapy has known potential 
for teratogenic or abortifacient effects 
□ 
□ 
 


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This subject is      ☐ eligible / ☐ ineligible     for participation in this study. 
 
OnCore Assigned PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility: _______________________  
 
Date: ___ ___ / ___ ___ / ___ ___ 
 
Signature of Treating Physician:  _____________________________________  
 
Date:  ___ ___ / ___ ___ / ___ ___ 
 
Signature of Principal Investigator**:  _____________________________________  
 
Date:  ___ ___ / ___ ___ / ___ ___ 
 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing the 
source, specifically state which document in the medical record was used to assess eligibility. Also include the date 
on the document. Example: “Pathology report, 01/01/14” or “Clinic note, 01/01/14” 
 
**Principal Investigator signature can be obtained following registration if needed 


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Appendix B – Protocol Registration Form 
 
DEMOGRAPHICS 
Patient: Last Name: _____________________ 
First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ 
DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
ZIPCODE:  
___ ___ ___ ___ ___ 
 
 
SEX:   
 ◻ Male     ◻ Female 
Ethnicity (choose one):   
◻ Hispanic 
◻Non-Hispanic 
Race (choose all that apply): 
◻ WHITE           ◻BLACK           ◻ ASIAN 
◻ PACIFIC ISLANDER                ◻ NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Primary Diagnosis: ____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
Performance Status: ___ ◻ ECOG   
 
 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to registration) 
◻ YES  ◻ NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by OnCore): 
___ ___ ___ ___ ___ ___ ___ ___ 
 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, Monday – Friday. 
 
Compete the eligibility checklist in WISER and then give the completed Eligibility Checklist and Protocol Registration 
Form must be hand delivered, faxed or e-mailed to the registrar at 336-713-6772 or registra@wakehealth.edu, 
respectively. 
 
 


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Appendix C - Race & Ethnicity Verification Form 
 
 
Thank you so much for helping us to verify your race and ethnicity to ensure the quality of our information. As a 
brief reminder, the information you provide today will be kept confidential. 
 
1. Are you: 
Hispanic or Latino/a 
Not Hispanic or Latino/a 
 
2. What is your race? One or more categories may be selected. 
White or Caucasian 
Black or African American 
American Indian or Alaskan Native 
Asian 
Native Hawaiian or Other Pacific Islander 
Other, Please Specify: ___________________________ 
          
      
 
 
Internal use only: 
 
 
 Name: ____________________ MRN#: ____________________  
 
Was the self-reported race and ethnicity of the participant verified at the time of consent? 
Yes        No 
 
Was a discrepancy found?       Yes         No 
         If yes, please provide what is currently indicated in the EMR:  
 
 
Ethnicity: ____________________  
Race: ____________________ 
Additional comments: __________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________


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Appendix D Safety and Toxicity Review Committee (STRC) Serious Adverse 
Event (SAE) Notification SOP 
 
Data and Safety Monitoring 
Committee (DSMC) Serious Adverse 
Event (SAE) Notification SOP 
Date: 02/11/2021 
 
Mandatory DSMC SAE Reporting Requirements in WISER 
This document describes reporting requirements of adverse events from WFBCCC 
Investigator Initiated interventional trials to the Data and Safety Monitoring 
Committee (DSMC). A trial is considered a WFBCCC Investigator Initiated interventional 
trial if the following criteria are met: 
 
1) The Principal Investigator (PI) of the trial is a member of a department at the 
Wake Forest University Baptist Medical Center. 
2) WFBCCC is considered as the primary contributor to the design, implementation 
and/or monitoring of the trial. 
3) The trial is designated as “Interventional” using the Clinical Research 
Categories definitions provided by the NCI in the Data Table 4 
documentation. 
(https://cancercenters.cancer.gov/GrantsFunding/DataGuide#dt4) 
 
There are two distinct types of WFBCCC Investigator Initiated interventional trials based 
on where patient enrollment occurs.  These include: 
 
1) Local WFBCCC Investigator Initiated interventional trials defined as trials where all 
patients are enrolled from one of the WFBCCC sites. These include the main 
outpatient Cancer Center clinics (located in Winston-Salem) as well as WFBCCC 
affiliate sites located in Bermuda Run (Davie Medical Center), Clemmons, 
Lexington, High Point, or Wilkesboro. 
2) Multi-Center WFBCCC Investigator Initiated interventional trials defined as trials 
where patients are enrolled from other sites in addition to WFBCCC sites.   
There are three types of trials that are included in this category: 
a. Trials sponsored by the NCI Community Oncology Research Program 
(NCORP) that are conducted at multiple sites where the PI is a member of a 
department at the Wake Forest University Baptist Medical Center. 
b. Trials sponsored by Industry that are conducted at multiple sites and the 
PI is a member of a department at the Wake Forest University Baptist 
Medical Center. 
c. Trials sponsored by WFBCCC that are conducted at multiple sites and the 
PI is a member of a department at the Wake Forest University Baptist 
Medical Center. 


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All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients 
enrolled on WFBCCC Investigator Initiated Interventional trials must be entered into the 
WISER system. The only exception to this requirement is for patients enrolled on NCORP 
trials at non- WFBCCC sites. AEs and SAEs for NCORP patients enrolled at WFBCCC sites 
must be entered into the WISER system. Once these AEs and SAEs are entered in WISER, 
certain actions must be taken regarding the reporting of specific Adverse Events to the 
DSMC. 
 
All Adverse Events that occur during protocol intervention (defined below) and are coded 
as either 1) unexpected grade 4, 2) unplanned inpatient hospitalization > 24 hours 
(regardless of grade), or grade 5 (death) must be reported to the DSMC using the using 
the SAE console in WISER. 
 
A research nurse or clinical research coordinator when made aware that an adverse event 
meets one of the above criteria has occurred on a WFBCCC Investigator Initiated 
interventional trial, is responsible for informing a clinical member of the DSMC by phone 
(or in-person) about the adverse event. The nurse/coordinator should contact the 
treating physician prior to calling the DSMC clinical member to obtain all details of the 
SAE, as well as all associated toxicities to be recorded along with the SAE. In addition, this 
nurse or coordinator is responsible for entering the adverse event information into the 
SAE console in WISER.  Once the adverse event has been entered into the SAE console an 
email informing the entire DSMC will be generated. 
 
