nrg oncology nrg-lu001 clinicaltrials.gov nct02186847
randomized phase ii trial of

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  
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  
| Henry Ford Health System 2799 W. Grand Blvd. Detroit, MI 48202 313-916-0234/FAX 313-916-3264 ADOEMER1@hfhs.org   |
|------------------------------------------------------------------------------------------------------------------|
nrg oncology nrg-lu001 randomized phase
randomized phase ii trial of

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:                                                                                               | Jennifer Presley                                                                                                                                                                                                                                                               |
| For questions concerning RT data submission                                                         | 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                                                                                                                                         |  
| 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 NRG Oncology 1-800-227-5463, ext. 4189  
| 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    |  
| 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.   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Table of Contents                                                                                                                                      |                                                                                                                                                                |
|--------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| SCHEMA                                                                                                                                                 |                                                                                                                                                                |
| 1.0                                                                                                                                                    | INTRODUCTION                                                                                                                                                   |
| Background and Rationale .                                                                                                                             |                                                                                                                                                                |
| 1.1                                                                                                                                                    | NSCLC Resistance to Cytotoxic Therapy: The Need for Rational Development of Sensitizing                                                                        |
| 1.2                                                                                                                                                    | T Therapies                                                                                                                                                    |
| 1.3                                                                                                                                                    | Pre-Clinical Evidence                                                                                                                                          |
| 1.4                                                                                                                                                    | Rationale for This Study: Selected Approach and Trial Design ...............................................................16                                 |
| 1.5                                                                                                                                                    | T The state of the content of the content to the conte                                                                                                         |
| 2.0                                                                                                                                                    | OBJECTIVES                                                                                                                                                     |
| 2.1                                                                                                                                                    | Primary Objective                                                                                                                                              |
| 2.2                                                                                                                                                    | Secondary Objectives .                                                                                                                                         |
| 3.0                                                                                                                                                    | PATIENT SELECTION                                                                                                                                              |
| 3.1                                                                                                                                                    | Conditions for Patient Eligibility                                                                                                                             |
| 3.2                                                                                                                                                    | Conditions for Patient Ineligibility .                                                                                                                         |
| 4.0                                                                                                                                                    | PRETREATMENT EVALUATIONS/MANAGEMENT  .                                                                                                                         |
| 4.1                                                                                                                                                    | Required Evaluations/Management                                                                                                                                |
| 5.0                                                                                                                                                    | REGISTRATION PROCEDURES                                                                                                                                        |
| Radiation-Specific Pre-Registration Reguirements .                                                                                                     |                                                                                                                                                                |
| 5.1                                                                                                                                                    |                                                                                                                                                                |
| 5.2                                                                                                                                                    | D Digital RT Data Submission to NRG Oncology Using TRIAD .                                                                                                     |
| REGULATORY PRE-REGISTRATION REGUIREMENTS .                                                                                                             |                                                                                                                                                                |
| 5.3                                                                                                                                                    |                                                                                                                                                                |
| 5.4                                                                                                                                                    | Registration                                                                                                                                                   |
| 6.0                                                                                                                                                    | RADIATION THERAPY                                                                                                                                              |
| 6.1                                                                                                                                                    | T Treatment Technology .                                                                                                                                       |
| 6.2                                                                                                                                                    | Immobilization and Simulation                                                                                                                                  |
| 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                                                                                                                  |
| 6.6                                                                                                                                                    | D Dose Prescription                                                                                                                                            |
| 6.7                                                                                                                                                    | Compliance Criteria                                                                                                                                            |
| 6.8                                                                                                                                                    | T Treatment Planning Priorities and Instructions                                                                                                               |
| 6.9                                                                                                                                                    | D DOSE CALCULATIONS                                                                                                                                            |
| 6.10                                                                                                                                                   | Patient-specific Quality Assurance                                                                                                                             |
| 6.11                                                                                                                                                   | T Treatment Delivery                                                                                                                                           |
| 6.12                                                                                                                                                   | R.T. Quality Assurance Reviews                                                                                                                                 |
