Phase II Trial of Standard Platinum Doublet Chemotherapy + Various Proton Beam Therapy (PBT) Doses in Order to Determine the Optimal Dose of PBT for Unresectable Stage 2/3 Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Recurrent Lung Non-Small Cell Carcinoma, Stage II Lung Cancer AJCC v8, Stage III Lung Cancer AJCC v8, Unresectable Lung Non-Small Cell Carcinoma
Sponsor: Mayo Clinic

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Mayo Clinic Radiation Oncology 
 
Phase II Trial of Standard platinum doublet chemotherapy +various proton beam therapy (PBT) doses in 
order to determine the optimal dose of PBT for unresectable stage 2/3 Non-Small Cell Lung Cancer 
 
 
 
 
Study Co-Chairs: 
 
 
  
 
 
 
 
 
 
Study Co-Investigators: 
 
 
 
 
 
 
 
          
 
  
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
Statistician: 
  
 
 
 
 
 
 
 
  
 
 
 
√Study contributor(s) not responsible for patient care. 
 
 
Document History 
Activation 
(Effective Date) 
30MAR2017 
 
Amendment 1: 
26OCT2017 
 
 
 
 
Amendment 2: 
31JAN2018 
 
Amendment 3: 
05NOV2018 
Amendment 4: 
21NOV2019 
Amendment 5: 
Pending 
 
 
 
 
 

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Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
 
 
Forms completion and submission 
 
 
 
Protocol document, consent form, 
regulatory issues 
 
 
 
*No waivers of eligibility allowed 
 
 

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Index 
Schema 
  1.0 
Background   
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Radiotherapy Dose Modifications Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation  
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Study Finances 
20.0 
Publication Plan 
21.0 
References 
Appendix I - ECOG Performance Status,  
 
Appendix II - LASA single item QOL assessment – Patient Information Sheet  
 
Appendix IIb – Stratification Factors 
 
 
 
 
 

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List of Abbreviations 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncologic Group  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
 
 
 
 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
PBT 
Proton Beam Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
 See section 3.0 and 6.0 for details 
Randomization 
See section 6.0 for details 
Arm C 
Concurrent platinum doublet 
chemotherapy & PBT to 72 Gy in 2 Gy 
daily fractions 
 
NOTE: Arm B was REMOVED 
from protocol Amendment 3. 
See protocol section 16 for 
additional details.  
 
Arm A 
Concurrent platinum doublet 
chemotherapy & PBT to 60 Gy in 
2 Gy daily fractions 
Consideration of adjuvant 
therapy is at the discretion of 
the treating Physician. 
Observation 
3 years of observation 
Event Monitoring 
(until death or 5 years 
after registration) * 
PD* at any time 
Unacceptable adverse  
 
  Event 
    events   
 
 
 Monitoring 
Patient refusal  
 
*unless otherwise specified 

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1.0 
Background   
 
Protons are used to irradiate and kill tumors by damaging tumor DNA. The chief advantage of 
proton therapy is the ability to more precisely localize the radiation dosage when compared with 
conventional types of external beam radiotherapy (photons or electrons). This advantage is 
specifically due to the relationship between energy deposition within tissues from protons 
compared to conventional radiotherapy. Protons release the majority of their kinetic energy in a 
tighter distribution of dose conforming better to a tumor target. The proton beam stops and does 
not exit beyond the deep edge of a targeted tumor. Protons result in a lower integral dose to the 
body for a given prescribed dose to the tumor than conventional radiotherapy since they can 
deliver less radiation to the tissues superficial to the tumor. This has led to fewer second 
malignancies. 1 
 
The use of proton therapy is standard practice for pediatric cancer patients.  Proton beam therapy 
has also resulted in very favorable clinical results for some uncommon tumors such as para-spinal 
& ocular tumors. Proton therapy has been used most often for prostate cancer with very favorable 
outcomes reported by Mendenhall et al.2 There are also reports of significantly less toxicity and 
promising outcomes in patients with unresectable lung cancers.3  
 
Concerns regarding proton therapy are not based on the physical advantages but rather on cost. 
Proton therapy facilities are more expensive to build, as they require huge accelerators to deliver 
the beam.  Though it is considered expensive compared to conventional forms of radiation, cost-
benefit studies have suggested cost-effectiveness in the long term due to decreased long-term 
toxicity.4, 5 However, much more research is needed to document when the physical dose 
advantages of proton therapy translate to substantial and lasting improvements in patient outcome 
in many common clinical situations.  
 
This trial focuses on determining the optimal dose of PBT that can be considered the standard 
conventionally fractionated dose to use in clinical practice and future trials. 
 
The current standard dose of RT for unresectable stage 2/3 NSCLC is 60 Gy/30 fractions  & 
concurrent carboplatin/paclitaxel followed by 2 cycles of consolidative chemotherapy (RTOG 
0617).6 This study (RTOG 0617) randomly assigned patients to the same chemotherapy plus 
either 74 Gy or 60 Gy (in 2 Gy daily fractions). Counter to expectations, higher doses of photon 
RT significantly decreased patient survival likely because of heart and/or lung damage from 
higher radiation doses. It has been well established that this dose (60 Gy in 30 daily fractions) is 
insufficient to sterilize most large masses of solid tumors based on the classic dose-response 
papers of Gilbert Fletcher.7 Thus, with available modern photon therapy (3-D radiotherapy (3-D 
RT) and intensity modulated radiotherapy (IMRT), this standard dose-fractionation based 
treatment regimen is unable to cure the vast majority of unresectable stage II/III lung cancer 
patients treated. Proton beam therapy can decrease the exposure of normal structures such as the 
heart and lungs when treating lung cancers, potentially allowing for safe administration of higher 
doses to the tumor.8 The current study will evaluate standard chemotherapy doublet therapy plus 
varying doses of conventionally fractionated proton RT  within a range that has already been 
tested (60-72 Gy) in patients but never directly compared in a randomized trial. An MD Anderson 
study of chemotherapy (weekly carboplatin (area under the curve=2) and paclitaxel (50 mg/m2)) 
plus 74 Gy (in 2 Gy daily fractions) of PBT resulted in median survival of 30 months and 5-year 
survival of 32% (Dr. Joe Chang, personal communication).9 No patient experienced grade 4 or 5 
proton-related adverse events. The most common non-hematologic grade 3 toxicities were 
dermatitis (n=5, 11%), esophagitis (n=5, 11%), and pneumonitis (n=1, 2%). This is far less than 
what would be expected with chemotherapy plus photon RT. Retrospective comparisons 

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performed at MD Anderson have shown significant decreases in toxicity with proton compared to 
photons.3 We have chosen the maximum dose in this study to be 72 Gy due to findings from both 
proton and photon therapy that 74 Gy does not appear to confer a survival advantage compared to 
doses up to 72 Gy.10, 11 
  
Adult stage II/III NSCLC patients with ECOG PS0-1 will receive concurrent platinum doublet 
chemotherapy plus proton radiation at 60Gy(RBE) or 72 Gy (RBE) at 2Gy per daily fraction. 
Dose will be allocated to each patient based on a randomization. The 1-year progression-free 
survival rates of all groups will be compared and the optimal dose determined by the 
preponderance of data.  
 

