Randomized Phase II Trial of Concurrent Chemoradiotherapy +/- Metformin HCL in Locally Advanced NSCLC
Phase: PHASE2
Conditions: Adenosquamous Lung Carcinoma, Bronchioloalveolar Carcinoma, Large Cell Lung Carcinoma, Lung Adenocarcinoma, Non-Small Cell Lung Carcinoma, Recurrent Non-Small Cell Lung Carcinoma, Squamous Cell Lung Carcinoma, Stage IIIA Non-Small Cell Lung Cancer, Stage IIIB Non-Small Cell Lung Cancer
Sponsor: NRG Oncology

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NRG-LU001; version date: November 1, 2018 
 
 
NRG ONCOLOGY  
 
NRG-LU001 
ClinicalTrials.gov NCT02186847 
 
 
RANDOMIZED PHASE II TRIAL OF CONCURRENT CHEMORADIOTHERAPY +/- 
METFORMIN HCL IN LOCALLY ADVANCED NSCLC 
 
This trial is sponsored by the National Cancer Institute (NCI) and will be led by NRG Oncology. 
 
 
 
Study Team (1-NOV-2018) 
 
 
Co-Principal Investigator/Radiation Oncology 
Radiology Co-Chair 
Theodoros (Theos) Tsakiridis, MD 
Jeremy Erasmus, MD 
Juravinski Cancer Center 
MD Anderson Cancer Center 
699 Concession Street 
1515 Holcombe Blvd., Unit 1478 
Hamilton, Ontario, Canada L8V 5C2 
Houston, TX 77030 
905-387-9495 /FAX 905-575-6326 
713-792-5878/FAX 713-794-4361 
tsakirid@hhsc.ca 
JErasmus@mdanderson.org 
 
 
Co-Principal Investigator/Radiation Oncology 
Medical Physicist Co-Chair 
Heath Skinner, MD, PhD 
Anthony J. Doemer, MS 
UPMC Hillman Cancer Center 
Research Pavilion, Suite 2.6a 
5117 Centre Avenue 
Pittsburgh, Pa  15213-1863 
412-623-3275/FAX 412-623-7761 
skinnerh@upmc.edu 
Henry Ford Health System 
2799 W. Grand Blvd. 
Detroit, MI 48202 
313-916-0234/FAX 313-916-3264 
ADOEMER1@hfhs.org 
 
 
 
Medical Oncology Co-Chair 
 
Senior Statistician 
Rafael Santana-Davila, MD 
Chen Hu, PhD 
Seattle Cancer Care Alliance 
NRG Oncology 
825 Eastlake Avenue E; Mailstop G4940 
1818 Market Street, Suite 1720 
Seattle, WA 98109 
Philadelphia, PA 19103 
206-288-2190/FAX 206-288-2226 
215-940-4842/FAX 215-928-0153 
rafaelsd@uw.edu 
huc@nrgoncology.org 
 
 
Translational Science Co-Chair 
 
Bo Lu, MD 
 
Thomas Jefferson University 
 
111 S. 11th Street 
 
Philadelphia, PA 19107 
 
215-955-6705/FAX 215-503-0013 
 
Bo.Lu@jeffersonhospital.org 
 
 
 
 
 
 
 

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NRG-LU001; version date: November 1, 2018 
 
 
NRG ONCOLOGY  
 
NRG-LU001 
 
RANDOMIZED PHASE II TRIAL OF CONCURRENT CHEMORADIOTHERAPY +/- 
METFORMIN HCL IN LOCALLY ADVANCED NSCLC 
 
Study Team (Continued) 
 
NRG Oncology Contact Information (1-NOV-2018) 
 
 
Data Manager:   
For questions concerning eligibility or data 
submission 
Jeff Serianni 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA  19103 
215-574-3248/Fax: 215-930-8840 
SerianniJ@NRGOncology.org 
 
Amy Krystkiewicz, RN 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA  19103 
267-940-9415 
KrystkiewiczA@NRGOncology.org 
 
 
RTQA:  
For questions concerning RT data submission 
Jennifer Presley 
IROC Philadelphia – RT QA Center 
ACR Clinical Research Center 
1818 Market Street, Suite 1720 
Philadelphia, PA  19103 
215-574-3153 
jpresley@acr.org 
 
 
RTQA:   
For questions concerning data submission to 
TRIAD 
Triad-Support@acr.org 
 
 
Protocol Development: 
For questions concerning protocol and informed 
consent versions & amendments  
Fran Bradley 
NRG Oncology  
1818 Market Street, Suite 1720 
Philadelphia, PA 19013 
215-940-8893/Fax: 215-928-0153 
BradleyF@NRGOncology.org  
 
 
NRG Oncology Lung Committee Chair 
Jeffrey D. Bradley, MD 
Washington University 
4921 Parkview Place 
St. Louis, MO 63110 
314-362-4633/Fax:  314-362-8521 
jbradley@wustl.edu 
 

1 
NRG-LU001; version date: November 1, 2018 
 
 
NRG ONCOLOGY  
 
NRG-LU001 
 
RANDOMIZED PHASE II TRIAL OF CONCURRENT CHEMORADIOTHERAPY +/- 
METFORMIN HCL IN LOCALLY ADVANCED NSCLC 
 
 
 
 
 
 
Protocol Agent (5/7/15) 
Agent 
Supply 
 
IND # 
Carboplatin 
Commercial 
 
Exempt 
Paclitaxel 
Commercial 
 
Exempt 
Metformin HCL 
Commercial 
 
Exempt 
 
 
 
  
Participating Sites 
 U.S. Only 
 Canada Only 
 U.S. and Canada 
 Approved International Member Sites 
 
 
 
 
Document History  
 
Version/Update Date 
Broadcast Date 
Amendment 3 
November 1, 2018 
N/A 
Closure 
August 10, 2016 
December 15, 2016 
Amendment 2 
August 10, 2016 
September 6, 2016 
Amendment 1 
May 7, 2015 
June 15, 2015 
Update 
August 25, 2014 
August 25, 2014 
Activation 
June 25, 2014 
August 25, 2014 
Update 
August 4, 2014 
August 4, 2014 
Pre-Activation 
June 25, 2014 
August 4, 2014 
 
                                                                                     
 
 
NRG Oncology 
1-800-227-5463, ext. 4189 
  
 
 
This protocol was designed and developed by NRG Oncology.  It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  
No other use or reproduction is authorized by NRG Oncology nor does NRG 
Oncology assume any responsibility for unauthorized use of this protocol. 

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NRG-LU001; version date: November 1, 2018 
 
 
Table of Contents 
SCHEMA ....................................................................................................................................................... 4 
ELIGIBILITY CHECKLIST  ............................................................................................................................ 5 
1.0 
 INTRODUCTION .............................................................................................................................. 9 
1.1 
Background and Rationale ............................................................................................................ 9 
1.2 
NSCLC Resistance to Cytotoxic Therapy: The Need for Rational Development of Sensitizing 
Therapies .................................................................................................................................... 10 
1.3 
Pre-Clinical Evidence .................................................................................................................. 10 
1.4 
Rationale for This Study: Selected Approach and Trial Design .................................................. 16 
1.5 
Translational Science  ................................................................................................................. 17 
2.0 
 OBJECTIVES ................................................................................................................................. 18 
2.1 
Primary Objective ........................................................................................................................ 18 
2.2 
Secondary Objectives ................................................................................................................. 18 
3.0 
 PATIENT SELECTION................................................................................................................... 19 
3.1 
Conditions for Patient Eligibility ................................................................................................... 19 
3.2 
Conditions for Patient Ineligibility ................................................................................................ 20 
4.0 
 PRETREATMENT EVALUATIONS/MANAGEMENT  ................................................................... 20 
4.1 
Required Evaluations/Management ............................................................................................ 20 
5.0        REGISTRATION PROCEDURES .................................................................................................. 20 
5.1  
Radiation-Specific Pre-Registration Requirements..................................................................... 21 
5.2 
Digital RT Data Submission to NRG Oncology Using TRIAD ..................................................... 22 
5.3  
Regulatory Pre-Registration Requirements ................................................................................ 22 
5.4  
Registration  ................................................................................................................................ 24 
6.0 
 RADIATION THERAPY.................................................................................................................. 25 
6.1 
Treatment Technology ................................................................................................................ 25 
6.2 
Immobilization and Simulation .................................................................................................... 25 
6.3 
Imaging for Structure Definition, Image Registration/Fusion and Follow Up  ............................. 25 
6.4 
Accounting for Tumor Motion Approaches and Internal and Setup Margins  ............................. 26 
6.5 
Definition of Critical Structures and Margins ............................................................................... 27 
6.6 
Dose Prescription ........................................................................................................................ 28 
6.7 
Compliance Criteria  .................................................................................................................... 28 
6.8 
Treatment Planning Priorities and Instructions  .......................................................................... 29 
6.9 
Dose Calculations ....................................................................................................................... 30 
6.10 
Patient-specific Quality Assurance  ............................................................................................ 31 
6.11 
Treatment Delivery  ..................................................................................................................... 31 
6.12 
R.T. Quality Assurance Reviews  ............................................................................................... 31 
6.13 
Radiation Therapy Adverse Events ............................................................................................ 31 
7.0 
 DRUG THERAPY ........................................................................................................................... 31 
7.1 
Treatment .................................................................................................................................... 31 
7.2 
Study Agents ............................................................................................................................... 34 
7.3 
Dose Modifications  ..................................................................................................................... 34 
7.4 
Modality Review .......................................................................................................................... 37 
7.5 
Adverse Events ........................................................................................................................... 37 
7.6 
CTEP-AERS Expedited Reporting Requirements ...................................................................... 38 
8.0 
 SURGERY ..................................................................................................................................... 40 
9.0 
 OTHER THERAPY ......................................................................................................................... 40 
9.1 
Permitted Supportive Therapy .................................................................................................... 40 
9.2 
Non-permitted Supportive Therapy ............................................................................................. 40 
10.0 
TISSUE/SPECIMEN SUBMISSION  ............................................................................................... 40 
10.1 
Tissue/Specimen Submission  .................................................................................................... 41 
10.2 
Specimen Collection for Tissue Banking and Translational Research ....................................... 41 
10.3 
Reimbursement ........................................................................................................................... 43 
10.4 
Confidentiality/Storage ................................................................................................................ 43 
11.0 
PATIENT ASSESSMENTS ............................................................................................................. 43 
11.1 
Study Parameters ....................................................................................................................... 43 

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NRG-LU001; version date: November 1, 2018 
 
 
11.2 
Details of Evaluations .................................................................................................................. 43 
11.3 
Measurement of Response ......................................................................................................... 44 
11.4 
Measurement/Definition of Progression/Recurrence .................................................................. 45 
11.5 
Criteria for Discontinuation of Metformin Treatment  .................................................................. 45 
12.0 
DATA COLLECTION ....................................................................................................................... 45 
12.1 
Summary of Data Submission..................................................................................................... 45 
12.2 
Summary of Dosimetry Digital Data Submission ........................................................................ 47 
12.3 
Summary of Required Diagnostic Imaging Digital Data Submission .......................................... 48 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 48 
13.1 
Primary Endpoint ......................................................................................................................... 48 
13.2 
Secondary Endpoints .................................................................................................................. 48 
13.3 
Stratification................................................................................................................................. 48 
13.4 
Sample Size and Power Justification .......................................................................................... 49 
13.5 
Statistical Analysis Plan .............................................................................................................. 49 
13.6 
Statistical Considerations for Translation Research ................................................................... 51 
13.7 
Gender and Minorities ................................................................................................................. 52 
REFERENCES ............................................................................................................................................ 53 
APPENDIX I STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS  ................................. 57 
APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT  ......................... 58 
APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW UP ..................................... 59 
APPENDIX II: ZUBROD PERFORMANCE SCALE .................................................................................... 60 
APPENDIX III: AJCC STAGING SYSTEM ................................................................................................. 61 
APPENDIX IV: BIOSPECIMEN COLLECTION  ......................................................................................... 63 
 
 
 
  

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NRG-LU001; version date: November 1, 2018 
 
 
NRG ONCOLOGY 
 
NRG-LU001 
 
Randomized Phase II Trial of Concurrent Chemoradiotherapy +/- Metformin HCL in Locally 
Advanced NSCLC  
 
 
SCHEMA 
 
 
 
 
 
 
S 
Zubrod Performance Score 
R 
Arm 1: Concurrent Chemoradiotherapy  
T 
1. 0 
A 
RT: 60 Gy/30 fx with chemotherapy for 6 weeks 
R 
2. 1 
N 
Followed by Consolidation Chemotherapy for 6 weeks 
A 
 
D 
 
T 
Histology 
O 
Arm 2:  
I 
1. Squamous 
M 
MET Dose Escalation: 1000 mg to 2000 mg daily for 2 weeks 
F 
2. Non-Squamous 
I 
 
Y 
 
Z 
Concurrent Chemoradiotherapy + MET: RT: 60 Gy/30 fx with 
Chemotherapy and MET (2000 mg, p.o. daily) for 6 weeks 
 
Clinical Stage 
E 
 
1. IIIA 
 
Consolidation Chemotherapy + MET: Consolidation 
chemotherapy for 6 weeks and MET (2000 mg p.o. daily) for 10 
weeks. 
 
2. IIIB 
 
 
 
 
 
 
See Section 7.0 for details/doses of study drugs. See Section 5.0 for details of pre-registration 
requirements. 
 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
Pathologically proven diagnosis of Stage IIIA or IIIB non-small cell lung cancer; patients must have 
unresectable disease, are medically inoperable, or are not willing to undergo surgical management. 
 
Required Sample Size: 168 
  
 
 

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NRG-LU001; version date: November 1, 2018 
 
 
ELIGIBILITY CHECKLIST (8/4/14) 
(page 1 of 4) 
NRG Oncology Institution #  
NRG-LU001 
Case #  
 
The following questions will be asked at Study Registration:  
3D-CRT and/or IMRT CREDENTIALING IS REQUIRED BEFORE REGISTRATION. See Section 5.0. 
 
 
         
1. 
Institutional person randomizing case. 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient’s Initials (Last First Middle) 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Method of Payment 
 
 
         
15. 
Any care at a VA or Military Hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization date 
 
 
         
18. 
Medical Oncologist’s name  
 
              (Y/N)   19. 
My samples and related information may be kept in a Biobank for use in future 
health research.   
 
              (Y/N)   20.  
I agree that my study doctor, or their representative, may contact me or my 
physician to see if I wish to participate in other research in the future.  
 
 
 

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NRG-LU001; version date: November 1, 2018 
 
 
ELIGIBILITY CHECKLIST (8/4/14) 
(page 2 of 4) 
NRG Oncology Institution #  
NRG-LU001  
Case #  
 
 
                         21. 
MedDRA disease code 
  
             (Y/N)    22. 
Specify use of IMRT 
 
              (0/1)    23. 
Zubrod Performance Score 
 
                         24.  
Histology (Squamous Cell Carcinoma or Non-Squamous Cell Carcinoma) 
 
         (IIIA/IIIB)  25. 
Clinical Stage 
 
 
         
26. 
Histologic Confirmation Date 
 
 
         
27. 
Lung Tumor Histology 
 
              (Y/N)   28. 
Does the patient have measurable disease? 
 
              (Y/N)   29. 
Does the patient have unresectable disease, are they medically inoperable, or 
are they unwilling to undergo surgical management? 
 
 
         
30. 
History and Physical Exam Date 
 
 
         
31. 
Date of CT scan or MRI of the chest and abdomen 
 
 
         
32. 
Date of MRI (or CT) of the brain with contrast (unless medically contraindicated) 
 
 
         
33. 
Date of whole body FDG-PET/CT 
 
 
         
34. 
Date CBC panel was performed 
 
 
         
35. 
ANC (cells/mm3) 
 
 
         
36. 
Platelets (cells/mm3) 
 
 
         
37. 
Hemoglobin (g/dL) 
 
                         38. 
Labs assessment date 
 
                         39. 
Serum creatinine 
 
                         40. 
Serum creatinine ULN 
 
                           41. 
Creatinine Clearance 
 
 

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NRG-LU001; version date: November 1, 2018 
 
 
ELIGIBILITY CHECKLIST (8/4/14) 
(page 3 of 4) 
NRG Oncology Institution #  
NRG-LU001  
Case #  
 
 
                          42. 
SGOT (AST)  
 
 
         
43. 
SGOT (AST) ULN 
 
 
         
44. 
SGPT (ALT) 
 
 
         
45. 
SGPT (ALT) ULN 
 
 
         
46. 
Alkaline Phosphatase 
 
 
         
47. 
Alkaline Phosphatase ULN 
 
 
         
48. 
Total Bilirubin 
 
 
         
49. 
Total Bilirubin ULN 
 
 
         
50. 
Fasting Glucose 
 
 
         
51. 
Serum albumin (g/dL) 
 
        (Y/N/NA)   52. 
If the patient is of childbearing potential, has she had a negative serum 
pregnancy test performed within 72 hours prior to registration? 
 
        (Y/N/NA)   53. 
If the patient has post-obstructive pneumonia, do they no longer require 
intravenous antibiotics at the time of registration? 
 
              (Y/N)   54. 
Was a thoracotomy performed within the last 3 weeks? 
 
        (Y/N/NA)   55. 
If a pleural effusion is present, were all of the criteria from Patient Eligibility met? 
 
        (Y/N/NA)   55. 
If the patient is a woman of childbearing potential or a male participant did they 
agree to practice adequate contraception throughout the study? 
 
              (Y/N)   57. 
Does the patient have a mixed small cell and non-small cell histology? 
 
              (Y/N)   58. 
Distant metastases present? 
 
              (Y/N)   59. 
Has the patient had a prior invasive malignancy (except non-melanomatous skin 
cancer) within the last 3 years? 
 
              (Y/N)   60. 
Has the patient had prior systemic chemotherapy for the study cancer? 
 
              (Y/N)   61. 
Has the patient had prior radiotherapy to the region of the study cancer that 
would result in overlap of radiation therapy fields? 
 
              (Y/N)   62. 
Is the patient currently using metformin, other oral hypoglycemic agents, or 
insulin? 
 
 

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NRG-LU001; version date: November 1, 2018 
 
 
ELIGIBILITY CHECKLIST (8/4/14) 
(page 4 of 4) 
NRG Oncology Institution #  
NRG-LU001  
Case #  
 
 
              (Y/N)   63. 
Prior allergic reaction to paclitaxel or other taxanes or carboplatin? 
 
               (Y/N)  64. 
Does the patient have a history of chronic kidney disease or lactic acidosis? 
 
              (Y/N)   65. 
Weight loss within the past month (%) 
 
              (Y/N)   66. 
Diagnosis of Type I or Type II Diabetes Mellitus? 
 