THESE REPORTING REQUIREMENTS APPLY TO any staff member on the study team for a WFBCCC 
Institutional Interventional trial. Ultimately, the protocol PI has the primary responsibility for AE 
identification, documentation, grading and assignment of attribution to the investigational 
agent/intervention. However, when an AE event as described above is observed, it is the 
responsibility of the person who observed the event to be sure that it is reported to the DSMC. 
 
What is considered during protocol intervention? 
During protocol intervention is considered to be the time period while a patient is on study 
treatment or during the time period within 30 days of last study treatment (even if patient 
begins a new (non-study) treatment during the 30 days). This window of 30 days should be 
the standard window to be used in all protocols unless a specific scientific rationale is 
presented to suggest that a shorter window can be used to identify events. If it is a trial 
sponsored by Industry and the sponsor requires a longer window for monitoring of SAEs, 
then the longer window of time specified by the sponsor should be followed. 
 
What is considered as an Unexpected Grade 4 event? 
Any grade 4 event that was not specifically listed as an expected adverse event in the 
protocol should be considered as unexpected. A grade 4 adverse event can be considered to 
be unexpected if it is an event that would not be expected based on the treatment being 
received or if it is unexpected based on the health of the patient. In either case, if there is 


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any uncertainty about whether a grade 4 adverse event is expected or unexpected it should 
be reported to DSMC. 
 
DSMC notification responsibilities of the person (e.g., nurse) handling the reporting/documenting of 
the SAE in WISER: 
1. Make a phone call (or speak in person) to the appropriate clinical member of the 
DSMC according to the schedule as listed below (page if necessary). 
2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console 
in WISER WITHIN 24 HOURS of first knowledge of the event. Information can be 
entered and saved, but the DSMC members will not be notified until a date is 
entered into the  DSMC Notification Date Field. This will ensure that all persons that 
need to be made aware of the event (i.e., PI, study team members and DSMC 
members) will be notified; remember to file a copy of the confirmation. 
3. Document that the appropriate person(s) on the DSMC has been contacted. Indicate 
the name of the DSMC clinician that was contacted and the date and time contacted 
in the Event Narrative field in the SAE console of the particular subject. 
4. Document whether or not the protocol should be suspended based on the 
discussion with the DSMC clinician. This is the major function of the email 
notification. Enter whether the protocol should be suspended in the Event 
Narrative Field. 
5. Follow up/update the clinical member(s) of DSMC regarding any new developments 
or information obtained during the course of the SAE investigation and reporting 
process. 
 
Elements needed to complete the SAE form in the Subject Console in WISER (see Screen Shot 3): 
1. Event Date 
2. Reported Date 
3. Reported by 
4. If Grade 5, enter Death Date 
5. If Grade 5, enter Death occurred: within 30 days 
6. Event Narrative: Brief description (include brief clinical history relevant to this event, 
including therapies believed related to event). Begin narrative with the DSMC 
clinician who was notified and Date/Time notified. In addition, state attribution by 
DSMC clinician as either “Unrelated”, “Unlikely”, “Possibly”, “Probably”, or 
“Definitely”.  Always include the following here: 
i. DSMC clinician name, date/time contacted and comments 
ii. Date of last dose before the event 
iii. Is suspension of the protocol needed? Y/N 
7. Treating Physician comments 
8. PI comments, if available 
9. Protocol Attribution after discussion with DSMC clinician 
10. Outcome (Fatal/Died, Intervention for AE Continues, Migrated AE, Not 
Recovered/Not Resolved, Recovered/Resolved with Sequelae, Recovered/Resolved 
without Sequelae, Recovering and Resolving) 


A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced 
NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 32 of 49 
 
11. Consent form Change Required? Y/N 
12. SAE Classification *This is required in order for the email notification to be sent* 
13. Adverse Event Details – Enter all details for each AE associated with the SAE. 
a. Course start date 
b. Category 
c. AE Detail 
d. Comments 
e. Grade/Severity 
f. Unexpected Y/N 
g. DLT Y/N 
h. Attributions 
i. Action 
j. Therapy 
k. Click ADD to attach the AE Detail to the SAE. 
14. Enter Date Notified DSMC -- *This is required for the email notification to be sent* 
15. Click Submit. The auto-generated notification email will disseminate within 5 
minutes. If you do not receive an email within 5 minutes, check that you have 
entered the “Date Notified DSMC” and the “SAE Classification”. If these have been 
entered and the email still has not been received, take a screen shot of the SAE in 
WISER and immediately email it out to all of the DSMC members listed in this SOP. In 
the subject line, indicate that this is a manual transmission of the SAE in lieu of the 
auto-generated email. It is required that a notification goes to the DSMC members 
immediately so that their assessment can be obtained within the 24 hour period 
requirement. Contact the Cancer Center Programmer/Analyst to alert that there is an 
issue with the auto-generated email. 
 
The Clinical Members of DSMC to Notify by Phone or Page: 
 
Monday 
Tuesday 
Wednesday Thursday 
Friday 
Saturday Sunday 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed Porosnicu
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
 
Glenn Lesser, MD – Hematology Oncology  
Mercedes Porosnicu, MD-- Hematology Oncology  
Ryan Hughes, MD – Radiation Oncology  
Michael Goodman, MD -- Hematology Oncology  
Daniel Reed, MD -- Hematology Oncology  
Mary Beth Seegars, MD -- Hematology Oncology  
 
 
Definition of Unavailable: 
As a general guideline if the first clinician that is contacted does not respond to the phone 


A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced 
NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 33 of 49 
 
call or page within 30 minutes, then initiate contact with the next DSMC clinician listed in 
the table above on the particular day the SAE is being reported. Allow up to 30 minutes for 
the new DSMC clinician to respond to a phone call or page before contacting the next 
member in the table. These times (30 minutes) are a general guideline. Best judgment as a 
clinical research professional should be used giving considerations of the time of day, 
severity of the SAE, and other circumstances as to when it is appropriate to contact backup 
clinicians. If the event occurs near the end of day, then leave messages (voice or email) as 
appropriate and proceed with submitting the DSMC notification form. It is important to take 
reasonable steps and to document that some type of contact has been initiated to one or 
more of the clinical members of DSMC. 
 
