Phase ? Study Of Liposomal Irinotecan(LY01610)in Patients With Advanced Esophageal Squamous Cell Carcinoma

Background:Esophageal cancer is the sixth driving cause of cancer-related death around the world.In Eastern Europe and Asia,esophageal squamous cell carcinoma(ESCC)remains the most prevalent histological subtype,accounting for roughly 90%of all esophageal cancer cases.Treatment options for patients with advanced ESCC are limited.Cisplatin combined with 5-fluorouracil is commonly used in the first-line setting.For ESCC patients whose disease has progressed with first-line therapy,irinotecan is among the preferred cytotoxic agents in the National Comprehensive Cancer Network Guidelines.This phase ? trial was performed to determine the maximum-tolerated dose(MTD),dose-limiting toxicities(DLTs),preliminary efficacy,and pharmacokinetics(PK)of LY01610,a novel liposome-encapsulated irinotecan,in patients with advanced ESCC.Methods:This trial was conducted in two stages.In the dose escalation stage,patients were enrolled to four dose cohorts(30,60,90 and 120 mg/m2)according to the modified '3+3' design.The second stage,dose extension study of LY01610,was based on the patient tolerance in the first stage.An appropriate dose(60mg/m2)was selected and given in additional patients.LY01610 was administrated by 90-minute intravenous infusion every 2 weeks without premedication,except that the first cycle in dose escalation stage was three weeks to allow observation of DLTs.Adverse events and DLTs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.Radiographical studies were conducted every 8 weeks,and responses were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1.Pharmacokinetic sampling was done during the first cycle of LY01610 administration.The primary endpoints were the MTD,DLT and safety profile of LY01610.Secondary endpoints were PK;objective response rate;disease control rate;progression-free survival;and overall survival.Results:Between February 2019 and August 2020,34 patients were screened for this trial and 24 patients with advanced ESCC were enrolled across four dose levels(30,60,90 and 120 mg/m2).The DLTs included vomiting and febrile neutropenia,and the MTD was 90mg/m2.The most common grade 3/4 adverse events were leukopenia in six patients(25.0%),anemia in six patients(25.0%)and neutropenia in five patients(20.8%).Additionally,we did not administer prophylactic atropine before LY01610 dosing,and no cholinergic reactions were observed throughout the study.One patient achieved complete response,and four had partial response,including one patient receiving LY01610 at the starting dose of 30 mg/m2.Median PFS was 1.9 months(95%:1.7-2.1),and median OS was 6.8 months(95%:3.9-9.7).Three patients were not assessed for response due to deterioration of cancer-related symptoms before the planned first imaging evaluation.Compared with conventional irinotecan,the PK profile of LY01610 was characterized by increased and prolonged exposure of total irinotecan and the active metabolite SN-38 in plasma.Conclusion:In our present first-in-human study,we evaluated the safety,PK and preliminary efficacy of LY01610,a novel nanoparticle formulation of irinotecan,in patients with advanced ESCC.LY01610 demonstrated manageable toxicity and promising antitumor activity in patients with advanced ESCC.PK results suggested a slow but durable release of free irinotecan and its active metabolite,SN-38.Future clinical development of LY01610 as single agent or in combination with other anti-cancer agents in treating ESCC patients is warranted.