NCI Protocol Version Date: October 11, 2016 (Broadcast: November 7, 2016) The protocol version date was updated

For Protocol Amendment 8 to: RTOG 1106 / ACRIN 6697, Randomized Phase II trial of individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT And Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: October 11, 2016 (Broadcast: November 7, 2016) Document Footer Title Page Document History table 5.7 5.7.1 The protocol version date was updated Dr. Kong s contact information and Dr. Siegel s email have been updated This amendment was added All changes made in this section to reflect CTSU s new language related to regulatory document submissions. 5.7.3 6.5.1 6.5.3 6.8 13.9.3 APPENDIX I DURING TREAT. To minimize protocol deviations, deleted Pericardium because the heart contour should start 1 slice below the level of pulmonary artery trunk passing the midline and should not include the pericardium above this level. Replaced specific imaging reviewers with a more accurate reference of an independent radiologist in the ACR Core Lab. In the 2nd sentence, corrected 13.1.1 to 13.1 and 57 to 59. Clarified this table by replacing the asterisk in Row 5, Col 2 with a double dagger and adding a corresponding footnote

Clarified this table: APPENDIX I FOLLOW UP Merged Col 2,3 and 4 in Row 6 Added not necessary when a CT scan is done in Row 8, Col 2 & 3 Added after end of RT in Row 12, Col 2 Merged Col 2 & 3 in Row 13 Added should be done by radiologist in Row 14, Col 1

For Consent Amendment 8 to: RTOG 1106 / ACRIN 6697, Randomized Phase II trial of individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT And Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: October 11, 2016 (Broadcast: November 7, 2016) Document header & footer When you are finished treatment The version date was updated 2 nd set of bullets: Bullet 2: 3 and 9 months was corrected to 1 month for consistency with Protocol Appendix I Bullet 5: the spelling of scan was corrected Bullet 6: CT or MRI of your brain (your doctor may use contrast) was added for consistency with Protocol Appendix I

For Protocol Amendment 7 of: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: January 26, 2016 (Broadcast: TBD) Document Footer Global Title Page Document History table Schema Eligibility Checklist The protocol version date was changed for this amendment. As broadcast on November 24, 2015, Cardinal Health discontinued production of the FMISO investigational radiopharmaceutical PET agent used in this study and no alternative option was successfully identified, so at the recommendation of the ACRIN DMSB, the FMISO sub-study was closed to accrual. References to the FMISO sub-study in the eligibility checklist and the Appendix I PRE TREATMENT ASSESSMENTS table were removed but all other references in the introduction, aims, scanning technique and image acquisition parameters, adverse event reporting, analysis plan and Appendices V and VI are maintained in the protocol for historical reference; Minor formatting errors were corrected. References to RTOG were amended to NRG Oncology to be consistent with NRG Oncology standard text. This trial is sponsored by the National Cancer Institute (NCI) and will be led by NRG Oncology was added to be consistent with the NRG NCTN protocol template; Dr. Xiao s contact information was amended. This amendment was added. To reflect closure of the FMISO sub-study, FMISO sub-study closed to accrual on November 24, 2015 was added to the 2 nd box of the graphic, and to the 2 nd footnote under the graphic. TBD in footnotes 1 & 2 was corrected to the date of this amendment. To reflect closure of the FMISO sub-study: Eligibility Question #23 was removed and the subsequent question renumbered; FMISO and was removed from the sentence under the NOTE after #23; Questions #28, 29 and 30 were removed from QUESTIONS TO BE ASKED AT STUDY REGISTRATION.

1.7 2.2 5.5.1 6.0 6.10 7.10 12.2 13.4 Appendix V Appendix VI 3.2.9 Reference to closure of FMISO sub-study was noted. Appendix I PRE TREATMENT ASSESSMENTS Reference to FMISO sub-study was deleted. 3.2.10 (now 3.2.9) This section was renumbered and massage was corrected to massive. 5.3.2 6.0 In the first bullet: RPC was corrected to IROC Houston per current NCTN terminology; The name of the Credentialing Status Inquiry Form was corrected with initial capitalization; The 3 rd sentence was deleted because it is redundant. The 4 th paragraph was corrected with deletion of rapid from the 1st sentence and addition of feedback to the 2 nd sentence. 6.3.2 fx was corrected to fraction in the 6 th paragraph under the Contour table. 7.1 For clarification of chemotherapy time points, if chemotherapy begins early or was deleted from the 1 st sentence, and the 2 nd and last sentences were added. 7.10 The NOTES were renumbered. 10.1 10.3 10.1 10.3.1 Appendix IV BIOSPECIMEN COLLECTION 10.2 10.3 10.3 11.1.3 To clarify baseline time point in regards to lab blood collections, within was added prior to 2 weeks. References to the NRG Oncology Biospecimen Bank and email address were amended. Per Biospecimen Bank current policies, 10-15 unstained slides was amended to 10 unstained slides. The 3 rd column of the Specimen Collection Summary table was corrected: In the 3 rd box, Paraffin-embedded tissue block or punch biopsy was corrected to Paraffin-embedded tissue or punch block ; In the 4 th & 5 th boxes, five to eight cryovials was amended to five. To clarify patient follow-up requirements, After 60 months, patients are seen once annually for life to assess for overall survival was added to the 3 rd bullet.