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2.0 
Goals  
 
 
2.1 
Primary 
2.11 
To compare the 1-year progression-free survival rates of 72 Gy and 60 Gy 
conventionally fractionated PBT (as part of concurrent combined modality therapy).  
 
2.2 
Secondary 
2.21 
To assess the adverse events, survival, quality of life, and patterns of failure 
(local regional, distant metastatic) associated with two dose levels of conventionally 
fractionated PBT (as part of concurrent combined modality therapy).  
 
3.0 
Patient Eligibility    
 
3.1 
Inclusion Criteria  
 
3.11 
Age ≥18 years. 
 
3.12 
Histological confirmation of non-small cell lung cancer 
 
3.13 
 Forced Expiratory volume in 1 second (FEV1)>1.0 L 
 
3.14 
Unresectable or medically inoperable stage 2-3 Non-small cell lung cancer 
(based on CT/PET, MRI or CT of brain, and Physical exam). 
• 
Eligible if recurrence after surgery and now has the equivalent stage 2-3 
NSCLC OR had sub totally resected stage 2-3 NSCLC. 
 
3.15 
ECOG Performance Status (PS) 0-1(Appendix I). 
 
3.16 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.17 
The following laboratory values in specified ranges: 
• 
WBC ≥3.0 x 109/L, 
• 
ANC ≥1.5 x 109/L, 
• 
Hgb ≥9g/dl 
• 
Plts >100 x 109/L 
• 
Serum creatinine<1.5 x upper limits of normal(ULN) 
• 
Serum bilirubin <1.5xULN  
 
3.18 
Provide informed written consent. 
 
3.19 
Willing to return to enrolling institution for follow-up for a minimum of 1 year. 
 
3.19a     Ability to undergo potentially curative chemotherapy plus radiotherapy  
 
 
3.2 
Exclusion Criteria  
 
3.21 
Any of the following because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 

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3.22 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.23 
Weight loss of >10% in the past 3 months  
 
3.24     Distant metastases (M1 disease) 
 
 
3.25 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, lupus,  unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
3.26 
Receiving any investigational agent, that would be considered as a treatment for 
the primary neoplasm. 
 
3.27 
Active second malignancy.  
 
3.28 
History of myocardial infarction ≤6 months, or congestive heart failure requiring 
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias. 
 
3.29 
Received Chemotherapy for lung cancer within 6 months of registration. 
 
3.30 
Previous chest radiotherapy that would overlap with the proton field. 
 
 

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4.0 
Test Schedule (these are all considered standard of care and are not experimental) 
 
 
Active Monitoring Phase 
 
 
 
Tests and procedures 
≤30 days 
prior to 
registration 
During 
course of 
RT (every 
7 days +/-
2 days) 
Observation 
Every 3 months 
(+/- 1 month) 
for 3 years post 
RT7 
Event Monitoring 
Every 6 months 
(+/- 3 months) 
For a total of 5 
years post- 
registration7 
History and exam,  
Wt, ECOG PS 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
Height 
X 
 
 
 
Pregnancy test1 
X 
 
 
 
Tumor measurement2 
X 
 
X 
X 
Pulm function tests 
DLCO, FEV1 
X4 
 
X6 
 
CT (chest preferably with 
contrast) 
X 
 
X 
 
X 
MRI, or CT of head  
X 
 
 
 
PET /CT 
X 
 
 
 
LASA/ QOL (appendix 
II) 
X 
 
X 
 
CBC/Chemistry panel3 
X 
X 
X 
 
Histologic confirmation 
of NSCLC5 
X 
 
 
 
1. For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
2. Refer to section 11.0 for lesion evaluation and response 
3. Glucose, Calcium, Albumin, Total Protein, Sodium, Potassium, CO2 (carbon dioxide, 
bicarbonate),Chloride, BUN (blood urea nitrogen),Creatinine, ALP (alkaline phosphatase),ALT 
(alanine amino transferase),AST (aspartate amino transferase),Bilirubin; chemistry and CBC will be 
monitored during chemotherapy per medical oncology standards 
4. PFT’s can be up to 90 days prior to registration 
5. The biopsy can be older than 30 days but must be done no more than 90 days prior to 
registration) 
6. To be completed at 1 year post only 
7. If participant is unable to return to research site then study staff will attempt to obtain outside 
records 
 
 
 

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5.0 
Stratification Factors: 
5.1 
Mayo prognostic score12:  32-37 vs 38-43 vs 44-47 vs 48-52 (appendix IIb) 
6.0 
Registration/Randomization Procedures 
6.1 
Registration Procedures 
 
Patient will be registered to the study when they have consented, met eligibility criteria, 
and have been logged into Research Participant Tracking (Ptrax). 
 
 
6.2 
Randomization  
 
Performed after registration. Patients will be randomized in equal proportions (1:1) to a 
single dose level (60 vs 72 Gy) balanced based on the stratification factors in Section 5.0.  
The balancing algorithm that we will use is a dynamic allocation procedure that is part of 
Medidata Rave, known as Balance. 
 
7.0 
Protocol Treatment 
Protocol treatment is to begin within 28 days of registration. Questions regarding treatment 
should be directed to the Study Chairs. 
 
 
7.1 
Radiation Therapy 
 
 
 
 
7.1.1 
Target Dose is based on the arm (60, 72 Gy(RBE) in 2 Gy daily fractions). 
 
7.1.2 
Treatment Technique: PBT  
 
7.1.3 
Simulation 
 
Simulation is performed based on the standard of each institution. 4D CT-
Simulation will be performed for most patients. The averaged CT and maximum 
intensity projection (MIP) CT will be generated from the 4D CT. If tumor 
movement exceeds 8 mm (Mayo Clinic Rochester) or 10 mm (Mayo Clinic 
Arizona), respiratory management is required (breath hold (BH) or gating). Other 
advanced techniques will be considered as they become available. For BH 
patients, the averaged CT will be generated from multiple BH scans, while for 
gating patients the averaged CT will be generated from the treatment phases. For 
free breathing, BH, and gating patients, the averaged CT will be used as the 
primary planning CT. For all patients we will conduct plan robustness 
quantification and motion evaluation. The patients with tumor motion less than 5 
mm may also have motion management if the evaluation results show that the 
plans are not resilient to motions given the thresholds defined in Sec. 7.1.12. 
 
7.1.4 
Immobilization 
The immobilization as shown below is an example how currently the 
immobilization is conducted in AZ. The participating institution may have its 
own established immobilization procedures, which can be adopted for this 
clinical trial.  