| 6.13                                                                                                                                                   | Radiation Therapy Adverse Events .                                                                                                                             |
| 7.0                                                                                                                                                    | DRUG THERAPY                                                                                                                                                   |
| 7.1                                                                                                                                                    | T Treatment                                                                                                                                                    |
| 7.2                                                                                                                                                    | Study Agents .                                                                                                                                                 |
| 7.3                                                                                                                                                    | Dose Modifications                                                                                                                                             |
| 7.4                                                                                                                                                    | Modality Review                                                                                                                                                |
| 7.5                                                                                                                                                    | Adverse Events .                                                                                                                                               |
| 7.6                                                                                                                                                    | CTEP-AERS Expedited Reporting Requirements .                                                                                                                   |
| 8.0                                                                                                                                                    | SURGERY                                                                                                                                                        |
| 9.0                                                                                                                                                    | OTHER THERAPY.                                                                                                                                                 |
| 9.1                                                                                                                                                    | Permitted Supportive Therapy ..................................................................................................................40              |
| 9.2                                                                                                                                                    | Non-permitted Supportive Therapy ...........................................................................................................40                 |
| 10.0                                                                                                                                                   | TISSUE/SPECIMEN SUBMISSION .                                                                                                                                   |
| Tissue/Specimen Submission  ........................................................................................................................41 |                                                                                                                                                                |
| 10.1                                                                                                                                                   | Specimen Collection for Tissue Banking and Translational Research ............................................41                                               |
| 10.2                                                                                                                                                   |                                                                                                                                                                |
| 10.3                                                                                                                                                   | Reimbursement                                                                                                                                                  |
| 10.4                                                                                                                                                   | Confidentiality/Storage ....................................................................................................................................43 |
| 1.0                                                                                                                                                    | PATIENT ASSESSMENTS                                                                                                                                            |
| 11.1                                                                                                                                                   | Study Parameters .........................................................................................................................................43   |
| 2                                                                                                                                                      | NRG-LU001; version date: November 1, 2018                                                                                                                      |  
| 11.2                                                                                                                            | D DETAILS OF EVALUATIONS                                                                                                                                         |
|---------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.3                                                                                                                             | Measurement of Response                                                                                                                                          |
| 1.4                                                                                                                             | Measurement/Definition of Progression/Recurrence ........................................................................45                                      |
| 1.5                                                                                                                             | Criteria for Discontinuation of Metformin Treatment  .........................................................................45                                 |
| 12.0                                                                                                                            | DATA COLLECTION                                                                                                                                                  |
| 12.1                                                                                                                            | Summary of Data Submission                                                                                                                                       |
| Summary of Dosimetry Digital Data Submission ................................................................................47 |                                                                                                                                                                  |
| 12.2                                                                                                                            |                                                                                                                                                                  |
| 12.3                                                                                                                            | Summary of Required Diagnostic Imaging Digital Data Submission ..............................................48                                                  |
| 13.0                                                                                                                            | STATISTICAL CONSIDERATIONS                                                                                                                                       |
| 13.1                                                                                                                            | Primary Endpoint                                                                                                                                                 |
| 13.2                                                                                                                            | Secondary Endpoints ..........................................................................................................................................48 |
| 13.3                                                                                                                            | Stratification                                                                                                                                                   |
| 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                                                                                                                                            |
| REFERENCES                                                                                                                      |                                                                                                                                                                  |
| 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                                                                     |                                                                                                                                                                  |
| APPENDIX II: ZUBROD PERFORMANCE SCALE                                                                                           |                                                                                                                                                                  |
| APPENDIX III: AJCC STAGING SYSTEM                                                                                               |                                                                                                                                                                  |
| APPENDIX IV: BIOSPECIMEN COLLECTION  .                                                                                          |                                                                                                                                                                  |
nrg oncology nrg-lu001
randomized phase ii trial of

