Do not make unauthorized copies. SCHEDULE OF ASSESSME NTS Procedure Prestudy Screening Day 1 of each Cycle1 (unless otherwise noted) End of TX Response Follow-Up (q 3mo±7 days) Until Progression Informed consent X X Medical History X Physical Examination X X X X X Toxicity (adverse events) from time of procurement X X Concomitant medications X X X X Performance Status X X X X Radiological Tumor Assessment (chest/abdomen/pelvis) within 4 weeks (must be post- procurement) every 6 weeks ± 7 days from Cycle 1 Within 45 days X CBC with differential X2 X X X X HIV testing, if applicable X Hepatitis testing, if applicable X Serum Chemistry X3 X X X X PBMC collection for Immune Function Analysis ≤ 1 week of tumor procurement X Cycles 2, 4, and 6 Day 1prior to chemotherapy administration X 3 months post EOT and q 6 months thereafter Plasma collection for ctDNA ≤ 1 week of tumor procurement X (Cycles 2, 3, 4, and 6 Day 1 prior to chemotherapy administration X Pregnancy Test (if applicable) X Vigil administration depending on randomization Day 15 q 21±3 days4 Injection Site Assessment Day 16 only (may be conducted at home)5 Temozolomide Days 1 – 5, q21 days Irinotecan Days 1 – 5, q21 days 1 Subjects who are stable at the end of Cycle 4, with prior approval by the Sponsor may conduct evaluations on Day 15 of each cycle (1 Cycle = 21 days ±3 days) 2 Obtain from medical records from standard preoperative hematology and chemistry panels. 3 Obtain from medical records from standard preoperative hematology and chemistry panels. 4 Cross- over subjects will receive Vigil on Day 1 5 Cross- over subjects will have assessment on Day 2 Statistical Analysis Plan IND 014205 Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide CL-SAP-00001 Version: 03 Page 9 of 19 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. Procedure Prestudy Screening Day 1 of each Cycle1 (unless otherwise noted) End of TX Response Follow-Up (q 3mo±7 days) Until Progression Survival Status X Long Term Follow Up6 Immunohistochemistry X7 SAMPLE SIZE JUSTIFIC ATION This is an open label randomized controlled Phase III clinical trial. Information concerning the predicted survival of the control group is limited, based on rarity of disease and few published reports. However expert advisors in the EWS field estimate a conservative one-year survival rate of 25% in the chemotherapy control group. The one-year survival rate of 60% in the Vigil treated group is estimated from EWS patients treated on the Vigil phase 1 protocol. These estimates correspond to a hazard ratio (HR) of 0.383 favoring Vigil over control. Assuming 1:1 randomization and the use of a two-sided log rank test at the alpha=0.0476 level of significance, 67 events will provide 90% power to detect an PFS HR of 0.45. Assuming a Group B (control group) median PFS of 6 months, a one-year accrual period, and a six-month follow -up period after randomization of the last subject, it is estimated that the total sample size (number of subjects) required to achieve 67 events is 114 (57 patients in each arm). An unblinded interim analysis will be conducted by an independent data monitoring committee (IDMC) when 40 PFS events have occurred. Based on the results of this interim analysis, the planned sample size may be increased to 120 events. If the sample size is increased to 120 events, then the study will have approximately 90% power to detect a true HR of 0.55. Note that if the sample size is increased to 120 events, then the accrual period will be extended to 24 months, with a 6-month follow -up period after randomization of the last patient. Under these assumpti ons, it is estimated that approximately 164 patients will need to be randomized in order to achieve 120 events. Section 16.6 provides further details. Definition of Progression Free Survival (PFS) • Progression free survival (PFS) is defined as the time from randomization to the event of disease recurrence/progression or death due to any cause. • Radiographic disease recurrence/progression will be assessed using the RECIST 1.1 criteria. If the disease recurrence/progression assessment involves more than one date, the earliest date will be used as the event date. 6 After progression, subjects will be contacted by phone quarterly for documentation of survival status. 7 These slides should correlate with tumor procured for vaccine manufacture. Statistical Analysis Plan IND 014205 Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide CL-SAP-00001 Version: 03 Page 10 of 19 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. • Patients who are alive and recurrence free at the time of analysis data cut-off, or who terminate the study for reasons other than disease progression or death, or who receive non-protocol treatment for Ewing’s Sarcoma, will be censored on the last assessment date at which a RECIST 1.1 evaluation of disease status was made. • Patients missing baseline disease assessment will be censored at date of randomization. • For equivocal findings of recurrence (e.g., very small and uncertain new lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If recurrence is confirmed at the next scheduled assessment, the date of recurrence should be the earlier date when recurrence was suspected. 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. Efficacy Analyses 8.1.1 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. 8.1.2 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 signific ant (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 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. Statistical Analysis Plan IND 014205 Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide CL-SAP-00001 Version: 03 Page 11 of 19 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.