2003;21(24):4642 -49. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/ MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 264 12.6. Appendix 6. Description of the iRECIST Process for Assessment of Disease Progression Assessment at Screening and Prior to RECIST 1.1 Progression Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST assessment. Assessment and Decision at RECIST 1.1 Progression For patients who show evidence of radiological PD by RECIST 1.1 as determined by the Investigator, the Investigator will decide whether to continue a patient on study treatment until repeat imaging is obtained (using iRECIST for patient management (see Table 10 and Figure 14 in earlier sections of this document) . This decision by the site investigator should be based on the patient’s overall clinical condition. Clinical stability is defined as the following: • Absence of symptoms and signs indicating clinically significant progression of disease • No decline in ECOG performance status • No requirements for intensified management, including increased analgesia, radiation, or other palliative care Any patient deemed clinically unstable should be discontinued from study treatment at site-assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging for confirmation of PD by iRECIST. If the Investigator decides to continue treatment, the patient may continue to receive study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/ MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 265 iRECIST, per Investigator assessment. Images should continue to be archived for potential retrospective BICR. Tumor flare may manifest as any factor causing radiographic progression p er RECIST 1.1, including: • Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and ≥5 mm from nadir o Note: the iRECIST publication uses the terminology “sum of measurements”, but “sum of diameters” will be used in this protocol, consistent with the original RECIST 1.1 terminology. • Unequivocal progression of non-target lesion(s) identified at baseline • Development of new lesion(s) iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors caused the progression. At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as usual. New lesions will be classified as measurable or non-measurable, using the same size thresholds and rules as for baseline lesion assessment in RECIST 1.1. From meas urable new lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. The sum of diameters of these lesions will be calculated, and kept distinct from the sum of diameters for target lesions at baseline. All other new le sions will be followed qualitatively as New Lesions – Non-target. Assessment at the Confirmatory Imaging SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/ MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 266 On the confirmatory imaging, the patient will be classified as progression confirmed (with an overall response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). Confirmation of Progression Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following occurs: • Any of the factors that were the basis for the initial iUPD show worsening o For target lesions, worsening is a further increase in the sum of diamete rs of ≥5 mm, compared to any prior iUPD time point o For non-target lesions, worsening is any significant growth in lesions overall, compared to a prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 1.1 o For new lesions, worsening is any of these: § An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time point § Visible growth of new non-target lesions § The appearance of additional new lesions • Any new factor appears that would have triggered PD by RECIST 1 .1 Persistent iUPD Progression is considered not confirmed, and the overall response remains iUPD, if: • None of the progression-confirming factors identified above occurs AND SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/ MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 267 • The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold (by RECIST 1.1) Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on which iUPD is seen. This may correspond to the next visit in the original visit schedule. The assessment of the subsequent confirmation imaging proceeds in an identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. Resolution of iUPD Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: • None of the progression-confirming factors identified above occurs, AND • The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold. The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR if all lesions resolve. In this case, the initial iUPD is considered to be pseudo -progression, and the level of suspicion for progression is “reset”. This means that the next visit that shows radiographic progression, whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a response of iCPD can be assigned. Management Following the Confirmatory Imaging If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the patient continues to be clinically stable, study treatment may continue and follow the regular imaging schedule. If PD is confirmed, patients will be discontinued from study treatment. NOTE: If a patient has confirmed radiographic progression (iCPD) as defined above, but the patient is achieving a clinically meaningful benefit, an exception to continue study treatment may be considered following consultation with the sponsor. In this case, if study treatment is SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/ MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 268 continued, tumor imaging should continue to be performed following the interva ls as outlined below. Detection of Progression at Visits After Pseudo-progression Resolves After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated by any of the following events: • Target lesions o Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) either for the first time, or after resolution of previous pseudo -progression. The nadir is always the smallest sum of diameters seen during the entire trial, either before or after an instance of pseud o-progression. • Non-target lesions o If non-target lesions have never shown unequivocal progression, their doing so for the first time results in iUPD. o If non-target lesions have shown previous unequivocal progression, and this progression has not resolved, iUPD results from any significant further growth of non-target lesions, taken as a whole. • New lesions o New lesions appear for the first time o Additional new lesions appear o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion sum of diameters, from the nadir value of that sum o Previously identified non-target lesions show any significant growth SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/ MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 269 If any of the events above occur, the overall response for that visit is iUPD, and the iUPD evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. Progression must be confirmed before iCPD can occur. The decision process is identical to the iUPD confirmation process for the initial PD, with one exception: if new lesions occurred at a prior instance of iU PD, and at the confirmatory imaging the burden of new lesions has increased from its smallest value (for new target lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD. Additional details about iRECIST are provided in the iRECIST publication (Seymour et al, 2017).