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1. We will position the patient as shown in the image below using Orfit board 
and thermoplastic mask; low arm incline, short poles w/ T-Bar, leg extension, 
and basic knee wedge 
2. The hands should reach the horizontal T bar and rest in an AccuForm cushion 
as seen in the image below.  
3. Localization points (lower 2pt tattoos inferior to mask, 3pt bb’s @ iso) 
4. Scan the patient – Pre BB 2 mm slice thickness 
5. Treatment Iso to be dropped by physician.  
6. Wherever the isocenter is dropped, place three points on mask (Triangulation 
BBs).   
7. Record Index of Orfit overlay 
8. Record Isocenter (top of overlay) 
 
7.1.5 
Image Guidance 
 
The Hitachi Patient Image Alignment System (PIAS) will be used for image 
guidance. PIAS provides 2D and 3D image guidance (CT on rails). Both are allowed 
under this protocol. If fiducials are not used, nearby landmarks (such as ribs and 
spinal column) will be used for image guidance 
 

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7.1.6 
Contouring and Target Definition 
 
1. For free breathing patients, the internal gross tumor volume (IGTV) will be 
generated using either a union of GTV on all respiratory phases or MIP and 
verified through all breathing phases. For BH patients, multiple BH CT scans 
will be acquired and the IGTV will be generated using a union of GTV defined 
on all BH scans. If gating is used, IGTV will be generated using a union of GTV 
on all treatment phases. The IGTV will include all lymph nodes >1.0cm in short 
diameter and gross tumor (all generally warmer than the mediastinal blood pool 
on PET). 
 
2. The clinical target volume (CTV) is defined as a margin of 5 to 10 mm 
(ordinarily 7-8 mm) isotropic expansion of the IGTV and edited clinically based 
on patterns of tumor spreading and anatomic boundaries such as vertebral bodies, 
chest wall, heart etc. 
 
3. For free breathing patients, plans will be evaluated on T0 and T50 phases using 
the CTV on these phases.  For BH patients, plans will be evaluated on each BH 
scan using the CTV on these BH scans. For gating patients, plans will be 
evaluated on the extreme treatment phases at either end of the respiratory gate, 
using the CTV on each of those phases. 
 
4. All normal structures will be contoured on the primary planning CT scans.  
 
5. Co-registration with contrast enhanced CT scans and/or PET scans may be used 
in identifying the GTV.  
 
7.1.7 
Treatment Planning 
 
i. IMPT plans will be generated on the primary planning CT. The 
prescription iso-dose line definition is up to the treating physician. However, 
we recommend that in the worst-case scenario the CTV D95% is at least 95% 
of the prescription dose (please see Sec. 7.1.12). 
 
ii. Beam angles will be selected to minimize the impact of motion and spare 
normal tissues.   
 
iii. The optimization method can be either multi-field optimization (MFO) 
or single-field optimization (SFO). SFO, also known as single-field 
uniform dose (SFUD), optimizes the spots of each proton field 
individually and creates a more uniform dose distribution from each 
beam than MFO. MFO is usually referred to as intensity-modulated 
proton therapy (IMPT). In MFO, spots from all the proton fields are 
optimized together. The inhomogeneous dose from each field is 
summed up to create homogeneous target coverage. 
 
iv. 4D treatment planning is the explicit inclusion of the temporal changes 

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in anatomy during the planning of radiotherapy. Usually it is based on 
4D CT. 
 
v. If possible patients will be planned using SFO technique. If SFO cannot meet 
the dose volume constraints and plan robustness requirement, robustly 
optimized 3D/4D MFO will be used.  
 
vi. “Verification” dose distributions will be generated by recalculating the dose 
on the T0 and T50 for the free breathing patients, on all BH scans for BH 
patients, and on the extreme treatment phases encompassing the respiratory 
gate for gating patients. The original plan generated on the primary 
planning CT will be adjusted until the verification and original dose 
distributions all meet the required prescription criteria (see Sec. 7.1.12). 
 
vii. 3D/4D robustness quantification to evaluate the impact of patient setup and 
proton beam range uncertainties will be performed. The inter-fractional setup 
uncertainty is assumed to be a minimum of 5 mm and proton beam range 
uncertainty is assumed to be a minimum of 3%. The intra-field setup 
uncertainty is assumed to be a minimum of 2 mm. These values are 
recommended by the PTCOG Thoracic/Lymphoma research subcommittee 
and are applicable to most patients. However, for some patients with much 
inhomogeneity, irregular breathing motion, larger values may be applied. For 
all patients, the plan robustness will be reviewed by a physicist co-chair. We 
recommend that in the worst-case scenario the CTV D95% is at least 95% of 
the prescription dose (please see Sec. 7.1.12).   
 
viii. Plans will require 2-3 fields in most cases. 
 
ix. Calculated dose distributions will be verified by comparison to a Monte 
Carlo calculation.  In cases where the CTV mean dose differs by more than 
5% between the analytical code and the Monte Carlo algorithm, the Monte 
Carlo derived dose distribution will be considered the dose of record.  
 
7.1.8 
Treatment Delivery 
 
The corresponding treatment delivery techniques as employed in the treatment 
planning will be used to deliver the plan.  
 
7.1.9 
Mitigation of interplay effect: Repainting 
 
Iso-layer repainting will be used to further reduce the impact of interplay effect. 
The effectiveness of repainting will be evaluated on a patient specific basis using 
in-house developed software. Dose evaluation software will be used to evaluate 
the impact of interplay effects by modelling time-dependent spot delivery to 
incorporate interplay effect with randomized starting phases of each field per 
fraction for either multiple fractions or single fraction (up to each participating 
institution’s choice). With interplay effects considered, we recommend that in the 
calculation with multiple fractions the difference of the CTV D95% is within 5% 

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of the CTV D95% of the original plan and the calculation with single fraction the 
difference of the CTV D95% is within 15% of the CTV D95% of the original 
plan (the exact number for the calculation with single fraction will be determined 
later). 
 
7.1.10 Adaptive re-planning 
 
1. All patients will undergo repeat CT simulation as defined in the CT simulation 
section (Sec. 7.1.4) weekly during treatment to determine whether adaptive re-
planning is needed to maintain target coverage and to avoid overdosing critical 
structures. The plan will be recalculated on the primary planning repeat CT 
scans. Contours will be deformed from the primary planning CT to the primary 
planning repeat CT, and the treating physician will review the new contours and 
doses. The same plan robustness quantification and motion evaluation procedures 
as defined for the original plan will be conducted. We recommend that in the 
worst-case scenario the difference of the CTV D95% is within 5% of the CTV 
D95% of the original plan.  
 
2. If an adaptive plan is deemed necessary, the plan will be developed using the 
treatment planning guidelines as described for the original plan.  
 
7.1.11 Critical Structures (see Table 7.1 for additional info) 
 
Table 7.1 Dose volume constraints for critical structures 
7.1.12 Definitions of Deviations in Protocol Performance 
 
 
 
 
• 
Prescription Dose: we recommend that in the worst-case scenario the 
CTV D95% is at least 95% of the prescription dose and the CTV D5% is 
at most 110% of the prescription dose.  
• 
Minor deviation: CTV D95%: 85-95% of the prescription dose, CTV 
D5%: 110-120% of the prescription dose in the worst-case scenario 
• 
Major deviation: CTV 95% : <85% of the prescription dose,  CTV D5%: 
>120% of the prescription dose  in the worst-case scenario  
• 
Volume: The GTV and CTV must be specified on any plans with dose –
volume histograms for these and all critical organs  
• 
Critical structures with an asterisk in Table 7.1 with the dose volume 
indices up to 110% of the limit will be considered a minor deviation.  
Critical structures with an asterisk in Table 7.1 with the dose volume 
Critical structure 
Dose limits (Gy[RBE]) 
Esophagus 
Guideline: 1/3 volume < 65 Gy[RBE]; 2/3 volume < 55 Gy[RBE],  
whole volume <= 45 Gy[RBE], as low as reasonably achievable, (try to avoid 
irradiating the full circumference of the esophagus) 
Liver* 
Whole volume <= 25 Gy[RBE]; 1/2 liver <= 35 Gy[RBE] 
Total Normal lung * 
V20 < 37% of volume is desirable V20>41% is a major deviation 
Spinal cord* 
Maximum dose < 50 Gy[RBE] 
Heart 
Guideline: V50 < 25% and mean heart dose < 20 Gy (exceeding this is a minor 
deviation) 
Skin 
Maximum dose < 55 Gy[RBE] (values will be decided by the treating physician) 

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indices more than 110% of the limit will be considered a major 
deviation. 
 
