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duhs institutional review board and

The protocol, informed consent form, advertising material, and additional protocol‐related documents must be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) for review. The study may be initiated only after the Principal Investigator has received written and dated approval from the CPC and IRB. The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol amendments and changes to the informed consent form. The CPC should be informed about any protocol amendments that potentially affect research design or data analysis (i.e. amendments affecting subject population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.).  
The Principal Investigator must obtain protocol re‐approval from the IRB within 1 year of the most recent IRB approval. The Principal Investigator must also obtain protocol re‐approval from the CPC within 1 year of the most recent IRB approval, for as long as the protocol remains open to subject enrollment.
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informed consent

The informed consent form must be written in a manner that is understandable to the subject population.  
Prior to its use, the informed consent form must be approved by the IRB.  
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of the research, methods, potential risks and benefits, subject concerns, and other study‐ related matters. This discussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility of coercion. Appropriate accommodations will be made available for potential subjects who cannot read or understand English or are visually impaired. Potential subjects will have the opportunity to contact the Principal investigator or authorized key personnel with questions, and will be given as much time as needed to make an informed decision about participation in the study.  
Before conducting any study‐specific procedures, the Principal Investigator must obtain written informed consent from the subject or a legally acceptable representative. The original informed consent form will be stored with the subject's study records, and a copy of the informed consent form will be provided to the subject. The Principal Investigator is responsible for asking the subject whether the subject wishes to notify his/her primary care physician about participation in the study. If the subject agrees to such notification, the Principal Investigator will inform the subject's primary care
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protocol deviations and violations

A protocol deviation is non‐adherence to protocol specific study procedures or schedules that does not involve inclusion/exclusion criteria, primaryobjective evaluation criteria, and/or Good Clinical Practice (GCP)
guidelines. A protocol violation is any significant divergence from the protocol such as non‐adherence on the part of the subject, the Investigator, or the sponsor to protocol specific inclusion/exclusion criteria, primary objective evaluation criteria, and/or GCP guidelines.  
As a matter of policy, the Lead PI (i.e. sponsor) will not grant exceptions to protocol specific entry criteria to allow subjects to enter a study. If it is found that a subject who did not meet protocol eligibility criteria was entered in a study (a protocol violation), the Lead PI and/or designee(s) at the Duke Thoracic Oncology Clinical Trials Office must be informed immediately. Such subjects will be discontinued from the study, except in an exceptional instance following review and written approval by the Lead PI and the responsible IRB/IEC.  
Protocol deviations and violations must be documented and reported to the Lead PI and/or designee(s) at the Duke Thoracic Oncology Clinical Trials Office. In accordance with applicable regulations, Investigators must report protocol deviations and violations to their local IRB/IEC according to their institutional guidelines.
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study documentation

Study documentation includes but is not limited to source documents, case report forms (CRFs), monitoring logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, and regulatory documents that can be found in the DCI‐mandated "Regulatory Binder", which includes but is not limited to signed protocol and amendments, approved and signed informed consent forms, FDA
Form 1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution records.  
Source documents are original records that contain source data, which is all information in original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source documents include but are not limited to hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x‐rays, subject files, and records kept at the pharmacy, at the laboratories and at medico‐technical departments involved in the clinical trial. When possible, the original record should be retained as the source document. However, a photocopy is acceptable provided that it is a clear, legible, and an exact duplication of the originaldocument.  
The electronic CRF will be the primary data collection document for the study. The CRFs will be updated within two weeks of acquisition of new source data. The electronic records of subject data will be maintained using a dedicated database (Medidata Rave and/or Redcap) which is housed in an encrypted and password protected DCI file server. Access to electronic databases will be limited to the PI and designated stud staff listed on key personnel. Subject data may be stored temporarily on encrypted and password‐protected portable memory devices such as flash drives and external hard drives, but only when absolutely necessary. Data stored on portable memory deviced will be de‐ identified.  
Subject data will be deleted from the portable memory device at the earliest opportunity. The security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine. Only approved study staff, are permitted to make entries, changes, or corrections in the CRF. An audit trail will be maintained automatically by the electronic CRF management system (Medidata Rave and/or Redcap). Designated personnel will complete user training, as required or appropriate per
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privacy confidentiality and data storage