DSMC CLINICAN RESPONSIBILITY: 
It is the responsibility of the DSMC clinician to review all reported events, evaluate the 
events as they are reported; and communicate a response to the Investigator, event reporter 
and the members of DSMC. The review will include but not be limited to the information 
reported; there may be times when additional information is needed in order for an 
assessment to be made and further communication directly with the investigator may be 
warranted. DSMC reserves the right to disagree with the Investigator's assessment. If DSMC 
does not agree with the Investigator, DSMC reserves the right to suspend the trial pending 
further investigation. If there is any immediate danger or harm that could be present for a 
future patient based on the information provided in the DSMC report then an immediate 
suspension of enrollment should be considered. 
 
 
AMENDMENTS TO PREVIOUS REPORTS 
If all pertinent information is unavailable with the initial submission, once the additional 
information is available do not submit a new report. Rather, go to the original email that 
was sent to the DSMC and using that email “reply to all”. Entitle this new email 
“Amendment for (list date of event and patient ID)” this will avoid duplications of the same 
event. List the additional information being reported. This information needs to be entered 
into WISER as well. To do this, go to the Subject console and click SAEs on the left column. 
Click on the appropriate SAE number that needs updating. Then click Update. This will 
allow additional  information to be added. 
 
 
Acronyms 
AE – Adverse Event 
DSMC-Data and Safety Monitoring Committee 
SAE-Serious Adverse Event 
WFBCCC – Wake Forest Baptist Comprehensive Cancer Center 
NCI-National Cancer Institute 
WISER –Wake Integrated Solution for Enterprise Research 
 
Screen Shots: 


A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced 
NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 34 of 49 
 
 
The following screen shots come from the SAE Console within the Subject Console in WISER. 
Screen Shot 1: 
 
 
 
 
 
 
 
Screen Shot 2:
 


 
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NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
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WFBCCC # 62220 
 
Page 35 of 49 
  
  
Screen Shot 3: 
 
 
 
Screen Shot 4: 
 
 
 
 
 
 


 
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NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 36 of 49 
  
  
Appendix  E:  BED Calculations for Dose Levels and Constraints 
 
𝑩𝑩𝑩𝑩𝑩𝑩 =  𝒅𝒅(𝒏𝒏)(𝟏𝟏+ 𝒅𝒅/(𝜶𝜶/𝜷𝜷) 
 
- 
Where: 
- 
BED = Biologic Effective Dose at a given alpha/beta ratio 
- 
d = dose per fraction 
- 
n = number of fractions 
- 
𝛼𝛼/𝛽𝛽= alpha/beta ratio 
 
𝑬𝑬𝑬𝑬𝑬𝑬𝑬𝑬 =  𝑩𝑩𝑩𝑩𝑩𝑩/(𝟏𝟏+ (𝟐𝟐/𝜶𝜶/𝜷𝜷)) 
 
- 
Where: 
- 
EQD2 = Equivalent dose in 2 Gy fractions 
 
 
BED and EQD2 Calculations 
Parameter 
Total 
Dose 
(Gy) 
Dose per 
fraction 
(Gy) 
Number of 
Fractions 
BED10 
(tumor) 
BED3 
(normal 
tissue) 
EQD210 
(tumor) 
EQD23 
(normal 
tissue) 
Standard Therapy 
60  
2 
30 
72 
100 
60 
60 
Prior Institutional 
HRT 
70.2 
2.7 
26 
89.15 
133.38 
74.3 
80.03 
Prior HRT with 
Low Dose 
Cisplatin 
66 
2.75 
66 
84.15 
126.5 
70.13 
75.9 
High Dose PTV 
70 
2.8 
25 
89.6 
135.33 
74.67 
81.2 
High Dose PTV 
(bronchial 
invasion) 
67.5 
2.7 
25 
85.73 
128.25 
71.44 
76.95 
Low Dose PTV 
57.5 
2.3 
25 
70.72 
101.58 
58.94 
60.95 
Volumetric PBT 
Constraint 
66.25 
2.65 
25 
83.81 
124.77 
69.84 
74.86 
Brachial Plexus 
Constraint* 
60 
2.4 
25 
74.4 
132 
62 
66 
* α/β of 2 used for normal tissue calculations for nervous system 


A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced NSCLC Patients who Decline or are 
Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 37 of 49 
  
  
 
Appendix F – Adverse Event Log 
 
WFBCCC Adverse Event (AE) Log 
PI: Farris_   Subject PID: ________________ 
MRN: ________________ 
Cycle #: _________            Cycle Start Date: ____________      Cycle Start Time: ___________         Cycle End Date: ____________           Cycle End Time: ____________                                                                     
Adverse Event 
CTCAE Term 
Lab 
Value 
Grade     
(1-5) 
per 
CTC 
Start 
Date 
End 
Date 
Attribution 
DEF=Definite  
PROB=Probable 
POSS=Possible 
UNLK=Unlikely 
UNRL=Unrelated 
Expected 
N=No   
Y=Yes 
Serious 
Adverse Event 
Detail        
NO=No               
LT=Life 
Threatening 
DTH=Death 
DIS=Disability 
HOS=Hospitali
zation  
CA=Caused 
congenital 
anomaly               
RI=Required 
intervention to 
prevent 
impairment  
Dose 
Limiting 
Toxicity 
(DLT)      
N=No      
Y=Yes 
Action Taken 
NO=None       
DR=Dose 
Reduced 
RI=Regimen 
Interrupted     
TD=Therapy 
discontinued 
INTR=Interru
pted then 
reduced 
Therapy 
Given   
NO=None  
SYM=Sympt
omatic  
SUP= 
Supportive    
VSUP=Vigo
rous 
supportive 
Reportable 
IRB-       
STRC-   
FDA     
Sponsor 
(Mark all 
that apply) 
Adverse 
Event 
Report 
(AER) 
Filed      
N=No   
Y=Yes 
Outcome  
R= 
Recovered 
TX=Still 
under 
treatment/ 
observation 
A=Alive 
with 
sequalae 
D=Died   
Treating 
MD 
Initials 
/Date 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serious Adverse Event: Hospitalization; Disability; Birth Defect; Life-threatening; Death. 
CTCAE Version 5 - https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf 
STRC- Safety and Toxicity Review Committee 
Version 1/10/18 


 
A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced 
NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 38 of 49 
  
  
Appendix G – Follow-up Form 
–  
Study Number: 62220   PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
Investigator: Michael Farris  M.D. 
Date: ___ ___/___ ___/___ ___ 
Instructions: Complete this form to follow-up with patients for adverse events.  
 