Randomized Phase II Trial of Concurrent Chemoradiotherapy +/- Metformin HCL in Locally Advanced NSCLC
nrg oncology nrg-lu001
schema

T Histology O Arm 2:  
F 2. Non-Squamous I  
A D
I 1. Squamous M **MET Dose Escalation**: 1000 mg to 2000 mg daily for 2 weeks 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 2. IIIB weeks.  
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 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
eligibility checklist (8/4/14) (page 1
schema

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.  
9. Race  
(Y) 2. Has the Eligibility Checklist been completed?  
| (Y)   | 3.                                     | In the opinion of the investigator, is the patient eligible?   |
|-------|----------------------------------------|----------------------------------------------------------------|
| 5.    | Patient's Initials (Last First Middle) |                                                                |  
4. Date informed consent signed  
6. Verifying Physician  
7. Patient ID  
8. Date of Birth  
10. Ethnicity  
11. Gender 12. Country of Residence  
13. Zip Code (U.S. Residents)  
14. Method of Payment 16. Calendar Base Date  
| 15.       | Any care at a VA or Military Hospital?                                                                                                                  |
|-----------|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| (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. |  
17. Randomization date  
18. Medical Oncologist's name
eligibility checklist (8/4/14)
schema

(page 2 of 4)
NRG Oncology Institution \# NRG-LU001 Case \#  
38. Labs assessment date  
39. Serum creatinine 40. Serum creatinine ULN  
41. Creatinine Clearance  
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)                                                                |
|-----------|-----------------------------------------------------------------------------------------------------------------------------------|
| (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                                                                                                      |  
(IIIA/IIIB) 25. Clinical Stage  
26. Histologic Confirmation Date 27. Lung Tumor Histology  
(Y/N) 28. Does the patient have measurable disease?  
35. ANC (cells/mm3)  
36. Platelets (cells/mm3)  
37. Hemoglobin (g/dL)  
(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?                                                             |
eligibility checklist (8/4/14) (page 4
schema

NRG Oncology Institution \# NRG-LU001 Case \#
(Y/N) 63. Prior allergic reaction to paclitaxel or other taxanes or carboplatin? 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  
| (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) 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)?                                                                                                    |  
(Y/N) 69. Transmural MI in last 6 months?
eligibility checklist (8/4/14) (page 4
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 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.
eligibility checklist (8/4/14) (page 4
1.2 nsclc resistance to cytotoxic

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 radiosensitization 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 noncancer 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
(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.
eligibility checklist (8/4/14) (page 4
figure 1b metformin (met) does

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.  
  
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 antiangiogenic 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  
  
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.  
  
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 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.  
  
  
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 ).
eligibility checklist (8/4/14) (page 4
fi g ur e 4

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.  
  
  
O n M e tfro m in N o t o n M e tfo rm in M e tfo r min o n M e tfo r min  
P = 0 .0 2 4 M o n th s a fte r st a rt o f R T  
0 2 0 4 0 6 0 8 0 M o n th s a fte r s ta rt o f R T  
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 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 M o n th s a fte r s ta rt o f R T  
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).  
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 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 phosphoproteomic 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; 18 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*).
eligibility checklist (8/4/14) (page 4
3.0 patient selection (8/10/16) note

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; 19 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.
eligibility checklist (8/4/14) (page 4
4.0 pretreatment evaluations/management (8/10/16) note

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 m2is not recommended.
eligibility checklist (8/4/14) (page 4
5.0 registration procedures (1-nov-2018) access

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)
(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 >.
eligibility checklist (8/4/14) (page 4
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
eligibility checklist (8/4/14) (page 4
credentialing

Requirements Web Link for Procedures and Instructions: http://irochouston.mdanderson.org  
| Treatment Modality Photons   | Key Information                                             |                                                              |
|------------------------------|-------------------------------------------------------------|--------------------------------------------------------------|
| X                            | Complete or update your online electronic Facility          |                                                              |
| Facility                     | Questionnaire. To access this FQ, email                     |                                                              |
| Questionnaire                | irochouston@mdanderson.org to receive your FQ link.         |                                                              |
| Credentialing                | To determine whether your institution needs to complete any |                                                              |
| Status Inquiry               | X                                                           | further credentialing requirements, complete this form under |
| Form                         | Credentialing on the IROC Houston web site (address above). |                                                              |
| X                            | See Section 5.0 above describing phantom irradiation        |                                                              |
| Phantom                      | requirements for specific motion management techniques.     |                                                              |
| Irradiation                  | Questions may be directed to IROC Houston.                  |                                                              |  
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.
eligibility checklist (8/4/14) (page 4
triad installations when a user

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).
eligibility checklist (8/4/14) (page 4
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 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.  
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 .
eligibility checklist (8/4/14) (page 4
for institutions that have an

All requirements indicated in your LOI Approval Notification must be fulfilled prior to enrolling patients to this study.
eligibility checklist (8/4/14) (page 4
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.
eligibility checklist (8/4/14) (page 4
6.0 radiation therapy (5/7/15) see