The Principal Investigator will ensure that subject privacy and confidentiality of the subject's data will be maintained. Research Data Security Plans (RDSPs) will be approved by the appropriate institutional Site Based Researchgroup.  
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course of the study. Prospective participants will be consented in an exam room where it is just the research staff, the patient and his family, if desired. For all future visits, interactions with research staff (study doctor and study coordinators) regarding research activities will take place in a private exam room. All research related interactions with the participant will be conducted by qualified research staff who are directly involved in the conduct of the researchstudy.  
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key accessible only by the researchstaff. Subjects will be identified only by a unique study number and subject initials. Electronic records of subject data will be maintained using a dedicated database (required: please specify database application, i.e. Microsoft Excel, Microsoft Access, eResearch, Oracle Clinical, Redcap, etc.),
which is housed in an encrypted and password‐protected (required: please specify storage device, i.e. laptop computer, desktop computer, DCI file server). Access to electronic databases will be limited to (please specify). Subject data may be stored temporarily on encrypted and password‐protected portable memory devices such as flash drives and external hard drives, but only when absolutely necessary. Data stored on portable memory devices will be de‐ identified. Subject data will be deleted from the portable memory device at the earliest opportunity. The security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine.  
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.  
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or publications in scientific journals.  
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 101
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protocol amendments

All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to implementation. IRB approval is not required for protocol changes that occur to protect the safety of a subject from an immediate hazard. However, the Principal Investigator must inform the IRB and all other applicable regulatory agencies of such action immediately.  
Though not yet required, the CPC should be informed about any protocol amendments that potentially affect research design or data analysis (i.e. amendments affecting subject population, inclusion/exclusion criteria, agent administration,etc.).
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records retention

The Principal Investigator will maintain study‐related records for the longer period of:
- At least two years after the date on which a New Drug Application is approved by the FDA (if an IND isinvolved).  
- At least two years after formal withdrawal of the IND associated with this protocol (if an IND isinvolved).  
- At least six years after study completion (Duke policy).
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publication plan

The results will be made public within 24 months of reaching the end of the study. The end of the study is the time point at which the last data items are to be reported, or after the outcome data are sufficiently mature for analysis, as defined in the section on statistical design. A report is planned to be published in a peer‐reviewed journal, thus the initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. A full report of the outcomes is planned to be made public no later than three (3) years after the end ofthe study. Duke Cancer Institute will forward a copy of the Publication to Genentech/Roche upon completion of the Study.
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study close out

Any study report submitted to the FDA by the Sponsor-Investigator should be copied to Genentech/Roche. This includes all IND annual reports and the Clinical Study Report (final study report). Additionally, any literature articles that are a result of the study should be sent to Genentech/Roche. Copies of such reports should be mailed to the assigned Clinical Operations contact for the study, and and to Genentech Drug Safety CTV oversight mail box at:
ctvist_drugsafety@gene.com
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queries

Queries related to the Study will be answered by Investigator-Sponsor. However, responses to all safety queries from regulatory authorities or for publications will be discussed and coordinated between the Parties. The Parties agree that Genentech/Roche shall have the final say and control over safety queries relating to the Product. Investigator-Sponsor agrees that it shall not answer such queries from regulatory authorities and other sources relating to the Product independently but shall redirect such queries to Genentech.  
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests for information or review of data are met. The Parties will clearly indicate on the request the reason for urgency and the date by which a response is required.
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safety crisis management