Name of Person Competing form_____________________________ 
 
Did the subject have any adverse events in the last 30 days?   Yes 
   No 
 
If yes, please describe nature and grade of AE (Note*: If an SAE occurs in this period, report the 
event as required in Appendix D): 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_______________________________ 
 
 
Was the subject removed from the study by the PI?  Yes 
   No 
 
 
Did the subject withdraw from the study?  Yes 
   No 
 
 
Did the subject complete the full course of SBRT and take the study drug?  Yes 
  No 
 
 
 
 
 
 
 
 
 
 
 
 


 
A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced NSCLC Patients 
who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 39 of 49 
  
  
 
Appendix H – Off-Study Form  
 
Study Number: 62220 
PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
Investigator:, Michael Farris M.D. Date: __ __/__ __/__ __ 
 
 
 
Off Study:  
 
Off Study Date: __/__/____ 
 
Off Study Reason:  
 Adverse Event/Side Effects/Complications 
 Death (if death fill out Survival Form) 
 Enrolling Physician Decision 
 Patient lost to follow-up;  
Date of last contact (mm/dd/yy): __ __/__ __/__ __ 
 Patient refused follow-up 
 Protocol-defined follow-up completed 
 Other 
  
Explain: 
_______________________________________________________________________________________________
_______________________________________________________________________________________________
__________________________________________________________________________________________ 
 


 
A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced 
NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 40 of 49 
  
  
Appendix I – Treatment Response Evaluation  
 
Study Number: 62220 
PID: ___ ___ ___ ___ ___ ___ ___ ___ 
Investigator: Michael Farris, M.D.  
Date: __ __/__ __/__ __ 
 
 
Study Visit: 
 
☐ After First Progression 
☐ Follow-Up 
☐ Other visit: (please specify) ________________ 
 
Date of Scan: ___ ___ /___ ___ /___ ___ 
 
Imaging Modality: ☐ CT ☐ PET/CT ☐ MRI  ☐ Other____________  
 
 
 
Overall Response this Visit 
☐   Complete Response (CR) 
☐   Partial Response (PR) 
☐   Progressive Disease (PD):  Date of progression ___ ___ /___ ___ /___ ___ 
☐   Stable Disease 
☐   NE  
 
Treating Physician Signature: ______________________ 
Date: ___ ___ /___ ___ /___ ___ 
 
PI Signature: ___________________________________ 
Date: ___ ___ /___ ___ /___ ___ 
 
 
 
 
 


 
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NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 41 of 49 
  
  
 
Appendix J Off Treatment Form 
 
Study Number: 62220  PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
PI: Michael Farris, MD  Date (mm/dd/yyyy): ___ ___/___ ___/___ ___ ___ ___ 
 
Instructions:  
 
Off Treatment:  
 
Off Treatment Date: __/__/____ 
 
Off Treatment Reason:  
 Adverse Event/Side Effects/Complications 
 Alternative Therapy 
 Cytogenetic resistance 
 Death on Study 
 Disease progression before active treatment 
 Disease progression, relapse before active treatment 
 Enrolling Physician Decision 
 Lost to followup 
 No treatment, per protocol criteria 
 Patient off treatment for other complicating disease 
 Patient withdrawal or refusal after beginning protocol therapy 
 Patient withdrawal or refusal prior to beginning protocol therapy 
 Treatment completed per protocol criteria 
 Other 
  
Explain: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_________________________ 
 
 
 
 
 
 
 
 


 
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NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
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Appendix K-Withdrawal of consent for the intervention and medical record 
use 
 
Study Number: 62220  PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
PI: Michael Farris, MD  Date (mm/dd/yyyy): ___ ___/___ ___/___ ___ ___ ___ 
 
Instructions:  
 
         I withdraw consent for further study intervention/treatment. 
Yes   
No Initials: ______ 
  
         I withdraw from further research activities (surveys, questionnaires, research assessments and other non-
invasive research activities). 
Yes   
No Initials: ______ 
  
         I withdraw my consent to allow the further collection of research-related information from my medical 
record to be used in this research project. 
Yes  
No Initials: ______ 
Specimen collection/use withdrawal ( no research specimen collection, skip section) 
I withdraw my consent for any use of my specimen for this current research.  
Yes 
 No Initials: ______ 
I withdraw my consent for any use of my specimen for future research. 
 
Yes 
No Initials: ______ 
 I acknowledge that any data or deidentified materials that have already been created from my specimen may still be 
used for research.  Initials: ______ 
Patient signature: ________________________________    Date (mm/dd/yy): ___ ___/___ ___/___ ___ 
Investigator signature: _____________________________ Date(mm/dd/yy): ___ ___/___ ___/___ ___ 
 
Comments: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
___________________________________________ 
 


 
A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced 
NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 43 of 49 
  
  
Appendix L-Vitals Form 
Only at pre treatment and at each follow-up, not during treatment 
Study Number: 62220  PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
PI: Michael Farris, MD 
 Date (mm/dd/yyyy): ___ ___/___ ___/___ ___ ___ ___ 
Instructions: Fill this form out at the baseline/pre-study visit, each cycle and  
Study Visit 
 
 Baseline 
 Visit ____ 
 Other visit: (please specify) ________________ 
1. Height (inches): ___ ___ 
 
 
2. Weight (lbs): ___ ___ ___  
 
3. BSA: (Calculated using Mosteller’s equation) 
 
4. BMI: (Calculated) 
 
5. Temperature (oF): ___ ___ ___.___ 
a. Route: ______________ 
 
6. Blood Pressure  
a. Systolic (mmHg): ___ ___ ___  
b. Diastolic (mmHg): ___ ___ ___ 
 
7. Heart Rate (beats per minute): ___ ___ ___ 
8. ECOG Status:  
 
  0:  Fully active, able to carry on all pre-disease performance without restriction. 
 
  1:  Restricted in physically strenuous activity but ambulatory and able to carry out work of a  
light or sedentary nature, e.g., light house work, office work.  
 
  2:  Ambulatory and capable of all self-care but unable to carry out any work activities. Up  
and about more than 50% of waking hours. 
 
  3:  Capable of only limited self-care. Confined to bed or chair more than 50% of waking hours. 
 
