A phase 1 study of CT-01, a dual molecular glue degrader of GSPT1 and NEK7, as monotherapy and in combination with everolimus in patients with hepatocellular carcinoma.

e15108 Background: Targeted protein degradation (TPD) using molecular glues enables pharmacological modulation of previously “undruggable” targets. CT-01 is a first-in-class molecular glue designed to induce the selective degradation of GSPT1 and NEK7. GSPT1 degradation triggers the Integrated Stress Response (ISR) and apoptosis in cancer cells, while NEK7 degradation reduces IL-1β production, a key pro-tumorigenic mediator. Reduction of IL-1𝛽 levels within the tumor microenvironment promote immune activation and enhance compound antitumor activity. Preclinical data has demonstrated that the combination of CT-01 with the mTOR inhibitor everolimus, an approved anticancer drug, results is clear synergy both in vitro and in vivo . Methods: Preclinical biological activity was assessed using CellTiter-Glo viability assay, Western blotting for protein degradation/MoA, and hepatocellular carcinoma (HCC) xenograft in vivo models to assess the therapeutic potential of CT-01. The ongoing clinical study is a Phase 1, open-label, multicenter, dose escalation, and dose expansion study to evaluate the safety, tolerability, PK and PD of CT-01 as monotherapy and combination therapy with everolimus in subjects with intermediate or advanced HCC. Up to 77 subjects may be enrolled in Part 1, including up to 37 dose-limiting toxicity (DLT)-evaluable subjects in Part 1a (monotherapy, dose escalation). Part 1b (monotherapy, randomized dose expansion) is optional where 2 CT-01 dose levels from phase 1a will be evaluated to determine the monotherapy RP2D. Part 1b can run in parallel to Part 2a (combination, dose escalation). Part 2b (combination, randomized dose expansion) will evaluate 2 doses of CT-01 in combination with a fixed dose of everolimus to determine the combination RP2D. Up to 64 subjects will be enrolled in Part 2, including up to 24 DLT-evaluable subjects in Part 2a (monotherapy, dose escalation). The study was opened in May 2025. Results: Preclinical studies demonstrated that CT-01 induces rapid degradation of GSPT1 and NEK7, leading to potent cytotoxicity and tumor growth inhibition in HCC xenografts. In NHP models, CT-01 showed a favorable PK profile and robust target engagement. The clinical study was initiated in May 2025. Conclusions: Targeted degradation of GSPT1 and NEK7 represents a promising new therapeutic strategy for cancer treatment. CT-01, a molecular glue, has successfully completed preclinical development. Its safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy is being evaluated in a Phase 1 clinical trial. This open-label study includes dose-escalation and dose-expansion cohorts assessing CT-01 administered as monotherapy and in combination with everolimus in patients with intermediate or advanced hepatocellular carcinoma.