              (Y/N)   67. 
Uncontrolled neuropathy greater than or equal to grade 2 regardless of cause? 
 
              (Y/N)   68. 
Hospitalized for unstable angina and/or CHF in last 6 months? 
 
              (Y/N)  69. 
Transmural MI in last 6 months? 
 
              (Y/N)  70. 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration? 
 
              (Y/N)  71. 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy within 30 days before 
registration? 
 
              (Y/N)  72. 
Severe hepatic disease, defined as a diagnosis of Child-Pugh Class B or C 
hepatic disease? 
 
              (Y/N)  73. 
Is the patient HIV positive with a CD4 count less than 200 cells/microliter? 
 
              (Y/N)   74. 
End-stage renal disease (on dialysis or dialysis has been recommended)? 
 
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, 
and dated checklist used at study entry must be retained in the patient’s study file and will be evaluated 
during an institutional NCI/NRG Oncology audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 

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NRG-LU001; version date: November 1, 2018 
 
 
1.0  
INTRODUCTION 
 
1.1 
Background and Rationale  
There is an urgent need to improve clinical outcomes in non-squamous cell lung cancer (NSCLC) 
patients for whom the current standard of care of concurrent chemoradiotherapy offers poor 
survival. It is estimated that each year in U.S. and Canada more than 250,000 people are 
diagnosed with lung cancer and more than 180,000 die from the disease (Jenak 2011). More than 
80% of lung cancer patients are diagnosed with NSCLC, which often presents at advanced 
stages in patients not eligible for surgical resection. Such patients are managed with concurrent 
chemoradiotherapy.  
 
This study, will investigate whether the addition of the anti-diabetic drug Metformin can be well 
tolerated and improve progression free survival (PFS) in patients with locally advanced NSCLC 
treated with standard concurrent chemoradiotherapy. 
1.1.1 
Radiotherapy Treatment (RT) of Locally Advanced NSCLC 
The dose of thoracic RT for locally advanced NSCLC (60-63 Gy, 2–2.1Gy per fraction) was 
established by an RTOG study more than 30 years ago (Perez 1980). RTOG-73-01 showed 
improved survival with 60 Gy RT in 30 fractions of 19% at 2 years. The radiographic response 
rate was approximately 60% (Perez 1980), local failure within the radiation field was 
approximately 25% and 45%, and distant metastasis rates were 15% and 35% at 6 and 12 
months, respectively. Other studies with RT doses of 60-64 Gy reported median survival of 10-14 
months for stage IIIA/B patients (Okawara 2006). Dillman (1996) reported OS of 70% and 40% at 
6 and 12 months, respectively, and probability for PFS 50% and 20% at the same time point 
when patients were treated with 60 Gy in 30 fractions. Also, Le Chevalier (1991) showed a 2-year 
overall survival (OS) rate of only 14% and 1-year local control of 15% after treating locally 
advanced NSCLC with RT alone (65 Gy in 26 fractions). A meta-analysis of individual patient 
data from 52 trials by the NSCLC Collaborative Group (1995) indicated OS of about 75% at 6 
months and 40% at 12 months in patients treated with RT alone (30–60 Gy). These data suggest 
that curative thoracic RT (60-63 Gy), when used alone without chemotherapy, offers locally 
advanced NSCLC patients a median survival of 10-12 months and OS of 42% at 12 months 
(NSCLC Group 1995). 
1.1.2 
Local Control with Radiotherapy 
A major cause of poor outcomes in locally advanced NSCLC is the high resistance of these 
tumors to RT. Radiographic assessments suggest local recurrences in up to 60% of lung cancers 
treated with high dose RT, but bronchoscopy studies have documented even greater local and 
regional failure rates of up to 85% in patients treated with RT alone (Le Chevalier 1992). Such 
results have led to an on-going search for radio-sensitizing agents. 
1.1.3 
Role of Chemoradiotherapy 
Over the last 3 decades, chemotherapy has been investigated as neo-adjuvant, concurrent, or 
adjuvant treatment to improve local control and distant metastases rates achieved with high-dose 
RT in locally advanced NSCLC. Meta-analyses and systematic reviews indicate an absolute 
survival advantage of 3-4% at 2 years and an increase in median survival by 1.7 months with the 
addition of chemotherapy to RT (Sandulache 2012, Pierotti 2013). Introduction of concurrent 
chemotherapy with high-dose chest radiation in trials performed between 1988 and 2003 
produced small improvements in progression-free survival (PFS) and more significant 
enhancement of OS compared to sequential chemoradiotherapy regimens. A meta-analysis of 6 
trials by Auperin (2010), showed average OS of 60% and 15.1% and PFS of 40.5% and 11.6%, 
at 1 and 5 years (vs. OS 59% and 10.6% and PFS of 37.9% and 9.4%, at 1 and 5 years, for 
sequential chemoradiotherapy). 
1.1.4 
Dose-Escalated RT 
A number of efforts have been made to improve these outcomes. Early phase studies of dose 
escalated radiotherapy and concurrent chemoradiotherapy showed promise to improve outcomes 
in this disease, with 2 recent meta-analyses exhibiting a benefit to this approach (Partridge 2011, 
Machtay 2012). Unfortunately, a recent phase III study of dose escalation (RTOG 0617) did not 
produce the expected results, with the dose-escalated arm closed early after an interim futility 
analysis (Bradley 2011). Although toxicity did not appear to be significantly different between the 

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NRG-LU001; version date: November 1, 2018 
 
 
2 arms, the number of treatment-related deaths in the dose-escalated arm (7 patients) 
underscores the need for radio-sensitizers that improve the therapeutic ratio with a minimum of 
toxicity. 
 
1.2 
NSCLC Resistance to Cytotoxic Therapy: The Need for Rational Development of 
Sensitizing Therapies 
NSCLC exhibits a high degree of resistance to chemoradiotherapy. We need to understand in 
depth NSCLC tumor and radiation biology in order to develop rational therapies that will reliably 
improve the efficacy of cytotoxic therapy and clinical outcomes in this disease. Pre-clinical 
laboratory work by the Co-Principal Investigators of the proposed trial suggests that RT activates 
the novel metabolic and genomic stress sensor AMPK-kinase (AMPK), which inhibits the survival 
mediator mammalian target of rapamycin (mTOR) and activates tumor suppressors and cell cycle 
regulators such as p53 and the cyclin-dependent kinase inhibitor p21cip1 to inhibit cancer growth 
and induce cell death. This pathway represents a promising therapeutic target, which can be 
engaged with well tolerated agents such as the anti-diabetic drug metformin (Jalving 2010, 
Pollack 2012). 
1.2.1 
Metformin (MET) in Combination with Radiotherapy and Chemotherapy 
Several epidemiologic studies have shown a reduction of NSCLC incidence with MET use in 
patients with type II diabetes mellitus (Hsieh 2012, Mazzone 2012, Noto 2012).  Furthermore, on 
meta-analysis of the available literature, MET use was found to be associated with a decrease in 
cancer mortality in all sites (RR 0.66, p=0.005) (Noto 2012).  Multiple studies have associated 
MET use to improved outcomes following radiotherapy or chemoradiotherapy in several disease 
sites (Sandulache 2013, Skinner 2012, Skinner 2012b, Skinner 2013).  Additionally, several 
studies have linked improved survival following lung cancer diagnosis and MET use (Currie 2012, 
Tan 2011).  Specifically, Tan and colleagues (2011) showed that LA-NSCLC patients taking MET 
had a median OS of 20 months. The remaining patients were then stratified by glucose control 
regimen (insulin vs. other); with median OS being approximately 13 months in both groups. This 
is in line with our own observations in a similar patient population, with MET use being 
independently associated with improved OS on multivariate analysis (Tsakiridis and Skinner 
unpublished observations; see Figure 4 below).  
 
MET is a well-tolerated anti-hyperglycemic agent used by more than 120 million patients 
worldwide. Furthermore, MET also is indicated for treatment of non-diabetic patients, specifically 
in poly-cystic ovarian syndrome (PCOS). Randomized controlled trials demonstrated the safety 
and efficacy of MET in preventing diabetes and improving metabolic and hormonal parameters in 
non-diabetic patients with insulin resistance and polycystic ovary syndrome (PCOS) (Tang 2012). 
Other studies also showed the safety of MET in patients with non-alcoholic fatty liver disease 
(Shyangdan 2011) and in breast cancer patients (Bayley 2012).   
 
1.3 
Pre-Clinical Evidence 
The investigators have significant experience examining the relationship between AMPK, 
metabolism, and radio-sensitivity (Skinner 2012, Sandulache 2012, Sanli 2010).  We have 
observed that radiation alone regulates AMPK expression and activity and inhibits mTOR (Sanli 
2010, Sanli 2012, Storozuk 2012). Studies from a number of laboratories, including those of the 
principal investigators, demonstrated that AMPK not only is a metabolic but also a genomic stress 
sensor that mediates cell cycle checkpoints and activates signaling events leading to radio-
sensitization and cancer cell death (Sanli 2013). Further, we observed that MET can perturbate 
the metabolic function of cancer cells (Sandulache 2012).  In early studies, we showed that lung 
cancer cells have significantly higher sensitivity to MET compared to other cancers,  such as 
breast and prostate cancer cells, while the drug does not alter the proliferation rates of non-
cancer cells at low microM doses of MET (Storozhuk 2013: supplemental data; see Figure 1A- B).   
 
Figure 1A: Metformin (MET) Decreases Proliferation of Various Human Cancer Cell Lines  
Lung carcinoma cells (A549, H1299, SK-MES1), prostate carcinoma cells (PC3) and breast 
cancer cells (MCF7 and MDA-MD231) were treated with increasing concentrations of MET 

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NRG-LU001; version date: November 1, 2018 
 
 
(0µmol-5mM) for a period of 48 hours. DNA content, as a marker of cell proliferation, was 
determined by crystal violet staining. Mean+/-SE of 3 independent experiments are shown. 
 
Figure 1B: Metformin (MET) Does Not Influence Proliferation of Normal Human Lung 
Embryonic Fibroblast Cells (MRC5) 
Cells were treated with increasing concentrations of MET (0µmol-25µmol) for 48 hours. DNA 
content, as a marker of cell proliferation, was determined by crystal violet staining. Mean+/-SE of 
three independent experiments are shown. 
 
A. 
 
 
 
 
 
 
 

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NRG-LU001; version date: November 1, 2018 
 
 
B. 
 
 
Most importantly, we observed that in a variety of pre-clinical models MET is a potent 
radiosensitizer (Skinner 2012, Sandulache 2012, Sanli 2010, Storozhuk 2013).  Specifically in 
lung cancer, the addition of low µM doses (2.5 – 25 µM) of MET to clinical doses of RT (2 - 8 Gy) 
radio-sensitizes human NSCLC cells (Figure 2A) and increases the cytotoxicity of radiotherapy in 
NSCLC tumors (Figure 2B) (Storozhuk 2013). Further, we observed that MET enhances the anti-
angiogenic and pro-apoptotic actions of RT in tumors (Storozhuk 2013). Figure 2C shows results 
of quantification of at least 3 separate immunoblotting experiments and Figure 2D shows 
representative immunohistochemistry images demonstrating increased expression of the 
apoptosis marker cleaved caspace 3 when MET was combined with RT treatments. Importantly, 
MET inhibits NSCLC cell proliferation at doses (µM) that can be safely achieved in the serum of 
patients treated with standard oral doses of MET (Graham 2011). Further, work by other groups 
suggested that MET enhances the cytotoxicity of chemotherapy in pre-clinical NSCLC models 
(Iliopoulos 2011, Rocha 2011). 
 
Figure 2: MET Increases Cytotoxicity of Chemotherapy and Radiation  
A. Two widely used in-vitro models of human NSCLC, A549 and H1299 cells were subjected to 
clonogenic assays after treatment with 0 (Basal) 5 or 25 M metformin (MET) and increasing 
doses of radiation (RT) (0-8 Gy). Colony formation was evaluated after 7 days, and the results 
were fitted into the linear quadratic model. Mean+/-SE of 3-4 independent experiments are 
shown. 
 
B. A549 and H1299 cells were grafted into immunodeficient nude mice and treated with or without 
oral MET 300 mg/kg/day for 8 weeks and/or a single fraction of conformal radiotherapy of 8 Gy 
when tumors reached 100mm3. Tumors were then left to grow for 60 days. * : P<0.05  ** : P < 
0.01 
 
C. Protein extracted from A549 xenograft tumors treated as indicated in B was analyzed by 
immunoblotting for the expression of the angiogenesis marker CD31 and the apoptosis markers 
PUMA and Bax. * : P<0.05  ** : P < 0.01 
 
 
0
20
40
60
80
100
120
0
1
5
10
25
Proliferation (% of control)
Metformin(M)
MRC5cells

13 
NRG-LU001; version date: November 1, 2018 
 
 
D. Fixed A549 xenografts from control and MET, RT, and MET+RT treated animals (as indicated 
in B) were processed for immunohistochemical analysis using an antibody specific for the 
apoptosis marker Cleaved Caspace-3 (CC3). Representative images from 3 independent 
experiments are shown. 
 
 
 
A.
Average Tumour Volume (mm3)
Average Tumour Volume (mm3)
Treatment Period (Days)
Treatment Period (Days)
B.

14 
NRG-LU001; version date: November 1, 2018 
 
 
 
 
 
The ability of MET to inhibit lung tumor cell growth and sensitize the cells to radiation at doses of 
the drug that can be achieved clinically with minimal toxicity suggested that MET may indeed 
have meaningful activity in human lung cancer. For that, we took steps to compare MET to 
common targeted therapy agents and to examine retrospectively the potential effects of MET in 
clinical outcomes in lung cancer patients treated with curative chemoradiotherapy.  
 
First, we compared MET to Epidermal Growth Factor Receptor (EGFR) inhibitor gefitinib and the 
widely used mTOR inhibitor rapamycin. MET (5 – 25 µM) in combination with 2 or 8 Gy RT 
achieved equal or better inhibition of lung cancer cell proliferation than clinically achievable doses 
of rapamycin (5nM) and gefitinib (1µM) (see Figure 3A). Furthermore, we examined the effect of 
MET on the Akt-mTOR pathway that is involved in cancer cell survival and resistance to cytotoxic 
therapies. Figure 3B shows that unlike rapamycin, which is known to inhibit mTOR but to cause 
activation of Akt, an event believed to contribute to the failure of drugs of this class to offer lasting 
anti-tumor effects, MET caused a consistent blockage of both Akt and mTOR signals in lung 
cancer cells. These results offer an additional line of evidence indicating the promise of MET for 
clinical activity in lung cancer. 
 
Figure 3: MET is a More Potent Radiosensitizer Compared to EGFR and mTOR inhibitors  
A. Comparison of the Anti-Proliferative Effects of MET with Rapamycin or Gefitinib in Untreated 
and Irradiated A549 Lung Cancer Cells  
A549 lung cancer cells were treated with MET (5µM-5mM), rapamycin (5nM-500nM), or gefitinib 
(1µM-4µM) for 24 hours before treatment with 0, 2, or 8 Gy RT. Cells were fixed 48 hours later. 
DNA content, as a marker of proliferation, was determined with crystal violet staining. Mean+/-SE 
of 3-4 independent experiments are shown. Statistically significant differences compared to 
corresponding control cells (not treated with either agent) within the 0 Gy, 2 Gy, and 8 Gy 
radiation treatment groups are shown (*:P<0.05, **:P<0.01 for MET treated cells, #:P<0.05, 
##:P<0.01 for rapamycin treatment, and ×:P< 0.05,××: P<0.01 for gefitinib treatment 
respectively). Grey horizontal lines facilitate a visual comparison of the effects of 5µM MET + 2 
Gy RT and 5µM MET + 8 Gy RT with the rest of the treatment conditions. Dashed black 
horizontal lines indicate the effects of 25µM MET alone or in combination with 2 or 8 Gy RT.  
 
B. Effects of MET and Rapamycin Without or With 2 and 8 Gy Radiation Treatment on 
Expression and Phosphorylation of Akt, mTOR and the mTOR Target Translation Initiation 
Inhibitor 4-EBP1 
C.
Change in marker expression (%)
D.
D.

15 
NRG-LU001; version date: November 1, 2018 
 
 
A549 cells were treated with MET 5 or 100 µM or rapamycin (0nM or 5nM) for 24 hours followed 
by an additional incubation of 24 hours after treatment with RT (0, 2, or 8 Gy). The cells were 
washed and lysed. Lysates were analyzed with immunoblotting using indicated antibodies. 
Representative images of 3 independent experiments are shown for total and phosphorylated Akt 
(S473 and T308), mTOR and phosphorylated 4EBP1. See arrows pointing at the differential 
effects of MET versus rapamycin on Akt phosphorylation. 
 
 
 
 
 
 
 
 
In addition, early clinical evidence suggests that MET may be well capable of enhancing 
treatment response in LA-NSCLC patients treated with curative doses of chemo-radiotherapy. 
Independent retrospective analyses from the Juravinski Cancer Center, ON, Canada and the 
M.D. Anderson Center, TX, USA (Tsakiridis et al., unpublished observations, Welsh et al., in 
review; see Figure 4 below), show that diabetic patients with LA-NSCLC have improved survival if 
their diabetes is treated with MET vs. insulin or insulin secretagogeus. Interestingly, it appears 
that such patients that are typically treated with 1000 – 2500mg of MET daily may reach OS rates 
that are higher than average rates of non-diabetic patients, while patients treated with insulin tend 
to have similar to or worse survival rates than control non-diabetics. These findings are supported 
by observations of benefits to MET treatment in outcomes in other tumors of the upper aero-
digestive tract (Sandulache 2013, Skinner 2013). To date, we have not detected any evidence of 
25 M MET
+ 2 Gy
25 M MET
+ 8 Gy
25 M MET
A. 
0 M
5M
100M
MET
IR:       0 Gy
8 Gy
B. 

1 6  
N R G - L U 0 0 1; v er si o n d at e: N o v e m b er 1, 2 0 1 8 
 
 
i n cr e a s e d c h e m or a di ot h er a p y t o xi cit y i n di a b eti c p ati e nt s tr e at e d wit h M E T w h o h a v e r e c ei v e d 
st a n d ar d c ur ati v e c o n c urr e nt c h e m or a di ot h er a p y f or l u n g c a n c er ( s e e Fi g ur e 4 C b el o w ). 
 
