Do not make unauthorized copies. 16.5 Safety Analyses Safety endpoints include all adverse events (CTCAE 5), laboratory safety assessments, and physical examination findings. 16.6 Interim Analysis An interim analysis for efficacy, futility, and potential sample size re-estimation will be conducted by an independent data monitoring committee (IDMC) when 40 PFS events have been achieved (60% information fraction). Based on the Lan-D eMets method for group sequential trials using O’Brien-Fleming boundaries (Reboussin, DeMets et al. 2000), the levels of significance for the interim and final analyses are alpha=0.00762 and alpha=0.0476, respectively. Based on the results of the interim analysis, the IDMC will make one of the following four recommendations to the sponsor: • Terminate the study for efficacy (p<0.00762 at the interim analysis); • Continue the study as planned; • Increase the sample size to 120 events; • Terminate the study for futility. Provided that the IDMC does not recommend terminating the study early for efficacy, the conditional power of the planned final analysis at 67 events will be computed using the methodology of (Jennison and Turnbull 2000) under the assumption that the observed hazard ratio at the interim analysis represents the true effect. In terms of the HR observed at the interim analysis, these rules can be translated (approximately) as follows: • If the HR is less than 0.43, terminate for efficacy • If the HR is in the range from 0.43 to 0.51, continue as planned. • If the HR is in the range from 0.51 to 0.61 (i.e., conditional power in the range from 50% to 80%), increase the sample size to 120 events. • If the HR is greater than 0.61 (i.e., conditional power less than 50%), terminate for futility. 17.0 DOCUMENTATION A log of all patients evaluated for this protocol must be maintained at each site. Patients excluded from admission will be provided with a clear explanation of the specific reasons why they have been excluded from the study. Patients who are included will be assigned a patient identification number. Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide IND 014205 CL-PTL-130 Version: 03 Page 66 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. For each patient treated with the study drug(s), the Investigator or their designee is required to prepare and maintain case histories that include all observations and other data pertinent to the investigation. This will include all source documents needed to verify the accuracy of all observations and other data contained in the eCRFs on each study patient. The Investigator or his/her designee is required to retain the records related to the trial for a period of 2 years following the date a marketing application is approved for the indication being investigated. If no application is to be filed or if the application is not approved for such indication, the records must be retained until 2 years after the investigation is discontinued and the regulatory agencies are notified. The Investigator shall retain study drug disposition records and source documents for the maximum period required by the country and institution in which the study will be conducted, or for the period specified by Gradalis, whichever is longer. The Investigator must contact Gradalis, Inc. prior to destroying any records associated with the study. If the Investigator withdraws from the study (e.g., relocation, retirement), the records shall be transferred to a mutually agreed upon designee (e.g., another investigator, IRB). Notice of such transfer will be given in writing to Gradalis, Inc. 17.1 Case Report Form (CRF) Procedures Data for this study will be captured in the EDC. The investigator or his/her designee is responsible for recording all data relating to the trial on the eCRFs in accordance with the site’s contract with Gradalis. The investigator must verify that all data entries on the eCRFs are accurate and correct. Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide IND 014205 CL-PTL-130 Version: 03 Page 67 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.