A phase Ib clinical study to evaluate the safety, tolerability, pharmacokinetic profile and preliminary anti-tumor efficacy of Hemay181 in patients with advanced solid tumors.

e15002 Background: Hemay181 is a broad-spectrum anti-tumor cytotoxic drug with tumor-targeting properties (about 44808 ASCO24). The prodrug conjugate is enzymatically cleaved by beta-glucuronidase (β-GU) in tumor tissues, with tumor selectivity associated with increased expression of β-GU in the tumor microenvironment. On enzymatic cleavage, SN-38 is released. In animal Xenograft models, a tumor-to-plasma ratio of 75 fold for Hemay181, 12x Govitecan, 0.3 for Irinotecan showing tumor concentration. Methods: An ascending dose exploration phase was completed under the US Investigational New Drug (NCT05749432); patients were enrolled with advanced treatment-refractory breast cancer, hepatocellular carcinoma, non-small cell lung cancer, colon, ovarian, and pancreatic cancer. Dosing was by intravenous infusion on day one of each cycle, with a 3-week treatment cycle. The clinical therapeutic dose range explored was 4.5-180 mg/m 2 . The accelerated titration phase enrolled subjects according to the “3+3” dose escalation principle; if there was no ≥ Grade 2 drug-related toxicity, the administration doses of subsequent dose groups were increased by 100%, 67%, 50%, 33%, and 25% according to the modified Fibonacci method. Based on the initial efficacy in the ascending phase, an expansion phase I explored efficacy at 150,120 and 90 mg/m 2 ), with no more than 12 cases per dose group as part 1 of a Simon 2 stage design. If sufficient responders occurred in Part 1, the cohort passes into Stage 2; Part 1 has been completed for the first breast cancer cohort. Responders were defined as having a 30% change in tumor shrinkage for the target leions (RECIST 1.1). Results: Dose-limiting toxicity was defined by Grade 3 diarrhea at 180mg/m 2 . The adverse events are those expected for the class of topoisomerase agents. The most frequent adverse events for Hemay181 were nausea (60%), vomiting (43%), anemia (50%), white blood cell count decreased (58%), neutrophil count decrease (45%) and hypocalcemia (28%). In the patients administrated Hemay181 at 4.5 mg/m2 to 180 mg/m2 dose, the concentrations of free SN38 were approximately 10-100 times lower than at therapeutic dose of Irinotecan or Govitecan (C max ng/ml; AUC 0-inf ng*h/mL): Govitecan 10mg/kg; C max 127; AUC 3900: Irinotecan 340mg/kg; C max 56; AUC 474: Hema181 150mg/m 2 ; C max 4.3; AUC 277. The clinical responses shown in the table (RECIST 1.1). Conclusions: Hemay181 in the dose range of 36mg/m 2 to 150mg/m 2 shows potential therapeutic benefits, with tumor shrinkage demonstrated in advanced breast, lung, and pancreatic cancers. The benefit-risk ratio is favorable, justifying further dose optimization and expansion. Clinical trial information: NCT05749432 . Tumor Type (36-180mg/m 2 ) Breast Cancer Lung Cancer Number 13 10 CR/PR 5 1 ORR (%) 38% 10% SD 6 5 CBR (%) 85% 60%