7.1.13 Quality Assurance Documentation  
 
All plans will be reviewed by the PI and or the co-PIs and rated as within guidelines 
(no deviations), minor deviation (any number of minor deviations mentioned above 
or major deviation (1 or more major deviations present) 
 
7.2 
Patient Outcomes Quality of Life Assessment [Database] 
 
 
7.2.1 A single item quality of life scale (LASA) will be assessed  for each patient per the 
scheduled tests 
 
 
7.3 
Chemotherapy  
 
 
 
7.3.1 
Patient will receive concurrent platinum based doublet chemotherapy under the 
direction of the treating medical oncologist. Treatment options can include standard 
weekly low dose Carboplatin and Paclitaxel, standard etoposide cisplatin or carboplatin 
or standard pemetrexed with cisplatin or carboplatin.,  Chemotherapy will be 
administered in standard doses as per institutional and standard regimen guidelines. Dose 
modifications will be done as per standard institutional guidelines.  
 
 
 
7.3.2 
Protocol therapy will consist of radiotherapy given with concurrent 
chemotherapy for six weeks of weekly chemotherapy. Consideration of adjuvant therapy 
is at the discretion of the treating Physician.. Patients will also be considered eligible for 
consolidation therapy clinical trials. 
 
 
7.3.3 
Standard premedications will be employed for chemotherapy according to 
institutional guidelines. 
 
 
 
 
 
 
 
7.4 
For this protocol, the patient must return to the consenting institution for evaluation at least 
every 7 days during proton treatment and every 3 months(+/-1 month) during observation 
(Active Monitoring Phase).  
 
 
8.0 Radiotherapy Dose Modifications Based on Adverse Events  
 
8.1 
If a patient develops any grade 3-4 toxicity felt to be due to radiation therapy, the table 
below will be followed and the patient will have a treatment break as directed and are to 
resume and complete therapy. This break in treatment is usually no more than 1 week. If 
the patient suffers neutropenic fever or requires hospitalization for any reason, treatment 
breaks will be given until the patient is dismissed from the hospital or deemed capable of 
safely receiving radiotherapy by the care team.  
 
In general, radiation therapy should continue to be delivered for ≤ grade 3 non-
hematologic toxicities in or outside the radiation treatment field. The only exception 

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being grade 3 pulmonary (see table below). RT should be held for all Grade 4 non-
hematologic toxicity in or outside the treatment field and resumed only when toxicity ≤ 
grade 2. 
 
If treatment is interrupted for more than 3 weeks due to toxicity, remove the patient from 
protocol treatment. 
 
 
Use the following treatment modification table for toxicities: 
In-field AE class 
CTCAE Toxicity 
Grade 
Radiation Therapy 
Esophagus/Pharynx 
4 
Hold treatment until ≤ grade 2 
Pulmonary 
4 
Hold treatment until ≤ grade 2 
Pulmonary 
3 
Hold treatment until ≤ grade 2 
Skin 
4 
Hold treatment until ≤ grade 2 
Heme (excluding 
lymphopenia) 
4 
Hold treatment until ≤ grade 2 
 
8.2 
Dose Modifications During Concurrent Chemotherapy will be at the discretion of the 
treating medical oncologist according to institutional guidelines 
 
8.2.1 
Hematologic Toxicities 
 
• 
Radiation therapy will be held for grade 4 hematologic toxicity until grade 
<2.(see table above) except lymphopenia. 
8.2.2 
Non-hematologic Toxicities 
Neurotoxicity: 
 
 
 
Based on treating oncologists’ opinion. 
8.3.1 
Hematologic Toxicity 
 
 
 
8.5 
Dosing for Obese Patients will follow published ASCO guidelines 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Patients should receive full supportive care while on this study.  This includes blood  
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such 
as anti-diarrheals, analgesics, and/or anti-emetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
 

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Chemotherapy interruptions will be determined by the Medical Oncology treating 
physician and will be assessed per standard clinical procedures for the particular 
chemotherapy being administered (as outlined in 8.2-8.5) 
9.2 
Skin changes are common complications of radiation therapy. Usual care will be 
provided. For dry skin, aloe vera based product or aquaphor can be prescribed. If the 
skin becomes erythematous and/or there is pruritis, topical steroid cream or topical 
Benadryl can be prescribed. Patients experiencing pain will be prescribed pain 
medication. 
9.3 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Other toxicities should be treated per standard of care: thrush/candida should be 
treated with antifungals (preferably nystatin as the first choice). Esophagitis should be 
treated with pain medications. Pneumonitis would be treated as clinically indicated 
(cough with anti-tussives (tessalon, dextromethoraphan,) shortness of breath (with 
inhalers and bronchodilators), poor oxygen saturation (with O2). Patients should be 
hospitalized when clinically warranted. 
9.5 
Patients will receive ancillary treatment and supportive care that would otherwise be                                   
considered standard of care in the setting of chemotherapy, radiation, and surgery. 
9.6 
Radiation treatment will be interrupted at the discretion of the treating physician, as 
per standard of care.  Generally, this would be for grade 4 in-field-toxicity (esophagus, 
pulmonary, skin) and/or grade 4 neutropenia with fever. (see 8.1 for specific 
recommendations) 
 
 
 
 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
10.1 
Definitions 
Adverse Event- An untoward or undesirable experience associated with the use of a 
medical product (i.e. drug, device, biologic) in a patient or research subject. 
Serious Adverse Event - Adverse events are classified as serious or non-serious.  Serious 
problems/events can be well defined and include; 
• 
death 
• 
life threatening adverse experience 
• 
hospitalization 
• 
inpatient, new, or prolonged; disability/incapacity 
• 
persistent or significant birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-
investigator may have adversely affected the rights, safety, or welfare of the subjects or 
others, or substantially compromised the research data. 
All adverse events that do not meet any of the criteria for serious, should be regarded as 
non-serious adverse events.  
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO)- Any 
unanticipated problem or adverse event that meets the following three criteria:  

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• Serious: Serious problems or events that results in significant harm, (which may 
be physical, psychological, financial, social, economic, or legal) or increased 
risk for the subject or others (including individuals who are not research 
subjects). These include: (1) death; (2) life threatening adverse experience; (3) 
hospitalization - inpatient, new, or prolonged; (4) disability/incapacity - 
persistent or significant; (5) birth defect/anomaly; (6) breach of confidentiality 
and (7) other problems, events, or new information (i.e. publications, DSMB 
reports, interim findings, product labeling change) that in the opinion of the 
local investigator may adversely affect the rights, safety, or welfare of the 
subjects or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not 
already described as potential risks in the protocol, consent document, not listed 
in the Investigator’s Brochure, or not part of an underlying disease. A problem 
or event is "unanticipated" when it was unforeseeable at the time of its 
occurrence. A problem or event is "unanticipated" when it occurs at an 
increased frequency or at an increased severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 
Preexisting Condition- A preexisting condition is one that is present at the start of the 
study.  A preexisting condition should be recorded as an adverse event if the frequency, 
intensity, or the character of the condition worsens during the study period. At screening, 
any clinically significant abnormality should be recorded as a preexisting condition.  At 
the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event must also be recorded and documented as an adverse event.  
 
