Multicenter phase 1-2 trial of trabectedin and low-dose irinotecan in relapse or refractory Ewing sarcoma

Ewing sarcoma (ES) is a bone and soft tissue sarcoma that is dependent on the EWS::FLI1 transcription factor for cell survival. Outcomes for relapsed ES patients are poor. Trabectedin above a threshold concentration reverse the activity of EWSFLI1 and is potentiated by low-dose irinotecan in vivo. The multicenter phase 1-2 SARC037 evaluated trabectedin plus low-dose irinotecan in 37 patients with relapsed/refractory ES. The primary objectives of phase 1 were to determine safety, tolerability, and recommended phase 2 dose (RP2D), and the primary objective of phase 2 was to determine the objective response rate (ORR). The RP2D was trabectedin 1.0 mg/m² over 1 hour (day 1) plus irinotecan 25 mg/m² (days 2 and 4) of a 21-day cycle. Toxicities were manageable with grade 3 or higher toxicities (>15%) of myelosuppression and alanine aminotransferase elevations at RP2D. The phase 2 ORR was 33% (39% including RP2D phase 1 patients), and 6-months progression-free survival rate was 48%. The authors conclude that these results provide the basis for further development of trabecteding-irinotecan for ES.