Do not make unauthorized copies. 16.3 Analysis Populations The intent-to -treat (ITT) population will include all randomized subjects. All efficacy analyses will be completed in the ITT population. The Safety population will include all patients who receive study treatment and patients will be analyzed according to actual treatment received. All safety analyses will be completed in the Safety population. 16.4 Efficacy Analyses 16.4.1 Primary Efficacy Analysis The primary endpoint of PFS is the time from randomization to progression according to RECIST version 1.1 or death. The distributions of PFS in the two arms will be compared using a two-sided log-rank test at the alpha=0.0476 level of significance 16.4.2 Secondary Efficacy Analyses A fixed sequence testing procedure will be used to control the overall level of significance for the analysis of the secondary endpoints of OS and ORR. If the primary analysis of PFS is statistically significant (p<0.0476), then OS will be analyzed using a two -sided test at the alpha=0.0476 level of significance. In addition, if the analysis of OS is statistically significant (p<00476), then ORR will be analyzed using a two-sided test at the alpha=0.0476 level of significance. However, if an earlier analysis is not statistically significant, the remaining analyses will be exploratory rather than confirmatory. The secondary endpoint of OS is defined as time from randomization to death or to the date of last follow -up. The date of last follow -up confirming survival will be used as the censoring date for subjects who are alive and/or do not have a known date of death. The analysis of OS will be conducted using the two -sided log-rank test. Kaplan-Meier OS curves will be displayed by treatment arm. Median OS and percent OS at fixed time points will be estimated. The secondary endpoint of ORR will be analyzed using Pearson’s chi -square test. Overall response rate (ORR) is defined as the proportion of patients who have a partial or complete response to therapy according to RECIST 1.1. ORR will be reviewed 6 months after treatment with Vigil. The analyses of all other secondary endpoints will be conducted using two-sided tests at the alpha=0.05 level of significance. Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide IND 014205 CL-PTL-130 Version: 03 Page 64 of 74 Confidential and proprietary information of Gradalis, Inc. Effective: 05-DEC-2018 It is the user’s responsibility to verify adequate training before executing a document. Do not make unauthorized copies. 16.4.3 Sensitivity Analyses of the Primary Endpoint Five sensitivity analyses of the primary endpoint will be conducted using each of the following modifications to the definition of PFS: • If the disease recurrence/progression assessment involves more than one date, the latest date will be used as the event date. • If disease recurrence or death occurs right after missing data for a scheduled radiographic disease assessment (including missing the assessment or assessment results in an unevaluable status for overall response per RECIST 1.1), the patient will be censored at the date of the last radiographic disease assessment. • If a patient receives non -protocol treatment for Ewing’s Sarcoma, the patient will be treated as having progression at the date of the last radiographic disease assessment. • Patients missing baseline disease assessment will be treating as had having progression at the date of randomization. • For equivocal findings of recurrence (e.g., very small and uncertain new lesions; cystic changes or necrosis in existing lesions) for whom treatment continues until the next scheduled assessment, and if recurrence is confirmed at the next scheduled assessment, the date of recurrence should be the date when recurrence was confirmed. 16.4.4 Sensitivity Analysis of Overall Survival A sensitivity analysis of OS will be conducted in which subjects who are crossed over to Vigil therapy will be censored at the time of crossover . 16.4.5 Subgroup Analyses of the Primary (PFS) and Key Secondary Endpoints (OS, ORR) Subgroup analyses will be conducted in the following subsets of the ITT population: • Race / ethnicity • Study site / region • Age group ( <15 years (low), ≥15 years (high) ) • Gender • Number of doses received (≤median number of doses administered, >median number of doses administered) • Number of lines of prior treatments including chemotherapy and radiation • At time of diagnosis: localized vs. metastatic disease • At time of diagnosis: skeletal vs. extraskeletal • At time of diagnosis: tumor volume/burden (<100ml or 8cm vs >100ml or 8cm) • Resp onse to frontline therapy (CR vs. PR vs. SD vs. progressive disease) • Time to first recurrence: <2 years, > 2 years Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide IND 014205 CL-PTL-130 Version: 03 Page 65 of 74 Confidential and proprietary information of Gradalis, Inc. Effective: 05-DEC-2018 It is the user’s responsibility to verify adequate training before executing a document.