12.2 Appendix I PRETREATMENT ASSESSMENTS Appendix IV SPECIMEN KIT INSTRUCTIONS To reflect current NRG Oncology RT parameters: the Arm 2 Initial Planning Data was amended; under ARM 2: ADAPTIVE PLANNING DATA TREATMENT PLAN: 1. the 5 th bullet was amended to 2 RT Plan Files ; 2. initial and adaptive was added to the 7 th bullet; 3. of Arm 2 was added to the NOTE. To clarify baseline time point in regards to lab blood collections, Prior to treatment was deleted from the 4 th column, last box and replaced with an X. To reflect current NRG Biospecimen Bank policy: In the FFPE instructions, the last sentence of STEP 1 was added and if you are not embedding it added to the end of STEP 2; The blood instructions were amended and tubes upright was added to #3 of the PROCESSING instructions for Whole Blood for DNA.

Sample consent form version: 1/26/16 To be attached to protocol version: 1/26/16 For Consent Amendment 7 of: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: January 26, 2016 (Broadcast: TBD) Header FMISO consent form Title Non-FMISO consent form During the study Non-FMISO consent form The version date was updated for this amendment. To be consistent with closure of the FMISO sub-study as noted in the protocol, the ICF template for Cancer Treatment Trials, Inclusive of FMISO Imaging Component was removed. To reflect the closure of the FMISO sub-study: APPENDIX I (Continued) was deleted since this consent is the primary study consent form and no longer an appendix; This informed consent form template includes the treatment component of the RTOG 1106 trial was deleted because it is superfluous; the study number was corrected to RTOG 1106/ACRIN 6697. To be consistent with changes made in the protocol, You also will have some blood tests weekly was deleted under During chemotherapy alone (after radiation) because blood tests are done weekly during concurrent chemo/rt but only done on Day 1 of each cycle during consolidation. What side effects or risks can I expect from being in the study? Non-FMISO consent form Since NRG Oncology maintains a lung radiation therapy risk profile and periodically adjusts it to be consistent with risks reported across all lung RT protocols, the RT side effects table was amended, and the header was changed from Possible Side Effects of Radiation Therapy to the Chest to Possible Side Effects of Lung Radiation. The Table Version Date for Carboplatin was amended to reflect CTEP s current Table Version Date, and s in vision was moved down in risk level from RARE AND SERIOUS to OCCASIONAL SOME MAY BE SERIOUS. About Using Tissue and Blood for Research Non-FMISO consent form The reference to the NCI tissue information sheet was deleted because it is no longer available on the cancer.gov website.

For Protocol Amendment 6 to: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: 2/16/2015 (Broadcast Date: March 16, 2015) Global Title pages Schema 1.8.2 1.9.6 The version date was updated throughout. The mailing address for the NRG Oncology Statistician was updated. This amendment was added to the Document History table on the 2 nd title page. In row 4, weeks 3-4 was deleted to be consistent with the table in 6.0. In row 5 Arm 2, in 6 weeks was deleted to be consistent with the table in 6.0. Due to the transition to the NCI National Clinical Trials Network (NCTN), RTOG in reference to member institutions was replaced by NRG Oncology (legacy RTOG) throughout this section and in Figures 2 & 3. Due to the transition to the NCI National Clinical Trials Network (NCTN), RTOG was replaced by NRG Oncology. 5.0 Formatting correction. 5.1.1 RTOG was replaced by NRG Oncology and legacy was added in reference to RTOG SBRT lung trials. 5.3.2 RTOG was replaced by NRG Oncology. 5.6 RTOG was replaced by NRG Oncology. 5.8 s were made in this section to be more in line with the new template. 6.1.1 & 6.1.2 6.4.1 in 6 weeks was deleted to be consistent with the Schema, and at least was added in reference to the progression outside of the original PTV because the progression can be 1 cm or greater. The 2 nd sentence was amended to clarify that the FDG-PET/CT scan is required and use of a flat palette is optional for the pre-treatment scan but required for the during treatment scan. 6.14 A typo was corrected (ACRPET). 7.0 RTOG was replaced by NRG Oncology. 7.9 RTOG was replaced by NRG Oncology.

12.0 The mailing address for NRG Oncology was updated. 12.3.2 RTOG was replaced by NRG Oncology. 13.12 RTOG was replaced by NRG Oncology. APPENDIX V: FMISO-PET/CT IMAGE SUBMISSION The mailing address for the ECOG-ACRIN Imaging Archive was updated.

Sample consent form version: 2/16/15 To be attached to protocol version: 2/16/15 For Consent Amendment 6 to: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: 2/16/2015 (Broadcast Date: March 16, 2015) Global The version date was updated. p. 3 Study Plan p. 9 Will my medical information be kept private? p. 15 What will happen if I take part in this research study? p. 16 Study Plan p. 17 During the study p. 21 Will my medical information be kept private? Row 5 Group 2 box formatting error was corrected so the box extends to include the last line of text ( with chemotherapy ). Row 6 All Patients box formatting error was corrected so the box extends to include the last 2 lines of text ( Chemotherapy every 21 days X 3 / total of 6 weeks ). Due to the transition to the NCI National Clinical Trials Network (NCTN), RTOG was replaced by NRG Oncology. Under First part of treatment: Radiation and Chemotherapy, the number of weeks was amended to be consistent with the corresponding section in the Consent Inclusive of FMISO. Under During-radiation FDG-PET/CT scan: same as above. Rows 3, 4 and 5 were amended to be consistent with the corresponding Study Plan section in the Consent Inclusive of FMISO. Row 6 box formatting error was corrected so the box extends to include the last line of text (total of 6 weeks). During the 4 th week correction was made in the first bullet in this section to be consistent with the corresponding section in the Consent Inclusive of FMISO. Due to the transition to the NCI National Clinical Trials Network (NCTN), RTOG and The Radiation Therapy Oncology Group (RTOG) was replaced by NRG Oncology.