In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), on the conduct of the Study, may lead to labeling changes or regulatory actions that limit or restrict the way in which the Product is used, or where there is media involvement, the Party where the crisis originates will contact the other Party as soon as possible.  
The Parties agree that Genentech/Roche shall have the final say and control over safety crisis management issues relating to the Product. Investigator-Sponsor agrees that it shall not answer such queries from media and other sources relating to the Product but shall redirect such queries to Genentech.  
1. Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 2. Soria JC, Ohe Y, Vansteenkiste J, et al: Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med, 2017 3. Remon J, Steuer CE, Ramalingam SS, et al: Osimertinib and other third- generation EGFR TKI in EGFR-mutant NSCLC patients. Ann Oncol 29:i20-i27, 2018 4. Gainor JF, Shaw AT, Sequist LV, et al: EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non- Small Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res 22:4585-93, 2016 5. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373:1627-39, 2015 6. Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540-50, 2016 7. Rittmeyer A, Barlesi F, Waterkamp D, et al: Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389:255-265, 2017 8. Lisberg A, Cummings A, Goldman JW, et al: A Phase II Study of Pembrolizumab in EGFRMutant, PD-L1+, Tyrosine Kinase Inhibitor Naive Patients With Advanced NSCLC. J Thorac Oncol 13:1138-1145, 2018 9. Langer CJ, Gadgeel SM, Borghaei H, et al: Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the openlabel KEYNOTE-021 study. Lancet Oncol 17:1497-1508, 2016 10. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al: Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med, 2018 11. Soria JC, Wu YL, Nakagawa K, et al: Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 16:990-8, 2015 12. Naumov GN, Nilsson MB, Cascone T, et al: Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res 15:3484-94, 2009 13. Ichihara E, Ohashi K, Takigawa N, et al: Effects of vandetanib on lung adenocarcinoma cells harboring epidermal growth factor receptor T790M mutation in vivo. Cancer Res 69:5091-8, 2009 14. Seto T, Kato T, Nishio M, et al: Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 15:1236-44, 2014 15. Furuya N, Fukuhara T, Saito H, et al: Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. Journal of Clinical Oncology 36:abstract 9006, 2018 16. Manegold C, Dingemans AC, Gray JE, et al: The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC. J Thorac Oncol 12:194-207, 2017 17. Tao L, Huang G, Shi S, et al: Bevacizumab improves the antitumor efficacy of adoptive cytokine-induced killer cells therapy in non-small cell lung cancer models. Med Oncol 31:777, 2014 18. Shi S, Wang R, Chen Y, et al: Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models. PLoS One 8:e65757, 2013 19. Kowanetz M, Socinski MA, Zou W, et al: IMpower150: Efficacy of atezolizumab plus bevacizumab and chemotherapy in 1L metastatic nonsquamous NSCLC across key subgroups. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois Abstract CT076, 2018 20. Socinski MA, Jotte RM, Cappuzzo F, et al: Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 378:2288-2301, 2018 21. Cappuzzo F, McCleod M, Hussein M, et al: Progression-free survival (PFS) and safety analysis from a randomized phase 3 study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab
(atezo) as first-line (1L) therapy in advanced non-squamous NSCLC. . Abstract presented at: the ESMO 2018 Congress; Munich, Germany: October 19-23, 2018. Abstract LBA53.  
22. Fehrenbacher L, Spira A, Ballinger M, et al: Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387:1837-46, 2016 23. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:1909-20, 2016 24. Fridman WH, Pages F, Sautes-Fridman C, et al: The immune contexture in human tumours:
impact on clinical outcome. Nat Rev Cancer 12:298-306, 2012 25. Angell H, Galon J: From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol 25:261-7, 2013 26. Tarhini AA, Edington H, Butterfield LH, et al: Immune monitoring of the circulation and the tumor microenvironme nt in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One 9:e87705, 2014 27. Frelinger J, Ottinger J, Gouttefangeas C, et al: Modeling flow cytometry data for cancer vaccine immune monitoring. Cancer Immunol Immunother 59:1435-41, 2010 28. Chan C, Feng F, Ottinger J, et al: Statistical mixture modeling for cell subtype identification in flow cytometry. Cytometry A 73:693-701, 2008 29. Sarzotti-Kelsoe M, Cox J, Cleland N, et al: Evaluation and recommendations on good clinical laboratory practice guidelines for phase I-III clinical trials. PLoS Med 6:e1000067, 2009 30. Nair SK, De Leon G, Boczkowski D, et al: Recognition and killing ofautologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. Clin Cancer Res 20:2684-94, 2014 31. Murdoch DM, Suchard MS, Venter WD, et al: Polychromatic immunophenotypic characterization of T cell profiles among HIV-infected patients experiencing immune reconstitution inflammatory syndrome (IRIS). AIDS Res Ther 6:16, 2009 32. Murdoch DM, Staats JS, Weinhold KJ: OMIP-006: phenotypic subset analysis of human T
regulatory cells via polychromatic flow cytometry. Cytometry A 81:281-3, 2012 33. Nixon AB, Pang H, Starr MD, et al: Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance). Clin Cancer Res 19:6957-66, 2013 34. Liu Y, Starr MD, Brady JC, et al: Biomarker signatures correlate with clinical outcome in refractory metastatic colorectal cancer patients receiving bevacizumab and everolimus. Mol Cancer Ther 14:1048-56, 2015 35. Nixon AB, Sibley A, Hatch AJ, et al: Blood-based biomarkers in patients (pts) with metastatic colorectal cancer (mCRC) treated with FOLFOX or FOLFIRI plus bevacizumab (Bev), cetuximab (Cetux), or bev plus Cetux: Results from CALGB 80405 (Alliance). Journal of Clinical Oncology 34:abstract 3597, 2016 36. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989 37. Jung SH, Kim KM: On the estimation of the binomial probability in multistage clinical trials.  
Stat Med 23:881-96, 2004 38. Koyama T, Chen H: Proper inference from Simon's two-stage designs. Stat Med 27:3145-54, 2008
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15.0 appendices