 
10.2 
Recording Adverse Events 
 
 
 
CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site: 
 
 
10.21 Adverse event monitoring and reporting are a routine part of every     
clinical trial. First, identify and grade the severity of the event using the CTCAE 
version 4.0. Next, determine whether the event is expected or unexpected and if 
the adverse event is related to the medical treatment or procedure. With this 
information, determine whether the event must be reported as an expedited report 
(see Section 10.3). 
 
 
 
10.22 Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 

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Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event. 
 
 
 
10.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log.  The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 
 
a. Serious Adverse Events will be reported as part of regular adverse event 
reporting mechanisms via the data capture system and logged for review 
reporting. 
b. General reporting instructions  
The Mayo IND and/or MCCC Compliance will assist the sponsor-investigator in 
the processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report form 
or investigational agents or 
commercial/investigational agents on the same arm. 
 
10.31 Investigator Reporting: Notifying the Mayo IRB: 
 
The IRB requirements reflect the guidance documents released by the Office of 
Human Research Protections (OHRP), and the Food and Drug Administration 
(FDA) in early 2007 and are respectively entitled “Guidance on Reviewing and 
Reporting Unanticipated Problems Involving Risks to Subjects or Others and 
Adverse Events” and “Guidance for Clinical Investigators, Sponsors, and IRBs: 
Adverse Event Reporting – Improving Human Subject Protection.” 
 
10.311 
According to Mayo IRB Policy any serious adverse event (SAE) 
which the Principal Investigator has determined to be a 
UPIRTSO must be reported to the Mayo IRB as soon as possible 
but no later than 5 working days after the investigator first learns 
of the problem/event. 
10.312 
Non-UPIRTSO – the investigator reports problems or events that 
do NOT meet criteria of an UPIRTSO in summary format at the 
time of the next continuing review. The investigator monitors the 
severity and frequency of subsequent non-UPIRTSOs. 
 
Consider the following information to collect when developing any forms for 
documentation of adverse events. 
Example 
Information collected on the adverse event worksheet (and entered in the 
research database):  

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• 
Subject’s name:  
• 
Medical record number:  
• 
Disease/histology (if applicable):  
• 
The date the adverse event occurred:  
• 
Description of the adverse event:  
• 
Relationship of the adverse event to the research (drug, procedure, or 
intervention):  
• 
If the adverse event was expected:  
• 
The severity of the adverse event: (use a table to define severity scale 1-
5) 
• 
If any intervention was necessary:  
• 
Resolution: (was the incident resolved spontaneously, or after 
discontinuing treatment) 
• 
Date of Resolution:  
 
The investigator will review all adverse event reports to determine if specific 
reports need to be made to the IRB and FDA.  The investigator will sign and date 
the adverse event report when it is reviewed.  For this protocol, only directly 
related SAEs/UPIRTSOs will be reported to the IRB. 
 
10.4 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
System Organ Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Skin and subcutaneous 
disorders 
Radiation dermatitis 
X 
X 
Resp, thoracic & med 
disorders 
Pneumonitis 
X 
x 
 GI disorders 
Esophagitis 
X 
x 
Blood & lymphatic 
Febrile neutropenia 
X 
x 
 
 
 
10.41 Submit via appropriate reporting mechanisms (i.e., paper or electronic) the 
following AEs experienced by a patient and not specified in Section 10.4: 
 
10.4.11 
Grade 2 AEs deemed possibly, probably, or definitely related to 
the radiation. 
 
 
 
10.4.12 
Grade 3 and 4 AEs regardless of attribution to the study 
treatment or procedure. 
 
10.4.13  
Grade 5 AEs (Death) 
 
 
10.4.131 
Any death within 30 days of the patient’s last 
study treatment or procedure regardless of 
attribution to the study treatment or procedure 
 
10.4.132 
Any death more than 30 days after the patients 
last study treatment or procedure that is felt to be 
at least possibly treatment related must also be 

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submitted as a Grade 5 AE, with a CTCAE type 
and attribution assigned. 
 
10.5 
Monitoring and Auditing  
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
and government regulatory agencies, of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The 
investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices 
 
10.51 Medical Monitoring  
It is the responsibility of the Principal Investigator to oversee the safety of the 
study at his/her site.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the 
construction and implementation of a site data and safety-monitoring plan (see 
section 10.5  “Monitoring and Auditing”).  Medical monitoring will include a 
regular assessment of the number and type of serious adverse events.  “Any 
serious adverse events will be followed up by the sentinel event reporting 
procedure” 
 
 
11.0 
Treatment Evaluation  
 
NOTE:  This study uses protocol RECIST v1.1 template dated 2/16/2011.  See the footnote for 
the table regarding measureable disease in Section 11.44, as it pertains to data collection and 
analysis. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1)13 Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the short axis measurements in the case of lymph nodes are used in the RECIST 
guideline. 
 
 
11.1 
Schedule of Evaluations:  For the purposes of this study, patients should be reevaluated 
every 12-16 weeks during the active phase.  
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21   Measurable Disease 
 
11.211 A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray,  or as ≥1.0 cm with CT scan, CT 
component of a PET/CT, or MRI.  
 
11.212   A superficial non-nodal lesion is measurable if its longest diameter is ≥ 
1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or imaging.  In the 
case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 

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11.213  A malignant lymph node is considered measurable if its short axis is >1.5 
cm when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).   
 
Tumor lesions in a previously irradiated area are considered measurable disease 
under the following conditions: to determine local-regional control. 
 
11.22 Non-Measurable Disease 
 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to <1.5 
cm).  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
 
 Note:  ‘Cystic lesions’ thought to represent cystic metastases can be 
 considered as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same patient, 
these are preferred for selection as target lesions.  In addition, lymph nodes that 
have a short axis <1.0 cm are considered non- pathological (i.e., normal) and 
should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:   
 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-
up. For patients having only lesions measuring at least 1 cm to less than 2 cm 
must use CT imaging for both pre- and post-treatment tumor assessments.   
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
 
11.32 Acceptable Modalities for Measurable Disease:       
 
• 
Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
or less. If CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.     
 
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease.  The lesions should be measured on the same pulse 
sequence.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  

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Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
• 
PET-CT:  If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.   
 
 
• 
Physical Examination:  For superficial non-nodal lesions, physical 
examination is acceptable, but imaging is preferable, if both can be done. In 
the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
 
• 
FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease.  
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid 
with an update greater than twice that of the surrounding tissue on the 
attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’  New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
 
 
11.33 Measurement at Follow-up Evaluation:   
 
• 
In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 12-16 
weeks (see Section 11.44). 
 
