First data disclosure from the first-in-human phase 1/2 trial of SMP-3124LP, the first investigational pegylated liposome CHK1 inhibitor, in patients with selected advanced solid tumors.

Abstract

3081 Background: Checkpoint kinase 1 (CHK1) is a critical in the DNA damage response pathway and an important target for anticancer therapy. However, clinical development of CHK1 inhibitors has been limited by myelosuppression and a narrow therapeutic window. The use of liposomal technology potentially widens the therapeutic window by lowering rates of hematologic toxicities minimizing drug exposure to healthy tissues and maximizing delivery to tumors. SMP-3124 is a structurally distinct CHK1-selective inhibitor designed to be optimally delivered in a PEGylated liposome formulation. SMP-3124LP is being developed for malignancies with high replication stress. Methods: This ongoing Phase 1/2 study evaluated the safety, tolerability, PK, and preliminary antitumor activity of SMP-3124LP given intravenously (NCT06526819). The dose escalation included patients (pts) with selected advanced solid tumors. Results: As of 28 Nov 2025, 42 pts were enrolled at 20, 40, 60, and 90 mg/m 2 every 2 weeks. 23 pts (55%) had ≥4 prior lines of therapy. No dose-limiting toxicities (DLTs) were observed at 20 or 40 mg/m 2 . A DLT of Grade (G) 4 thrombocytopenia was noted at 60 mg/m 2 and one pt had 2 DLTs of reversible G4 thrombocytopenia and G3 febrile neutropenia at 90 mg/m 2 . Most common treatment-related adverse events (≥20%) were neutropenia (45%), infusion-related reactions (IRR, 38%), thrombocytopenia (36%), anemia (24%) and leukopenia (21%). Treatment-related G3/4 neutropenia was 33%, G3/4 thrombocytopenia and G3 anemia were 9.5% each. Cytopenias were generally transient and none led to treatment discontinuation. All IRRs were G1/2 and manageable with premedications, supportive care, and/or slower infusion rates. Dose-proportional increases in C max (4.3-fold) and AUC (6.0-fold) were observed from 20 to 90 mg/m 2 with low volume of distribution (1.99 to 2.68 L) and a geometric mean half-life of 23 to 31 hours. As of 13 Jan 2026, disease control rate (DCR) was 49%, with 5 RECIST v1.1 partial responses (PR) + 12 RECIST v1.1 stable disease (SD) out of 35 efficacy evaluable patients. Among the PRs, 2 platinum-resistant ovarian cancer (PROC, one with prior PARPi), 2 anal SCC, and 1 colorectal cancer with FBXW7 mutation. 2 other advanced PROC pts had SD with tumor shrinkage 20% or more (one with -88% CA125 response). The anal SCC and rectal cancer pts all received ≥4 prior lines of therapy. Duration of response has not been reached. Conclusions: SMP-3124LP was generally well tolerated and had a manageable safety profile. The liposomal formulation appears to reduce the incidence of cytopenias compared to historical data with non-liposomal CHK1 inhibitors. Dose-proportional increases in PK were observed. Promising signals of antitumor activity were observed with 5 RECIST v1.1 PRs and 49% DCR in pts with heavily pretreated cancers. Clinical trial information: NCT06526819 .