Journal: Nature medicine
Phase 1/2 trial design
- Population: 37 patients with relapsed/refractory Ewing sarcoma.
- Regimen: Trabectedin as a 1-hour IV infusion on day 1 combined with low‑dose irinotecan on days 2 and 4 of a 21‑day cycle.
- Primary aims: Define safety, tolerability, recommended phase 2 dose (RP2D), and objective response rate.
- Secondary aims: Progression-free survival (PFS), 6‑month PFS, duration of response, and F‑FLT PET avidity, plus translational correlatives (molecular profiling, ctDNA, PK, transcriptomics).
Dose and safety
- RP2D:
- Trabectedin: 1.0 mg/m² over 1 hour (day 1)
- Irinotecan: 25 mg/m² (days 2 and 4) every 21 days.
- Toxicity: Generally manageable; grade ≥3 events >15% at RP2D were myelosuppression and ALT elevation.
Efficacy
- Phase 2 objective response rate: 33%.
- Objective response rate including RP2D patients treated in phase 1: 39%.
- 6‑month PFS: 48%.
Mechanistic/biologic findings
- Ewing sarcoma dependency: Strictly dependent on the EWS::FLI1 fusion transcription factor; no prior agent had shown clinical reversal of its activity.
- Trabectedin mechanism: Above a threshold concentration can reverse EWS::FLI1 transcriptional activity, and is potentiated by low‑dose irinotecan in vivo.
- Transcriptional profiling: In patient tumors showed reversal of the EWS::FLI1‑driven transcriptome in a subset of cases, consistent with on‑target activity.
Implications
- Clinical activity: The combination demonstrates clinically meaningful activity with a tolerable safety profile in relapsed/refractory Ewing sarcoma.
- Mechanistic support: The mechanistic data support that this regimen can modulate the EWS::FLI1 program in patients, justifying further development in international cooperative group trials (NCT04067115).