0 Dead. J1790 / Version 7.0/ December 10, 2020 78 APPENDIX B : Management Algorithms These general guidelines constitute guidance to the Investigator and may be supplemented by discussions with the Protocol Chair representing the IND Sponsor. The guidance applies to all immuno -oncology (I -O) agents and regimens. A general principle is tha t differential diagnoses should be diligently evaluated according to standard medical practice. Non -inflammatory etiologies should be considered and appropriately treated. Corticosteroids are a primary therapy for immuno -oncology drug -related adverse even ts. The oral equivalent of the recommended IV doses may be considered for ambulatory subjects with low - grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticostero ids. Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or therapeutic procedure, is recommended . The frequency and severity of the related adverse events covered by these algorithms will depend on the immuno -oncology agent or regimen being used. J1790 / Version 7.0 / December 10, 2020 79 J1790 / Version 7.0 / December 10, 2020 80 J1790 / Version 7.0 / December 10, 2020 81 J1790 / Version 7.0 / December 10, 2020 82 J1790 / Version 7.0 / December 10, 2020 83 J1790 / Version 7.0 / December 10, 2020 84 J1790 / Version 7.0 / December 10, 2020 85 J1790 / Version 7.0 / December 10, 2020 86 J1790 / Version 7.0/ December 10, 2020 87 APPENDIX C: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating Response in Solid Tumors RECIST version 1.1 will be used in this study for assessment of tumor response. While either CT or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. Disease Parameters Measurable disease : Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x -ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decim al fractions of centimeters). Note: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable unless there is evidence of progression in the irradiated site. Malignant lymph nodes. To be considered pathologically enlarged and 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 measu red 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, leptomen ingeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non -measurable. Note: Cystic lesions that meet the criteria for radiog raphically defined simple cysts should not be considered as malignant lesions (neither measurable nor non -measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesi ons, if they meet the definition of measurability described above. However, if non -cystic lesions are present in the same subject , these are preferred for selection as target lesions. 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 it self 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 calcu lated 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 tumor regression in the measurable dimension of the disease. Non-target lesions : All other lesions (or sites of disease) including any measurable lesions over J1790 / Version 7.0/ December 10, 2020 88 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. 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. 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 -patholog ical in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a subject 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 Principal Investigator). 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 subject 's best r esponse assignment will depend on the achievement of both measurement and confirmation criteria. For Subjects with Measurable Disease (i.e., Target Disease) J1790 / Version 7.0/ December 10, 2020 89 Target Lesions Non-Target Lesions New Lesions Overall Response Best Overall Response when Confirmation is Required* CR CR No CR >4 wks. Confirmation** CR Non-CR/Non - PD No PR >4 wks. Confirmation** CR Not evaluated No PR PR Non-CR/Non - PD/not evaluated No PR SD Non-CR/Non - PD/not evaluated No SD Documented at least once >4 wks. from baseline** PD Any Yes or No PD no prior SD, PR or CR Any PD*** Yes or No PD 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 primary endpoint. *** In exceptional circumstances, unequivocal progression in non -target lesions may be accepted as disease progression. Note : Subjects with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “ symptomatic deterioration.” Every effort should be made to document the objective pr ogression even after discontinuation of treatment. Reference E.A.