For Protocol Amendment 5 to: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: December 9, 2014 (Broadcast Date: January 12, 2015) Global Title pages Abbreviations Schema Page 1.8.3 As required by CTEP, references to Radiation Therapy Oncology Group were replaced with NRG Oncology. References to the RTOG Biospecimen Resource were replaced with NRG Oncology Biospecimen Bank. References to ACRIN and the ACR Imaging Core Laboratory have been clarified to adequately address the roles and responsibilities of ECOG- ACRIN, ECOG-ACRIN Diagnostic Imaging headquarters and its staff, and the ACR Imaging Core Lab (also known as the ACR PET Core Lab or the ACR core lab). Version date has been updated throughout. The email address for the NRG Oncology Statistician was updated. This amendment was added to the Document History table on the 2 nd title page. ECOG- ACRIN has been added to the Abbreviations page ( Eastern Cooperative Oncology Group- ). NRG Oncology has been added to the Abbreviations page. In order to be consistent with the Eligibility Checklist, 1.3.1, and 3.1.4, the Schema and corresponding footnote 1 was amended to clarify that the baseline FDG-PET/CT scan is required within 4 weeks prior to registration. In the footnote 1 on the Schema, conditions were added for acceptability of FDG-PET/CT not performed on a flat palette in treatment planning position as a baseline scan. In footnote 2, a sentence was added to clarify that the FMISO PET/CT must be done after the subject has been registered. In the footnote 2 on the Schema, 3 rd sentence has been corrected to read: FMISO-PET/CT on a different day than FDG-PET/CT, and within 28 days prior to the start of radiotherapy. A sentence has also been added to clarify that the FMISO PET/CT must be done after the subject has been registered. A sentence was added to clarify that PET and CT images must be submitted to the ACR Imaging Core Laboratory. 3.0 This section was amended to direct eligibility questions to the study data manager. 3.1.4 In the final bullet, dl was corrected to dl. 5.0 The note was deleted in order to conform to standard NRG template language. The title of the second table was amended from RTOG to RT. 5.1.2 The last line of the second bullet was deleted.

5.5.1 5.8.1 The second bullet has been extensively revised to read as follows For this study, it is strongly recommended that the institution use a flat palette imaging couch for scanning for imaging registration match with simulating CT for the baseline FDG- PET/CT. The mid-treatment FDG-PET/CT must be performed on a flat palette in treatment planning position. An institution participating in the FMISO PET/CT substudy must use a flat palette imaging couch for scanning for imaging registration match with simulating CT for the FMISO-PET/CT. Accurate imaging registration is essential before enrolling any patient for this protocol. Instructions to call the RTOG Randomization desk were deleted from the instructions for performing registrations to trials accessed via the CTSU mechanism. 6.3.1 Previous was added for clarity. 6.4.1 This section was amended to be consistent with the changes made to details in section 5.5.1 above, and revised to recommend flat palette imaging couch as follows recommended pre-treatment and required during-treatment for contouring. 6.5.1 DICOM Structure Names was added as a header on the table. 6.10.3 In the first bullet, PET/CT imaging has been revised to the emission PET scan. 6.14 6.14.1 6.14.3 10.4 The section regarding the use of a flat palette imaging couch was amended to be consistent with the changes detailed in section 5.5.1 above. In the fourth sentence of the second paragraph, the language around flat palette imaging couch was changed from required to recommended for the baseline scan and required for the mid-treatment scan. A new final paragraph has been added as follows: If the baseline FDG-PET/CT is not performed on a flat palette in treatment planning position, it can still be used as the baseline scan only if all of the following conditions are met: done within 4 weeks prior to registration acceptable imaging parameters: 4 hour fast, blood glucose < 200 mg/dl, 8-20 mci F-18 FDG dose, injection to scan interval 50-70 minutes conducted on an ACR Imaging Core Laboratory qualified scanner, which is the same scanner or same model to be used for the mid-treatment FDG PET/CT imaging can be acceptably registered to the simulation CT; the simulation CT must also be submitted as a reference scan for registration In the third bullet, ideally within one hour of FDG administration was added. A new forth bullet was added to read If the serum glucose concentration is found to be greater than 200 mg/dl, the study should be rescheduled. The referring physician or primary physician of the patient will be contacted to optimize blood glucose control. In the first bullet, imaging has been revised to the emission PET scan. The last bullet was amended to read An emission scan from the skull base to thighs will be performed. The number of bed positions and the acquisition time per bed position will be scanner specific. Typical parameters are 6 bed positions and an acquisition of 2-5 min per bed position. Biospecimen reimbursement information was amended with new NCTN Program requirements.

11.2.1 CT has been added to the subsection header. A final sentence was added: CT submission is required. 12.1 The footnotes regarding Image Transmittal Worksheets were revised to include baseline scans as scan submission requirements. 12.2 The reference to 6.5 under Arm 1 was corrected to 6.5.1. Appendix I Study Parameter Table: Pre-Treatment Assessments: the baseline FDG- PET/CT and FMISO-PET/CT pre-treatment assessments were revised per the changes detailed in the Schema Page section above to clarify that they are required within 4 weeks prior to registration. Study Parameter Table: Assessments During Treatment: The phrase Continued Concurrent Chemo was replaced with Consolidation Chemo and under the CBC w/ diff & ANC Assessment, weekly was replaced with on day 1 of each cycle.