Fi g ur e 4: R etr o s p e cti v e Cli ni c al E vi d e n c e of L u n g C a n c er Tr e at m e nt wit h C o m bi n e d 
M etf or mi n a n d C h e m or a di ot h er a p y 
A & B : R etr o s p e cti v e a n al y si s of 1- y e ar s ur vi v al of st a g e III N S C L C p ati e nt s tr e at e d at t h e 
J ur a vi n s ki C a n c er C e nt er ( A) a n d t h e U ni v er sit y of T e x a s M D A n d er s o n C a n c er C e nt er wit h 
c h e m o -r a di ot h er a p y ( B). Di a b eti c p ati e nt s w er e s e p ar at e d i n t h o s e tr e at e d wit h M E T  v er s u s t h o s e 
tr e at e d wit h ot h er h y p o gl y c e mi c a g e nt s.  
C : T o xi cit y d u e t o t h er a p y i n t h e p ati e nt s d e s cri b e d i n B.  N o si g nifi c a nt diff er e n c e i n t o xi cit y 
b et w e e n gr o u p s w a s o b s er v e d. 
 
 
 
1. 4   
R ati o n al e f or T hi s St u d y: S el e ct e d A p pr o a c h a n d Tri al D e si g n 
W e pr o p o s e a n o p e n-l a b el r a n d o mi z e d p h a s e II st u d y of st a n d ar d t h er a p y wit h c o n c urr e nt 
c h e m or a di ot h er a p y +/- m etf or mi n ( M E T).  1: 1 r a n d o mi z ati o n a n d str atifi c ati o n v ari a bl e s of 
p erf or m a n c e st at u s, cli ni c al st a g e, a n d hi st ol o g y of N S C L C t u m or will b e utili z e d.  
 
M E T h a s a f a v or a bl e s af et y r e c or d, wit h n o si g nifi c a nt l o n g-t er m t o xi cit y a n d h a s b e e n u s e d f or 
t h e tr e at m e nt of di a b et e s m ellit u s i n N ort h A m eri c a f or o v er 1 5 y e ar s. Alt h o u g h di a b eti c p ati e nt s 
o n M E T ar e b ei n g tr e at e d fr e q u e ntl y wit h hi g h d o s e c h e st c h e m or a di ot h er a p y, t h er e ar e n o 
r e p ort s of i n cr e a s e d c h e m or a di ot h er a p y t o xi cit y wit h t h e dr u g. 
 
P h a s e I a n d II st u di e s s h o w e d t h e s af et y of M E T u s e i n n o n- di a b eti c p ati e nt s ( W u 2 0 1 2, Bitt n er 
2 0 1 1, B o ult o n 2 0 1 1, Kj øtr ø d 2 0 1 1, Ki m 2 0 9 9, S c h wi m m er 2 0 0 5). M etf or mi n d o e s n ot c a u s e 
h y p o gl y c e mi a a n d h a s f a v or a bl e m et a b oli c eff e ct s o n i n s uli n r e si st a n c e a n d o b e sit y ( M c C art h y 
2 0 0 4, B o si 2 0 0 9). U nli k e it s p ar e nt dr u g p h e nf or mi n, M E T d o e s n ot c a u s e si g nifi c a nt l a cti c 
a ci d o si s i n st a n d ar d t h er a p e uti c d o s e s ( S al p et er 2 0 1 0).  
D ia b e tic
D ia b e tic
N o n -d ia b e tic
O n M e tfro m in
N o t o n
M e tfo rm in
5 2 .6 %
4 2 .2 %
3 9 .6 %
P ro p o rtio n o f p a tie n ts A liv e a t 1 Ye a r
(n :4 2 )
(n :4 2 )
(n :7 8 1 )
9 5 % C I
P ro p o rtio n  o f p a tie n ts  A liv e  a t 1  y e a r
D ia b e tic o n   D ia b e tic n o t   N o n -Di a b e tic
M e tfo r min
o n M e tfo r min
%  S y m p o m a tic
p n e u m o n itis
N o  M e tfo rm in u s e
M e tfo rm in u s e
N o  M e tfo r min u s e
M e tfo rm in u s e
%  o f p a tie n ts
re q u irin g  n a rc o tic s
0 
Pr o p orti o n of p ati e nt s ali v e at 1 yr 
2 0 
4 0 
6 0 
8 0 
1 0 0 
O v e ra ll S u rv iv a l
M o n th s  a fte r s ta rt o f R T
O v e ra ll S u rv iv a l
M o n th s  a fte r s ta rt o f R T
P = 0 .0 2 4  
O v e ra ll S u rv iv a l 
0  
0 .2 5  
0 .5  
0 .7 5  
1  
M o n th s a fte r st a rt o f R T  
0 
2 0 
4 0 
6 0 
8 0 
N o m e f or mi n 
M e tf or mi n us e   
N o m e f or mi n 
M e tf or mi n us e  

17 
NRG-LU001; version date: November 1, 2018 
 
 
 
In the last decade, several epidemiologic studies have shown that the use of MET is associated 
with a decreased incidence of cancer. Furthermore, MET use has been associated with improved 
outcomes when used with RT or chemotherapy. Currently, there are more than 80 clinical trials 
registered at clinicaltrials.gov investigating MET in different cancer sites, including more than 40 
trials actively recruiting patients. Only 3 of these studies investigate MET in lung cancer, including 
1 study in the setting of chemoprevention and 2 studies in stage IV NSCLC in combination with 
chemotherapy or targeted therapy. 
 
Based on the information discussed above, currently, there is no substantial basis or need for a 
phase I study with MET in patients with LA-NSCLC. 
 
A randomized phase II approach will be a properly controlled study to demonstrate early evidence 
of efficacy of the intervention, substantiate further the safety of MET when combined with curative 
chemoradiotherapy. 
 
The presence of the control arm will provide appropriate comparison because: 
 
Significant improvements in lung cancer staging and radiotherapy delivery over the last 
decade diminish the value of historical control data; 
 
It allows the  expansion of eligible chemotherapy regimens in this study;  
 
Patients on the control arm will provide valuable samples for biomarker studies . 
 
An open label is utilized since the early low grade gastrointestinal toxicity of MET use (gas and 
mild diarrhea) make the intervention obvious while a double blind placebo control study would be 
significantly more costly with little additive benefit. 
 
1.5 
Translational Science (8/10/16) 
Development of predictive biomarkers of MET action is a valuable secondary objective of this 
study. These studies will provide useful information for the rational design of future clinical trials 
with this drug in NSCLC and other disease sites. To achieve this goal, it is vital to collect blood 
and tumor tissue bio-specimens during the trial to be used for future analysis depending on the 
outcomes of this trial. Submission of tissue/blood is optional for patients enrolled on this trial. All 
specimens will be sent to the NRG Oncology Biospecimen Bank – San Francisco for banking for 
this future translational science study. 
 
Tissue banking is predicated by 2 separate hypotheses.  These hypotheses will be tested after 
the study is complete, and additional funding will be obtained from other sources to test these 
hypotheses. 
 
1. Mutation in TP53, STK11 (LKB1) and/or KRAS predicts improved PFS in patients treated with 
metformin. 
 
Multiple pre-clinical studies have linked mutation in TP53 to sensitivity to the antineoplastic 
and therapeutic sensitizing effects of metformin (Skinner 2012, Buzzai 2007, Sandulache 
2012 (Pierotti 2013).  However, this may not be a universal effect, particularly in combination 
with radiotherapy (Storozhuk 2013, Ben Sahra 2010).  Additional work has linked inactivation 
of LKB1 (STK11) with increased sensitivity to biguanides in vivo in a KRAS mutated NSCLC 
model (Shackleford 2013).  As NSCLC has a preponderance of mutations in all of the above 
sites (TCGA Lung: TP53~50-80%, STK11 ~2-15%, KRAS~2-27%), an increased sensitivity to 
metformin conferred by these mutations would be advantageous, and result in an even 
greater improvement in PFS following metformin administration.   
 
Biopsy tissue of consenting patients will be collected at baseline. Tumor tissue will be evaluated 
by an experienced pathologist for tumor content.  DNA extraction from tissue blocks will be 
performed. This will be followed by PCR analysis of mutation status and immunohistochemistry of 

18 
NRG-LU001; version date: November 1, 2018 
 
 
selected fixed tumor tissue to detect expression levels.  Analysis of the mutation status and 
expression levels of p53, LKB1 and K-RAS, will help demonstrate whether these genes can serve 
as potential biomarkers predictive of MET response in the future. 
 
Blood samples of consenting patients will be collected at baseline, weeks 1 and 6 of chemo/RT 
(corresponding to weeks 3 and 8 of the metformin treatment period for patients randomized to 
Arm 2), and at 6 month follow-up visit  (see Section 10.2). Serum and EDTA plasma will be 
isolated from blood samples and stored for future analysis. Whole blood samples also will be 
collected and stored for future analysis. The time points of collection are designed to help extract 
the effect of MET on serum/plasma markers at the time when the drug has reached its full 
treatment dose and before chemoradiotherapy is initiated (week 3 of metformin treatment period 
for patients randomized to Arm 2), at the time when steady state maximum drug levels will be 
combined with chemoradiotherapy (week 8 of metformin treatment period for patients randomized 
to Arm 2) and at the time at which both concurrent chemoradiotherapy and MET treatments 
would be complete (week 32). 
 
 
In blood based studies, we will examine whether:  
i. 
plasma MET levels and modulation of plasma fasting insulin level and lipid profile by the 
drug correlate with the clinical response to MET;  
 
Studies in non-diabetic breast cancer patients showed that MET treatment reduces 
significantly fasting insulin levels by 22.4% and LDL-cholesterol by 9.1% (insulin: from 
70.7+30.4  to 54.9+30.0 pmol/L (Mean+SD) and fasting LDL-cholesterol: 2.86+0.86 to 
2.6+0.63 mmol/L) (Goodwin 2008). We will investigate whether plasma MET levels and 
metabolic response of patients in terms of reduction of fasting insulin and LDL-cholesterol 
levels in response to MET correlate with tumour response to the drug in terms of PFS.  
 
ii. 
levels of phosphorylated AMPK, p70S6k and 4EBP1 (P-AMPK, P-p70S6k, P-4EBP1) in 
blood cell lysates can correlate with plasma MET levels and predict response to the drug.  
 
The work of the Co-Principal Investigators (Storozhuk 2013) and others (Rocha 2011) 
shows that MET mediates its action through activation of AMPK leading inhibition of the 
mTOR-p70S6k / 4EBP1 pathway. This is detected as inhibition of the phosphorylation 
and activity of p70S6k, which leads to inhibition of this ribosomal kinase and inhibition of 
4EBP1 phosphorylation, which permits 4EBP1 to inhibit gene translation (see Figure 3 
above). Collection of buffy coats will allow us to test the novel hypothesis that phospho-
proteomic analysis of this bio-specimen could provide useful biomarkers of MET action.  
 
To achieve these objectives we will use the following:  
i. 
standard biochemical analysis platforms; 
ii. 
lysates of blood cells and immunoblotting using phosphorylation specific 
antibodies.  
 
2.0  
OBJECTIVES 
2.1 
Primary Objective 
To determine whether MET added to chemoradiotherapy can improve progression-free survival 
(PFS) in patients with locally advanced NSCLC 
 
2.2 
Secondary Objectives 
 
Determine the effects of MET on overall survival (OS), time to local-regional progression 
(LRP), and time to distant metastasis (DM); 
 
Evaluate the effect of MET on chemoradiotherapy toxicity (CTCAE, v. 4) within 1 year of 
completion of all treatment;  
 
Collect biospecimens to develop biomarkers of MET activity: 
 Investigate potential serum biomarkers of MET response: serum MET levels, insulin 
and lipid levels; 

19 
NRG-LU001; version date: November 1, 2018 
 
 
 Evaluate MET activity on peripheral blood cells (in a subset of patients); 
 Investigate potential tumor biomarkers of MET response: tumor NSCLC histology and 
tumor mutational status (TP53, STK11 [LKB], K-RAS). 
 
3.0  
PATIENT SELECTION (8/10/16) 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
3.1 
Conditions for Patient Eligibility 
For questions concerning eligibility, please contact the study data manager. 
3.1.1 
Pathologically (histologically or cytologically) proven diagnosis of Stage IIIA or IIIB non-small cell 
lung cancer within 84 days of registration; eligible histologies include adenocarcinoma, 
adenosquamous, large cell carcinoma, squamous carcinoma, non-lobar and non-diffuse 
bronchoalveolar cell carcinoma or non-small cell lung cancer NOS).  
3.1.2 
Patients must have measurable disease;  
3.1.3 
Patients must have unresectable disease, be medically inoperable, or unwilling to undergo surgical 
management; 
3.1.4 
Appropriate stage for protocol entry, including no distant metastases, based upon the following 
minimum diagnostic workup: 
 
History/physical examination, including documentation of height, weight, BSA, and vital signs, 
within 30 days prior to registration; 
 
CT scan with IV contrast or MRI imaging (if CT scan with contrast is medically contraindicated) 
of the lung and upper abdomen through the adrenal glands, required within 45 days prior to 
registration (recommended within 30 days prior to registration);  
 
MRI of the brain with contrast (or CT with contrast if MRI is medically contraindicated) within 
45 days prior to registration; note: The use of intravenous contrast is required for the MRI or 
CT. An MRI without contrast is only permitted if the patient has a contrast allergy. 
 
Whole-body FDG-PET/CT required within 45 days prior to registration (recommended within 
30 days prior to registration; note: patients do not need to have a separate CT of the chest and 
upper abdomen with contrast if PET/CT imaging includes a high quality CT with contrast. 
3.1.5 
Zubrod Performance Status 0-1; 
3.1.6 
Age ≥ 18; 
3.1.7 
CBC/differential obtained within 14 days prior to registration on study, with adequate bone marrow 
function defined as follows: 
 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;  
 
Platelets ≥ 100,000 cells/mm3;  
 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 
g/dl is acceptable.); 
3.1.8 
Adequate renal function within 14 days prior to registration, defined as serum creatinine within 
normal institutional limits or creatinine clearance must be at least 60 ml/min;  
3.1.9  
Adequate hepatic function within 14 days prior to registration, defined as total bilirubin ≤ 1.5 x upper 
limit of normal (ULN) for the institution and  ALT, AST, and alkaline phosphatase ≤ 2.5 x ULN for 
the institution; 
3.1.10 Fasting blood glucose ≤ 125 mg/dL within 14 days prior to registration; 
3.1.11 Serum albumin > 3.0 g/dl within 14 days prior to registration; 
3.1.12 For women of childbearing potential, a serum pregnancy test within 72 hours prior to registration; 
3.1.13 Patients with post-obstructive pneumonia are eligible provided they no longer require intravenous 
antibiotics at registration; 
3.1.14 Patients must be at least 3 weeks from prior thoracotomy (if performed); 
3.1.15 If a pleural effusion is present, the following criteria must be met at registration to exclude malignant 
involvement (incurable M1a disease): 
 
When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is 
required to confirm that the pleural fluid is cytologically negative; 
 
Effusions that are minimal (i.e. not visible under ultrasound guidance) and that are too small 
to safely tap are eligible. 
3.1.16 Women of childbearing potential and male participants must practice adequate contraception 
throughout the study; 

20 
NRG-LU001; version date: November 1, 2018 
 
 
3.1.17 Patient must provide study specific informed consent prior to study entry. 
 
3.2 
Conditions for Patient Ineligibility 
3.2.1 
Patients with mixed small cell and non-small cell histologies; 
3.2.2 
Patients with distant metastasis; 
3.2.3 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a 
minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all 
permissible); 
3.2.4 
Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different 
cancer is allowable;  
3.2.5 
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy 
fields; 
3.2.6 
Patients currently using metformin, other oral hypoglycemic agents or insulin; 
3.2.7 
Patients with any history of allergic reaction to paclitaxel or other taxanes or carboplatin; 
3.2.8 
Patients with a history of chronic kidney disease or lactic acidosis; 
3.2.9 
Patients with ≥ 10% weight loss within the past month; 
3.2.10 Severe, active co-morbidity, defined as follows: 
 
Diagnosis of Type I or Type II Diabetes Mellitus; 
 
Uncontrolled neuropathy ≥ grade 2 regardless of cause; 
 
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 
months; 
 
Transmural myocardial infarction within the last 6 months; 
 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; 
 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy within 30 days of registration;  
 
Severe hepatic disease, defined as a diagnosis of Child-Pugh Class B or C hepatic disease. 
 
HIV positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are 
eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) 
and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration. Note also that 
HIV testing is not required for eligibility for this protocol. 
 
End-stage renal disease (ie, on dialysis or dialysis has been recommended). 
3.2.11 Pregnancy or women of childbearing potential and men who are sexually active and not willing/able 
to use medically acceptable forms of contraception; this exclusion is necessary because the 
treatment involved in this study may be significantly teratogenic.  
 
4.0  
PRETREATMENT EVALUATIONS/MANAGEMENT (8/10/16) 
NOTE: This section lists baseline evaluations needed before the initiation of protocol 
treatment that do not affect eligibility. 
4.1 
Required Evaluations/Management 
Note: Failure to perform one or more of these tests may result in assessment of a protocol violation.  
4.1.1 
The patient must be evaluated by a Radiation Oncologist and Medical Oncologist within 42 days 
prior to the start of treatment and must be approved to proceed prior to initiation of study treatment. 
4.1.2 
Before starting metformin, obtain the patient’s eGFR. Starting metformin in patients with an eGFR 
between 30-45 mL/minute/1.73 m2 is not recommended.  
 
5.0 
REGISTRATION PROCEDURES (1-NOV-2018) 
Access requirements for OPEN, Medidata Rave, and TRIAD: 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring 
write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 

21 
NRG-LU001; version date: November 1, 2018 
 
 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 
1572 in RCR to allow the following: 
 Added to a site roster 
 Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
 Act as the site-protocol PI on the IRB approval 
 
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
 
5.1  
Radiation-Specific Pre-Registration Requirements (1-NOV-2018) 
5.1.1    Phantom Irradiation for IMRT   
Instructions for requesting and irradiating the phantom are available on the IROC Houston web site 
at http://irochouston.mdanderson.org; select “Credentialing” and “NRG”. Upon review and 
successful completion of the phantom irradiation, IROC Houston will notify both the registering 
institution and NRG Oncology Headquarters that the institution has completed this requirement. 
Subsequently, NRG Oncology Headquarters will update RSS at CTSU.  Credentialing for IMRT 
allows the institution to also use 3D-CRT and no additional phantom irradiation is needed for this 
treatment modality.  
 
