Trabectedin and low-dose irinotecan to target EWS::FLI1 in Ewing sarcoma: a phase 1/2 trial
Mené sur 37 patients atteints d'un sarcome d'Ewing récidivant ou réfractaire, cet essai de phase I/II détermine la dose maximale tolérée de la trabectidine en combinaison avec de faibles doses d'irinotécan puis évalue l'efficacité, du point de vue du taux de réponse objective, de cette combinaison
Ewing sarcoma (ES) is a bone and soft tissue sarcoma that is absolutely dependent on the EWS::FLI1 transcription factor for cell survival. No compound has been shown to reverse EWS::FLI1 activity in patients, and outcomes for relapsed patients remain poor. Trabectedin above a threshold concentration reverses the activity of EWS::FLI1 and is potentiated by low-dose irinotecan in vivo. This open-label phase 1/2 trial of trabectedin with irinotecan (SARC037) enrolled 37 relapsed/refractory patients with ES. The primary objectives were to determine the safety, tolerability, recommended phase 2 dose (RP2D; phase 1) and objective response rate (ORR; phase 2) of trabectedin administered as a 1-hour infusion in combination with low-dose irinotecan in patients with ES. The secondary objectives were to determine the progression-free survival (PFS), 6-month PFS, duration of response and 18F-fluorothymidine positron emission tomography (18F-FLT PET) avidity of ES tumors. The RP2D was trabectedin 1.0 mg m−2 over 1 hour (day 1) and irinotecan 25 mg m−2 (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-month PFS was 48%. Transcriptional profiling demonstrated reversal of the EWS::FLI1 transcriptome in tumors from a subset of patients. Additional correlative objectives captured molecular profiling, circulating tumor DNA levels, pharmacokinetics and 18F-FLT PET avidity. Here we provide the basis for further development of trabectedin/irinotecan for patients with ES by the international cooperative groups. ClinicalTrials.gov: NCT04067115.
Nature Medicine , résumé, 2026