For Consent Amendment 5 to: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: Dec. 9, 2014 (Broadcast Date: January 12, 2015) Global Header What will happen if I take part in this research study? Study Plan During the study Possible side effects of paclitaxel Possible side effects of carboplatin Note: The changes described below were made in the sample consent that includes the treatment and imaging components AND in the sample consent that includes only the treatment component. References to RTOG were changed to NRG Oncology and references to ACRIN were changed to ECOG-ACRIN. Version date was updated throughout. The version date was changed for this amendment. Under Before-treatment PET/CT scans, a sentence was added to specify that all images will be provided to ECOG-ACRIN. Under First part of treatment: Radiation and Chemotherapy, the timeframe of radiation treatment for groups 1 and 2 was amended from 5 weeks (group 1) and 3-4 weeks (group 2) to 6 weeks for both groups to be consistent with the protocol. During-radiation FDG-PET/CT scan was amended to indicate that both groups have the imaging during the 4 th week of radiation therapy to be consistent with the protocol. In the 3 rd row, the timeframe of treatment for both groups was amended from 6-7 weeks to 6 weeks to be consistent with the protocol. Group 1 was also amended from 5 weeks to 3-4 weeks. In the 4 th row, the timeframe for group 1 was amended from between weeks 4 and 5 to between weeks 3 and 4 to be consistent with the protocol. In the 5 th row, Standard Radiation Therapy for group 1 was amended from 1 remaining week to for remaining weeks and Adaptive Radiation Therapy for group 2 was amended from once a day, M-F, for 2-3 weeks to starting during the 5 th week once a day, M-F, for remaining treatments. The second bullet was amended to clarify that the FDG-PET/CT scan will be done during the 4 th week of radiation therapy instead of between the 4 th and 5 th weeks. The side effects tables in the first section of the consent (treatment and imaging components of RTOG 1106 and ACRIN 6679) and in the second section of the consent (treatment component of RTOG 1106) were updated with the current information listed on CTEP s website. The side effects tables in the first section of the consent (Treatment and imaging components of RTOG 1106 and ACRIN 6679) and in the second section of the consent (treatment component of RTOG 1106) were updated with the current information listed on CTEP s website.

For Protocol Update of: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: March 13, 2014 (Broadcast Date: March 13, 2014) 6.5.3 In the table, SpinalCanal was corrected to SpineCanal.

For Protocol Amendment 4 to: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: 2/25/14 Global Title pages Schema page As required by CTEP, references to the Adverse Event Reporting System (AdEERS) have been changed to CTEP Adverse Event Reporting System (CTEP-AERS) throughout the protocol. As required by CTEP, Radiation Therapy Oncology Group was replaced with NRG Oncology on the 1 st and 2 nd title pages. This amendment was added to the Document History table on the 2 nd title page. The 3 rd title page was deleted, as the CTSU contact information is not required for this trial. As required by CTEP, Radiation Therapy Oncology Group was replaced with NRG Oncology. Eligibility Checklist On page 1, question 6 was amended to be consistent with changes made in 3.1.4. On page 2, in the 2 nd bulleted item under the note, a parenthetical phrased was added for clarity. 3.1.4 The 3 rd and 4 th bulleted items were amended to recommend IV contrast unless medically contraindicated. 5.0 In the RTOG Credentialing table, the note was amended for clarity. 5.0, 5.1, 5.2, 5.3, 5.4, 5.7, 6.1.3, 5.3.2 5.4.1 Throughout these sections, the Radiologic Physics Center or RPC was amended to IROC Houston, and when included, the web address for RPC was amended to the web address for IROC Houston. In the 3 rd bulleted item, the 3 rd sentence was amended to direct sites to the IROC Houston web site. In the 4 th bulleted item, rapid review was replaced with Pre-treatment review. The last sentence of the 1 st paragraph was amended for clarity. The 1 st and 2 nd paragraphs were amended to direct sites to the IROC Houston web site. 5.4.2 The phrase, rapid review, was replaced with Pre-treatment review. 5.4.3 In the 3 rd sentence, rapid review, was replaced with Pre-treatment review. In the 4 th and 5 th sentences, RT Quality Assurance (RTQA) was replaced with IROC-Philadelphia-RT. 5.5.3 This section was amended to direct sites to the IROC Houston web site.