  4:  Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
 
  5:  Dead 
 
 
9. Respiration Rate____________________ 
 
 
 


 
A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced 
NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 44 of 49 
  
  
Appendix M-Con-med PRN Form 
Only prior to treatment  
Study Number: 62220  PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
PI: Michael Farris 
 Date (mm/dd/yyyy): ___ ___/___ ___/___ ___ ___ ___ 
 
Instructions: Fill this form out to capture Medications 
 
1. Concurrent medications 
a. List all prescription and over-the-counter medications. For PRN, circle “yes” or “no.”     
Medication Name 
Is it PRN? 
Medication Name 
Is it PRN? 
1. 
yes          no 
11. 
yes         no 
2. 
yes          no 
12. 
yes         no 
3. 
yes          no 
13. 
yes         no 
4. 
yes          no 
 
14. 
yes         no 
5. 
yes          no 
 
15. 
yes         no 
6. 
yes          no 
 
16. 
yes         no 
7. 
yes          no 
 
17. 
yes         no 
8. 
yes          no 
 
18. 
yes         no 
9. 
yes          no 
 
19. 
yes         no 
10. 
yes          no 
 
20. 
yes         no 
 
 
 


 
A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced 
NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 45 of 49 
  
  
Appendix N:  Mandatory Target Coverage/Dose Constraint Compliance 
Confirmation. 
Study Number: 62220  PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
PI:  Michael Farris, MD Date (mm/dd/yyyy): ___ ___/___ ___/___ ___ ___ ___ 
 
 
 
Structure 
Protocol 
Coverage/Constraint 
Coverage/Constraint 
Met (yes/no) 
Plan value 
PTV_5750 
95% receives at least 
54.63 Gy 
 
 
PTV_5750 
99% of PTV_5750 
receives at least 51.75 
Gy 
 
 
Spinal Cord 
D0.03 cm3 < 45 Gy 
 
 
Esophagus 
D0.03 cm3 < 73.5 Gy 
 
 
Lungs-GTV 
V20 Gy ≤ 35% 
 
 
Proximal Bronchial Tree 
D0.03 cm3 < 73.5 Gy 
 
 
Heart 
D100% < 30 Gy 
 
 
Stomach 
D0.03cm3 < 60 Gy 
 
 
Liver 
Mean dose < 30 Gy 
 
 
Liver 
at least 700 cm3 of 
normal liver to < 15 Gy 
 
 
Maximum dose PTV_7000 
< 80.50 Gy 
 
 
Maximum dose PTV_6750 
< 77.63 Gy 
 
 
 
 
Treating Radiation Oncologist Signature: _____________________________________________________ 
 
Date: ____________ 
 
 


A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced NSCLC Patients who Decline or are 
Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 46 of 49 
  
  
Appendix O: Pre-Toxicity  
OnCore PID: __ __ __ __ __ __ __ __   
Date Completed: __ __ / __ __ / __ __ 
PI:, Michael Farris, MD.   
Study Number: 62220 
Evaluation 
Date  
Onset Date  
Toxicity 
Code 
Grade   
(1-5) per 
CTC  
Lab 
value 
UOM
   
Lower 
Limit 
Normal 
Upper Limit 
Normal 
Related to 
Disease 
N=No       
Y=Yes  
Symptom 
Description  
Comments 
_ _/_ _/_ _ 
_ _/_ _/_ _ 
   
   
   
   
 
 
   
   
   
_ _/_ _/_ _ 
_ _/_ _/_ _ 
 
 
 
 
 
 
 
 
 
_ _/_ _/_ _ 
_ _/_ _/_ _ 
   
   
   
   
 
 
   
   
   
_ _/_ _/_ _ 
_ _/_ _/_ _ 
   
   
   
   
 
 
   
   
   
_ _/_ _/_ _ 
_ _/_ _/_ _ 
   
   
   
   
 
 
   
   
   
_ _/_ _/_ _ 
_ _/_ _/_ _ 
   
   
   
   
 
 
   
   
   
_ _/_ _/_ _ 
_ _/_ _/_ _ 
   
   
   
   
 
 
   
   
   
 
CTCAE Version 5 - https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf  
 
Version 1/10/18  
 
 
 


 
A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced 
NSCLC Patients who Decline or are Ineligible for Surgery or Chemotherapy 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62220 
 
Page 47 of 49 
  
  
 
Appendix P:  Pattern of Progression Collection 
 
Study Number: ___ ___ ___ ___ ___  PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
PI:  
_________________________ Date (mm/dd/yyyy): ___ ___/___ ___/___ ___ ___ ___ 
 
 
 
 
Yes 
No 
Local Progression 
 
 
Regional Progression 
 
 
Distant Progression 
 
 
 
 
Pattern of Failure: 
 
☐   Isolated local Progression: (Local Progression = Y; Regional Progression = N; Distant Progression = N) 
☐   Isolated Regional Progression: (Local Progression = N; Regional Progression = Y; Distant Progression = N) 
☐   Isolated Distant Progression: (Local Progression = N; Regional Progression = N; Distant Progression = Y) 
☐   Locoregional Progression: (Local Progression = Y; Regional Progression = Y; Distant Progression = N) 
☐   Local and Distant Response: (Local Progression = Y; Regional Progression = N; Distant Progression = Y) 
☐   Regional and Distant Progression: (Local Progression = N; Regional Progression = Y; Distant Progression = Y) 
☐   Local, Regional, and Distant Progression: (Local Progression = Y; Regional Progression = Y; Distant 
Progression = Y) 
 
 
Treating Radiation Oncologist Signature: _____________________________________________________ 
 
Date: ____________


 
 
Page 48 of 49 
  
  
Appendix Q: RECIST  
TUMOR RESPONSE WORKSHEET (RECIST v1.1)                              WFBCCC # _____________________ 
 
Patient Name: ________________________________              Patient MRN: _____________________ 
 
Has patient had localized RT @ baseline? □ No □ Yes If yes, which lesions? :____________________________________ 
  
Target Lesions 
TARGET Lesions 
Lesion 
Site 
 
 
Imaging 
(ie,CT, MRI) 
Baseline  
Date: 
(Se, Im) 
Cycle_____ 
Date: 
(Se, Im) 
Cycle_____ 
Date: 
(Se, Im) 
Cycle_____ 
Date: 
(Se, Im) 
Cycle_____ 
Date: 
(Se, Im) 
01 
 
