Journal article
Trabectedin and low-dose irinotecan to target EWS::FLI1 in Ewing sarcoma: a phase 1/2 trial
Nature medicine
04/16/2026
DOI: 10.1038/s41591-026-04340-7
PMID: 41991689
Abstract
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
F-fluorothymidine positron emission tomography (
F-FLT PET) avidity of ES tumors. The RP2D was trabectedin 1.0 mg m
over 1 hour (day 1) and irinotecan 25 mg m
(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
F-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 .
Details
- Title: Subtitle
- Trabectedin and low-dose irinotecan to target EWS::FLI1 in Ewing sarcoma: a phase 1/2 trial
- Creators
- Patrick J Grohar - C. S. Mott Children's HospitalRachel Heise - Cornell UniversityMary Frances Wedekind - National Institutes of HealthKarla Ballman - Mayo Clinic in ArizonaLeo Mascarenhas - Cedars-Sinai Medical CenterSteven G DuBois - Harvard UniversityRobert G Maki - Memorial Sloan Kettering Cancer CenterElissa A Boguslawski - C. S. Mott Children's HospitalJenna M Gedminas - University of IowaElizabeth R Wilson - Children's Hospital of PhiladelphiaElaine Thomas - National Cancer InstituteBlair Segers - Children's Hospital of PhiladelphiaLea F Surrey - Children's Hospital of PhiladelphiaCora Ricker - Harvard UniversityKelly Klega - Harvard UniversityFariba Navid - Children's Hospital of Los AngelesGretchen Y Lam - University of MichiganStephanie The - University of MichiganRebecca Kaufman - Children's Hospital of PhiladelphiaRyan D Roberts - Nationwide Children's HospitalMasanori Hayashi - Center for Cancer and Blood DisordersEsther Mena - National Institutes of HealthLindsey Overman - Sarcoma Alliance for Research through CollaborationCody Peer - National Institutes of HealthKeith Schmidt - National Institutes of HealthMark S Diamond - University of PennsylvaniaWilliam D Figg - National Cancer InstituteRochelle Bagatell - Children's Hospital of PhiladelphiaM Liza Lindenberg - National Cancer InstitutePeter L Choyke - National Institutes of HealthBrian D Crompton - Harvard UniversityBrigitte C Widemann - National Institutes of HealthJohn W Glod - National Institutes of HealthTheodore W Laetsch - Children's Hospital of PhiladelphiaDenise K Reinke - University of MichiganRashmi Chugh - University of Michigan
- Resource Type
- Journal article
- Publication Details
- Nature medicine
- DOI
- 10.1038/s41591-026-04340-7
- PMID
- 41991689
- NLM abbreviation
- Nat Med
- ISSN
- 1546-170X
- eISSN
- 1546-170X
- Publisher
- Springer Nature
- Grant note
- ZIC SC 006537 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01CA188314 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) ZIA BC 010656 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) Center of Excellence / Alex's Lemonade Stand Foundation for Childhood Cancer (Alex's Lemonade Stand Foundation) ZIE BC 011516 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) U01CA236220 / U.S. Department of Health & Human Services | National Institutes of Health (NIH)
- Language
- English
- Electronic publication date
- 04/16/2026
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9985153359402771
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