6.0 In the 4 th paragraph, RTOG-RTQA was amended to IROC Philadelphia- RT. In Table 6.0, for Arm 1, the dose range at which the FDG-PET/CT is performed was amended from 39.6 to 36-38 Gy. In Table 6.0, under Adaptive Phase, the reference to Table 6.5.2 was replaced with Table 6.5.3. 6.1.2 The 2 nd paragraph was amended for clarity. 6.3 Table 6.3.2 was amended for clarity. Below Table 6.3.2, the 1 st, 5 th, 6 th, 7 th, and last paragraphs were amended for clarity. 6.4.2 and 6.4.3 These sections were amended for clarity. 6.4.4 6.5.1 6.5.3 Table 6.4.4 was amended for clarity. In the last footnote below the table, a reference to Table 6.5.2 was corrected to Table 6.5.3. A note was added in the 2 nd paragraph to provide instructions to sites. The table was updated. In the 1 st sentence a reference to Table 6.5.2 was replaced with Table 6.5.3. In Table 6.5.3, the following changes were made: The text in the Description columns of Lungs and of NonPTV was amended. The DICOM Structure Name for the spinal cord was amended. 6.7.2 References to 6.4.4 were replaced with Table 6.5.3. 7.1 10.3 A note was added to permit 7 weeks of concurrent chemotherapy in cases in which chemotherapy begins early or radiation extends past 6 weeks. In the heading, Central Review was deleted as it was included in error and doesn t pertain to this trial. 12.2 This section was updated to current IROC-Philadelphia-RT standards. Appendix I, Pre- Treatment Assessments Appendix I, Assessments in Follow Up Appendix V The imaging of the chest and brain was amended to be consistent with changes made in 3.1.4. The timeframe for collection of blood for research was corrected to be consistent with 10.0. An explanation of the symbol next to Blood for research ( ) was added below the table. In the 2 nd to last paragraph, the e-mail address for the TRIAD help desk was updated.

For Consent Amendment 4 to: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: 2/25/14 Note: The changes described below were made in the sample consent that includes the treatment and imaging components AND in the sample consent that includes only the treatment component. 1 st page The version date was changed for this amendment. What will happen if I take part in this research study? Study Plan Before you begin the study Under First part of treatment: Radiation and Chemotherapy, the timeframe of treatment for groups 1 and 2 was amended from 6 weeks to 6-7 weeks to be consistent with changes made in 7.1 of the protocol. During-radiation FDG-PET/CT scan was amended to indicate that both groups have the imaging at the same time point, between weeks 3 and 4 of radiation therapy, to be consistent with the protocol. In the 3 rd row, the timeframe of treatment for groups 1 and 2 was amended from 6 weeks to 6-7 weeks to be consistent with changes made in 7.1 of the protocol The 4 th and 6 th bulleted items were revised to be consistent with changes made in the protocol.

For Protocol Update of RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: 8/19/13 Update broadcast: 12/19/13 Title pages Table of Contents On the 2 nd title page, the headings, protocol designation, and title (as on the 1 st title page) were added to update the protocol to current RTOG standards. This update was added to the Document History table on the 2 nd title page. A 3 rd title page was added to accommodate the CTSU contact information (for consistency with s 5.7 and 5.8). The table was regenerated to include the addition of 5.6. 3.0 The 2 nd sentence was updated to current RTOG standard text. 5.0 RTOG is now using TRIAD to collect RT digital data. TRIAD provides sites participating in RTOG clinical trials with a secure method to transmit DICOM RT and other digital data. TRIAD anonymizes and validates the images and information objects as they are transferred via the internet. TRIAD was added to the heading above the 1 st paragraph and the 2 nd paragraph was added to be consistent with changes made in s 5.0 and 6.0 In the table, RTOG Credentialing, the link, For All, was updated. 5.1.2 This section was updated to current RTOG RTQA standard text. 5.2.2 In the 1 st bulleted item, the last sentence was deleted to update this section to current RTOG RTQA standard text. 5.3.2 In the 1st bulleted item, the link to the questionnaire was updated. 5.4.1 This section was updated to current RTOG RTQA standard text. 5.5.3 This section was updated to current RTOG RTQA standard text. 5.6 5.7 This section was added to update the protocol with instructions regarding submission of digital RT data using TRIAD (and subsequent sections were appropriately renumbered). The first 4 paragraphs were added to update the protocol to current RTOG standard text. 5.7.1 The 1st sentence was updated to be consistent with the added text in 5.7. 6.0, 6.5, 12.2 These sections were updated to include logistics for TRIAD for RT digital data submission. 7.8, 7.8.1 These sections were updated to current RTOG standard text. 7.8.2 This section was updated with CTEP s current text concerning reporting of pregnancy of a study participant.

10.3 Appendix IV The 2 nd row under Submitted as was updated to current RTOG Biospecimen Resource text. The 1 st page of the appendix was updated to current RTOG Biospecimen Resource text.

For Protocol Amendment 3 to: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: 8/19/13 The version date was added to the footer as required by CTEP s new formatting Global requirements. On the 1 st title page, Dr. Kong s affiliation and contact information were amended. Title pages On the 2 nd title page, this amendment was added to the document history table. Abbreviations OAR was corrected to OARs. The primary goal of this amendment is to simplify the treatment planning process to encourage and enable participation by a larger number of RTOG institutions while still allowing the study question to be answered. The study chairs believe these changes will enable this paradigm of adaptive therapy to be more easily implemented by the radiation therapy community and will result in the trial being successful in a multiinstitutional setting. If this trial of adaptive therapy is successfully completed, and this therapy proves to be effective, adaptive therapy eventually could become standard practice. As the proposed amendment removes the screening plan (which occurs prior to randomization), the original stratification variables, e.g. MLD and PreGTV (acquired by doing a screening plan) were no longer available and were replaced with 2 equally relevant variables. Information for these 2 variables has been collected from the activation of the trial; therefore, for patients who already are accrued to the study, the information on Stage and Primary Tumor Size are available. The planned statistical analysis thus will not be affected by the proposed amendment, as the planned primary efficacy analysis is based on a logrank test without stratification, and the multivariate analyses for efficacy will be adjusted for treatment assignment and for stratification variables. Schema The following changes were made to the Schema: The Screening Plan was deleted to make treatment planning more streamlined. The stratification variables, MLD and PreGTV (acquired by doing a screening plan), were replaced with Stage and Primary Tumor Size. Under Arm 1: Concurrent Chemoradiotherapy, the phrase, in 5 weeks, was replaced with (nominally 5 fx/week). Under Arm 2: Concurrent Chemoradiotherapy, the RT dose, number of fractions, and timeframe were amended. The text for ALL PATIENTS: During-RT FDG-PET/CT Scan, was amended, and the text for Arms 1 and 2 was deleted, as the timeframe for both arms is now the same. Under Arm 1: Continuation of radiotherapy, the 4 th and 5 th sentences were amended. In the 2 nd paragraph, the phrase, in 6 weeks, was replaced with (nominally 5 fx/week). Under Arm 2: Adaptive radiotherapy, the dose, number of fractions, and total dose were amended. In footnote 1, the fractions at which the during-rt FDG-PET/CT scan is done for both arms were amended to be consistent with changes made in the Schema. In addition, the word, imaging, was added prior to acquisition for clarity. In footnote 2, the parenthetical phrase, when FMISO is available, was added after FMISO-PET/CT. In footnote 3, the stratification variables were amended to be consistent with changes made in the Schema.

