Do not make unauthorized copies. INTRODUCTION This document describes the statistical methods and data presentations to be used in the summary and analysis of safety and efficacy data from Gradalis Protocol CL-PTL-130. Background information is provided for the overall study design and objectives. The reader is referred to the study protocol and case report forms (CRFs) for details of study conduct and data collection. STUDY RATIONALE The results from the Phase I Vigil trial show product safety (both short-term and long-term through 3+ years), confirm effective transgene expression (GMCSF) and RNAi [furin] silencing, and support the rationale of the immunotherapeutic triad, i.e., autologous tumor cell therapy with increased GMCSF expression and decreased TGFβ production shown to effectively modulate immunogenicity as evidenced by the correlation of IFNγ -ELISPOT responsiveness with overall survival and the elicitation of the CD4+ mediated circulating antibody responses against CT47 in two of the Phase 1 Ewing’s sarcoma patients. The preliminary evidence of safety, immune stimulation and clinical benefit from Vigil in patients with E wing’ s sarcoma treated in the Phase I setting supports evaluation of this therapy in a larger and randomized study and at earlier stage of recurrence (first recurrence). A lower tumor burden is typically associated with greater delay in progression with other immunotherapies. Mathematical modeling supports the concept of better control of disease progression with the combined use of effective chemotherapy (e.g., temozolomide/irinotecan as second line treatment in Ewing’s sarcoma) and immunotherapy (i.e., Vigil) in first relapse patient population (de Pillis, Gu et al. 2006). The utilization of the standard of care temozolomide/irinotecan regimen at investigator consensus defined dose and schedule appears to be minimally immunosuppressive and thus a reasonable option for combination with Vigil. Moreover, the temozolomide and irinotecan regimen at effective dose levels has low myelosuppressive toxicities (irinotecan 50mg/m 2/dose and temozol omide 100mg/m2/dose) and may increase the tumor antigen release and surface exposure of calreticulin (part of the specific danger -signaling system) as well as reduce the frequency of CD4+ CD25+ regulatory T-cells (Kim, Kim et al. 2010). In addition, given that Ewing’s sarcoma expression levels of type-1 associated chemokine ligands CXCL9, CXCL10, and CCL5 correlate with TIL expression chemokine receptors (CXCR3 and CCR5) (Berghuis, Santos et al. 2011) it is notable that temozolomide has been shown to enhance tumor matrix presentation of CXCL9 and CXCL10 in certain tumor models (Tan, Evrard et al. 2015). Temozolomide and irinotecan in combination have shown benign safety profiles without any Grade 3 treatment-related adverse events in seven combination treated Ewing’s Sarcoma patients of Part 2 of CL-PTL-121. Furthermore, clinical antitumor activity was demonstrated in 4 of the 7 combination treated patients, all of whom had previously failed temozolomide and irinotecan, as evidenced by 2 partial responses, one histological CR (autopsy) and one prolonged SD currently near 1 year in duration. Thus, the combination of Vigil, irinotecan and temozolomide may not only increase anti-tumor responses but also prolong time to progression and improvement of quality of life in Ewing’s sarcoma patients. Statistical Analysis Plan IND 014205 Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide CL-SAP-00001 Version: 03 Page 6 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. OBJECTIVES Primary objective(s) • To compare the progression free survival of subjects dosed with Vigil immunotherapy in combination with irinotecan and temozolomide vs. irinotecan and temozolomide. Secondary objective(s) • To determine and compare the overall survival of subjects with relapsed or refractory Ewing’s sarcoma dosed with Vigil immunotherapy in combination with irinotecan and temozolomide. • To determine the objective response rate (RECIST 1.1) of patients w ith metastatic Ewing’s sarcoma refractory or intolerant to 1 prior line of systemic chemotherapy treated with Vigil immunotherapy or dosed with Vigil immunotherapy in combination with irinotecan and temozolomide. • To determine the Vigil manufacturing success rate by gathering data from tumor tissue collection, Vigil construction, and test procedures. END POINTS Prima ry Endpoint The primary endpoint of PFS is the time from randomization to progression according to RECIST version 1.1 or death. Incomplete data resulting from patients who terminate the study for reasons other than disease progression or death will be censored in time-to-event analyses on the last assessment date at which a RECIST 1.1 evaluation of disease status was made. The distributions of PFS in the two arms will be compared using a two-sided log-rank test. Secondary Endpoint 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. All secondary analyses will be conducted using two-sided tests at the alpha=0.05 level of significance. Statistical Analysis Plan IND 014205 Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide CL-SAP-00001 Version: 03 Page 7 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. STUDY DESIGN This is a multicenter, 1:1 randomized Phase III study of intradermal autologous Vigil immunotherapy (1.0 x 106 cells/injection cells/injection; minimum of 4 to a maximum of 12 administrations) in combination with irinotecan and temozolomide in subjects with metastatic Ewing’s sarcoma Family of Tumors (ESFT) refractory /intolerant or recurrent to 1 prior line of chemotherapy. Participants undergoing a standard surgical procedure (e.g., tumor biopsy or palliative resection) may have tumor tissue harvested for manufacture of investigational product. Subjects meeting eligibility criteria including manufacture of a minimum of 4 immunotherapy doses of Vigil will receive: Group A (i) oral temozolomide 100 mg/m2 daily (Days 1 – 5, total dose 500 mg/m2/cycle), (ii) oral irinotecan 50 mg/m2 daily (Days 1 – 5, total dose 250mg/m2/cycle), and (iii) Vigil 1.0 x 106 cells/injection, intradermally on Day 15. OR Group B (i) oral temozolomide 100 mg/m2 daily (Days 1 – 5, total dose 500 mg/m2/cycle), and (ii) oral irinotecan 50 mg/m2 daily (Days 1 – 5, total dose 250mg/m2/cycle) If chemotherapy study drugs cannot be administered orally (i.e. size of capsule, nausea, etc.) it is physician ’s discretion to request iv administration of temozolomide at 100 mg/m 2 daily and/or irinotecan 20 mg/m2 daily intravenously. One cycle = 21 days. Screening for the main portion of the study may occur as early as one week but no later than 8 weeks following tumor procurement. Vigil is typically released approximately 3 weeks after the completion of the two-day manufacturing process. At the time of analysis t he subjects will be stratified by initial response to frontline treatment (recurrent versus refractory (progressive)). Participants will be managed in an outpatient setting. Hematologic function, liver enzymes, renal function and electrolytes will be monitored. Blood for immune function analyses including IFNγ -ELISPOT analysis of cytotoxic T cell response to autologous tumor antigens will be collected at tissue procurement, post-procurement screening and prior to chemotherapy administration on Day 1 of Cycles 2, 4, and 6, end of treatment (EOT), 3 months after EOT and every 6 months thereafter. Blood for exploratory ctDNA analysis will be collected at tissue procurement, prior to chemotherapy administration at baseline, prior to chemotherapy administration on Day 1 of Cycle s 2, 3, 4, and 6, and EOT. Statistical Analysis Plan IND 014205 Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide CL-SAP-00001 Version: 03 Page 8 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.