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.
eligibility checklist (8/4/14) (page 4
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 CTsimulation 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).  
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 posttreatment 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 superiorinferior 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.  
| Standard DICOM                                                               | Description                                                                                                                                                                       | Detailed Specification                                                                                                                                                                                                                                                                                                                                                                                                                              |
|------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Name GTV_6000                                                                | GTV to receive 60 Gy                                                                                                                                                              | 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 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) over the course of a  respiratory cycle.                                                                                                                                                                                                                                                          |
| Required when a 4DCT is used to  encapsulate entire  breathing cycle  volume |                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| CTV_6000                                                                     | CTV to receive 60 Gy                                                                                                                                                              | The CTV is defined to be the GTV plus a  0.5cm to 1cm margin as appropriate to  account for microscopic tumor extension.                                                                                                                                                                                                                                                                                                                            |
| Required when GTV  is drawn                                                  |                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| ITV_6000                                                                     | ITV to receive 60 Gy                                                                                                                                                              | The ITV will be equal to the iGTV plus a  0.5cm to 1cm clinical margin as appropriate to  account for microscopic tumor extension.                                                                                                                                                                                                                                                                                                                  |
| Required when iGTV  is drawn                                                 |                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| PTV_6000                                                                     | PTV to receive 60 Gy                                                                                                                                                              | 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). |
| Required                                                                     |                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| 6.5                                                                          | Definition of Critical Structures and Margins (5/7/15)                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |  
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   | Description                                                                           | Detailed Specification   |
|------------------|---------------------------------------------------------------------------------------|--------------------------|
| Name SpinalCord  | Boundaries: The bony limits of the spinal canal Cranial Top of C1 (or first CT slice) |                          |
| 27               | 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) | Boundaries: Use Lung OAR Atlas* Other notes: Both lungs merged into 1 structure  and excluding the overlap with GTV_6000 or iGTV                                            |                 |
| Required                                                                                                      |                                            |                                                                                                                                                                             |                 |
| 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                         | The ipsilateral brachial plexus should be contoured                                                                                                                         |                 |
| lobe tumors                                                                                                   | 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   | Dose (Gy)   | Fraction   | # of                     | Dose                          |
|-------------------|-------------|------------|--------------------------|-------------------------------|
| Name              | Size (Gy)   | fractions  | 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                                             | Dosimetric* parameter | Per Protocol | Variation                         |
| Structure                                           | 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.      |                       |              |                                   |  
**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        | Per Protocol | Variation |
| parameter                                                                                      | 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 |                   |              |           |  
| Delivery Compliance Criteria Per Protocol Variation  Acceptable                                                     |           |            |
|---------------------------------------------------------------------------------------------------------------------|-----------|------------|
| Overall Treatment time                                                                                              | < 45 days | 46-51 days |
| Interruptions (other than                                                                                           | 0-2 days  | 3-7 days   |
| holidays or weekends) Note: Cases will be scored as Deviation Unacceptable when the time limits given above are not |           |            |  
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.  
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 resimulate 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 1 st re-simulation, 2 for the 2 nd resimulation). 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.
eligibility checklist (8/4/14) (page 4
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 breathhold/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.  
6.10 **Patient-specific Quality Assurance (QA)**
Any patient-specific QA that needs to be acquired should follow institutional guidelines.
eligibility checklist (8/4/14) (page 4
6.11 treatment delivery (8/10/16) daily

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.
eligibility checklist (8/4/14) (page 4
7.0 drug therapy patients randomized

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 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/m2IV) 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. 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 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.  
  
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.
eligibility checklist (8/4/14) (page 4
7.3 dose modifications (5/7/15) 7.3.1

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  |                          |       |       |
| ≥ 1              | Hold* | Continue same dose level |       |       |
| ANC  x1000 ANC   |       | <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 |                          |    |    |    |
| ≥ 1.5            | Hold* | Continue same dose level |    |    |    |
| A                | N     | C  x1 00 0               | A  | N  | C  |  
<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        |                     |                                                              |
| Hold* and recheck                                                                                     | Hold* and evaluate                                           |                 |                     |                                                              |
| ≥ 1.5 ULN                                                                                             | weekly                                                       | as medically    |                     |                                                              |
| necessary, recheck  weekly.                                                                           | Hold* and evaluate as  medically necessary,  recheck weekly. |                 |                     |                                                              |
| Bilirubin                                                                                             | < 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 |                                                              |                 |                     |                                                              |  
*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.
eligibility checklist (8/4/14) (page 4
7.3.10 all other non-hematological treatment-related

