1998, Klingebiel, Pertl et al. 1998, Leavey and Collier 2008, Stahl, Ranft et al. 2011) . Presentation with localized disease is associated with a 6-year event free survival (EFS) rate of 69% and overall survival (OS) rate of 72% (Leavey, Mascarenhas et al. 2008). If patients present with metastatic disease at diagnosis, the 6-year event free survival in this analysis significantly deteriorated to 28% with OS 29% (Guerney, Swensen et al. 1999, Miser, Goldsby et al. 2007, Leavey, Mascarenhas et al. 2008). Other reports have shown worse overall survival in p atients who relapse with a marked reduction in overall survival of only 12% at 5 years, and 19% at 2 years (Leavey, Mascarenhas et al. 2008). Factors like site of recurrence (localized, metastatic, combined localized and metastatic) and time to relapse (<2 years or >2 years) play im portant prognostic factors for survival in recurrent Ewing’s sarcoma ( Table 1). For relapses that occur Ph III Ewing’s Sarcoma Vigil ± Irinotecan +Temozolomide IND 014205 CL-PTL-130 Version: 03 Page 18 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. within the first 2 years after initial diagnosis, which make up 72% of relapses (Stahl, Ranft et al. 2011) , the 2 -year OS was 7% (Shankar, Ashley et al. 2003) , 5-year EFS was 5% (Bacci, Ferrari et al. 2003), and 5-year OS was 7% (Stahl, Ranft et al. 2011). In addition, response status to frontline therapy like recurrence (initial response followed by relapse) versus refractory (disease progression on first line regimen) appear to correlate with clinical outcome, while the survival rate is dismal for patients that do not respond to frontline therapy (Casey, Wexler et al. 2009) . Table 1 . Relapse from Time of Initial Treatment PI Number Patients Primary Metastati c Disease at Diagnosis 5-year Overall Survival After First Relapse 5-year OS: Relapse < 2 years from Initial Diagnosis 5-year OS: Relapse ≥ 2 years from Initial Diagnosis Stahl 2011 714 35% 13.0% 7.0% 29.0% Leavey 2008 262 46% 12.0% 7.0% 30.0% Bacci 2003 195 0% 13.8% 2.5% 14.3% Rodriguez - Galindo 2002 71 42% 23.7% 5.0% 34.9% Shankar 2003 64 0% 10.0% 7.0% 45.0% Barker 2005 55 38% 23.0% 12.0% 48.0% McTiernan 2006 114 47% 15.2% 6.7%* 31.6% *Relapse free interval defined as < or ≥ 18 months. The NCCN guidelines do not provide standard of care recommendations for second-line treatment and only 9-13% of patients achieve a second disease free remission (Bacci, Ferrari et al. 2003, Barker, Pendergrass et al.