For detailed information on the specific technology requirement required for this study, please refer 
to the table below and utilize the web link provided for detailed instructions. The check marks under 
the treatment modality columns indicate whether that specific credentialing requirement is required 
for this study. IROC Houston will be the entity to notify your institution when all credentialing 
requirements have been met and the institution is RT credentialed to enter patients onto this study.   
RT 
Credentialing 
Requirements 
 
Web Link for Procedures and Instructions:  http://irochouston.mdanderson.org  
 

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NRG-LU001; version date: November 1, 2018 
 
 
 
 
5.2 
Digital RT Data Submission to NRG Oncology Using TRIAD (1-NOV-2018) 
TRIAD is the image exchange application used by NRG Oncology. TRIAD provides sites 
participating in NRG Oncology clinical trials a secure method to transmit DICOM RT and 
other objects. TRIAD anonymizes and validates the images as they are transferred. 
 
TRIAD Access Requirements: 
 
Site physics staff who will submit images through TRIAD will need to be registered with 
The Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP 
Identity and Access Management (IAM) account and be registered as an AP, NPIVR or 
IVR.  Please refer to the CTEP Registration Procedures section for instructions on how to 
request a CTEP-IAM account and complete registration in RCR. Please refer to Section 
5.0 of the protocol for instructions on how to request a CTEP-IAM account. 
 
To submit images, the site physics user must be on the site’s affiliate rosters and be 
assigned the 'TRIAD site user' role on the relevant Group or CTSU roster. Users should 
contact the site’s CTSU Administrator or Data Administrator to request assignment of the 
TRIAD site user role.  
 
RAs are able to submit standard of care imaging through the same method. 
 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, he/she will 
need to have the TRIAD application installed on his/her workstation to be able to 
submit images. TRIAD installation documentation can be found on the IROC 
website https://www.irocqa.org/Resources/TRIAD.    
 
This process can be done in parallel to obtaining your CTEP-IAM account username and 
password. 
 
If you have any questions regarding this information, please send an e-mail to the TRIAD 
Support mailbox at TRIAD-Support@acr.org. 
 
5.3  
Regulatory Pre-Registration Requirements (1-NOV-2018) 
5.3.1 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval  
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
Treatment Modality 
Key Information 
 
Photons 
 
Facility 
Questionnaire 
X 
 
Complete or update your online electronic Facility 
Questionnaire. To access this FQ, email 
irochouston@mdanderson.org to receive your FQ link. 
Credentialing 
Status Inquiry 
Form 
X 
To determine whether your institution needs to complete any 
further credentialing requirements, complete this form under 
Credentialing on the IROC Houston web site (address above).  
Phantom 
Irradiation 
X 
 
See Section 5.0 above describing phantom irradiation 
requirements for specific motion management techniques.  
Questions may be directed to IROC Houston. 

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NRG-LU001; version date: November 1, 2018 
 
 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following: 
 
An active Federal Wide Assurance (FWA) number 
 
An active roster affiliation with the Lead Network or a participating organization 
 
A valid IRB approval 
 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
 
Active registration status 
 
The IRB number of the site IRB of record listed on their Form FDA 1572 
 
An active status on a participating roster at the registering site. 
 
 
Requirements for NRG-LU001 site registration: 
 IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted ) 
 For applicable NCTN studies with a radiation and/or imaging (RTI) component, the 
enrolling site must be aligned to a RTI provider.  To manage provider associations 
access the Provider Association tab on the CTSU website at 
https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove associated 
providers.  Sites must be linked to at least one IROC credentialed provider to 
participate on trials with an RT component. Enrolling sites are responsible for ensuring 
that the appropriate agreements are in place with their RTI provider, and that 
appropriate IRB approvals are in place.   
 IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC to 
begin the modality credentialing process.   
 
5.3.2 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab   
Regulatory Submission 
 
When applicable, original documents should be mailed to: 
      CTSU Regulatory Office 
      1818 Market Street, Suite 3000 
      Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
Non-English Speaking Canadian and Non-North American Institutions: 
 
Translation of documents is critical. The institution is responsible for all translation costs. All 
regulatory documents, including the IRB/REB approved consent, must be provided in English and 
in the native language. Certification of the translation is optimal but due to the prohibitive costs 
involved, NRG Oncology will accept, at a minimum, a verified translation. A verified translation 
consists of the actual REB approved consent document in English and in the native language, 
along with a cover letter on organizational/letterhead stationery that includes the professional title, 
credentials, and signature of the translator as well as signed documentation of the review and 
verification of the translation by a neutral third party. The professional title and credentials of the 
neutral third party translator must be specified as well. 

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NRG-LU001; version date: November 1, 2018 
 
 
5.3.3 
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
 
Prior to clinical trial commencement, Canadian institutions must also complete the following 
documents and submit to the CTSU Regulatory Office via the Regulatory Submission portal: 
 
Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site Information Form,  
 
Qualified Investigator Undertaking Form, and  
 
Research Ethics Board Attestation Form.  
5.3.4 
Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS 
 
For institutions that do not have an approved LOI for this protocol: 
International sites must submit an LOI to NRG Oncology to receive approval to participate in this 
trial. For more details see link below: 
http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx .  
 
For institutions that have an approved LOI for this protocol: 
 
All requirements indicated in your LOI Approval Notification must be fulfilled prior to enrolling 
patients to this study. 
 
5.4  
Registration (1-NOV-2018) 
5.4.1  
OPEN Registration Instructions 
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have 
been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients must have signed 
and dated all applicable consents and authorization forms.   
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). 
OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site 
user must have an active CTEP-IAM account (check at < https://ctepcore.nci.nih.gov/iam >) and 
a 'Registrar' role on either the LPO or participating organization roster. Registrars must hold a 
minimum of an AP registration type.  See Section 5.0 for obtaining a CTEP-IAM account.  
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
position in the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN 
tab on the CTSU members’ side of the web site https://www.ctsu.org.  To assign an IVR or 
NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number 
used on the site’s IRB approval. 
 
Prior to accessing OPEN site staff should verify the following: 
 
All eligibility criteria have been met within the protocol stated timeframes. Site staff should 
use the registration forms provided on the group or CTSU web site as a tool to verify 
eligibility. 
 
All patients have signed an appropriate consent form and HIPPA authorization form (if 
applicable).  
 
The OPEN system will provide the site with a printable confirmation of registration and treatment 
information.  Please print this confirmation for your records.  
 
Further instructional information is provided on the CTSU members' side of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
In the event that the OPEN system is not accessible, participating sites can contact web support 
for assistance with web registration: websupport@acr.org or call the Registration Desk at (215) 
574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax 
in the eligibility checklist and will need the registering individual’s e-mail address and/or return fax 
number.  

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NRG-LU001; version date: November 1, 2018 
 
 
 
6.0  
RADIATION THERAPY (5/7/15) 
See Section 5.2 for information on installing TRIAD for submission of digital RT data prior 
to enrolling patients. 
 
Patients randomized to Arm 1 (concurrent chemotherapy and radiation therapy) must begin 
treatment within 14 days after randomization. 
 
Patients randomized to metformin (Arm 2) must begin metformin within 14 days after 
randomization and every effort must be made to begin concurrent chemotherapy and 
radiation therapy 14 days after beginning metformin. Concurrent chemoradiotherapy and 
metformin ideally should start on a Monday. 
 
Protocol treatment will be scored according to the Compliance Criteria table in Section 6.7. 
 
It is recommended that radiation therapy be delivered after chemotherapy per Section 7.0. 
 
6.1 
Treatment Technology 
This protocol requires photons and 3D-CRT or IMRT techniques are permitted. *Tomotherapy 
and VMAT are allowed. Use of CyberKnife is not permitted for this trial.  
 
*Note: Institutions that previously have been credentialed for one IMRT delivery technique (e.g. 
standard gantry mounted linear accelerator using fixed gantry angles) must repeat the 
credentialing process if the institution elects to use tomotherapy. Contact IROC Houston with any 
questions concerning further credentialing requirements. 
 
Daily IGRT is required for all patients enrolled on this trial.  
  
6.2 
Immobilization and Simulation 
6.2.1 
Immobilization 
Proper immobilization is critical for this protocol.  Patient setup reproducibility must be achieved 
using appropriate clinical devices. 
6.2.2 
Simulation Imaging 
Efforts should be made so that simulation CTs take place before initiation of metformin therapy. 
Contiguous CT slices of 3 mm slice thickness should be obtained starting from the level of the 
cricoid cartilage and extending inferiorly through the entire liver volume.  Contrast-enhanced CT-
simulation is recommended but not required in this study. If simulation is performed prior to the 
initiation of metformin therapy, I.V. contrast may be administered during CT-simulation to assist in 
treatment volume delineation.  If simulation is performed after initiation of metformin therapy, 
contrast enhancement during CT-simulation should be avoided and contrast-enhanced diagnostic 
CTs and PET/CTs should be used to guide tumor and normal organ volume definition. In the 
event that contrast-enhanced datasets are used for treatment planning, the density of the contrast 
should be overridden to a representative background electron density. 
6.2.3 
Motion Management Technique 
Motion management is highly recommended for this protocol.  In instances in which motion 
management is not possible, larger expansion volumes will be used to adequately cover the 
motion-related uncertainties.  The types of motion management allowed on this study are 4DCT, 
active breath-hold, gated breathing, and abdominal compression. 
 
6.3 
Imaging for Structure Definition, Image Registration/Fusion and Follow Up (5/7/15) 
A whole-body FDG-PET/CT and a CT scan with IV contrast or MRI imaging (if CT scan with 
contrast is medically contraindicated) of the lung and upper abdomen through the adrenal glands 
are required within 45 days prior to registration (recommended within 30 days prior to registration) 
as part of staging and to assist in volume delineation in all eligible patients (see Section 3.1.4 for 
details).  
 

26 
NRG-LU001; version date: November 1, 2018 
 
 
The Imaging and Radiation Oncology Core (IROC) group will be involved in the collection of the 
pre-treatment PET/CT and CT with contrast. IROC also will be involved in the collection of the 
follow-up CT scans (or MRIs) of the chest and upper abdomen with contrast at 3 months post-
treatment and at the time of progression as well as the time point immediately prior to 
progression. (See Section 12.3 for digital imaging data submission.)  If there is no progression 
per institutional assessment, the patient should continue to have a CT scan or MRI imaging of the 
chest and upper abdomen as indicated in Section 11.2.3 (see also Appendix I, Table of Follow Up 
Assessments) but those scans do not need to be submitted. 
 
IROC Imaging also will be involved in the future analysis of CT imaging data as part of a central 
review of radiographic response/recurrence.    
 
6.4 
Accounting for Tumor Motion Approaches and Internal and Setup Margins (5/7/15) 
 
Internal margin (IM): The IM used will be dictated by the motion management decision made at 
time of simulation.  It is required for all cases, with the exception of instances in which simulation 
is done with 4DCT to develop a MIP of tumor volume. 
1. If the simulation is done with a free-breathing CT only, the IM will be 1 cm in the superior-
inferior direction and 0.5 cm in the axial direction.   
2. If simulation is done with abdominal compression, the IM will be 0.8 cm in the superior-inferior 
direction and 0.5 cm in the axial direction.   
3. If simulation is done using an active breath-hold or gated breathing technique, the IM will be 
0.5 cm in all directions.   
4. If simulation is done using a 4DCT to develop a maximum intensity projection or a summation 
of all phase contours of the tumor volume, no IM is needed.   
 
Setup margin (SM):  Daily IGRT is a requirement for this trial; therefore, the SM will be 0.5 cm in 
all directions.   
6.4.1 Definition of Target Volumes and Margins (8/10/16) 
All structures must be labeled for digital RT data submission as listed in the table below.  Capital 
letters, spacing and use of underscores must be applied exactly as indicated.  Resubmission of 
data may be required if labeling of structures does not conform to the standard DICOM name 
listed.    
 
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan.      
 
 

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NRG-LU001; version date: November 1, 2018 
 
 
 
Standard DICOM 
Name 
Description 
Detailed Specification 
GTV_6000 
GTV to receive 60 Gy 
 
Required for free 
breathing, active 
breath hold or gating 
motion management 
techniques 
The primary tumor and clinically positive 
lymph nodes seen on the planning CT 
(> 1cm short axis diameter) and pre-treatment 
PET scan (SUV > 3) will constitute the GTV.  
This volume(s) may be disjointed.  In the 
event of a collapsed lobe or lung segment, the 
use of PET to distinguish tumor from 
fluid/atelectasis is encouraged.  An ITV is 
defined at this point as the enveloping GTV 
motion over the course of a respiratory cycle. 
iGTV_6000 
Defined as the 
enveloping GTV motion 
over the course of the 
entire respiratory cycle 
 
 
Required when a 
4DCT is used to 
encapsulate entire 
breathing cycle 
volume   
The primary tumor and clinically positive 
lymph nodes seen on the planning CT (> 1cm 
short axis diameter) and pre-treatment PET 
scan (SUV > 3) over the course of a 
respiratory cycle. 
CTV_6000 
CTV to receive 60 Gy 
 
Required when GTV 
is drawn 
The CTV is defined to be the GTV plus a 
0.5cm to 1cm margin as appropriate to 
account for microscopic tumor extension.   
ITV_6000 
ITV to receive 60 Gy 
 
Required when iGTV 
is drawn 
The ITV will be equal to the iGTV plus a 
0.5cm to 1cm clinical margin as appropriate to 
account for microscopic tumor extension.  
PTV_6000 
PTV to receive 60 Gy 
 
Required 
The PTV will be equal to the CTV+IM+SM OR 
ITV+SM.  IM and SM are defined in Section 
6.4 above.  In cases in which the PTV 
expansion extends outside of the skin, 
towards the spinal cord or into the spinal 
canal, it can be assumed that tumor motion 
will not occur in this direction, and the PTV 
margin in this direction can be limited.  PTV 
margin can be limited up to 0.5cm towards 
this particular dimension (skin or spinal cord). 
 
 
 
 
 
 
 
6.5 
Definition of Critical Structures and Margins (5/7/15)  
Note: All required structures must be labeled for digital RT data submission exactly as listed in 
the first column of the table below.  Capital letters and spacing must be used exactly as indicated. 
Resubmission of data may be required if labeling of structures does not conform to the DICOM 
Standard Name listed.  
 
Standard DICOM 
Name 
Description 
Detailed Specification 
SpinalCord 
 
 
Boundaries: The bony limits of the spinal canal 
Cranial 
Top of C1 (or first CT slice) 

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NRG-LU001; version date: November 1, 2018 
 
 
Required 
Caudal 
Bottom of L2 (or last slice of CT) 
Lungs 
 
Both Lungs minus 
GTV 6000 (or iGTV 
6000) 
 
Required 
Boundaries: Use Lung OAR Atlas* 
Other notes: Both lungs merged into 1 structure 
and excluding the overlap with GTV_6000 or iGTV 
Esophagus 
Required 
Boundaries: The esophagus contour should include 
the mucosa, submucosa, and all muscular layers 
out to the fatty adventitia. 
Cranial 
Bottom of cricoid 
Caudal 
GE junction 
BrachialPlexus 
Required for upper 
lobe tumors 
The ipsilateral brachial plexus should be contoured 
for upper lobe tumors 
Heart 
Required 
Cranial 
Ascending aorta 
Caudal 
apex 
External 
Required 
External contour of patient encompassing all 
internal organs on each slice 
NonPTV 
Required 
External (as described above) minus PTV 
*Investigators can access the Lung OAR Atlas at 
http://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx 
 
 
6.6 
Dose Prescription 
Note: The information provided in this section can be used for adjusting the dose constraints for 
treatment planning purposes.  This table together with the planning priorities in Section 6.8 should 
be used during dose optimization.  It is important to remember that ideal plans might not be 
achievable in all cases.  Thus, the Compliance Criteria table could be different than the 
information given here.  Cases will be scored using the Compliance Criteria table. 
 
Target Standard 
Name 
Dose (Gy) 
Fraction 
Size (Gy) 
# of 
fractions 
Dose 
specification 
technique 
PTV_6000 
60 
2.0 
30 
Covering 
exactly 95% of 
PTV 
 
6.7 
Compliance Criteria (8/10/16) 
The compliance criteria listed below will be used to score each case.  Given the limitations inherent 
in the treatment planning process, the numbers given in this section can be different than the 
prescription table.  The Per Protocol and Variation Acceptable categories are both considered to 
be acceptable.  The Per Protocol cases can be viewed as ideal plans, and the Variation Acceptable 
category can include more challenging plans that do not fall at or near the ideal results.  A final 
category, called Deviation Unacceptable, results when cases do not meet the requirements for 
either Per Protocol or Variation Acceptable. Plans falling in this category are considered to be 
suboptimal and additional treatment planning optimization is recommended. 
 
Target Volume Constraints and Compliance Criteria 
Name of 
Structure 
Dosimetric* parameter 
Per Protocol 
Variation 
Acceptable** 
 
PTV_6000 
 
D95%(Gy) 
 
60 Gy 
58.8 to 61.2Gy (excluding 60 
Gy) 
Dmin(Gy) 
≥ 57 Gy 
≥54 Gy 
 
Dmax(Gy) 
≤ 72 Gy 
 ≤75 Gy 
 
*All values are for a small volume of  0.03 cc. 

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NRG-LU001; version date: November 1, 2018 
 
 
**The Variation Acceptable category extends the Per Protocol category numbers to allow for more 
challenging treatment planning problems.  The Variation Acceptable range does not include the 
Per Protocol values.  Plans will be scored as Deviation Unacceptable when Per Protocol and 
Variation Acceptable constraints are not met. 
Normal Structure Constraints and Compliance Criteria 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable* 
 
SpinalCord 
D0.03cc(Gy) (max) 
≤ 50 Gy 
na 
 
Lungs 
V5Gy(%) 
≤ 65% 
 ≤70% 
 
V20Gy(%) 
≤ 35% 
 ≤37% 
 
Dmean(Gy) 
≤ 20 Gy 
 ≤22 Gy 
 
Esophagus 
V35Gy(%) 
≤ 50 % 
≤55 % 
 
V70Gy(%) 
≤ 20 % 
 ≤25 % 
 
Dmean(Gy) 
≤ 34 Gy 
≤37 Gy 
 
BrachialPlexus 
D0.03cc(Gy) (max) 
≤63 Gy 
  ≤66 Gy 
 
Heart 
V30Gy(%) 
≤ 50%  
≤55% 
 
V45Gy(%) 
≤ 35% 
≤ 40% 
 
D0.03cc(Gy) (max) 
≤ 70 Gy 
  ≤ 75 Gy ** 
 
*The Variation Acceptable category extends the Per Protocol category numbers to allow for more 
challenging treatment planning problems.  The Variation Acceptable range does not include the 
Per Protocol values.  Plans will be scored as Deviation Unacceptable when Per Protocol and 
Variation Acceptable constraints are not met. 
** When this value cannot be achieved, treatment plans must be modified to move dose 
distribution hotspots away from the heart to avoid having the case scored as a Deviation 
Unacceptable. 
 