Appendix 1: Performance status criteria Appendix 2: Measurement of effect Appendix 3: Cockcroft‐Gault equation  
| APPENDIX 1: PERFORMANCE STATUS CRITERIA: ECOG Grade Description 0 Fully active,abletocarryon all prediseaseactivities  withoutrestriction (Karnofsky 90‐100). 1 Restricted in physically strenuous activity but ambulatory and able to carryout work of a light or sedentary nature,e.g.,light housework,officework  (Karnofsky 70‐80). 2 Ambulatory andcapable of allself‐care,butunableto  carry outany workactivities.Up and aboutmorethan  50 percentof waking hours (Karnofsky 50‐60). 3 Capable of only limited self‐care, confined to bed or chair 50 percentor moreofwakinghours  (Karnofsky 30‐40). 4 Completely disabled. Cannot carryon anyself‐care. Totallyconfined to bed or chair (Karnofsky 10‐20) 5 Dead   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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appendix 2 measurement of effect

Although response is the primary endpoint of this trial, participants with measurable disease will be assessed by standard criteria. For the purposes of this study, participants should be re‐evaluated every as per time and events table in section 10.
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antitumor effect - solid tumors

Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).1. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
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definitions

Evaluable for Target Disease response. Only those participants who have measurable disease present at baseline, have received at least one dose of study therapy, and have had their disease re‐evaluated will be considered evaluable for target disease response. These participants will have their response classified according to the definitions stated below Evaluable Non‐Target Disease Response. Participants who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one dose of study therapy, and have had their disease re‐evaluated will be considered evaluable for non‐target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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disease parameters

Measurable disease. Measurable lesions are defined as those that can be accuratelymeasured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x‐ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in millimeters(or decimal fractions of centimeters). Note: Tumor lesions that are situated in a previously irradiated area are considered measurable if the lesion is not in bone. Malignant lymph nodes. To be considered pathologically enlargedand measurable, a lymph node must be
≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow‐up, only the short axis will be measured and followed.  
Non‐measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non‐ measurable disease.  
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non‐measurable.  
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non‐measurable) since they are, by definition, simplecysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non‐cystic lesions are present in the same participant, these are preferred for selection astargetlesions.  
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non‐ nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumorregressionin themeasurable dimension of the disease. Non‐target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non‐target lesions** and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow up.
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methods for evaluation of disease

All measurements should be taken and recorded in metric notation using a ruler, calipers, or a digital measurement tool. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow‐up. Imaging‐based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial (*e.g.*, skin nodules and palpable lymph nodes) and ≥10 mm in diameter as assessed using calipers (*e.g.*, skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x‐ray. Lesions on chest x‐ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung; however, CT is preferable. Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size of a measurable lesion should be twice the slice thickness. MRI is also acceptable in Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type andsite of disease. Furthermore, as with CT, the modality used at follow‐up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence.  
It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath‐hold scanning techniques, if possible.  
FDG‐PET. While FDG‐PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG‐PET scanning to complement CT scanning in assessment of progression
(particularly possible 'new' disease). New lesions on the basis of FDG‐PET imaging can be identified according to the following algorithm:
(a) Negative FDG‐PET at baseline, with a positive FDG‐PET at follow‐up is a sign of PD based on a new lesion.  
(b) No FDG‐PET at baseline and a positive FDG‐PET at follow‐up: If the positive FDG‐PET at follow‐up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG‐
PET at follow‐up is not confirmed as a new site of disease on CT, additional follow‐up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG‐PET scan). If the positive FDG‐PET at follow‐up corresponds to a pre‐existing site of disease on CT that is not progressing on the basis of the anatomic images, this is notPD.  
(c) FDG‐PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG‐PET in this circumstance should be prospectively described in the protocol and supported by disease‐specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG‐
PET and biopsy resolution/sensitivity.  
Note: A 'positive' FDG‐PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.  
PET‐CT. At present, the low dose or attenuation correction CT portion of a combined PET‐CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET‐CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET‐CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed.  
Response Criteria required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 113
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evaluation of target lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non‐
target) must have reduction in short axis to <10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD,
taking as reference the smallest sum diameters while on study.
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evaluation of non-target lesions