Eligibility Checklist Page 1, Question 6: the phrase, or sim CT was added after CT scan to be consistent with changes made to 3.1.4. Page 2: Under Note: The Following are required prior to registration, Dry-Run was replaced with Benchmark in the 2 nd bulleted item and the 3 rd bulleted item was deleted to be consistent with changes made in 6.0 and the Schema. Page 2: The heading, The following questions will be asked at Study Registration, was moved to directly above the list of questions for clarity. Page 3, Questions 26 and 27 were amended to be consistent with changes to the stratification variables made in the Schema. 1.3.1 In the 5 th paragraph, item 6, the number of patients was amended from 5 to 2 to be consistent with changes made in s 5.4.3 and 6.0 regarding pre-treatment reviews. 1.8 In the 7 th sentence, the dose at which the during-rt FDG-PET/CT scan is done was amended to be consistent with changes made in the Schema. The 8 th, 10 th, and 11 th sentences were amended to be consistent with changes made in the Schema and 6.0. 2.1.1 The objective was amended to be consistent with changes made in the Schema. 3.0 The 2 nd sentence was added to update the protocol to current RTOG standard text. 3.1.4 4.1 5.0 In the 3 rd bulleted item, the phrase, or sim CT was added to provide this alternative to investigators. This section was titled, Required Evaluations, and the required electrolytes were added to be consistent with 11.1 and Appendix I. The subsequent section was appropriately renumbered. In the Table 5.0, Dry-Run was replaced with Benchmark to be consistent with changes made in s 5.4.3 and 6.0, and a note was added regarding credentialing for clarity. 5.1.1 5.2.2 5.3.2 5.4 5.4.1 and 5.4.2 In the 2 nd footnote below the table, the 1 st sentence was amended for clarity. The last sentence of the 2 nd paragraph was added to provide information to sites regarding credentialing. In the 3 rd bulleted item, Dry-Run was replaced with Benchmark to be consistent with changes made in 5.4.3, and the 6 th sentence was amended. In the 4 th bulleted item, Dry-Run was replaced with Benchmark and Rapid was replaced with Pre-Treatment to be consistent with changes made in 5.4.3. In the 3 rd bulleted item, Dry-Run was replaced with Benchmark to be consistent with changes made in 5.4.3. In the 4 th bulleted item, Rapid was replaced with Rapid to be consistent with changes made in 5.4.3. In the heading the word, Dry-Run was replaced with Benchmark to be consistent with changes made in s 5.4.3 and 6.0. Throughout these sections, Dry-Run was replaced with Benchmark to be consistent with changes made in s 5.4.3 and 6.0. 5.4.3 This section was amended to explain pre-treatment reviews. 5.5.3 Dry-Run was replaced with Benchmark to be consistent with changes made in s 5.4.3 and 6.0.

6.0 6.1.2 6.1.3 6.3.1 In the 1 st paragraph, the RT screening plan was deleted to be consistent with changes made in the Schema. The 2 nd paragraph was amended to be consistent with changes made in 5.4.3. The 3 rd paragraph was amended to be consistent with changes made in the 2 nd paragraph and in 5.4.3. The 4 th paragraph was amended to refer sites to RTOG RTQA. Table 6.0 was amended to be consistent with the changes made in the Schema to streamline treatment planning and with changes made to the stratification variables. The 1 st and 4 th paragraphs were amended to be consistent with changes made in the Schema and 6.0. In the 2 nd paragraph, the dose was amended in the 2 nd sentence. The 3 rd paragraph and Table 6.1.2a were deleted. The paragraph between Tables 6.1.2a and 6.1.2b was amended. Table 6.1.2b was re-designated as Table 6.1.2, and the table was amended. The asterisked (*) phrase and the note below Table 6.1.2 were deleted. This section was deleted, and the subsequent section was appropriately renumbered. In the renumbered section, the 3 rd paragraph was amended. The 4 th paragraph, Simulation, was amended. 6.3.2 6.4 The 1 st sentence and Table 6.3.2 were added. All of the paragraphs below the table were amended. The 1 st paragraph regarding the screening plan was deleted to be consistent with changes made in the Schema and 6.0. 6.4.2 The 3 rd sentence and the bulleted items were deleted. 6.4.3 6.4.4 6.5.2 The 1 st paragraph was amended. The 2 nd through 4 th paragraphs, Arm 2 Dose Prescription Procedure and Implementation Examples, were deleted. Under Arm 2 Adaptive Radiation Plan Procedure, item a was amended, and the 4 plans under item d were deleted. Table 6.4.3, Target Contours was deleted. The paragraph below Arm 2 Adaptive Radiation Plan Procedure, beginning Tumor target are defined was amended. Steps for Dosimetric Planning for Arm 2 was amended. In Table 6.4.4, for the last row, DurPTV, the columns, Dose covering 95% volume and Deviation Unacceptable, were amended. 6.7.2 This section was amended. The 1 st and 2 nd sentences were amended. The 2 nd paragraph was added. The list of individual organs was deleted. The heading for Table 6.5.2 and the table itself were amended. 6.7.3 The last sentence was deleted. 6.7.4 6.8 7.1.2 In the table, the heading of the 2 nd column was amended to the RTOG standard, Variation Acceptable. The 1 st and 2 nd paragraphs were amended to be consistent with changes made in in s 5.4.3 and 6.0. The lists below paragraph 2, For Arm 1 and For Arm 2, were deleted. Two sentences were added below the equations to provide instructions regarding the maximum carboplatin dose.