Delivery Compliance Criteria 
 
Per Protocol 
Variation 
Acceptable 
 
Overall Treatment time 
< 45 days 
46-51 days 
 
Interruptions (other than 
holidays or weekends) 
0-2 days 
3-7 days 
 
Note: Cases will be scored as Deviation Unacceptable when the time limits given above are not 
met.  
 
6.8 
Treatment Planning Priorities and Instructions (8/10/16) 
6.8.1 
Planning priorities are listed in order of decreasing importance: 
1. SpinalCord 
2. Lungs 
3. PTV 
4. Esophagus 
5. Heart 
6. BrachialPlexus 
 
 
If lung dose constraints are exceeded, several solutions can be entertained: 
 
For 3D-CRT: Increase the weighting of AP/PA treatments by 1, and reduce the obliques. 
This can be done as long as the cord dose, which takes precedence, is not exceeded. 
 
For 3D-CRT or IMRT: ‘Make sure that the GTV (or ITV) to CTV margin is reduced to no 
less than the minimum allowable amount of 0.5 cm as suggested in the table of section 
6.4.1 above’ and/or reduce the PTV by choosing another motion management option with 
smaller internal margins. 

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NRG-LU001; version date: November 1, 2018 
 
 
It is recommended that the esophagus not to be circumferentially irradiated with > 60 Gy (i.e. the 
60 Gy isodose line should not encompass the entire axial cross-section of the esophagus at any 
level). 
6.8.2 
Re-planning due to Atelectasis or Pleural Effusion 
Due to various physiological reasons, it may be in the interest of best clinical practice to re-
simulate the patient and re-plan to account for drastic anatomical changes (adaptive therapy 
regimens excluded). 
Re-simulation 
 
Repeat CTs will be of the same type (4D, breath-hold, etc.) as the initial planning CT 
depending upon the motion management strategy being used.  
Re-contouring 
 
The GTV or iGTV, spinal canal, lungs and other OARs will be reviewed by a physician. 
Any modifications to an OAR must be denoted by the structure name (see Table in 
Section 6.5) followed by the number of the scan (1 for 1st re-simulation, 2 for the 2nd re-
simulation). GTV or iGTV do not require modifications, unless they lie > 3mm outside the 
originally contoured GTV or iGTV. GTV or iGTV should be re-contoured if tumor 
regression develops within the previously contoured region, but the CTV (or ITV) and 
PTV should remain the same. Re-contouring may also be necessary if the GTV shifts 
relative to other anatomy or deforms. In this case the CTV should be adjusted to the new 
iGTV/GTV + margin, and a new PTV should be created.  
Important note: Even though the GTV may change substantially during the course of 
radiotherapy, the CTV is assumed to retain its volume. Therefore, the CTV (or ITV) 
should not be reduced even if the GTV or iGTV has regressed in the repeat CT scans. 
The assumption is that there is likely to be microscopic disease present where GTV or 
iGTV was initially positioned. The CTV (or ITV) shape may change depending on 
changes in the surrounding anatomy. 
Re-planning 
 
Re-planning should be performed assuming this new CT will receive 30 fractions of 
treatment at 2Gy/fx.  Planning goals should be to meet the protocol’s dosimetric 
criteria before adjusting the number of fractions to the number intended to treat with 
the re-plan. 
 
For patients requiring re-planning, the following procedure is to be used to estimate 
the summed dose distributions. Beam configurations for the original and the re-plans 
used for treatments will be applied to the re-simulation CT.  The dose distributions 
computed for each of the configurations will be summed weighted according to the 
number of fractions each distribution used.  
 
All plans developed and used for treatments and the corresponding CT images will 
be submitted to IROC Philadelphia-RT Core Lab. 
 
6.9 
Dose Calculations 
6.9.1 
Required algorithms 
Acceptable choices of algorithm are listed at 
http://irochouston.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TPS%20-
%20algorithm%20list%20updated.pdf.  Any algorithm used for this study must be credentialed by 
IROC Houston.   
6.9.2 
Primary dataset for dose calculation 
The primary dataset for dose calculation must be a free-breathing CT that was acquired along 
with 4DCT, an average intensity pixel CT (AveIP) generated from the 4DCT, the breath-
hold/gated CT, or the free-breathing CT acquired with no other motion management.  Maximum 
Intensity Pixel (MIP) generated images from 4DCTs may not be used as the primary dose 
calculation dataset.   
6.9.3 
Dose matrix resolution 
Dose grid size should be ≤ 3 mm in all directions.   

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NRG-LU001; version date: November 1, 2018 
 
 
 
6.10 
Patient-specific Quality Assurance (QA) 
Any patient-specific QA that needs to be acquired should follow institutional guidelines.   
 
6.11 
Treatment Delivery (8/10/16) 
Daily Treatment Localization/IGRT  
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate accuracy 
and precision throughout its entire process from target and normal tissue delineation, to radiation 
delivery, to adaptation of therapy to anatomic and biological changes over time in individual 
patients. In this section we use the terminology IGRT to focus on image-guidance at the time of 
radiation delivery to ensure its adherence to the planned treatment. 
 
6.12 
R.T. Quality Assurance Reviews (5/7/15) 
The Co-Principal Investigators, Theos Tsakiridis, MD, and/or Heath Skinner, MD will perform an 
RT Quality Assurance Review after complete data for the first 20 cases enrolled has been received 
at IROC Philadelphia-RT. Drs. Tsakiridis and Skinner will perform the next review after complete 
data for the next 20 cases enrolled has been received at IROC Philadelphia-RT. The final cases 
will be reviewed within 3 months after this study has reached the target accrual or as soon as 
complete data for all cases enrolled has been received at IROC Philadelphia-RT, whichever occurs 
first.  
 
6.13 
Radiation Therapy Adverse Events 
6.13.1 Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and  esophagitis are 
expected side effects of radiation therapy. Radiation induced myocarditis or transverse myelitis 
rarely occur at doses lower than 50 Gy. Radiographic evidence of radiation change and 
subsequent fibrosis of the lung will occur within lung volume receiving ≥ 20 Gy, usually within the 
first 6 months after initiation of treatment. It is essential to spare as much normal lung as possible 
in order to avoid symptomatic lung injury. 
6.13.2 Esophagitis 
Esophageal complaints are common with combined modality therapy. Esophagitis does not 
constitute a reason to interrupt or delay radiotherapy or chemotherapy provided oral intake is 
sufficient to maintain hydration. Patients should be advised to avoid alcoholic, acidic, or spicy 
foods or beverages. Viscous Xylocaine, Carafate, or other medications should be used for 
symptomatic relief. Occasionally, narcotics may be required. 
 
It is not necessary to biopsy acute esophagitis in the first 2 weeks of combined therapy since it 
is rarely due to underlying viral or fungal disease. Acute esophagitis may persist for 4-6 weeks. 
If Grade 4 (CTCAE, v. 4) esophagitis occurs, and a treatment interruption is being considered, 
every effort should be made to limit it to ≤ 3 treatment days. Patients requiring hospitalization 
because of esophagitis may have their treatment interrupted. In this event, investigators must  
notify the Co-Principal Investigators, Drs. Skinner and Tsakiridis. 
 
7.0  
DRUG THERAPY 
Patients randomized to Arm 1 (concurrent chemotherapy and radiation therapy) must begin 
treatment within 14 days after randomization. 
 
Patients randomized to metformin (Arm 2) must begin metformin within 14 days after 
randomization and every effort must be made to begin concurrent chemotherapy and 
radiation therapy 14 days after beginning metformin. Concurrent chemoradiotherapy and 
metformin ideally should start on a Monday. 
 
 
7.1 
Treatment 
Chemotherapy and radiation therapy (RT) must begin on the same day. It is recommended that 
RT be delivered after chemotherapy. All chemotherapy doses must be calculated by the 

32 
NRG-LU001; version date: November 1, 2018 
 
 
investigator based on actual body weight. All standard of care chemotherapy is administered as 
per respective institutional guidelines. 
7.1.1 
Chemotherapy Concurrent with Radiation 
Patients will receive paclitaxel (50 mg/m2 IV) and carboplatin (AUC-2 IV) weekly on days 1, 8, 15, 
22, 29, and 36 from start of chemoradiotherapy, intravenously weekly concurrent with thoracic 
radiation.  
7.1.2 
Consolidation Chemotherapy 
 
Patients will receive two 21-day cycles of consolidation treatment beginning 28-42 days after 
completion of radiation therapy with paclitaxel (200 mg/m2) and carboplatin (AUC 6) on days 1 and 
22 administered intravenously. 
7.1.3 
Chemotherapy Administration (8/10/16) 
Carboplatin dose should be calculated using the Calvert formula [(Total carboplatin dose mg) 
= (target AUC) x (CrCl + 25)]. 
 
CrCl (ml/min) = (140-age) (Actual weight in kg) x 0.85 (females only)/72 x serum Creatinine (mg/dl). 
 
The GFR should not exceed 125 ml/min. If the calculated GFR based on the Calvert formula is 
greater than 125 ml/min, a GFR of 125 ml/min should be used. The maximum carboplatin dose 
for an AUC = 2 should not exceed 300 mg, and for an AUC = 6 should not exceed 900 mg. 
A measured CrCl from a 24 hour urine collection may also be used. Note: For subsequent weekly 
doses, a > 10% change in the serum creatinine, based on weekly calculated creatinine clearance 
or a > 10% change in weight, will warrant a recalculation of the carboplatin and paclitaxel dose 
 
Chemotherapy drugs will be administered intravenously by intravenous drip. The paclitaxel during 
the concurrent phase will be given over 1 hour with standard premedication consisting of 
diphenhydramine 25-50 mg, an H2- blocker, and dexamethasone (oral or intravenous is acceptable 
according to local custom) at least 30 minutes prior to paclitaxel. The carboplatin will be given after 
the paclitaxel over 30 minutes with standard antiemetics. During the consolidation phase, the 
administration of carboplatin and paclitaxel should follow institutional standards in regards to 
duration of infusion, premedications and standard antiemetics. 
7.1.4 
Timing of Treatment 
If the day of chemotherapy falls on a holiday, chemotherapy should be administered on the next 
full working day following the holiday (e.g., if the day 8 dose falls on Thanksgiving, the next 
chemotherapy dose would be given the following Monday). Doses that are missed during the 
weekly schedule concurrent with RT will not be made up but will be documented. If breaks from 
chemotherapy are required for longer than 15 days, protocol chemotherapy will be discontinued. 
RT will continue, and the patient will remain on study and will be followed as specified in the 
protocol. 
7.1.5 
Metformin Treatment (5/7/15) 
 
All patients randomized to metformin (Arm 2) will go through metformin dose escalation.  
Patients will start metformin within 14 days after randomization, ideally on a Monday 2 weeks 
prior to initiation of concurrent chemotherapy and radiation. The starting dose is 500 mg p.o. BID 
(before breakfast and dinner) 7 days/week. On day 8, this dose will be escalated to 500 mg TID 
before meals for a total daily dose of 1500 mg. On day 15, ideally a Monday that should coincide 
with the initiation of concurrent chemotherapy and radiation, the midday dose will increase by an 
additional 500 mg for a total daily dose of 2000 mg (500 mg in the morning, 1000 mg midday, and 
500 mg in the evening). If day 15 falls on a holiday or there are unforeseen circumstances that 
delay the initiation of chemotherapy and radiation, the patient should continue on the 1500 mg 
daily dose until the start of chemoradiation when the patient will begin a total daily dose of 2000 
mg daily.  
  
When concurrent chemotherapy and radiation is completed, Arm 2 patients will continue daily 
metformin for a total of 10 more weeks. Consolidation chemotherapy begins 4-6 weeks after the 
end of concurrent chemoradiotherapy.  
 

33 
NRG-LU001; version date: November 1, 2018 
 
 
Metformin should be taken 1-2 hours before meals and before chemotherapy on days on which 
this occurs.  For compliance assessment, patients will be required to track daily doses of 
metformin by maintaining a daily medication diary that is located here: 
http://www.rtog.org/LinkClick.aspx?fileticket=Hztq94-tFCw%3d&tabid=290. 
  
Supply 
In this study the investigational agent (metformin) will not be supplied to centers.  Metformin HCL 
is commercially available and very economical.  Therefore, sites are strongly encouraged to 
provide the required amount of metformin to patients from the site pharmacy free of charge by 
using a small portion of the site’s case reimbursement to cover the cost.  Because Metformin HCL 
is investigational in this trial, in most cases the patient’s health plan/insurance company will not 
pay for the drug. 
7.1.6 
Temporary Interruption, Reduction, and Re-Initiation of Metformin Treatment (8/10/16) 
The risk of hypoglycemia in euglycemic patients is exceedingly low, as hypoglycemia does not 
occur in patients receiving metformin alone under usual circumstance. Because patients in this 
trial might have a low caloric intake due to complications of treatment, patients randomized to 
metformin (Arm 2) will undergo weekly blood glucose monitoring.  If based on these lab values or 
associated symptoms, the treating physician diagnoses hypoglycemia, study drug treatment will 
be halted, while concurrent chemoradiation or chemotherapy continues.  Once blood glucose 
normalizes, metformin will be restarted and the dose should be decreased by 500 mg with daily 
monitoring of blood glucose. Acceptable doses of metformin are 2000, 1500, 1000, or 500 mg 
every day. If there are no symptoms or signs of hypoglycemia in 1 week, daily monitoring is no 
longer needed. The site will record any dose de-escalation and re-escalation in source 
documentation. 
 
 
In the event of grade 2 or 3 gastrointestinal toxicity (typically involving flatulence or diarrhea), 
patients will be supported with loperamide, at dosing schedules recommended in the package 
insert. Gastrointestinal side effects typically subside within 4-6 weeks of initiating metformin 
treatment. In the event that grade 2 gastrointestinal toxicity persists during or following the 
completion of concurrent chemotherapy and radiation, metformin dose de-escalation will be 
permitted when symptoms are deemed to be due to metformin alone and not due to systemic 
therapy or other reasons. Efforts should be made to maintain the dose as close to the suggested 
total daily treatment dose (2000 mg) as much as possible. Alterations to the daily intake schedule 
of metformin should be the first steps to be taken to reduce gastrointestinal symptoms, including 
taking metformin with food rather than before meals or modifying drug intake from the TID schedule 
to a BID dosing of  1000 mg (2 tablets of 500 mg with morning and evening meals), keeping the 
doses 12 hours apart. If alterations in schedule are insufficient in reducing gastrointestinal toxicity 
to ≤ grade 1, the metformin dose should be decreased by 500 mg  for 1 week with loperamide 
support until symptoms subside. If GI toxicity has not resolved in 1 week, then decrease the dose 
by another 500 mg; do this weekly until GI toxicity resolves. Efforts should be made to re-escalate 
the dose of metformin back to 2000 mg total daily dose 2 weeks after patients remain free of grade 
2 toxicity. At least 2 attempts should be made to re-escalate the dose to 2000 mg/day after each 
dose de-escalation takes place.  
 
 
In the event that re-escalation to a higher dose cannot be achieved without grade 2 toxicity, patients 
will be maintained at the highest tolerable dose for the remainder of the metformin treatment period. 
Acceptable doses of maintenance metformin are 2000, 1500, 1000 or 500 mg every day. The site 
will record any dose de-escalation and re-escalation in source documentation. 
 
 
Metformin treatment interruption will be permitted according to local guidelines at the time of routine 
CT scans with contrast infusion. Obtain an eGFR annually in all patients taking metformin. 
Discontinue metformin if eGFR ≤ 30 mL/minute/1.73 m2. If eGFR is between 30-45 mL/minute/1.73 
m2, perform eGFR every 1-2 weeks until recovery to ≥45, then resume normal metformin doses. 
 
 
 
 
Patients whose treatment is interrupted for any reason except intolerable toxicity will be encouraged 
to resume and continue with their assigned therapy. Sites will record compliance (and reasons for 

34 
NRG-LU001; version date: November 1, 2018 
 
 
non-compliance) in source documentation. The visit schedule for those patients who discontinue 
therapy should not be modified as endpoints will be assessed for all patients regardless of study 
drug discontinuation as an intent-to-treat analysis will be performed. 
 
Metformin Timeframe and Dose 
Dose Escalation 
Concurrent Treatment 
Consolidation Treatment 
Days 1-7 
Days 8-14 
Days 15-56 
Days 57-126 
1000 mg  
1500 mg  
2000 mg  
2000 mg  
500 mg AM 
500 mg PM 
500 mg AM 
500 mg Noon 
500 mg PM 
500 mg AM 
1000 mg Noon 
500 mg PM 
500 mg AM 
1000 mg Noon 
500 mg PM 
 
 
 
7.2 
Study Agents  
Please see Section 7.1 for administration instructions. Please refer to the current FDA-approved 
package insert provided with each drug and the site-specific pharmacy for toxicity information and 
instructions for drug preparation, handling, and storage. 
 
Non-Canadian International Institutions: 
Please refer to your LOI Approval Notification. Your institution will be responsible for acquiring any 
drug noted in the protocol.  
 
7.3 
Dose Modifications (5/7/15) 
7.3.1 
Dose Modifications during Concurrent Chemoradiation 

35 
NRG-LU001; version date: November 1, 2018 
 
 
The following dose levels are used for dose modifications during the concurrent chemoradiation 
phase. There will be no dose reduction below level -1. 
 
Dose Level 
Carboplatin 
Paclitaxel 
0 
AUC 2 
50 mg/m2 
-1 
AUC1 
40 mg/m2 
Hematologic Toxicity during Concurrent Chemoradiation 
 
Dose Modification on Day of Administration of Concurrent Chemotherapy And Radiation 
 
 
Platelet count 
 
 < 80K  
>80K  
ANC 
x1000 
 ANC 
≥ 1 
 
Hold* 
Continue same dose level 
<1 
 
Hold* 
Hold* 
 
*Check weekly and resume therapy at previous dose (no dose reduction) when counts recover to 
ANC ≥ 1,000 and platelets ≥ 80,000/mcl. There will be no dose reduction for hematologic toxicities 
during the concurrent phase.  
 
If dose reduction is required during chemoradiation, no re-escalation is allowed in subsequent 
chemoradiation cycles. However, paclitaxel and carboplatin will be started at dose level 0 for the 
consolidation cycles. 
 
If paclitaxel and/or carboplatin are held for greater than 2 consecutive weeks, the drugs will be held 
permanently for the duration of concurrent therapy but should be restarted for the consolidation 
phase. If during the consolidation phase chemotherapy is held for more than 3 weeks, then it should 
be discontinued. 
 