 
 
mm 
mm 
mm 
mm 
mm 
02 
 
 
 
mm 
mm 
mm 
mm 
mm 
03 
 
 
 
mm 
mm 
mm 
mm 
mm 
04 
 
 
 
mm 
mm 
mm 
mm 
mm 
05 
 
 
 
mm 
mm 
mm 
mm 
mm 
Sum of Diameters 
mm 
mm 
mm 
mm 
mm 
% Change (% ∆)  from Baseline or Nadir* & 
absolute value (AbV) 
 
NA 
        
          NA 
% ∆ 
                        
        AbV 
 
 
 
Target Lesion Response 
      N/A 
 
 
 
 
 
Non-Target Lesions 
NON-TARGET Lesions 
Lesion 
Site 
 
Imaging 
Baseline 
Cycle_____ 
Cycle_____ 
Cycle_____ 
Cycle_____ 
01 
 
 
 
 
 
 
 
 
02 
 
 
 
 
 
 
 
 
03 
 
 
 
 
 
 
 
 
04 
 
 
 
 
 
 
 
 
05 
 
 
 
 
 
 
 
 
Non-Target Lesion Response 
N/A 
 
 
 
 
 
New Lesions 
New 
1 
 
 
 
N/A 
 
 
 
 
2 
 
 
 
N/A 
 
 
 
 
3 
 
 
 
N/A 
 
 
 
 
Overall Tumor Response 
Cycle_____ 
Cycle_____ 
Cycle_____ 
Cycle_____ 
 
Radiologist Signature/Date: 
 
 
 
 
 
Treating Physician Signature/Date: 
 
 
 
 
 
PI Signature: 
 
 
 
 
 


 
 
Page 49 of 49 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current SLD – Baseline or Nadir SLD      X 100% 
               Baseline or Nadir SLD 
*Terms & Calculations 
 
 
Baseline: The set of data collected prior 
to randomization 


 
 
Page 50 of 49 
  
  
 

ICF_000.pdf: 
Title:  A Single Arm Phase II Study of Hypofractionated Radiotherapy Alone in Locally Advanced Nonsmall Cell Lung 
Cancer Patients Who Decline or Are Ineligible for Surgery or Chemotherapy  
NCT04398199
Date: 5/24/21


Page 1 of 13
Adult Consent Form
Departments of Radiation Oncology and Hematology Oncology
WAKE FOREST School of Medicine
Informed Consent
A SINGLE ARM PHASE II STUDY OF HYPOFRACTIONATED 
RADIOTHERAPY ALONE IN LOCALLY ADVANCED NON-SMALL CELL 
LUNG CANCER PATIENTS WHO DECLINE OR ARE INELIGIBLE FOR 
SURGERY OR CHEMOTHERAPY
WFBCCC # 62220
Informed Consent Form to Participate in Research
Michael Farris, M.D., Principal Investigator
SUMMARY
You are invited to participate in a research study. The purpose of this research study is to 
improve control of lung cancer with high doses of very targeted radiation alone for patients who 
cannot be treated with surgery or chemotherapy. You are being asked to take part in this study 
because you have lung cancer that has not spread to distant parts of your body and is either 
confined to the lung where it started (Stage II) or has spread locally within your chest (Stage III)  
and your physicians do not feel that you are a good candidate for chemotherapy or surgery. Your 
participation in this research will involve multiple visits for treatment with radiation therapy.  
Radiation therapy will last for approximately five weeks. After treatment is completed, you will 
be seen for routine follow up visits that typically last 1 - 2 hours. They will occur one month 
after the last day of radiation and every 3 months after that for the next 2 years.
All research studies involve some risks. A risk to this study that you should be aware of is 
possible irritation of the lungs called pneumonitis. This also happens with standard 
chemotherapy and radiation therapy.  Another risk is damage to the airways in your lungs or 
your swallowing tube called the esophagus.  Damage to these organs can lead to narrowing or 
bleeding and death, but there is risk of these toxicities with standard chemotherapy and radiation 
as well. There is the possibility that you may benefit from participation in this study.  
Your participation in this study is voluntary. You do not have to participate in this study if you 
do not want to. There may be other choices available to you. Some other choices may include 
lower doses of standard radiation therapy alone. You will not lose any services, benefits, or 
rights you would normally have if you choose not to participate. 
The rest of this form contains a more complete description of this study. Please read this 
description carefully. You can ask any questions if you need help deciding whether to join the 
study. The person in charge of this study is Michael Farris M.D. If you have questions, 
suggestions, or concerns about this study or you want to withdraw from the study his contact 
information is: 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 2 of 13
Adult Consent Form
Michael Farris, M.D.
If you have any questions, suggestions or concerns about your rights as a volunteer in this 
research, contact the Institutional Review Board at 
 or the Research Subject 
Advocate at Wake Forest at 
.
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have lung cancer that has spread to the lymph nodes in the middle of your 
chest and your physicians do not feel that you are a good candidate for chemotherapy or surgery. 
Your participation is voluntary. Please take your time in making your decision as to whether you 
wish to participate or not. Ask your study doctor or the study staff to explain any words or 
information contained in this informed consent document that you do not understand. You may 
also discuss the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to find out what effects (good or bad) may come from a 
new way of doing radiation therapy for lung cancers that involve lymph nodes in the middle of 
the chest, are very large, or located very close to major blood vessels or airways. This study is 
for patients who are not able to get surgery, stereotactic body radiation therapy (SBRT) or 
chemotherapy with their radiation.
The standard way of doing radiation in patients who cannot get chemotherapy with radiation 
therapy or SBRT for lung cancer is called hypofractionated radiation, where slightly larger 
amounts of radiation are given per day than when radiation is given with chemotherapy.  A 
newer, more complex way of planning radiation that was not previously available on older trials 
has now become a standard technique across the country.  This is called a simultaneous 
integrated boost or SIB.  Planning radiation with an SIB allows the actual tumor to get an extra 
radiation dose while still protecting the organs that are near the tumor.  This is how 
hypofractionated radiation will be planned in this study.  It allows us to give the biggest parts of 
the tumors that are the most difficult to control a little more radiation every day than the lower 
risk areas.  There is evidence that this might be a safer way to give radiation therapy than SBRT 
in patients with tumors very close to the center of the chest.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 3 of 13
Adult Consent Form
 