7.4.7 The reference to etoposide was deleted, as it was included in error. 7.8 7.8.1 and 7.8.2 7.8.3 7.9 10.2 10.2.1 10.3 11.1.1 11.1.2 11.1.3 12.2 12.2.1 13.6 A phrase was added to the end of the 2 nd paragraph to update the protocol to current RTOG standard text. These sections were updated to the current RTOG standard text. The 2 nd sentence in the 1 st paragraph was deleted, and 2 subsections were added to update this section to CTEP s current text. The 1 st 4 paragraphs and bulleted list were added to update this section to current RTOG standard text. The 1 st and 2 nd bulleted items were amended and the 3 rd bulleted item added to update the text to current RTOG Biospecimen Resource standard text. In the 5 th and 6 th bulleted items, ST was added parenthetically after Specimen Transmittal. In the last sentence, Specimen Transmittal was replaced by the ST to update the section to current RTOG Biospecimen Resource standard text. In the last row of the table, the abbreviation for the Specimen Transmittal Form was amended from STF to ST, as STF conflicts with case report form terminology. In the 2 nd bulleted item, the phrase, or sim CT, was added to be consistent with changes made in 3.1.4. The last bulleted item was added to be consistent with Appendix I. The 2 nd bulleted item was amended to be consistent with changes made in the Schema. In the last bulleted item, the parenthetical phrase, weekly during RT/chemo, was added to be consistent with Appendix I. In the 1 st bulleted item, the phrase, +/- 2 weeks, was added parenthetically after every 3 months and every 6 months to provide flexibility to sites. In addition, a note was added to provide instructions for follow-up imaging of patients who progress. In the 4 th bulleted item, the timing of follow up was corrected from From 2 months to 15 months to From 1 month to 12 months. In the 5 th bulleted item, the phrase, and when CT evidence indicates tumor progression, was added. Under Item, the Arm 1 and Arm 2 Screening Plan was deleted to be consistent with changes made in the Schema and 6.0. In addition, under Due, the 1 st 2 timeframes, Within 1 week of registration were deleted to be consistent with the deletion of these items. Under Arm 1: RT Planning Data, the note was deleted to be consistent with changes made in 5.3.4 and 6.0. In addition, the word, Updated, was deleted from the 5 th bulleted item. Under Arm 2: Initial Planning Data, the word, Updated was deleted from the 4 th bulleted item and the link to the Datasheet was corrected. The schedule and note next to Arm 2: Initial Planning Data were amended to be consistent with changes made in s 5.4.3 and 6.0. Under Arm 2: Adaptive Planning Data Treatment Plan, the link was corrected. The schedule and note next to Arm 2: Initial Planning Data were amended to be consistent with changes made in s 5.4.3 and 6.0. In the note above Final Dosimetry Information the last phrase was amended to read, Benchmark or other. Under Final Dosimetry Information, the bracketed phrase, copy to HQ and ITC, was deleted next to the T1 and T5 forms. The 2 nd paragraph and the phrase, ATTN: Roxana Haynes were deleted to update this section to current text. The stratification variables were amended to be consistent with changes made in the Schema.

Appendix I Appendix IV In the Pre-Treatment Assessments table, the phrase, or sim CT, was added to be consistent with changes made in 3.1.4. In the Pre-Treatment Assessments table, for the CT scan of the chest and upper ab, IV was added before contrast to be consistent with 11.1.1 In the Pre-Treatment Assessments table, Electrolytes was moved into a separate row from Creatinine, and the timeframe column was appropriately amended for both assessments. In the Assessments during Treatment table, a reference to 11.1 was added below the heading, and the parenthetical phrase, complete panel was added next to Electrolytes for clarity. In the Assessments in Follow Up table: A reference to 11.1 was added below the heading. In the timeframe columns, after tx was clarified to after end of protocol treatment. For CT scan of the chest, upper ab, IV was added prior to contrast for clarity, and a reference to 11.1.3 was added for further information about patients who progress. The asterisk (*) prior to CT with contrast of brain or MRI of brain was deleted, and the x in the timeframe column was replaced with As clinically indicated. The parenthetical phrase, complete panel, was added next to Electrolytes for clarity. Throughout this appendix, the abbreviation for the Specimen Transmittal Form was amended from STF to ST, as STF conflicts with case report form terminology.