• 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline.  These lesions can be non-

26                                                               MC1623 
 
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nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.   
 
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node), which can be measured 
reproducibly should be selected.   
 
• 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD).  The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.   
 
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph 
nodes will be calculated and reported as the post-baseline sum of dimensions 
(PBSD).  If the radiologist is able to provide an actual measure for the target 
lesion (or target lymph node), that should be recorded, even if it is below 0.5 
cm.  If the target lesion (or target lymph node) is believed to be present and is 
faintly seen but too small to measure, a default value of 0.5 cm should be 
assigned.  If it is the opinion of the radiologist that the target lesion or target 
lymph node has likely disappeared, the measurement should be recorded as 0 
cm. 
 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
 
 
11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at   
baseline.  These lesions and lymph nodes should be followed in accord with 
11.433. 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by 
 
CT/MRI/PET-CT/ /physical examination must be measured on re-
evaluation at evaluation times specified in Section 11.1.  Specifically, a 
change in objective status to either a PR or CR cannot be done without 
re-measuring target lesions and target lymph nodes.  
 

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Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response.  In selected circumstances, certain non-target 
organs may be evaluated less frequently.  For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
 
11.432 Evaluation of Target Lesions 
 
• Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have 
reduction in short axis to <1.0 cm. 
 
 
• Partial Response (PR): 
At least a 30% decrease in PBSD (sum of 
the longest diameter for all target lesions 
plus the sum of the short axis of all the 
target lymph nodes at current evaluation) 
taking as reference the BSD (see Section 
11.41). 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, 
which also includes any lymph node 
that was normal at baseline (< 1.0 cm 
short axis) and increased to ≥ 1.0 cm 
short axis during follow-up.  
 
b. At least a 20% increase in PBSD (sum 
of the longest diameter for all target 
lesions plus the sum of the short axis 
of all the target lymph nodes at current 
evaluation) taking as reference the 
MSD (Section 11.41).  In addition, the 
PBSD must also demonstrate an 
absolute increase of at least 0.5 cm 
from the MSD.  
 
c. See Section 11.32 for details in 
regards to the requirements for PD via 
FDG-PET imaging. 
  
• Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR, nor sufficient increase to qualify for 
PD taking as reference the MSD. 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 

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• Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance of all non-target 
lesions.  
 
b. Each non-target lymph node must 
have a reduction in short axis to <1.0 
cm. 
 
 
• Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, 
which also includes any lymph node that 
was normal at baseline (< 1.0 cm short 
axis) and increased to ≥ 1.0 cm short axis 
during follow-up.   
 
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes.  (NOTE:  Unequivocal 
progression should not normally 
trump target lesion and target lymph 
node status.  It must be representative 
of overall disease status change.)  
   
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
 
11.44 Overall Objective Status 
 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-target 
lymph nodes, and new disease as defined in the following tables:  
 
 
 
For Patients with Measurable Disease  
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 

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Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE:  This study uses the protocol RECIST v1.1 template dated 2/16/2011.  For data collection 
and analysis purposes the objective status changed from SD to PR in the MCCC protocol RECIST 
v1.1 template as of 2/16/2011 and to match RECIST v1.1 requirements. 
 
 
12.0 
Descriptive Factors  
 
• 
See stratification factors section 5.0 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
13.1 
Patients found ineligible will be replaced, as will cancels.  
13.2 
Patients who are stable will continue treatment per protocol. 
13.3 
Patients who develop PD while receiving therapy or once in observation will go to the 
event-monitoring phase. 
13.4 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 18.0. 
13.5 
Observation/Event Monitoring: If the patient has completed therapy and remained stable, 
the patient will be observed every 3 months (+/- 1 month) for 3 years (observation phase) 
post RT. Then, every 6 months (+/- 3 months) (event monitoring) for an additional 2 
years.  For a total of 5 years observation/event monitoring from time of registration  
13.6 
If a patient fails to complete the entire course of treatment for reasons other than toxicity 
or PD, the patient will be regarded as inevaluable and will be replaced.    
13.7 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 

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monitoring will be required per Section 18.0 of the protocol.  
13.8 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable, which is to be determined by the Biostatistician and Principal 
Investigator.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient may continue treatment off-protocol at the discretion of the 
physician as long as there are no safety concerns, and the patient was properly registered.  
Event monitoring will be required per Section 18.0 of the protocol. If a treatment 
deviation occurs wherein a patient is administered an alternative standard of care 
chemotherapy the patient will be followed and data will continue to be collected 
according to section 4.0. 
13.9 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 
 
14.0 
Body Fluid Biospecimens   
 
None 
 
 
 15.0 
Drug Information 
 
 
Radiation will be accompanied by concurrent standard platinum doublet chemotherapy under the 
direction of the treating medical oncologist. 
 
 
16.0 
Statistical Considerations and Methodology  
 
16.1 Overview: This protocol is designed to compare proton beam dose levels of 72 Gy and 60 
Gy in patients receiving proton beam therapy for newly diagnosed lung cancer using a flexible 
“pick the winner”  randomized phase II study design (Sargent & Goldberg, 2001).  Patients will 
be randomized to a single dose level using a dynamic allocation procedure (Pocock & Simon, 
1975) that balances the marginal distributions of the stratification factors (see Section 5.0) 
between the treatment regimens. 
 
16.11 Primary Endpoint:  The primary endpoint of this trial is progression-free survival 
(PFS).  PFS time is defined as the time from randomization to the earliest date of 
documentation of disease progression or death due to any cause.  If a patient dies without 
a documentation of disease progression the patient will be censored on the last date the 
disease was evaluated.  In the case of a patient starting treatment and then never returning 
for any evaluations, the patient will be censored for progression on day 1 post-
randomization.  All patients meeting the eligibility criteria who have signed a consent 
form, have begun treatment, and have not been declared a major treatment violation will 
be evaluable.   Analysis will be conducted after all patients have been followed for at 
least one year.    
 
16.2 Statistical Design:  
 
16.21 The selected design is a flexible “pick the winner”  randomized phase II design. .  
Patients will be randomized to either 60or 72 Gy and followed for a minimum of one 
year This study will randomize 42 evaluable patients (21 per dose level x 2 dose levels  If 
the observed PFS rate at 1 year of one arm is at least 15% greater than the PFS rate of the 

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other arm, then that arm will be considered the winning arm.  This design has a 
probability of an inconclusive result  <8% and an approximate 80% probability of 
selecting the true winner.   
 
If the difference is <15%, then the trial will be considered stistiatically ambiguous and 
the selection of a winning arm will be allowed to include other factors (i.e. adverse event 
data and patient-reported quality of life) in addition to the PFS rate at 1 year.   
 
Based on this flexible "pick the winner" design, if both arms have a PFS rate at 1-year of 
48%, then each arm has a 44% probability of being picked the winner based on PFS rate 
at 1-year and the probability that the trial is statistically ambiguous and selection of a 
winning arm will be allowed to include other factors in addition to the PFS rate at 1-year 
is 12%.   
 