Radiation therapy to the tumor is a standard treatment.  However, it is not typically planned in 
this way.  In standard radiation, all parts of the tumor are given the same amount of radiation 
every day.  However, this does not always work as well, and we think there may be a better 
approach. There are still questions we need to answer to make sure that this is a safe and 
effective treatment option.  We do not know that this special radiation technique will be better at 
controlling the tumor.  We also are not sure that the specialized radiation planning will not 
increase the risks compared to standard radiation.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
There will be 30 patients on this study.  This is the only institution where this study is being done. 
WHAT IS INVOLVED IN THE STUDY?
We will make sure you qualify for the study by performing a PET/CT scan and a brain MRI 
before you are enrolled on the trial.  These two scans tell us exactly where the cancer has spread. 
If you do qualify for the study, you will be asked to provide written informed consent (by signing 
this form) to join the study. Then you will undergo a standard radiation planning CT scan, and 
start radiation therapy around 2 weeks after that.  You will get radiation therapy once a day for 
25 days, Monday through Friday (around 5 weeks).     
Before you take part in this study, you will have the following standard tests and procedures:

History and Physical examination 

Whole Body Positron Emission Tomography (PET/CT) to assess where cancer has 
spread

Magnetic Resonance Imaging (MRI) of the brain to determine if cancer has spread to the 
brain 

Blood or urine pregnancy test for women who can become pregnant
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 4 of 13
Adult Consent Form
The history and physical examination, PET/CT scan, MRI brain scan, and pregnancy test would 
be standard tests before any radiation therapy, regardless if you were enrolled on this trial or not. 
Before radiation begins, you will have a treatment planning session. You will lie in a specific 
position, possibly within a frame device or on a large plastic bag filled with tiny foam balls like a 
bean bag. The purpose of the frame or bag is to hold your body as still as possible for planning 
and treatment. After you are positioned, doctors will check your breathing and see how your 
organs move. The doctors will try to limit the effect of that movement on the position of your 
tumor by timing your breathing. They may use a device to control the depth of your breathing. 
They may use a device to monitor the rate and pattern of your breathing. This is so that they will 
be able to deliver the radiation to the tumor while accounting for the effect of breathing.  In order 
to plan the radiation, you will have a CT scan that may use contrast.  Contrast would be given as 
an injection in the vein and helps us see the areas that we are trying to treat more clearly.  
Radiation treatments will be given over the course of 25 treatments, one treatment per day given 
Monday through Friday.  The radiation will be planned with a simultaneous integrated boost 
(SIB).  This means that the biggest parts of the tumor that are the most difficult to control will 
receive slightly more radiation per day than other areas at lower risk of tumor spread.  
After completing radiation you will have routine follow-up visits. You will have CT scans of 
your chest, and abdomen at 1 month, then every 3 months for the next two years.  These CT 
scans may be performed with contrast that is given as in injection in the vein.  You and your 
doctor will decide if contrast is needed.  After this, you will likely continue to be followed by 
your physician for the rest of your life but will not continue to be followed for the purposes of 
the study.  
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for a total of 25 months after completion of radiation therapy.  After this 
you will likely continue to follow with your oncologists but will not be specifically followed per 
this study protocol and results will not be collected past 2 years.
You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences.  
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. 
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, researchers don’t know all the side effects that may 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 5 of 13
Adult Consent Form
happen. Side effects may be mild or very serious. Your health care team may give you medicines 
to help lessen side effects. Many side effects go away soon after you stop taking the radiation. In 
some cases, side effects can be serious, long lasting, or may never go away. There also is a risk 
of death.  The side effects of hypofractionated radiation therapy are similar for tumors that are 
typically treated with surgery or SBRT and chemotherapy and radiation because the organs that 
can be hurt by radiation are the same.
Risks and side effects related hypofractionated radiation to the chest: 
Likely 

Difficulty, pain, or a burning sensation when swallowing, which is temporary 

Damage to surrounding normal lung and/or collapse of a portion of treated lung

Changes in the lungs as the tumor shrinks; these changes will be recognized by your 
radiation doctor on your x-rays or scans as expected "scarring" that is developing. In 
most patients, no noticeable symptoms will result from this lung damage.

Fatigue, which is temporary 

Tanning, redness of the skin, and hair loss within the treatment area, which is temporary 

Skin in the treatment area may remain permanently dry, and chest hair may not grow 
back 
Less Likely 

Cough and some difficulty in breathing due to lung inflammation, which can require 
steroids or supplemental oxygen, either short term or permanently, and may in rare case 
be life-threatening 

Narrowing of the esophagus causing difficulty swallowing meals (rarely requiring 
internal dilation or a feeding tube) 
Rare but serious (late) 

Pericarditis – irritation of the heart sac causing a rapid heart rate, or chest pain.   

Myocarditis – irritation of the heart muscle causing shortness of breath, chest pain, or 
permanent heart muscle damage 

Damage to the spinal cord, which can cause numbness, weakness, tingling, and/or 
inability to use the arms and/or legs 

Bleeding from the airway 

Narrowing of the airway causing shortness of breath

Damage to the stomach or bowel which can lead to ulceration or perforation with a risk 
of infection and death. 

Damage to the large blood vessels surrounding the heart, which could cause coughing up 
of blood and possibly death 

