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<p>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 <sup>18</sup>F-fluorothymidine positron emission tomography (<sup>18</sup>F-FLT PET) avidity of ES tumors. The RP2D was trabectedin 1.0 mg m<sup>−</sup><sup>2</sup> over 1 hour (day 1) and irinotecan 25 mg m<sup>−</sup><sup>2</sup> (days 2 and 4) of a 21-day cycle. Toxicities were manageable with grade 3 or higher toxicities (&gt;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 <sup>18</sup>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: <a href="http://clinicaltrials.gov/study/NCT04067115">NCT04067115</a>.</p>

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Trabectedin and low-dose irinotecan to target EWS::FLI1 in Ewing sarcoma: a phase 1/2 trial

  • 期刊论文

  • 发表日期：

    2026年4月16日

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  • Patrick J. Grohar,
  • Rachel Heise,
  • Mary Frances Wedekind,
  • Karla Ballman,
  • Leo Mascarenhas,
  • Steven G. DuBois,
  • Robert G. Maki,
  • Elissa A. Boguslawski,
  • Jenna M. Gedminas,
  • Elizabeth R. Wilson,
  • Elaine Thomas,
  • Blair Segers,
  • Lea F. Surrey,
  • Cora Ricker,
  • Kelly Klega,
  • Fariba Navid,
  • Gretchen Y. Lam,
  • Stephanie The,
  • Rebecca Kaufman,
  • Ryan D. Roberts,
  • Masanori Hayashi,
  • Esther Mena,
  • Lindsey Overman,
  • Cody Peer,
  • Keith Schmidt,
  • Mark S. Diamond,
  • William D. Figg,
  • Rochelle Bagatell,
  • M. Liza Lindenberg,
  • Peter L. Choyke,
  • Brian D. Crompton,
  • Brigitte C. Widemann,
  • John W. Glod,
  • Theodore W. Laetsch,
  • Denise K. Reinke,
  • Rashmi Chugh

摘要

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.