Complete Response (CR): Disappearance of all non‐target lesions and normalization of tumor marker level. All lymph nodes must be non‐pathological in size (<10 mm short axis).  
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response.  
Non‐CR/Non‐PD: Persistence of one or more non‐target lesion(s) and/or maintenance of tumor marker level above the normal limits.  
Progressive Disease (PD): Appearance of one or more new lesions and/or *unequivocal progression* of existing non‐target lesions. *Unequivocal progression* should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.  
Although a clear progression of "non‐target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or PI).
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evaluation of new lesions

The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning technique, imaging modality, or findings thought to represent something other than tumor (for example, some 'new' bone lesions may be simply healing or flare of pre‐existing lesions). However, a lesion identified on a follow‐up scan in an anatomical location that was not scanned at baseline is considered new and will indicate PD. If a new lesion is equivocal (because of small size etc.), follow‐up evaluation will clarify if it truly represents new disease and if PD is confirmed, progression should be declared using the date of the initial scan on which the lesion was discovered.
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evaluation of best overall response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmationcriteria.  
| Target Lesions   | Non‐Target                                                                                                           | New Lesions               | Overall   | Best Overall Response when      |
|------------------|----------------------------------------------------------------------------------------------------------------------|---------------------------|-----------|---------------------------------|
| Lesions          | Response                                                                                                             | Confirmation is Required* |           |                                 |
| CR               | CR                                                                                                                   | No                        | CR        | >4 wks Confirmation**           |
| CR               | Non‐CR/Non‐PD                                                                                                        | No                        | PR        |                                 |
| CR               | Not evaluated                                                                                                        | No                        | PR        | >4 wks Confirmation**           |
| PR               | Non‐CR/Non‐                                                                                                          | No                        | PR        |                                 |
| PD/not evaluated |                                                                                                                      |                           |           |                                 |
| SD               | Non‐CR/Non‐                                                                                                          | No                        | SD        | Documented at least once >4 wks |
| PD/not evaluated | from baseline**                                                                                                      |                           |           |                                 |
| PD               | Any                                                                                                                  | Yes or No                 | PD        |                                 |
| Any              | PD***                                                                                                                | Yes or No                 | PD        | no prior SD, PR or CR           |
| Any              | Any                                                                                                                  | Yes                       | PD        |                                 |
| ∗                | See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.                                   |                           |           |                                 |
| **               | Only for non‐randomized trials with response as primaryendpoint.                                                     |                           |           |                                 |
| ***              | In exceptional circumstances, unequivocal progression in non‐target lesions may be  accepted as disease progression. |                           |           |                                 |
13 administrative and ethicalconsiderations
for participants with measurable disease

progression even after discontinuation of treatment.
For Participants with Non‐Measurable Disease (*i.e.*, Non‐Target Disease)  
Non‐Target Lesions New Lesions Overall Response  
| CR                | No                                                                                                                                                                                                                                         | CR             |
|-------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|
| Non‐CR/non‐PD     | No                                                                                                                                                                                                                                         | Non‐CR/non‐PD* |
| Not all evaluated | No                                                                                                                                                                                                                                         | not evaluated  |
| Unequivocal PD    | Yes or No                                                                                                                                                                                                                                  | PD             |
| Any               | Yes                                                                                                                                                                                                                                        | PD             |
| ∗                 | 'Non‐CR/non‐PD' is preferred over 'stable disease' for non‐target disease since SD is  increasingly used as an endpoint for assessment of efficacy in some trials so to assignthis category when no lesions can be measured is not advised |                |  
Duration of Response Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the lastdisease evaluation).  
Duration of overall complete response: The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented, or death due to any cause. Participants without eventsreportedare censored at the last disease evaluation.  
Duration of stable disease: Stable disease is measured from the start ofthe treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.  
Appendix 3:  
  
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 119