Death from treatment complications above.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 6 of 13
Adult Consent Form
During the process of treatment planning we decide where the radiation will go in your body.  
You will lie in a specific position on a firm flat surface and hold very still.  We will take pictures 
of the inside of your body with CT scans.  You might be inside a frame device.  Sometimes 
patients can get nervous while they are being scanned but we can give medications to make you 
feel more comfortable if needed.  Also, your study doctor may give you pain medication before 
each treatment if needed. This would decrease discomfort from laying on a hard surface while 
receiving treatment or from holding your arms up over your head for a long time.   The focused 
radiation treatments involve exposure to radiation from a machine called a linear accelerator. 
This machine is used to treat cancer using high energy x-rays.  These radiation planning scans 
are no different than the planning scans that you would have if you were being treated off 
protocol.
Reproductive risks:  Due to unknown risks and potential harm to the unborn fetus, sexually 
active women of childbearing potential must use a reliable method of birth control while 
Participating in this study. Reliable methods of birth control are: abstinence (not having sex), 
oral contraceptives, intrauterine device (IUD), DepoProvera, tubal ligation, or vasectomy of the 
partner (with confirmed negative sperm counts) in a monogamous relationship (same partner). 
An acceptable, although less reliable, method involves the careful use of condoms and 
spermicidal foam or gel and/or a cervical cap or sponge. We encourage you to discuss this issue 
further with your physicians if you have any questions. If you are a woman able to have children 
and are unwilling to use adequate birth control measures to prevent pregnancy, you should not 
participate in this study. If you should become pregnant or suspect that you have caused anyone 
to become pregnant while you are on this study, you must tell your study doctor immediately. 
Risks of Radiation Exposure
If you participate in this study, you will be exposed to amounts of radiation above what you 
would normally receive in daily life. To be sure that you do not receive an unhealthy amount of 
radiation from your participation in this study, you should let your study doctor know if you have 
had, or are going to have, any other scans or x-rays as part of your medical or dental care. It is 
very important that you let your study doctor know if you already are participating in, or plan to 
participate in, any other research study that involves radiation exposure. 
Risks Associated with Providing Confidential Information
Taking part in this research study may involve providing information that you consider 
confidential or private. Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe. There is a slight risk of a breach of confidentiality.  We will do our best to 
protect your confidential information.  There also may be other side effects that we cannot 
predict. You should tell the research staff about all the medications, vitamins and supplements 
you take and any medical conditions you have. This may help avoid side effects, interactions and 
other risks.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 7 of 13
Adult Consent Form
Reproductive Risks and other Issues to Participating in Research
Pregnant women are excluded from participation in this study. Because some methods of birth 
control are not 100% reliable, a pregnancy test is required at least 10 days from your last normal 
menstrual period, if you are a sexually active woman of childbearing potential. There could be a 
risk of radiation affecting sperm in men, and these sperm usually are replaced with healthy sperm 
in your body every 3 – 6 months. This could be harmful to any children that are fathered by men 
immediately after they receive radiation. We strongly encourage men not to father children for at 
least 6 months to 1 year following treatment with radiation. 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. We hope 
that this treatment will increase the control of the tumor, but this is not certain. We hope the 
information learned from this study will aid in the understanding of cancer and help in the 
development of new approaches to its treatment and benefit other people in the future
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor about all 
the choices you have. The usual treatment for your disease radiation therapy with chemotherapy 
followed by immunotherapy if possible, or in some cases surgery or SBRT.
You could be treated with hypofractionated radiation even if you do not take part in the study.
WHAT ARE THE COSTS? 
The costs of all medications, radiation treatment, x-rays, tests, physician’s fees, diagnostic and 
laboratory studies, drug handling charges, transportation, and hospital or clinic visits will be 
billed to you. Some of these costs may or may not be covered by your insurance provider. In 
addition, the use of medications to help control side effects could result in added costs.
You will receive no payment or other compensation for taking part in this study. Parking 
validation will be provided for all study-related visits.
WHO IS SPONSORING THIS STUDY? 
This study is being sponsored by Wake Forest Baptist Comprehensive Cancer Center. The 
sponsor is providing money or other support to help conduct this study. The researchers do not, 
however, hold a direct financial interest in the study.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 8 of 13
Adult Consent Form
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified. 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
The purpose of this research study is to obtain data or information on the safety and effectiveness 
of radiation treatment with pembrolizumab or pembrolizumab alone; the results will be provided 
to the sponsor, the Food and Drug Administration and other federal and regulatory agencies as 
required.
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other 
scientific research, as allowed by federal regulations protecting research subjects. 
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by National Institutes of Health which is funding this project or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA).  You should understand that a Certificate of Confidentiality does 
not prevent you from voluntarily releasing information about yourself or your involvement in 
this research. If you want your research information released to an insurer, medical care 
provider, or any other person not connected with the research, you must provide consent to allow 
the researchers to release it.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 9 of 13
Adult Consent Form
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call Michael Farris M.D. at 
, or 
.
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and/or information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes: History and 
physicals, pathology, labs, imaging and lung function tests.
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study will be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations.  
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.  
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 10 of 13
Adult Consent Form
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA) or the Office of Human Research Protections (OHRP), 
the Department of Health and Human Services (DHHS) and similar agencies in other countries.  
1) The study investigator and his/her staff, or others at Wake Forest University Health Sciences 
who oversee research 
2) Other people or laboratories providing services for this research project on behalf of Wake 
Forest University Health Sciences and Wake Forest University Baptist Medical Center 
3) Representatives from government agencies such as the Food and Drug Administration (FDA), 
NCI (National Cancer Institute), the Department of Health and Human Services (DHHS) and 
similar agencies in other countries.
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
Monitors, auditors, IRB or other regulatory agencies will be granted direct access to the 
participant’s original medical record for verification of clinical trial procedures or data, without 
violating confidentiality of the participant and to the extent permitted by other applicable laws.
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups, it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for at least six years after the study is finished. At that time any 
research information not already in your medical record will either be destroyed, or it will be de-
identified. Any research information entered into your medical record will be kept for as long as 
your medical record is kept by the Medical Center. You will not be able to obtain a copy of your 
Protected Health Information in the research records until all activities in the study are 
completely finished.
You can tell Dr. Farris that you want to take away your permission to use and share your 
Protected Health Information at any time by sending a letter to this address:
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 11 of 13
Adult Consent Form
Michael Farris, M.D.
 
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form, you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time. 
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part, or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study, we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


Page 12 of 13
Adult Consent Form
at any time. This could be because it is felt by the treating physician to be in your best medical 
interest, your condition worsened, new information becomes available, or you had an unexpected 
reaction. Additionally, this could occur because you failed to follow instructions, or because the 
entire study has been stopped
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Michael Farris MD Michael Farris M.D. at 
, or 
. 
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
 or the 
Research Subject Advocate at 
.
You will be given a copy of this signed consent form. 
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022


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Adult Consent Form
Legally Authorized Representative Name (Print):_________________________
 
The above named Legally Authorized Representative has legal authority to act for the research 
subject based upon (specify health care power of attorney, spouse, parent, etc.)
Relationship to the Subject:_____________________________
Legal Representative Signature: _________________________ Date:_________ Time:________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00065905
Meeting Date Approved 5/24/2021          
Version Valid Until: 5/9/2022