For Consent Amendment 3 to: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG-1106/RTOG 1106/ACRIN 6697 NCI Protocol Version Date: 8/19/13 Note: The changes described below were made in the informed consent template that includes the treatment and imaging components and in the informed consent template that includes only the treatment component. 1 st page The version date was changed for this amendment. What will happen if I take part in this research study? What side effects or risks can I expect from being in the study? What are the costs of taking part in this study? Consent Form for Use of Tissue and Blood for Research Under When you are finished treatment, in the 2 nd paragraph, an FDG-PET/CT scan was added under If you doctor recommends, to be consistent with 11.1.3 of the protocol. The risks associated with paclitaxel and carboplatin were replaced with CTEP s standard tables for these agents. In addition, the risks associated with radiation were reformatted to correspond to CTEP s tables for agents. The 3 rd and 4 th paragraphs were deleted at CTEP s request, as the information is no longer current. Under Risks, 5 paragraphs were added to update the consent form to current RTOG standard text.

For Protocol Amendment #2 to: RTOG 1106/ACRIN 6697, Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) NCI/Local Protocol #: RTOG 1106 NCI Protocol Version Date: December 5, 2012 (Broadcast date 12/19/12) Global To comply with CTEP s new formatting/document requirements, the protocol was reformatted and the sample consent was removed from the appendices. The appendices were appropriately renumbered throughout the protocol. The informed consent continues to be available via MS Word on the protocol documents section of the main protocol page. 2nd Title Page The document history table was updated with the date for Amendment 2. Schema Arm 1 and 2: Additional text was added for clarification. Footnote 1: The range of the FDG dose has been revised from 10-20 mci to 8-20 mci. The range of the FDG dose was reduced to accommodate a dose reduction strategy at one of the participating institutions. 3.1.1 The phrase, (from PET scan of any date, any scanner), was added for clarification. 3.1.2 3.2.7 The last sentence has been amended to permit the treating radiation oncologist and medical oncologist (as well as a pulmonologist to review patients who are clearly nonresectable. The last sentence in this section was deleted and moved to 11.3. This information was incorrectly added to this section, and patients who become pregnant while on study will be advised according to an investigator s or an institution s standard process. 3.2.9 This section was amended for clarity.. 5.2.2 Fourth bullet, fourth sentence: ITV was added prior to techniques. 5.4.1 The sentence The dry run should be submitted for review according to 12 was added to the last paragraph as a reference to see section 12. 5.4.3 The words and create protocol compliant treatment plans was added to the first sentence. The information regarding rapid reviews was amended for clarification.

6.0 2 nd paragraph, sentence 2 and 3 have been removed and replaced with Subsequent patients cannot be enrolled until these 3 rapid review cases have successfully passed the complete rapid review process. See 5.4.3 for more details. The timeframe for rapid reviews has been amended from 2 to 3 business days. Table 6.0 In the 5 th row, PET-CT and CT has been added prior to resimulation for clarification. 6.1.2 The words, and resimulation, were added to the sentence after table 6.1.2a. 6.2 The MV value was changed from 6-18 to 6-10 MV. This was updated to current RTOG standards. 6.3.1 Paragraph 5 was added for further clarification of the adaptive simulation process. 6.3.2 The 4 th,, 7 th, and 8 th paragraphs was deleted and the 5 th and 6 paragraphs were amended for clarification. 6.4.1 The words treatment planning were deleted and replaced with contouring 6.4.2 In the 1 st sentence, PTV was amended to PrePTV. The 2 nd and 3 rd sentences were added for clarity. Table 6.4.3 The table and the note after the table were amended for clarification. 6.4.4 The words, and meet all normal tissue constraints, were added to the first sentence. Table 6.4.4 The table was amended for clarity.

Table 6.5.2 The No Deviation and Deviation Acceptable columns were amended. 6.6 s 6.6.2 and 6.6.3 were deleted and replaced with see section 12 for data submission requirements In 6.6.1. 6.8 The timeframe for review of plans was amended from 2 to 3. to be consistent with changes made in 6.0. 6.14.2 In the 2 nd bullet, the range of the FDG dose has been revised from 10-20 mci to 8-20 mci, and the phrase, and in accordance with manufacture recommendations was added 10.2 The reference to see Appendix I has been amended to see sample consent form 11.3 The 5 th bullet was added: patients who become pregnant while on study will be advised according to the investigator s or institution s standard process 12.1 The time points for the submission of follow-up CT scans and Image Transmittal Worksheets have been clarified. Hyperlinks to RTOG 1106 Datasheet have been updated in Arm 2: Initial Planning Data and Arm 2: Adaptive Planning Data Treatment Plan. 12.2 13.8 Arm 2: Initial Planning Data, 1 st sentence: or, prior to start of RT if rapid review is required was added. Arm 2: Adaptive Planning Data Treatment Plan, 1 st sentence: or, prior to start of Adaptive RT if rapid review is required was added. Hard copy was deleted throughout this section. Second paragraph: the reference to the RTOG concept was deleted, as this was inadvertently included. Fifth paragraph, last sentence has been corrected from a maximum of 58 patients to a minimum of 58 patients. Appendix I The table was updated to reflect the tissue banking frequency and the FDG-PET/CT.