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;  
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.
eligibility checklist (8/4/14) (page 4
7.6 ctep-aers expedited reporting requirements

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 24hour notification must be followed by an CTEP-AERS 5 Calendar Day Report. Serious 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**
eligibility checklist (8/4/14) (page 4
fda reporting requirements for serious

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.  
| via CTEP-AERS within the timeframes detailed in the table below. Grade 1  Grade 2  Grade 3   | Grade 4 & 5        |                  |            |            |
|----------------------------------------------------------------------------------------------|--------------------|------------------|------------|------------|
| Hospitalization                                                                              | Timeframes         | Timeframes       | Timeframes | Timeframes |
| Resulting in                                                                                 |                    |                  |            |            |
| Hospitalization                                                                              | 10 Calendar Days   |                  |            |            |
| ≥ 24 hrs                                                                                     | 24-Hour 5 Calendar |                  |            |            |
| Not resulting in                                                                             | Days               |                  |            |            |
| Hospitalization                                                                              | Not required       | 10 Calendar Days |            |            |
| ≥ 24 hrs                                                                                     |                    |                  |            |            |  
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
eligibility checklist (8/4/14) (page 4
expedited ae reporting timelines are

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
eligibility checklist (8/4/14) (page 4
additional instructions or exceptions to

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.
eligibility checklist (8/4/14) (page 4
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 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 radioand 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.
eligibility checklist (8/4/14) (page 4
10.2 specimen collection for tissue

(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.  
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 (-70C to -90C) until ready to ship. If a -80C 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.  
| Specimens for Tissue Banking/Translational Research                                                                                                                                |                                                                                                                                                                                                             |                                                                                               |                                                            |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------|------------------------------------------------------------|
| Specimens taken from                                                                                                                                                               | Collected when:                                                                                                                                                                                             | Submitted as:                                                                                 | Shipped:                                                   |
| patient:                                                                                                                                                                           |                                                                                                                                                                                                             |                                                                                               |                                                            |
| Representative H&E  stained slides of the primary  tumor                                                                                                                           | Pre-treatment                                                                                                                                                                                               | H&E stained slide                                                                             | Slide shipped ambient                                      |
| Pre-treatment                                                                                                                                                                      |                                                                                                                                                                                                             |                                                                                               |                                                            |
| 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                                                                                                                                                                                               | 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 |
| 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.                         |                                                                                                                                                                                                             |                                                                                               |                                                            |
eligibility checklist (8/4/14) (page 4
u. s. postal service mailing

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**
eligibility checklist (8/4/14) (page 4
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 NCIsponsored 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.
eligibility checklist (8/4/14) (page 4
11.0 patient assessments 11.1 study

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 43 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.  
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 rightcorner 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.
eligibility checklist (8/4/14) (page 4
12.1 summary of data submission

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 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)                                                                |                                                                                 | Metformin                                                                            |
| (Only if randomized to Arm 2)                                                           |                                                                                 | Any Adverse Events?                                                                  |
|                                                                                        | Adverse Events (if any adverse events? =  'yes'                                  |                                                                                      |
|                                                                                        | On Treatment Labs MET                                                            |                                                                                      |
| Dose Escalation (Week 2)                                                                |                                                                                 | Metformin                                                                            |
| (Only if randomized to Arm 2)                                                           |                                                                                 | 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) |                                                                                      |  
| 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                                                     |                                                                                 | 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'                               |                                                                                                                   |
| 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 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                                                                                                                                                                                       |                                                                                 | SOC Imaging (these will only be used if the  patient progresses after 12 months off                               |
| Imaging - Prior to Progression                                                                                                                                                                                          | treatment)                                                                       |                                                                                                                   |  
| (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:   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
|    | 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                                      |
eligibility checklist (8/4/14) (page 4
12.3 summary of required diagnostic

(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 postradiotherapy                                                                     |
|                                                                                                       | 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 | At progression                                                      |
| imaging), if used to document distant progression.                                                     |                                                                 |                                                                     |