An open-label, two-cohort, phase 1a/b study of weekly irinotecan hydrochloride liposome injection combined with vincristine and temozolomide (NALIRI-VT) in patients with advanced Ewing sarcoma.

PURPOSE: To determine the recommended phase II dose (RP2D), safety, and preliminary efficiency of liposomal irinotecan combined with vincristine and temozolomide (NALIRI-VT) in children and adult with relapsed/refractory Ewing sarcoma.

PATIENTS AND

METHODS

This open-label, non-randomized, two-cohort, two-part phase Ia/b study enrolled pediatric(Cohort A) and adults(Cohort B) with relapsed or refractory Ewing sarcoma. In phase 1a, NALIRI was administered as a weekly infusion using 3 + 3 dose-escalation design staring at 25 mg/m2 (level 1) and escalating to 30, 35, and 40 mg/m2 (levels 2-4). Vincristine (1.5 mg/m² Dmax 2 mg D1i.v.) and temozolomide (100 mg/m² D1-5 p.o.) were administered every 21 days. Primary objectives were safety and tolerability. The phase 1b portion expanded patient enrollment at the established recommended phase II dose (RP2D) to further evaluate safety and preliminary efficacy.

RESULTS

From April 15 to December 30, 2024, 24 children and 24 adults were enrolled (phase 1a: 16 and 19; phase 1b: +8 and +5, respectively). No dose-limiting toxicity (DLT) occurred at levels 1-2. At level 3, DLTs occurred in 0/3 children and 1/6 adults. At level 4, DLTs were observed in 2/6 patients in each cohorts. The RP2D was level 3 (NALIRI 35 mg/m²). At RP2D (11 children and 11 adults), confirmed objective response was 54.5% in both cohorts; clinical benefit rate was 81.8%(children) and 63.6%(adults). Median progression-free survival was 3.6 (95% confidence interval [CI], 2.7-NA) months, and median overall survival was 12.5 (95% CI, 7.9-NA) months. Grade 3/4 toxicities were mainly hematologic; common adverse events included anorexia, fatigue, nausea/vomiting, pain, and diarrhea.

CONCLUSIONS

NALIRI-VT shows manageable toxicity and promising activity in advanced Ewing sarcoma, justifying further investigation in phase II trials.