Anlotinib, Vincristine and Irinotecan (AVI) for Advanced Ewing Sarcoma after Failure of Standard Multimodal Therapy: A Two-cohort, Phase Ib/II Trial
Mené sur 41 patients atteints d'un sarcome d'Ewing de stade avancé, cet essai de phase IB/II évalue la dose maximale tolérée d'irinotécan en combinaison avec la vincristine et l'anlotinib et l'efficacité de cette combinaison du point de vue du taux de réponse objective
Background : Both protracted irinotecan and anti‐angiogenesis therapy have shown promising efficacy against Ewing sarcoma (EWS). We conducted a phase Ib/II trial to first define the proper dose of irinotecan in combination with vincristine and anlotinib in refractory or recurrent EWS patients (phase Ib) and subsequently evaluate their efficacy (phase II). Methods : Patients diagnosed with recurrent or refractory EWS were enrolled and further categorized into cohort A (≥ 16 years) or cohort B (< 16 years). In the dose‐defining phase Ib portion, anlotinib was given daily at a fixed dose of 12 mg or 8 mg on days 1–14 within a 21‐day cycle, while a 3+3 design with dose de‐escalation was used to determine the most appropriate dose of irinotecan in each cohort starting from an initial dose of 20 mg/m2/d dx5x2. Recommended phase 2 dose (RP2D) was defined as the highest dose at which no more than 30% patients experienced a dose‐limiting toxicity (DLT) during the first two treatment courses. The next dose‐expanding phase II portion employed a conventional two‐stage study design model. The primary endpoint was objective response rate at 12 weeks (ORR12w), while the secondary endpoints included overall survival (OS), progression‐free survival (PFS) and failure‐free survival (FFS). Results : A total of 41 patients finally received the treatment regimen, including 29 in cohort A and 12 in cohort B. For cohort A, the first five patients were treated at initial level in phase Ib portion, and two of them subsequently experienced delayed‐onset diarrhea as a DLT. Additional six patients were then treated at a lower dose of 15 mg/m2. At the end of phase Ib trial, no DLT was found and the RP2D was determined. Notably, 23 out of 24 patients in cohort A in phase II portion were available for response evaluation at 12 weeks, with one complete response (CR), 14 partial response (PR) [including two complete metabolic response (CMR) who had a negative PET/CT scan but exhibited abnormal lesions on MR scan], two stable disease (SD) and six progressive disease (PD). ORR12w was determined to be 62.5%. For cohort B, no DLT was observed in the first six patients treated at the initial dose level which was then used as RP2D. At last, 12 patients were included in cohort B. The ORR12w was 83.3% with four CR, six PR (including one CMR) and two PD. Although high efficacy, cohort B was halted prematurely due to slow enrollment. The most frequently observed Grade 3/4 adverse events were leukopenia (28.5%), neutropenia (24.4%), anemia (8.7%) and diarrhea (3.7%). Conclusion : The combination of vincristine, irinotecan and anlotinib demonstrated an acceptable toxicity profile and promising clinical efficacy in patients with advanced EWS. Implications for Practice : This is the first trial to evaluated irinotecan‐based regimen in combination with anti‐angiogenesis TKIs in Ewing sarcoma. A 3+3 design with dose de‐escalation was used to determine the most appropriate dose of irinotecan in each cohort. The next dose‐expanding phase II portion employed a conventional two‐stage study design model. The objective response rate was 62.5% for adults and 83.3% for children. Median overall survival was not matured. We demonstrated that the combination of vincristine, irinotecan and anlotinib demonstrated an acceptable toxicity profile and promising clinical efficacy in patients with advanced EWS.
The Oncologist 2021