If one arms has true PFS rate of 53% and 1 arm has a true PFS rate of 63%, then the arm 
with 53% PFS rates has a 21% chance of being picked the winner based on PFS rate at 1-
year; the arm with the 63% PFS rate has a 69% chance of being picked the winner based 
on PFS rate at 1-year alone; and the probability that the trial is statistically ambiguous is 
10%. 
 
Properties of the proposed "pick the winner" design were computed using the "pselect" 
function within the "clinfun" package in R.  
 
No interim analyses will be conducted for PFS. 
 
16.211 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making process. Analyses involving over accrued patients are discussed 
in Section 16.313. 
 
16.22 Sample Size:  As of May 16, 2018 7 patients (nA=3, nB = 2, nC=2) have been 
enrolled in 3 cohorts onto this trial.  As of Amendment 3 we remove the 66 Gy (Arm B) 
dose level, and amend the necessary sample size.  In order to sufficiently power this 
amended protocol, 42 total (n=21 per arm) evaluable patients will need to be accrued 
onto this randomized phase II study unless undue adverse events are encountered. We 
anticipate accruing an additional 6 patients (3 per dose level) to account for ineligibility, 
cancellation, major treatment violation, or other reasons. Maximum projected accrual is 
therefore 48 patients total (including the five patients enrolled prior to Amendment 3).  
Therefore, we will need to accrue 43 additional patients from the time of Amendment 3.  
The inclusion of the two patients enrolled into the previously open arm (66 Gy) dictates 
that a total of 50 patients will be accrued for the duration of this trial. 
 
16.23 Accrual Time and Study Duration:  The anticipated accrual rate is approximately 
2 patients per month based on physician estimate. Therefore, the accrual period for this 
randomized phase II study is expected to be 24 months.  The final analysis can begin 
approximately 36 months after the trial begins, i.e., as soon as the last patient has been 
observed for 12 months. 
 
16.24 Power and Significance Level:  For the primary analysis, it is assumed that the 1-
year PFS rate for 60 Gy is 48% whereas the 1-year PFS rates for 72 Gy is 63% (the later 
based on Chang et al., 2015), .  It is also assumed that the distributions of PFS times for 

32                                                               MC1623 
 
Protocol Version Date: 13DEC2019 
each dose group follow an exponential distribution. and the probability of declaring that 
evidence exists that PFS is superior for 72 Gy relative to 60 Gy is selected for futher 
studies under various PFS rates is shown in the following table: 
 
 
 
 
N per 
arm 
PFS 
rate 
Trt 1 
PFS 
rate 
Trt 2 
Probability of 
a statistically 
ambiguous 
result* 
Probability 
of 
selecting 
Trt 1† 
Probability 
of 
selecting 
Trt 2† 
21 
0.48 
0.48 
0.12 
0.44 
0.44 
21 
0.48 
0.53 
0.12 
0.31 
0.57 
21 
0.48 
0.63 
0.08 
0.12 
0.80 
21 
0.53 
0.63 
0.10 
0.21 
0.69 
*See section 16.21 
† Selection based on PFS rate at 1-year alone. 
 
16.25 Other Considerations:  Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or changes in 
standard care will be taken into account in any decision to terminate the study. 
 
16.3 Analysis Plan:  The analysis for this trial will commence at planned time points (see 16.2) 
and at the time the patients have become evaluable for the primary endpoint. Such a decision will 
be made by the Statistician and Study Chair in accordance with CCS Standard Operating 
Procedures, availability of data for secondary endpoints (e.g., laboratory correlates), and the level 
of data maturity. It is anticipated that the earliest date in which the results will be made available 
via manuscript, abstract, or presentation format is 3 years after the trial commences. 
 
16.31 Primary Endpoint 
 
16.311 Definition:  The primary endpoint of this trial is PFS.  PFS time is 
defined as the time from randomization to the earliest date of documentation of 
disease progression or death due to any cause.  If a patient dies without a 
documentation of disease progression the patient will be censored on the last date 
the disease was evaluated.  In the case of a patient starting treatment and then 
never returning for any evaluations, the patient will be censored for progression 
on day 1 post-randomization.  Progression events will be reviewed and confirmed 
by a central review panel and the primary analysis will be based on these central 
reads.  A patient will be considered censored at the last follow-up date if 
progression or death had not been observed at that time.  
 
16.312 Estimation:  A Cox proportional hazards model stratified by 
stratification factors (see Section 5.0) will be used to model PFS as a function of 
dose to test for an overall dose effect (a one-sided p-value<0.10 will be 
considered as significant evidence of a dose effect).  Subsequently, descriptive 
statistics and separate Cox models stratified by stratification factors (see Section 
5.0) will compare PFS between 72 Gy and 60 Gy (for each, a one-sided p-
value<0.10 will be considered as significant evidence of superiority).  Kaplan-
Meier estimates and curves by dose level will also be generated. 
 

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Protocol Version Date: 13DEC2019 
16.32 Definitions and Analyses of Secondary Endpoints 
 
16.321 Overall survival time is defined as the time from randomization to death 
due to any cause.  Overall survival will be modeled similarly to PFS as described 
above using Cox models.  Kaplan-Meier estimates and curves by dose level will 
also be generated.  Overall survival will be analyzed at the time of the final PFS 
analysis.  OS will again be analyzed as exploratory analysis after 25 deaths per 
primary pairwise comparison have occurred or after all patients have completed 
follow-up (whichever occurs first). 
 
16.323 Adverse events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s). The maximum grade for 
each type of adverse event will be recorded for each patient, and frequency tables 
will be reviewed to determine patterns by dose level (60 and72 Gy).  
Additionally, the relationship of the adverse event(s) to dose level will be taken 
into consideration. 
 
16.324 Local-regional failure time is defined as the time from randomization to 
the earliest date of documentation of local recurrence (at the site of the original 
primary tumor and adenopathy, i.e., GTV).  The cumulative incidence of local 
failure will be estimated using Gray’s methodology and compared across dose 
levels using Fine-Gray quadratic regression (with death as a competing risk). 
 
16.324 Distant metastasis time is defined as the time from randomization to the 
earliest date of documentation of distant metastasis.  The cumulative incidence of 
distant metastasis will be estimated using Gray’s methodology and compared 
across dose levels using Fine-Gray quadratic regression (with death as a 
competing risk). 
 
16.33   Correlative Research 
 
16.331 Quality of life will be assessed prior to review of disease status and 
discussions of patient’s general health since last treatment evaluation.  QOL will 
be measured using the single item LASA scale described in Sloan et al.14 The 
questionnaires will be scored according to published scoring criteria.  Descriptive 
statistics by dose level at each time point will include means, standard deviations, 
medians, and ranges for each scale.  Descriptive graphical techniques will 
include mean plots by dose over time for each scale.  Mixed models will be used 
to compare each scale across dose levels at each post-baseline time point while 
adjusting for the baseline value of scale.  To handle missing data, we will 
graphically explore patterns of missing data and will employ pattern mixture 
models for longitudinal analyses.  For interpreting the clinical significance of 
effects, 0.2, 0.5, and 0.8 standard deviation effects will be considered as small, 
moderate, and large based on Cohen (1988) throughout. 
 
16.332 Prior to Amendment 3 there were three arms in this trial. Patients 
(n=2) involved in a previously open arm (66Gy) will be followed per protocol 
and descriptive statistics will be implemented to describe the outcomes 
associated within the 66Gy arm in congruence with the trial objectives.   
 