7.3.2 
Febrile Neutropenia during Concurrent Chemoradiation 
Febrile neutropenia occurring during chemoradiation will result in a decrease of the carboplatin 
and paclitaxel dose level by –1. Febrile neutropenia occurring despite dose reduction during 
chemoradiation will result in discontinuation of carboplatin, but continuation of paclitaxel at the 
previous dose (-1 dose level). Radiation therapy is held for neutropenia (ANC < 500/mcl); 
radiation therapy may be restarted when the ANC ≥ 1000/mcl. Filgrastim, sargramostim or 
pegfilgrastim are not allowed during radiation treatment. 
 
7.3.3 
Dose Modifications during Consolidation Chemotherapy 
The following dose levels are used for dose modifications during the consolidation phase. There 
will be no dose reduction below level -1. 
 
Dose Level 
Carboplatin 
Paclitaxel 
0 
AUC 6 
200 mg/m2 
-1 
AUC 4.5 
150 mg/m2 
 
Hematologic Toxicity during Consolidation Chemotherapy 
 
Dose Modification on Day of Administration of Consolidation Cycle 
 
 
 
Platelet count 
 
 < 100K  
>100K  
A
N
C 
1
≥ 1.5 
 
Hold* 
Continue same dose level 

36 
NRG-LU001; version date: November 1, 2018 
 
 
<1.5 
 
Hold* 
Hold* 
*Check weekly and resume therapy at previous dose (no dose reduction) if counts recover within 
1 week to ANC ≥ 1,500 and platelets ≥ 100,000/mcl. If not, decrease by 1 dose level when ANC 
1,500 mm3 platelets ≥ 100,000/mcl. Use of growth factors for neutropenia during consolidation are 
allowed at the discretion of the treating oncologist. Dose delays greater than 3 weeks will warrant 
discontinuation of chemotherapy for the consolidation cycles. 
7.3.4 
Febrile Neutropenia during Consolidation Chemotherapy 
Febrile neutropenia occurring during consolidation will result in a decrease of both the carboplatin 
and paclitaxel doses by 1 dose level. Filgrastim, sargramostim or pegfilgrastim are allowed during 
the consolidation phase at the discretion of the treating medical oncologist. 
7.3.5 
Renal Toxicity during Concurrent or Consolidation Chemotherapy 
Renal Toxicity: There are no dose modifications for renal toxicity. It is not necessary to change 
the dose of carboplatin unless the calculated dose changes by ≥ 10%. 
7.3.6 
Neurotoxicity during Concurrent or Consolidation Chemotherapy 
 
Paclitaxel doses should be modified for neurologic toxicity (see below). Serum 
magnesium and calcium levels should be checked; folate and vitamin B12 levels may 
need to be evaluated especially in older patients. 
 
Grade 1: Give paclitaxel at full dose. 
 
Grade ≥ 2: Hold paclitaxel until neurotoxicity resolves to ≤ grade 1, then resume with one 
dose level reduction. Continue treatment with carboplatin. If paclitaxel is held for ≥ 21 
days, discontinue paclitaxel, but continue treatment with carboplatin. 
7.3.7 
Hepatic Toxicity during Consolidation Chemotherapy (8/10/16) 
Give the following doses for paclitaxel only: 
 
 
AST 
 <2.5x ULN  
2.5-5 x ULN  
>5 x ULN  
Bilirubin 
≥ 1.5 ULN 
 
Hold* and recheck 
weekly 
Hold* and evaluate 
as medically 
necessary, recheck 
weekly. 
Hold* and evaluate as 
medically necessary, 
recheck weekly. 
< 1.5 ULN 
Same dose level  
Reduce 1 dose level 
Hold* and evaluate as 
medically necessary, 
recheck weekly.  
*Hold paclitaxel until AST ≤ 5 x ULN and bilirubin < 1.5 ULN, then resume treatment at one dose level 
lower. (Continue treatment with carboplatin. If paclitaxel is held for ≥ 21 days, discontinue paclitaxel 
therapy (continue treatment with carboplatin). 
 
7.3.8 
Hypersensitivity Reactions to Carboplatin 
 
Grade 1: Slow the infusion until symptoms resolve, then restart the infusion at the initial 
planned rate. 
 
Grade 2: Stop the infusion. Administer H1 and/or H2 blockers +/- dexamethasone, according 
to physician discretion/institutional guidelines. Restart carboplatin when symptoms resolve 
and pretreat before all subsequent doses of carboplatin. 
 
Grade 3 or 4: Patient should be removed from all protocol therapy. 
7.3.9 
Hypersensitivity Reactions to Paclitaxel 
 
Grade 1: Slow the infusion until symptoms resolve, then restart the infusion at the initial 
planned rate. 
 
Grade 2: Stop the infusion. Administer H1 and/or H2 blockers +/- dexamethasone according 
to physician discretion/institutional guidelines. Restart when symptoms resolve and pretreat 
before all subsequent doses. 
 
Grade 3 or 4: Discontinue therapy with paclitaxel. 

37 
NRG-LU001; version date: November 1, 2018 
 
 
7.3.10 All Other Non-Hematological Treatment-Related Toxicities that Exceed Grade 2 during 
Concurrent or Consolidation Chemotherapy (5/7/15) 
For all other treatment-related toxicities that exceed grade 2: (except alopecia, nausea, vomiting, 
fatigue and anorexia), hold paclitaxel and carboplatin until the toxicities have resolved to grade 2 
or less and resume carboplatin and paclitaxel with one dose level reduction. 
 
7.4 
Modality Review 
The Medical Oncology Co-Chair, Rafael Santana-Davila, MD, will perform a Chemotherapy 
Assurance Review of all patients who receive or are to receive chemotherapy in this trial.  The goal 
of the review is to evaluate protocol compliance.  The review process is contingent on timely 
submission of chemotherapy treatment data as specified in Section 12.1. The scoring mechanism 
is: Per Protocol/Acceptable Variation, Unacceptable Deviation, and Not Evaluable.  A report 
is sent to each institution once per year to notify the institution about compliance for each case 
reviewed in that year. 
   
Dr. Santana-Davila will perform a Quality Assurance Review after complete data for the first 20 
cases enrolled has been received at NRG Oncology. Dr. Santana-Davila will perform the next 
review after complete data for the next 20 cases enrolled has been received at NRG Oncology. 
The final cases will be reviewed within 3 months after this study has reached the target accrual or 
as soon as complete data for all cases enrolled has been received at NRG Oncology, whichever 
occurs first. 
 
 
7.5 
Adverse Events (1-NOV-2018) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for all AE reporting, 
CTEP-AERS, and case report forms. CTCAE version 5.0 will be utilized for CTEP-AERS 
reporting beginning April 1, 2018; all study case report forms will continue to use CTCAE version 
4.0. All appropriate treatment areas should have access to a copy of CTCAE versions 4.0 and 
5.0, which can be downloaded from the CTEP web site (https://ctep.cancer.gov/ 
protocolDevelopment/electronic_applications/ctc.htm). 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be 
reported via the CTEP-AERS (CTEP Adverse Event Reporting System) application accessed via 
the CTEP web site (https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613)  
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
NRG Oncology Operations Center by phone (215-574-3191). Once internet connectivity is 
restored, an AE report submitted by phone must be entered electronically into CTEP-AERS. 
7.5.1 
Adverse Events (AEs) 
 
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not considered related 
to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or 
definite). (International Conference on Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements.  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]   
7.5.2 
Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited reporting 
criteria defined in the table in section 7.6 will be reported via CTEP-AERS.  SAEs that require 24 
hour CTEP-AERS notification are defined in the expedited reporting table in section 7.6.  Contact 
the CTEP-AERS Help Desk if assistance is required. 
 
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results in 
any of the following outcomes: 
 
Death; 
 
A life-threatening adverse drug experience; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 

38 
NRG-LU001; version date: November 1, 2018 
 
 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect;  
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy 
of a study participant must be reported via CTEP-AERS in an expedited manner.  
7.5.3 
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in 
patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS system within 
30 days of AML/MDS diagnosis. 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event: 
 
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
 
Myelodysplastic syndrome (MDS) 
 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported 
via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified.  
 
7.6 
CTEP-AERS Expedited Reporting Requirements (1-NOV-2018) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table below 
will be reported via CTEP-AERS, the Adverse Event Expedited Reporting System, accessed via 
the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613  
. 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG 
Oncology requirements for expedited adverse event reporting. 
 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve 
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only 
pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
NRG Oncology Operations Center by phone (215-574-3191). Once internet connectivity is 
restored, an AE report submitted by phone must be entered electronically into CTEP-AERS. 
 
 
Per CTEP NCI Guidelines for Adverse Events Reporting, a CTEP-AERS 24-hour notification 
must be submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 24-
hour notification must be followed by an CTEP-AERS 5 Calendar Day Report. Serious 

39 
NRG-LU001; version date: November 1, 2018 
 
 
adverse events that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table below. 
 
Supporting source document is not mandatory.  However, if the CTEP-AERS report indicates 
in the Additional Information section that source documentation will be provided, then it is 
expected.  If supporting source documentation accompanies an CTEP-AERS report, include 
the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and 
fax supporting documentation to the NRG Oncology Operations Center (215-574-3191) for 
source document submission assistance. 
 
A serious adverse event that meets expedited reporting criteria outlined in the AE Reporting 
Tables but is assessed by the CTEP-AERS as “an action not recommended” must still be 
reported to fulfill NRG safety reporting obligations. Sites must bypass the “NOT 
recommended” assessment; the CTEP-AERS allows submission of all reports regardless of 
the results of the assessment.  
 
CTEP defines expedited AE reporting requirements for phase 1 trials as described in the table 
below. Important: All AEs reported via CTEP-AERS also must be reported on the AE section of 
the appropriate case report form (see Section 12.1).  
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies Utilizing Commercial Agents within 30 Days of the Last 
Administration of the Commercial Agent 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 

40 
NRG-LU001; version date: November 1, 2018 
 
 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing a Commercial Agent 
The following are protocol-specific exceptions to expedited reporting via CTEP-AERS. Report the 
following adverse events (AEs) in an expedited manner only if the AEs exceed grade 3 (CTCAE, v. 
5): Nausea, vomiting, diarrhea, and dehydration. Report the following AEs in an expedited manner 
only if the AEs exceed grade 2 (CTCAE, v. 5): Esophagitis, dysphagia. Routine adverse event 
reporting on the case report form fulfills safety reporting requirements for these events at the 
aforementioned grades.  
 
8.0  
SURGERY 
 
Not applicable to this study. 
 
9.0  
OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
 
All supportive therapy for optimal medical care will be given during the study period at the discretion 
of the attending physician(s) within the parameters of the protocol and documented on each site’s 
source documents as concomitant medication.  
9.1.1 
Filgrastim, sargramostim or pegfilgrastim are allowed during consolidation chemotherapy at the 
discretion of the treating medical oncologist. 
 
9.2 
Non-permitted Supportive Therapy 
9.2.1 
Filgrastim, sargramostim or pegfilgrastim are not allowed during radiation treatment. 
 
 
10.0 
TISSUE/SPECIMEN SUBMISSION (5/7/15) 
NOTE: Patients must be offered the opportunity to participate in the correlative components 
of the study, such as tissue/specimen submission. If the patient consents to participate in the 
tissue/specimen component of the study, the site is required to submit the patient’s specimens as 

41 
NRG-LU001; version date: November 1, 2018 
 
 
specified in Section 10.0 of the protocol. Note: Sites are not permitted to delete the tissue/specimen 
component from the protocol or from the sample consent. 
10.1 
Tissue/Specimen Submission (5/7/15) 
The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and 
maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved 
through careful block storage and processing. NRG Oncology encourages participants in protocol 
studies to consent to the banking of their tissue. The NRG Oncology Biospecimen Bank – San 
Francisco provides tissue specimens to investigators for translational research studies. 
Translational research studies integrate the newest research findings into current protocols to 
investigate important biologic questions. The NRG Oncology Biospecimen Bank – San Francisco - 
also collects tissue for Central Review of pathology. Central Review of tissue can be for eligibility 
and/or analysis. 
 
In this study, tissue, plasma and whole blood will be submitted to the NRG Oncology Biospecimen 
Bank for the purpose of tissue banking for future translational research. Specific hypotheses 
include: 
1. TP53, LKB1 and K-RAS mutation status can predict the ability of MET to offer overall radio- 
and chemo-sensitization action in patients with LA-NSCLC. The clinical value of developing a 
reliable selection biomarker for future MET studies can be very significant, as that could 
spare unnecessary treatment of non-responsive patients. For that, we will collect tumor tissue 
and investigate those markers at the gene and protein level. 
2. Fasting MET plasma levels predict response to therapy. 
3. Reduction of fasting plasma insulin and LDL-cholesterol correlate with plasma MET levels 
and response to the drug. 
 
Testing these markers in the samples obtained in this trial will help us determine whether future 
studies can utilize serum MET levels, response of insulin levels and lipid profile or 
phosphorylation of AMPK, p70S6k or 4EBP1 as predictive markers of MET response in a specific 
patient. These markers may be able to help monitor on-going patient response to MET therapy. 
 
10.2 
Specimen Collection for Tissue Banking and Translational Research (Recommended) 
(8/10/16) 
For patients who have consented to participate in the tissue/blood component of the study (See 
sample informed consent). 
 
The following must be provided in order for the case to be evaluable for the Biospecimen Bank:  
10.2.1 One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic slide (block); it 
does not have to be the diagnostic slide itself.) 
10.2.2 A corresponding paraffin-embedded tissue block of the tumor (the block must match the H&E being 
submitted) or a 2 mm diameter core of tumor tissue, punched from the tissue block containing the 
tumor with a punch tool and submitted in a plastic tube labeled with the surgical pathology number.  
If sites are unable to provide block or punch, 10-15 unstained slides are an acceptable alternative.  
Note: A kit with the punch, tube, and instructions can be obtained free of charge from the 
Biospecimen Bank. Block or core must be clearly labeled with the pathology identification number 
and block number that corresponds to the Pathology Report. 
 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
10.2.3 A Pathology Report documenting that the submitted block or core contains tumor. The report must 
include the NRG Oncology protocol number and patient’s case number. The patient’s name and/or 
other identifying information should be removed from the report. The surgical pathology numbers 
and information must NOT be removed from the report. 
10.2.4 A Specimen Transmittal (ST) Form clearly stating that tissue is being submitted for the NRG 
Oncology Biospecimen Bank – San Francisco - if for translational research, this should be stated 
on the form. The form must include the NRG Oncology protocol number and patient’s case number.   

42 
NRG-LU001; version date: November 1, 2018 
 
 
10.2.5  Three tubes of blood (2 tubes x 10 ml each for plasma collection and 1 tube x 5-10 ml for whole 
blood) will be collected from participating patients at baseline, 2 tubes of blood x 10 ml each for 
plasma at weeks 1 and 6 of concurrent chemoradiotherapy (corresponding to weeks 3 and 8 of the 
metformin treatment period for patients randomized to Arm 2) and at the 6 month follow up visit as 
described below in Table 10.2.7. 
.  
The following materials must be provided to the NRG Oncology Biospecimen Bank: A Specimen 
Transmittal (ST) Form documenting the date of collection of the biospecimen; the NRG Oncology 
protocol number, the patient’s case number, time point of study, and method of storage, for 
example, stored at -80 C, must be included. 
10.2.6 Storage Conditions 
Store frozen specimens at -80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not 
available:  
 
Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out 
Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; 
Canada: Monday-Tuesday). 
 
Please indicate on the ST Form the storage conditions used and time stored. 
 
 
10.2.7 Specimen Collection Summary (8/10/16) 
 
Specimens for Tissue Banking/Translational Research 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
Representative H&E 
stained slides of the primary 
tumor 
Pre-treatment 
H&E stained slide 
Pre-treatment 
Slide shipped ambient 
A paraffin-embedded tissue 
block of the primary tumor 
taken before initiation of 
treatment or a 2 mm 
diameter core of tissue, 
punched from the tissue 
block with a punch tool  
Pre-treatment 
Paraffin-embedded 
tissue block or punch 
biopsy (must match the 
H&E slide being 
submitted)   
 
Block or punch shipped 
ambient 
 
PLASMA: 2 X 10 mL of 
anticoagulated whole blood 
in EDTA tubes #1 (purple/ 
lavender top) and centrifuge 
At baseline, weeks 1 and 
6 of chemo/RT 
(corresponding to weeks 3 
and 8 of metformin 
treatment period for 
patients randomized to 
Arm 2), and at 6 month 
follow-up visit (as 
indicated in Appendix I). 
Frozen plasma samples 
containing 0.5 mL per 
aliquot in 1 mL cryovials 
(five to ten) 
Plasma sent frozen on dry 
ice via overnight carrier 
Whole blood for DNA: 1x 5-
10 mL of anticoagulated 
whole blood in EDTA tube 
#2 (purple/lavender top) 
and mix 
Pre-treatment 
 
Note: If site missed this 
collection time point they 
may collect whole blood 
for DNA at a later time 
point instead but must 
note this on the ST Form. 
Frozen whole blood 
samples containing   
1 mL per aliquot in 1ml 
cryovials (three to five) 
Whole blood sent frozen 
on dry ice via overnight 
carrier 
 

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NRG-LU001; version date: November 1, 2018 
 
 
10.2.8 Submit materials for Tissue Banking and Translational Research as follows:   
 
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen 
Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
Questions: 415-476-7864/FAX 415-476-5271;  NRGBB@ucsf.edu 
 
10.3 
Reimbursement 
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per 
the requirements/methods specified by the new NCTN Program. This information will be made 
available with the other registration materials in the Oncology Patient Enrollment Network (OPEN) 
portal system. OPEN will serve as the registration system for all patient enrollments onto NCI-
sponsored NCTN trials, including this study, which will be transitioned into the new Program from 
the NCI-sponsored Cooperative Group Clinical Trials Program. 
  
10.4 
Confidentiality/Storage  
(See 
the 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx 
for 
further details.) 
10.4.1 Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient’s 
case number only. The NRG Oncology Biospecimen Bank database only includes the following 
information: the number of specimens received, the date the specimens were received, 
documentation of material sent to a qualified investigator, type of material sent, and the date the 
specimens were sent to the investigator. No clinical information is kept in the database. 
10.4.2 Specimens for tissue banking will be stored for an indefinite period of time. Specimens for the 
translational research component of this protocol will be retained until the study is terminated, 
unless the patient has consented to storage for future studies. If at any time the patient withdraws 
consent to store and use specimens, the material will be returned to the institution that submitted 
it. 
 
