Liposomal irinotecan together with vincristine and temozolomide (NALIRI-VT) for patients with relapsed or refractory Ewing sarcoma: A two-cohort, phase 1a/1b study.

Abstract

11518 Background: To define the safety and preliminary efficacy of liposomal irinotecan together with vincristine and temozolomide in children and adults with Ewing sarcoma, respectively. Methods: Patients with relapsed or refractory Ewing sarcoma were enrolled in cohort A (children) or cohort B (adults), respectively. For each cohort, a fixed dose of vincristine (1.4mg/m 2 max 2mg i.v. D 1,8,15 ) and temozolomide (100mg/m 2 /d p.o. D 1-5 ) q21d were given. In phase 1a portion, four dose levels of weekly infused liposomal irinotecan (level 1-4, 25mg/m 2 , 30mg/m 2 , 35mg/m 2 and 40mg/m 2 ) were designed. 3+3 dose-escalation method was used to explore the maximum tolerated dose (MTD), defined as no more than 30% patients appeared dose-limited toxicity (DLT) in first two cycles (six weeks). In the phase 1b portion, MTD would be used and a maximum of 12 patients were allowed in each cohort at this level in total. Results: 15 children and 18 adults were enrolled in phase 1a portion. 9 more children and 5 more adults were enrolled in phase 1b portion. Finally, 12 children and 11 adults were treated at MTD level. In phase 1a portion, no DLT was found at level 1-2. For level 3, no DLT (0/3) was found in cohort A, while one DLT (1/6) of hematologic toxicity was found in cohort B. For level 4, two DLTs (2/6) were found in cohort A, both of whom were due to hematologic toxicity. For cohort B, two DLTs (2/6) was found at this level. One of them was serious anorexia. The other one was hematologic toxicity together with serious nausea and vomiting, anorexia, fatigue. Level 3 was chosen for MTD. Grade 3/4 toxicities were found in hematologic toxicity (most common), anorexia, fatigue, nausea or vomiting, pain and diarrhea. Better efficacy was shown at higher levels (level 3 and level 4) in both cohorts. For cohort A, objective response rate (ORR) was 0 (0/3), 33.3% (1/3), 66.7% (2/3) and 66.7% (4/6) at level 1-4, respectively. For cohort B, ORR was 33.3% (1/3), 33.3% (1/3), 83.3% (5/6) and 66.7% (4/6). Data for survival in phase 1a and data of phase 1b were not matured. Conclusions: We showed that liposomal irinotecan infused weekly at 35mg/m 2 in NALIRI-VT regimen was well tolerated and showed promising efficacy in both children and adults. Clinical trial information: NCT06340204 . Summary of DLTs and responses in phase 1a portion. Dose level Liposomal Irinotecan IV Dose (mg/m 2 /d) D 1,8,15 # of Evaluable Patients # of DLTs in the first two cycles Best of Response (BOR) Cohort A Children 1 25 3 0 1 SD, 2 PD 2 30 3 0 1 PR, 1 SD, 1 PD 3 35 3 0 1 CR, 1 PR, 1 SD 4 40 6 2 1 CR, 3 PR, 2 PD Cohort B Adults 1 25 3 0 1 SD->CR * , 2 SD 2 30 3 0 1 PR, 2 SD 3 35 6 1 5 PR, 1 PD 4 40 6 2 1 CR, 3 PR, 2 SD * One patient was first treated at level 1, showed no AE at this level and SD was recorded at first evaluation. When safety of the next level 2 dose was confirmed, this patient received the higher level 2 dose, and CR was recorded at the following evaluations.