 

34                                                               MC1623 
 
Protocol Version Date: 13DEC2019 
16.4 Data & Safety Monitoring: 
 
16.41 The study chair(s) and the study statistician will review the study at least twice a 
year to identify accrual, adverse event, and any endpoint problems that might be 
developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring Board 
(DSMB) is responsible for reviewing accrual and safety data for this trial at least twice a 
year, based on reports provided by the MCCC Statistical Office. 
 
16.42 Adverse Event Stopping Rules: The stopping rules specified below are based on 
the knowledge available at study development. We note that the Adverse Event Stopping 
Rule may be adjusted in the event of either (1) the study re-opening to accrual or (2) at 
any time during the conduct of the trial and in consideration of newly acquired 
information regarding the adverse event profile of the treatment(s) under investigation. 
The study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe events 
considered at least possibly related to study treatment (i.e., an adverse event with attribute 
specified as “possible”, “probable”, or “definite”) that satisfy either of the following: 
 
o if 6 or more patients in the first 20 treated patients experience a grade 4 or 
higher non-hematologic adverse event (excluding skin toxicity which can be 
significant after proton therapy but does not result in mortality) 
o if after the first 20 patients have been treated, 30% of all treated patients 
experience a grade 4 or higher non-hematologic adverse event (excluding skin 
toxicity).  
 
This adverse event stopping rule is applied to each arm separately.  If the adverse 
event stopping rule is crossed for any one (or more) arm, accrual to the entire study will 
be halted to allow for full review of the safety data. 
  
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related adverse event. 
 
16.5 Results Reporting on 
:  At study activation, this study will have been 
registered within the “
” website. The Primary and Secondary Endpoints (i.e., 
“Outcome Measures”) along with other required information for this study will be reported on 
 For purposes of timing of the Results Reporting, the initial estimated 
completion date for the Primary Endpoint of this study is 36 months after the study opens to 
accrual. The definition of “Primary Endpoint Completion Date” (PECD) for this study is at the 
time the last patient registered has been followed for at least 12 months. 
 
16.6 Inclusion of Women and Minorities 
 
16.61 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.62 There is no information currently available regarding differential effects of these 
regimens in subsets defined by race, gender, or ethnicity, and there is no reason to expect 
such differences to exist. Therefore, although the planned analysis will, as always, look 

35                                                               MC1623 
 
Protocol Version Date: 13DEC2019 
for differences in treatment effect based on racial and gender groupings, the sample size 
is not increased in order to provide additional power for subset analyses. 
 
16.63 The geographical region served by MMC has a population that includes 
approximately 5% minorities. Based on prior MMC studies involving similar disease 
sites, we expect about 5% of patients will be classified as minorities by race and about 
45% of patients will be women. Expected sizes of racial by gender subsets for patients 
registered to this study are shown in the following table: 
 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
2 
4 
Not Hispanic or Latino 
45 
68 
113 
Ethnic Category: Total of all subjects 
47 
70 
117 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
1 
1 
Black or African American 
2 
2 
4 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
45 
67 
112 
Racial Category: Total of all subjects 
47 
70 
117 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
17.0  
Pathology Considerations/Tissue Biospecimens   
 
Tissue documenting the presence of non-small cell lung cancer is obtained as per standard 
institutional practice.

MC1623 
 
Protocol Version Date: 13DEC2019 
18.0 
Records and Data Collection Procedures   
 
CRF completion: this study will use Medidata Rave for remote data capture (rdc) of all study data. 
 
            
 
 
19.0  
Study Finances 
 
 
 
19.1 
Costs charged to patient:  routine clinical care 
 
 
19.2 
Tests to be research funded: none 
 
 
 
 
 
 
 
 
 

MC1623 
 
Protocol Version Date: 13DEC2019 
20.0 
References 
 
 
Chung, C. S. et al. Incidence of second malignancies among patients treated with proton versus photon 
radiation. Int J Radiat Oncol Biol Phys 87, 46-52 (2013).  
 
 
Mendenhall, N. P., et al. Five-year outcomes from 3 prospective trials of image-guided proton therapy for 
prostate cancer. International journal of radiation oncology, biology, physics 88, 596-602 (2014).  
 
 
Sejpal, S. et al. Early findings on toxicity of proton beam therapy with concurrent chemotherapy for 
nonsmall cell lung cancer. Cancer 117, 3004-3013 (2005).  
 
 
Lundkvist, J. et al. Cost-effectiveness of proton radiation in the treatment of childhood medulloblastoma. 
Cancer 103, 793-801 (2005).  
 
 
 
Lundkvist, J. et al. Proton therapy of cancer: potential clinical advantages and cost-effectiveness. Acta 
oncologica 44, 850-861 (2005).  
 
 
Bradley, J. D. et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and 
consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB 
non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet 
Oncol 16, 187-199 (2015).  
 
 
Fletcher, G. H.  et al. The interplay of radiocurability and tolerance in the irradiation of human cancers. J 
Radiol Electrol Med Nucl 56, 383-400 (1975).  
 
 
Chang, J. Y. et al. Significant reduction of normal tissue dose by proton radiotherapy compared with 
three-dimensional conformal or intensity-modulated radiation therapy in Stage I or Stage III non-small-
cell lung cancer. Int J Radiat Oncol Biol Phys 65, 1087-1096 (2006).  
 
 
Chang, J. Y. et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for 
unresectable stage III nonsmall cell lung cancer. Cancer 22 (2011).  
 
 
Nguyen, Q. N. et al. Long-term outcomes after proton therapy, with concurrent chemotherapy, for stage 
II-III inoperable non-small cell lung cancer. Radiother Oncol 115, 367-372 (2015).  
 
 
Oro, F. et al. Identifying the Optimal Radiation Dose in Locally Advanced Non-Small Cell Lung Cancer 
(NSCLC) Treated With Definitive Radiation Therapy Without Concurrent Chemotherapy. Int J Radiat 
Oncol Biol Phys 93, S89 (2015).  
 
 
Schild, S. et al. A new scoring system for predicting survival in patients with non-small cell lung cancer. 
Cancer Med 4, 1334-1343 (2015).  
 
 
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). European journal of cancer 45, 228-247 (2009).  
 
 
Sloan, J. A. et al. Relationship between deficits in overall quality of life and non-small-cell lung cancer 
survival. J Clin Oncol 30, 1498-1504 (2012).  
 
Sargent DJ, Goldberg RM. A flexible design for multiple armed screening trials. Stat Med. 2001 Apr 
15;20(7):1051-60.  
 

MC1623 
 
Protocol Version Date: 13DEC2019 
Appendix I 
ECOG Performance Status 
Developed by the Eastern Cooperative Oncology Group.* 
GRADE 
ECOG PERFORMANCE 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 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of 
the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
 

MC1623 
 
Protocol Version Date: 13DEC2019 
Appendix II 
 
Quality of Life Measure 
 
How would you rate your quality of life today? 
 
0          10          20          30          40          50          60          70          80          90          100 
 
As bad as it can be                                                                                                            As good as it can be 
 
 
 
 
Appendix IIb