11.0 
PATIENT ASSESSMENTS 
11.1 
Study Parameters 
See Appendix I  
 
 
11.2 
Details of Evaluations  
11.2.1 Pre-Treatment Evaluations 
 
Tumor measurements: Measure in at least 1 dimension and record the longest dimension as 
≥ 10 mm with CT scan  (or MRI) of the chest and upper abdomen. The CT scan or MRI must 
be performed from the lung apices through the adrenal glands. Note: A baseline CT of the 
chest and upper abdomen is required  and must be submitted for central evaluation (see 
Section 6.3) 
 
Institutions are highly encouraged to utilize the same imaging modality (CT or MRI) for each 
follow-up scan, if possible. 
 
A baseline whole body FDG-PET/CT scan must be performed from skull base through 
perineum and is required to complete staging and assist in treatment volume delineation. 
Serum glucose must be measured (ideally within 1 hour of FDG administration). If the serum 

44 
NRG-LU001; version date: November 1, 2018 
 
 
glucose concentration is found to be > 200 mg/dL, the study should be rescheduled. The 
referring physician or primary physician will be contacted to optimize blood glucose control. 
Use of iodine or gadolinium contrast is required unless medically contraindicated. The 
PET/CT scan must be submitted for central evaluation (see Section 6.3). 
 
All imaging with IV contrast must be performed prior to initiating treatment with metformin. 
11.2.2 Evaluations During Treatment 
 
History and physical examination must include recording of pulse, BP, weight and body 
surface area.  
 
BSA should be recalculated if there is a change of more than 10% of body weight, compared 
to the registration weight. 
 
Patients should have a CBC with differential, serum creatinine, and for Arm 2 patients, blood 
glucose weekly during concurrent chemotherapy and radiation. 
 
Patients should have a CBC with differential bilirubin, AST/ALT, alkaline phosphatase, and 
for Arm 2 patients, blood glucose within 48 hours prior to every cycle of consolidation 
chemotherapy. Note: If hypoglycemia was detected in an Arm 2 patient during concurrent 
chemotherapy, then the patient should have weekly monitoring during consolidation 
treatment. 
11.2.3 Evaluations in Follow Up (8/10/16) 
 
History and physical examination must include recording of pulse, BP, weight and body 
surface area. 
 
All patients must have a follow-up CT scan of the chest and upper abdomen with contrast or 
MRI at 3 months from end of radiotherapy and the CT or MRI must be submitted for central 
evaluation (see Section 6.3).  
 
All patients must have a follow-up CT scan of the chest and upper abdomen or MRI at 6, 9, 
and 12 months from the end of radiotherapy or until progression, whichever comes first. 
 
Follow-up CT scans of the chest and upper abdomen with contrast or MRIs are 
recommended every 3 months for year 2, every 6 months for years 3-5, then annually, until 
patients show evidence of progression. Central submission of these chest CTs/MRIs is not 
required unless progression occurs at any of these time points.  If progression occurs the 
imaging for the time point at which progression occurred and the imaging for the time point 
immediately preceding the progression must be submitted centrally. 
 
Other imaging sites (e.g. extremities, head) should be imaged per institutional routine if 
there is a suspicion of new metastatic disease.  If new metastatic disease at any such 
anatomic site is confirmed and contributes to the declaration of progressive disease, this 
imaging must be submitted centrally. 
 
Current ACR guidelines do not require cessation of metformin following iodinated contrast 
administration in patients with normal renal function and no comorbidities that would 
increase the risk of iodinated contrast induced nephropathy (ACR Manual on contrast 
media, v.9, 2013). Nevertheless, local institutional policy can be used regarding temporary 
cessation of metformin following administration of iodinated contrast for CT scan or MRI.   
 
11.3 
Measurement of Response  
Response will be evaluated in this study using the revised RECIST guideline. Version 1.1 will be 
sued as a guideline to determine study eligibility. 
(https://www.eortc.be/Recist/documents/RECISTGuidelines.pdf). 
 
 
Complete Response (CR): Disappearance of all target lesions; 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) 
of target lesions, taking as reference the baseline sum LD; 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to quality for Progressive Disease (PD), taking as reference the smallest sum LD since the 
treatment started. 
 

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NRG-LU001; version date: November 1, 2018 
 
 
11.4 
Measurement/Definition of Progression/Recurrence 
Progression is defined as change in a known lesion(s) not related to post-treatment effects as 
defined below: 
 
At least a 20% increase in the sum of the LD of target lesions, taking as reference 
the smallest sum LD recorded since the treatment started or the appearance of one 
or more new lesions.  Additionally the absolute increase must be greater than 5 mm. 
 
Appearance of ≥1 new lesions not related to post-treatment effect.  
 
Progression is further divided into local, regional or distant progression: 
 
Local: Progression within the PTV. 
 
Regional: Progression outside the PTV but within the same lobe of the lung as the 
primary tumor or in regional lymph nodes (AJCC 7th edition) 
 
Distant: Progression at any other site (including pleural or pericardial effusion) 
 
11.5 
Criteria for Discontinuation of Metformin Treatment (5/7/15) 
 
Unacceptable toxicity; see Section 6.0 and Section 7.0 for further information. 
 
Progression of disease; 
 
Development of a 2nd primary upper aerodigestive tract malignancy (lung, esophagus, head 
and neck); 
 
A delay in protocol treatment, as specified in Sections 6.0 and/or 7.0. 
 
If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. 
 
12.0 
DATA COLLECTION (8/10/16) 
This study will utilize Medidata Rave® for remote data capture (RDC) of all data. Access to the trial 
in Rave is granted through the iMedidata application to all persons with the appropriate roles in 
RSS.  To access iMedidata/Rave see Section 5.0 of the protocol. 
 
Each person responsible for data entry must be on the NRG Oncology roster in order to receive 
access to Medidata Rave®.  
 
Upon initial site registration approval for the study in RSS (Regulatory Support System), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata (iMedidata-Notification@mdsol.com) to activate their account.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper right-
corner of the iMedidata page.  Once an account is activated, eLearning modules will be available 
for Rave RDC instructions. Please note, site users will not be able to access the study in Rave 
until all required Medidata and study specific trainings are completed.  Trainings will be listed in 
the upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave accounts will also receive a 
separate invitation from iMedidata to activate their account.  Account activation instructions are 
located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance).  Additional information on iMedidata/Rave is 
available on the CTSU website under the Rave tab at www.ctsu.org or by or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
12.1 
Summary of Data Submission (8/10/16) 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during the trial using Medidata Rave. Additionally, certain adverse events must be reported 
in an expedited manner for more timely monitoring of patient safety and care. The following 

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NRG-LU001; version date: November 1, 2018 
 
 
sections provide information about expedited reporting.  For this trial the {form name} is used for 
routine AE reporting in Rave.   
 
For reporting of secondary cancers or other report forms available in Rave:  
Indicate form for reporting in Rave, timeframes, and if loading of the pathology report is required. 
 
Folder 
Form/Item 
Registration via the OPEN System 
 Subject Enrollment 
Enrollment Forms 
When pushed into RAVE there will be 
4 forms representing registration 
 
 
Eligibility Checklist 
 
Step Information 
 
Treatment Assignment  
 
Demography 
 
Baseline 
 
Diagnostic Staging 
 
Work Up 
 
SOC Imaging 
 
Lymph Node Assessment 
 
Patient History (formerly known as the A5) 
 
Pathology Report 
RT Plan Upload 
 Digital Data-(Upload of e-mail confirmation 
from TRIAD submission required) 
Concomitant Medications 
 
Concomitant Medication (only required if 
patient is taking concomitant medications) 
Dose Escalation (Week 1) 
(Only if randomized to Arm 2) 
 Metformin 
 Any Adverse Events? 
 Adverse Events (if any adverse events? = 
‘yes’ 
 On Treatment Labs MET 
Dose Escalation (Week 2) 
(Only if randomized to Arm 2) 
 Metformin 
 Any Adverse Events? 
 Adverse Events (if any adverse events? = 
‘yes’ 
 On Treatment Labs MET 
Concurrent Treatment 
 
 
RT Administration 
 
RT Treatment-if was radiation therapy 
given = ‘yes’ 
 
Protocol Specific RT Questions If was 
radiation therapy given = ‘yes’ 
 
Any Adverse Events? 
 
Adverse Events – if any adverse events? = 
‘yes’ 
 
Carboplatin (concurrent) 
 
Paclitaxel (concurrent) 
 
Metformin (if randomized to Arm 2) 
 
On Treatment Labs 01 (up to 11 additional 
weeks may be added by user if needed) 

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NRG-LU001; version date: November 1, 2018 
 
 
End of All RT 
 
End of All RT (this form should be completed 
for all patients after their final day of any 
protocol RT) 
Consolidation Treatment 
 
Any Adverse Events? 
 
Adverse Events – if any adverse events? = 
‘yes’ 
 
Carboplatin (consolidation) 
 
Paclitaxel (consolidation) 
 
Metformin (if randomized to Arm 2) 
 
On Treatment Labs 01 (up to 11 additional 
weeks may be added by user if needed) 
Years 1-2 
4-6 Week Follow-Up 
3 Month Follow-Up 
6 Month Follow-Up 
9 Month Follow-Up 
1 Year Follow-Up 
15 Month Follow-Up 
18 Month Follow-Up 
21 Month Follow-Up 
2 Year Follow-Up 
 
Years 3-5 
30 Month Follow-Up 
3 Year Follow-Up 
42 Month Follow-Up 
4 Year Follow-Up 
54 Month Follow-Up 
5 Year Follow-Up 
 
Years 6-10+ 
6 Year Follow-Up 
7 Year Follow-Up 
8 Year Follow-Up 
9 Year Follow-Up 
10 Year Follow-Up 
 
Any Adverse Events? 
 
Adverse Events – if any adverse events? = 
‘yes’ 
 
Patient Contacted 
 
Follow-up - if Patient able to be Contacted 
= ’yes’ 
 
Disease Assessment- if Documented 
clinical assessment = ‘yes’ 
 
New Primary Cancer- If New Primary 
Cancer= ‘yes’ 
 
Non-Protocol Treatment- if non-protocol 
cancer therapy= ‘yes’ 
 
Pulmonary Function Tests – if PFTs 
performed = ‘yes’ 
 
Primary Cause of Death – If Vital Status = 
‘dead’ 
 
CTEP-AERS 
 
CTEP-AERS Upload Form – used by HQ to 
upload CTEP-AERS reports, sites have read 
only access to this folder/form 
Source Documentation Upload 
 
Source Documentation Upload – used by 
sites in the event that source documentation 
needs to be uploaded to HQ 
IROC Imaging Progression and IROC 
Imaging – Prior to Progression 
 
 
SOC Imaging (these will only be used if the 
patient progresses after 12 months off 
treatment) 
 
 
12.2 
Summary of Dosimetry Digital Data Submission (8/10/16) 
(Submit to TRIAD; see Section 5.0 for account access and installation instructions.) 
(Note:  Choose RT Plan Upload for the TimePoint ID in TRIAD for items below in Sec. 12.2) 
Item 
Due 
Preliminary Dosimetry Information  
 
Digital Data Submission – Treatment  
Within 1 week of start of RT  
Digital data submission includes the following, all in DICOM format: 
 

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NRG-LU001; version date: November 1, 2018 
 
 
 
Planning CT and PET 
 
 
RT Structure File: must include all required target volumes and 
critical  structures, labeled exactly as defined per Sec. 6.4.1 
(Target Volumes) and 6.5 (Critical Structures) 
 
 
RT Plan File:   Digital beam geometry beam sets   
 
 
RT Dose File:  Doses for  concurrently treated beams   
 
 
The “LU-0001 Datasheet” is available in the Forms section of the 
of the NRG Oncology/RTOG web site, 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx
?study=1327&mode=html&ptid=383. Submit via TRIAD with the 
digital data listed above. 
 
 
Upon submission of digital RT data via TRIAD, complete an 
online Digital Data Submission Form (DDSI Form), found on the 
NRG Oncology/RTOG web site under the ‘Core Lab’ section        
http://www.rtog.org/CoreLab/TRIAD.aspx 
 
 
12.3 
Summary of Required Diagnostic Imaging Digital Data Submission (8/10/16) 
(Submit to TRIAD; see Section 5.0 for account access and installation instructions.) 
(Note:  Choose appropriate Imaging TimePoint ID in TRIAD for items below in Sec. 12.3) 
 
Item 
Timepont 
Digital data submission includes the following, all in DICOM format: 
 
 
Pre-treatment Whole body PET/CT 
Baseline 
 
Pre-treatment Chest CT/MRI 
Baseline 
 
Follow-up Chest CT/MRI  
At 3 months post-
radiotherapy 
 
Follow-up Chest CT/MRI  
At progression (first scan 
demonstrating evidence of 
progression) 
 
Follow-up Chest CT/MRI  
Immediately prior to 
progression 
 
Other post therapy imaging (e.g. brain CT/MR, CT A/P, extremity 
imaging), if used to document distant progression. 
At progression 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Primary Endpoint 
Progression-free survival (PFS), defined as the interval from randomization to progression or death 
due to any cause, whichever occurs first. 
 
13.2 
Secondary Endpoints 
 Overall survival (OS), defined as the interval from randomization to death due to any cause  
 Time to local-regional progression (LRP), defined as the interval from randomization to 
local or regional progression; 
 Time to distant metastasis (DM), defined as the interval from randomization to distant 
metastasis; 
 Adverse events definitely, probably, or possibly related to treatment (CTCAE, v. 4) within 1 
year of completion of all treatment. 
 
13.3 
Stratification 
Patients will be stratified by Zubrod Performance Score (0 vs. 1); histology (squamous vs. non-
squamous); and clinical stage (IIIA vs. IIIB). 
 

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13.4 
Sample Size and Power Justification 
In LA-NSCLC, the expected 1-year progression-free survival (PFS) with the concurrent 
chemoradiotherapy is assumed to be 50% based on RTOG 0617 (Bradley 2011). The target 
improvement for the added MET is to increase the 1-year PFS to 65%.  Assuming the PFS are 
exponentially distributed (at least approximately) with constant hazards in the both treatment arms, 
the primary hypothesis is equivalent to reduce the monthly hazard λ from 0.0578 to 0.0359, i.e., a 
hazard ratio of 0.622 or 37.8% relative hazard reduction.  This study will be a randomized phase II 
screening trial as proposed by Rubinstein et al (2005).  The randomization of experimental and 
standard arms is set to be 1:1.  With 152 analyzable patients (76 analyzable patients per arm) and 
102 PFS events, there will be 85% power to detect a 37.8% relative reduction in hazard at a 
significance level of 0.1 (one-sided).  Adjusting for a 10% rate of ineligibility, a maximum of 168 
patients is required for this trial. 
 
For the most recently completed RTOG trial in the same patient population, the randomized phase 
III study RTOG 0617, the average monthly accrual rate was more than 10 cases/month. Therefore, 
a monthly accrual rate of 7 patients is assumed in this study, and the total accrual is expected to 
be completed in 2 years.  The study is expected to reach the required number of PFS events 1 
year after accrual completion.  During the first 6 months following activation, little accrual is 
anticipated while the trial is being approved by institutional review boards (IRBs).  A total of 3.5 
years is projected to observe the required number of PFS events and conduct the final analysis (if 
applicable).  
 
 
13.5 
Statistical Analysis Plan 
13.5.1 Statistical Methods 
PFS is defined as the time from randomization to disease progression or death from any cause, 
whichever occurs first.  A rigorous definition of disease progression is provided in Section 11.4 (a 
second primary cancer is not treated as a PFS event). PFS rates will be estimated using the Kaplan-
Meier method (1958), and the differences between arms will be tested using a log-rank test (Mantel 
1966).  A multivariate analysis with the Cox proportional hazard model (1972) for PFS will be 
performed with the stratification variables as fixed variables to assess the treatment effect adjusting 
for patient-specific risk factors.   
 
Overall survival (OS) is similarly analyzed as time-to-event data, where the OS rates will be 
estimated using the Kaplan-Meier method, and the differences between treatment arms will be 
tested using the log-rank test. A competing risks analysis approach also will be used when 
analyzing time to local-regional progression (TTLRP) and time to distant metastasis (TTDM).  For 
TTLRP, only local-regional progression will be counted as events (failures), and patients who die 
or have a distant metastasis without a local-regional progression will be treated as competing risk. 
Analogously, for TTDM, only distant metastasis will be counted as events, and deaths or local-
regional progression without distant metastasis will be treated as competing risks. A cumulative 
incidence approach will be used to estimate the respective rates, and the corresponding differences 
in LRP and DM will be evaluated using Gray’s test (Gray 1988). 
  
Due to the concerns of potential subjective bias introduced in investigator-determined progression 
(Dodd 2008), all PET/CT scans will be collected and archived for a planned retrospective central 
radiologic review.  These PET/CT scans will be blindly reviewed by the Radiologic Co-Chair.  The 
centrally-reviewed progression results will be properly incorporated in the sensitivity analyses (FDA 
2007) to assure the robustness of analysis results.   
 
The rate of treatment-related adverse events using NCI Common Terminology Criteria for Adverse 
Events (CTCAE, v. 4) will be reported with the frequency and severity (e.g., type, grade, and 
attribution) by arm, and analyzed using Chi-square test or Fisher’s exact test wherever applicable. 
The analysis will be performed at the time of primary endpoint analysis. Logistic regression (Agresti 
1990) will be used to model the distribution of adverse events with and without adjustment for 
covariates. Both unadjusted and adjusted odds ratios and the respective 95% confidence intervals 
will be computed and tested at a significance level of 0.05 (2-sided).  

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NRG-LU001; version date: November 1, 2018 
 
 
13.5.2 Significance Testing for Early Termination and Reporting 
A group sequential test with one planned interim analysis and a final analysis will be performed.  
The interim analysis will be based on the primary endpoint as defined in Section 13.1.1, and will 
be carried out when half of the number of expected PFS events (51 events) is reached.  At the 
planned interim analysis, the p-value from the log-rank test will be compared to 0.01 for rejecting 
the null hypothesis, and the observed hazard ratio (experimental/standard) will be compared with 
1.0 (Wieand 1994) for futility. If the p-value associated with the resulting test statistics is less than 
or equal to 0.01, then we will stop accrual to the trial (if applicable) and conclude MET improves 
PFS of these patients; if the observed hazard ratio is greater than or equal to 1.0, a decision 
about whether to terminate accrual and release the results will be made after consultation with 
the NRG Oncology Data Monitoring Committee (DMC) and NCI/CTEP.  If the efficacy boundary is 
not crossed and the observed hazard ratio is less than 1.0, the final analysis will occur when 
there are at least 102 PFS events observed.  A significance level of 0.09 for the final analysis was 
derived in order to preserve a 0.1 significance level (1-sided) for the entire study. 
 
At the protocol-planned interim analysis, the results from the test assessing the treatment efficacy 
and futility will be reported to the NRG Oncology Data Monitoring Committee (DMC). The protocol 
statistician may recommend early reporting of the results and/or stopping accrual (if applicable) of 
the trial if either efficacy or futility boundary is crossed. The accrual rate, treatment compliance, 
safety of the treatments, and the importance of the study also are considered in making such a 
recommendation. The results will be reported to the NRG Oncology DMC. The DMC will then make 
a recommendation about the trial to the NRG Oncology Group Chairs. 
13.5.3 Significance Testing for Final Analysis 
The final analysis will be performed on an intent-to-treat basis, such that all eligible cases will be 
included in the arm to which the patient was randomized regardless of what treatment the patient 
actually received. The major analysis will occur after at least 102 PFS events have been observed, 
unless an early stopping rule is satisfied.  It will include: 
 
Tabulation of all cases entered and those excluded from the analyses with the reasons for 
exclusion given; 
 
Distributions of important prognostic baseline variables; 
 
The frequencies and severity of AEs by treatment arms; 
 
Compliance rate of treatment delivery; 
 
Observed results with respect to the primary and secondary endpoints. 
 
All eligible patients randomized will be included in the comparison and will be grouped by assigned 
treatment in the analysis.  The primary hypothesis of treatment benefit will be tested using the 
stratified log-rank statistic with a significance level of 0.1 (1-sided), given that the interim analysis 
will have been carried out.  Additional analyses of treatment effect will be performed using the Cox 
proportional hazards model with the stratification factors included as fixed covariates, as well as 
any factors that show an imbalance between the arms and any other factor known to be associated 
with outcome. 
13.5.4 Interim Analysis to Monitor Study Progress 
The NRG Oncology Data Monitoring Committee (DMC) will review the accrual to the study and the 
rate of adverse events on the study at least twice per year until the initial results of the study have 
been presented to the scientific community.  In general, the interim reports will contain information 
about the patient accrual rate, a projected completion date for the accrual phase, patient exclusion 
rates and reasons following registration, compliance rate of treatment delivery, distributions of 
pretreatment characteristics and important prognostic baseline variables, and the frequencies and 
severity of treatment-related adverse events. The interim reports will not contain the results from 
the treatment comparisons with respect to the efficacy endpoints. 
 
Interim reports with statistical analyses are prepared every 6 months until the initial publication 
reporting the treatment results has been submitted. The reports contain: 
 
Patient accrual rate with a projected completion date (while the study is still accruing) 
 
Total patients accrued 

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 
Distributions of important pretreatment and prognostic baseline variables 
 
The frequencies and severity of adverse events by treatment arm 
 
Compliance rates of treatment delivery 
13.5.5 CDUS Reporting 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative 
CDUS data will be submitted quarterly by electronic means. Reports are due January 31, April 30, 
July 31, and October 31. 
 
13.6 
Statistical Considerations for Translation Research 
The translational research objectives are considered in exploratory nature.  The predictive and 
prognostic potential for the proposed biomarkers may become scientifically obsolete or the assay 
technology may evolve over time, making the technology outlined in the current protocol obsolete 
when the study is finished. As such, no marker assays will be conducted on the collected 
specimens. When sufficient information is available from the parent study, a full correlative study 
protocol for the marker studies detailing the scientific hypothesis, research plan, clinical outcome, 
assay methods for each biomarker, and a more complete statistical section (with adequate power 
justification and analysis plan) will be submitted and subjected to CTEP review in accordance with 
National Clinical Trials Network (NCTN) policies. 
 
To determine if the study may offer exploratory yet still meaningful findings whether a mutation of 
interest may predict PFS changes in patients treated with metformin, we summarize the following 
table as a preliminary evaluation for the interaction effects between marker status (such as TP53, 
STK11 (LKB1) or KRAS) and treatment assignments.  Based on the design parameters and the 
method proposed by Peterson and George [Peterson 1993], we summarize the statistical power 
to detect interaction effects (ratio of hazard ratios) of 0.33, at 2-sided significance level of 0.05.  
We denote monthly hazard rates as λ, expected number of events of respective subgroups as 
E[N], and the hazard ratio between marker + and - as Δ.  The subscripts indicate the 
corresponding treatment arms. The assumed monthly hazard rates and associated expected 
number of events are listed in the following Table accordingly. 
 
 
Prevalence 
of Marker 
+/- 
 
Arm 1 
Arm 2 
Interaction 
 
 
Marker - 
Marker + 
Δ1 
Marker - 
Marker + 
Δ2 
Δ21= Δ2/ Δ1 
Power 
0.33 
λ 
0.0578 
0.0578 
1.0 
0.0487 
0.0161 
0.33 
0.33 
63.2% 
 
E[N] 
38 
19 
35 
8 
 
λ 
0.0505 
0.0758 
1.5 
0.0442 
0.0219 
0.5 
0.33 
70.4% 
 
E[N] 
35 
21 
33 
11 
 
λ 
0.0459 
0.0918 
2.0 
0.0408 
0.0269 
0.67 
0.33 
72.1% 
 
E[N] 
34 
22 
32 
12 
0.5 
λ 
0.0578 
0.0578 
1.0 
0.0586 
0.0193 
0.33 
0.33 
74.7% 
 
E[N] 
28 
28 
 
28 
14 
 
 
 
 
λ 
0.0471 
0.0707 
1.5 
0.0497 
0.0246 
0.5 
0.33 
77.2% 
 
E[N] 
26 
31 
 
26 
17 
 
 
 
 
λ 
0.0407 
0.0813 
2.0 
0.0438 
0.0289 
0.67 
0.33 
77.8% 

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E[N] 
24 
32 
 
25 
19 
 
 
 
Based on the table above, the proposed study will have a reasonably good power to detect a 
strong predictive (interaction) effect (HR=0.33).      
 
13.7 
Gender and Minorities 
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
4 
6 
10 
Not Hispanic or Latino 
66 
92 
158 
Ethnic Category: Total of all subjects 
70 
98 
168 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
1 
1 
Asian 
2 
2 
4 
Black or African American 
7 
10 
17 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
61 
84 
145 
Racial Category: Total of all subjects 
70 
98 
168 
 
  

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APPENDIX I STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (8/10/16) 
*See Section 11.2 for details and exceptions 
 
 
Assessments 
Prior to Registration 
 (calendar days) 
Prior to Treatment 
(calendar days) 
History/physical exam, including 
height, weight, BSA, and vital 
signs 
30 
 
Performance status 
X 
 
CT scan with contrast or MRI of 
lung and upper ab through 
adrenals (see. 3.1.4) 
45 
 
MRI or CT of brain with contrast 
45 
 
Whole-body FDG-PET/CT 
45 
 
CBC/differential; ANC, platelets; 
hemoglobin 
14 
 
Serum creatinine or creatinine 
clearance and eGFR 
14 
 
Total bilirubin, ALT, AST, Alk 
Phos, Blood glucose 
14 
 
Serum albumin 
14 
 
Serum pregnancy (if applicable) 
72 hrs. prior to registration 
 
Examination by Rad Onc & Med 
Onc 
 
42 
 
 
 
†Tissue submission for banking 
X 
†Whole blood and plasma 
submission for banking 
X 
†For patients who consent to participate in this component of the study 
 
 

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APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT (8/10/16) 
*See Section 11.2 for details and exceptions 
 
 
Assessments 
During Treatment 
Weekly during MET 
Dose Escalation  
(Arm 2 Only) 
Weekly during 
Concurrent Treatment 
Within 48 hours Prior to 
Each Cycle of 
Consolidation Treatment 
History & Physical 
exam 
 
X 
X 
BSA Recalculation 
 
If there is a change of more than 10% of body 
weight, compared to the registration weight 
CBC/differential and 
serum creatinine 
 
X 
X 
Bilirubin, AST/ALT, alk 
phos 
 
 
X 
Blood glucose for Arm 2 
patients 
X 
X 
X 
See Section 11.2 for 
details. 
Adverse events 
evaluation 
X 
X  
X 
†Plasma submission for 
banking 
 
At week 1 and 6 of 
chemo/RT 
(corresponding to 
weeks 3 and 8 of 
metformin treatment 
period for patients 
randomized to Arm 2) 
(see Section 10.2.5) 
 
†For patients who consent to participate in this component of the study 
 
 
 

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APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW UP (8/10/16) 
*See Section 11.2 for details and exceptions 
 
 
Assessments 
Follow Up 
 
At 4-6 weeks from 
end of RT 
At 3 months from 
end of RT 
At 6, 9, and 12 
mos. from end 
of RT or until 
progression, 
whichever is first 
q3 mos. x 2 years; 
q6 mos. x 3 years; 
then annually 
History & Physical 
exam 
X 
X 
 
X 
Performance status 
X 
X 
 
X 
 
 
 
 
 
Follow-up CT scan 
of chest and upper 
abdomen with 
contrast  or MRI 
 
X 
X 
See 
recommended 
timeframes in 
Section 11.2 
Imaging of other 
sites (e.g. 
extremities, head) 
These sites should be imaged per institutional routine if there is suspicion of 
new metastatic disease; see Section 11.2. 
Biopsy 
 
 
Recommended for any recurrence, 
whether based on CT scan or 
PET/CT 
Adverse event 
evaluation 
X 
X 
 
X 
†Plasma 
submission for 
banking 
 
 
At 6 month 
follow up visit 
(see Section 
10.2.5) 
 
   †For patients who consent to participate in this component of the study 
 
 
 

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APPENDIX II: ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without 
restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry work of a light or sedentary nature.  For example, light 
housework, 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 50% or 
more of waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to 
bed  
 
5 
Death  
 
 
 
 

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APPENDIX III: AJCC STAGING SYSTEM 
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 
 
LUNG 
Primary Tumor (T) 
TX 
Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in 
sputum or bronchial washings but not visualized by imaging or bronchoscopy 
T0 
No evidence of primary tumor.   
Tis 
Carcinoma in situ 
T1 
Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without 
bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the 
main bronchus)* 
T1a 
Tumor 2 cm or less in greatest dimension 
T1b 
Tumor more than 2 cm but 3 cm or less in greatest dimension 
T2 
 
Tumor more than 3 cm but 7 cm or less with any of the following features (T2 tumors with 
these features are classified T2a if 5 cm or less):  Involves main bronchus, 2 cm or more 
distal to the carina; Invades the visceral pleura PL1 or PL2);  Associated with atelectasis or 
obstructive pneumonitis that extends to the hilar region but does not involve the entire lung 
T2a 
Tumor more than 3 cm but 5 cm or less in greatest dimension 
T2b 
Tumor more than 5 but 7 cm or less in greatest dimension 
T3 
Tumor more than 7 cm or one that directly invades any of the following:  parietal (PL3), chest 
wall (including superior sulcus tumors),  diaphragm, phrenic nerve, mediastinal pleura, 
parietal pericardium; or tumor in the main bronchus (less than 2 cm distal to the carina* but 
without involvement of the carina; or associated atelectasis or obstructive pneumonitis of 
the entire lung or separate tumor nodule(s) in the same lobe 
T4 
Tumor of any size that invades any of the following: mediastinum, heart, great vessels, 
trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor 
nodules in a different ipsilateral lobe 
*The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial 
wall, which may extend proximally to the main bronchus, is also classified as T1a. 
 
 
Regional Lymph Nodes (N) 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph nodes metastasis 
N1 
Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and 
intrapulmonary nodes including involvement by direct extension 
N2 
Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) 
N3 
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral 
scalene, or supraclavicular lymph node(s) 
 
 
Distant Metastasis   (M) 
M0 
 
No distant metastasis 
M1 
 
Distant metastasis  
M1a 
Separate tumor nodule(s) in a contralateral lobe tumor with pleural nodules or malignant 
pleural (or pericardial) effusion* 
M1b 
Distant metastasis 
* Most pleural (and pericardial effusions with lung cancer are due to tumor. In a few patients, however, 
multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is 
nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is 
not related to the tumor, the effusion should be excluded as a staging element, and the patient should be 
classified as M0. 
 

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STAGE GROUPING  
Occult Carcinoma 
TX, N0, M0 
Stage 0 
Tis, N0, M0 
Stage IA 
T1a-b, N0, M0 
Stage IB 
T2a, N0, M0 
Stage IIA 
T2b, N0, M0 
 
T1a-b, N1, M0 
 
T2a, N1, M0 
Stage IIB 
 
T2b, N1, M0 
 
T3, N0, M0 
Stage IIIA 
T1a-b, N2, M0 
 
T2a-b, N2, M0 
 
T3, N1-2, M0 
 
T4, N0-1, M0 
Stage IIIB 
T1a-b, N3, M0 
 
T2a-b, N3, M0 
 
T3, N3, M0 
 
T4, N2-3, M0 
Stage IV 
Any T, Any N, M1a-b 
 
 
 
 
 
  

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APPENDIX IV: BIOSPECIMEN COLLECTION (5/7/15) 
 
Shipping Instructions: 
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS, etc.): For ALL Frozen or Trackable Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341  
San Francisco, CA 94115 
 
 
Include all NRG Oncology paperwork in pocket of biohazard bag.  
 
Check that the Specimen Transmittal (ST) Form has the consent boxes checked off.  
 
Check that all samples are labeled with the NRG Oncology study and case number, and include 
date of collection as well as collection time point (e.g., pretreatment, post-treatment). 
 
 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top 
of the container. If you can hear the slides shaking it is likely that they will break during 
shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do 
not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you 
shake the container the blocks are not shaking. If you can hear the block shaking it might break 
during shipping.   
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States 
Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address 
(94115). Do NOT ship on Dry Ice. 
 
 
Frozen Specimens:  
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate 
bag and clearly identified. If possible keep Serum, Plasma, and Whole Bloods in separate 
bags. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at 
least 7 lbs). There should be plenty of dry ice under and above the specimens. If the volume of 
specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two 
separate boxes. Any Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and 
the site will be notified.  
o Send frozen specimens on dry ice via overnight courier to the address above. Specimens 
should only be shipped Monday through Wednesday (Monday-Tuesday for Canada) to prevent 
thawing due to delivery delays. Saturday or holiday deliveries cannot be accepted. Samples 
can be stored frozen at -80 C until ready to ship. 
 
 
For Questions regarding collection/shipping please contact the NRG Oncology 
Biospecimen Bank – San Francisco by e-mail: NRGBB@ucsf.edu or phone: 415-476-7864 
or Fax: 415-476-5271. 

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APPENDIX IV: BIOSPECIMEN COLLECTION)  
NRG Oncology FFPE SPECIMEN PLUG KIT INSTRUCTIONS 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen 
Bank – San Francisco. The plug kit contains a shipping tube and a punch tool.    
 
Step 1 
If the block is stored cold, allow it to equilibrate for 30 minutes at 
room temperature. Place the punch tool on the paraffin block over 
the selected tumor area. (Ask a pathologist to select area with 
tumor.) Push the punch into the paraffin block. Twist the punch tool 
once around to separate the plug from the block. Then pull the 
punch tool out of the block. The punch should be filled with tissue 
sample. 
 
 
 
Step 2 
Label the punch tool with the proper specimen ID and block ID.  
DON’T remove specimen from the punch. 
 
 
Use a separate punch tool for every specimen. Call or e-mail us if 
you have any questions or need additional specimen plug kits. 
 
 
 
 
 
Step 3 
Once punch tool is labeled, place in shipping tube and mail to 
address below. Please do not mix specimens in the same tube.    
 
 
 
   
 
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. 
 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please 
send the entire block to the NRG Oncology Biospecimen Bank – San Francisco and we will sample a plug 
from the block and return the remaining block to your facility.  Please indicate on the submission form the 
request to perform the plug procedure and return of the block. 
Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below. For 
Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact 
the NRG Oncology Biospecimen Bank by e-mail: NRGBB@ucsf.edu or call 415-476-
RTOG(7864)/Fax 415-476-5271. 
 
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
 

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APPENDIX IV: BIOSPECIMEN COLLECTION  
 
Courier Address (FedEx, UPS, etc.): For ALL Frozen Specimens or Trackable 
shipments 
NRG Oncology Biospecimen Bank  
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
 

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APPENDIX IV: BIOSPECIMEN COLLECTION  
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS 
 
This Kit is for collection, processing, storage, and shipping of Plasma, or whole blood (as 
specified by the protocol): 
 
Kit contents: 
 
Two Purple Top EDTA tube for plasma (A) 
 
One Purple Top EDTA tube for Whole Blood (B) 
 
Thirty-five (15) 1 ml cryovials for pre-tx; 45 1 ml cryovials for other plasma time point 
 
Biohazard bags (2) and Absorbent shipping material (2) 
 
Styrofoam container (inner) and Cardboard shipping (outer) box 
 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
 
Specimen Transmittal (ST) Form and Kit Instructions 
 
PREPARATION AND PROCESSING OF PLASMA AND WHOLE BLOOD: 
 
 

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APPENDIX IV: BIOSPECIMEN COLLECTION  
 
 
(A) Plasma (If requested): Purple Top EDTA tube #1 
 
Label as many 1ml cryovials (5 to 8) as necessary for the plasma collected. Label them with 
the NRG Oncology study and case number, collection date, time, and time point, and clearly 
mark cryovials “plasma”. 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 
RPM for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then 
spinning at room temperature is acceptable if done within 2 hours of draw but must be noted 
on the ST Form.  
3. If the interval between specimen collection and processing is anticipated to be more than one 
hour, keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are necessary for the 
plasma collected (5 to 8)  labeled with the NRG Oncology study and case numbers, collection 
date/time, time point collected and clearly mark specimen as “plasma”.  Avoid pipetting up the 
buffy coat layer. 
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C. 
6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
the ST Form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(B) Whole Blood for DNA (if requested): Purple Top EDTA tube #2 
 
Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with 
the NRG Oncology study and case number, collection date/time, and time point, and clearly mark 
cryovials “blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can 
also be mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the 
blood collected (3 to 5) labeled with the NRG Oncology study and case numbers, collection 
date/time, time point collected and clearly mark specimen as “blood”. 
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 

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NRG-LU001; version date: November 1, 2018 
 
 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
ST Form. 
 

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APPENDIX IV: BIOSPECIMEN COLLECTION  
 
Freezing and Storage: 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for 
up to one week (please ship out Monday-Wednesday only; Canada: Monday-
Tuesday only). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(please ship out on Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only; Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to 
prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the 
Styrofoam box. 
 
Wrap frozen specimens of same type (i.e., all plasma together and whole bloods together) in 
absorbent shipping material and place each specimen type in a separate biohazard bag.  Place 
specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  
Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag 
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from 
breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-
mail NRGBB@ucsf.edu or call (415)476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For ALL Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: NRGBB@ucsf.edu