Abstract
PURPOSE: This first-in-human phase I, open-label study (NCT04882917) evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and maximum tolerated dose (MTD) of the highly potent and selective oral ataxia-telangiectasia-mutated kinase inhibitor lartesertib. PATIENTS AND METHODS: Patients with advanced solid tumors received oral doses of lartesertib for a dose range of 100 to 400 mg once daily. Dose escalation was based on PK, PD, and safety data guided by a Bayesian two-parameter logistic regression model. Molecular responses were assessed in ctDNA samples. RESULTS: Twenty-two patients received lartesertib at doses of 100 mg (n = 2), 200 mg (n = 7), 300 mg (n = 9), and 400 mg (n = 4) once daily. Maculopapular rash was the most common dose-limiting toxicity (four events in four patients). The MTD was 300 mg once daily. The most common grade ≥3 treatment-emergent adverse event was anemia (four patients). Five patients experienced ≥1 treatment-related adverse events of grade ≥3 (including one grade 4 event of hypersensitivity). Exposure increased in a dose-related manner, with median time to maximum plasma concentration ranging from 1 to 2 hours and mean elimination half-life from 5 to 7 hours across the dose range. PD analysis showed a trend of reduction of γ-H2AX levels, with highest target inhibition of 80% to 100%. Best overall response was stable disease in two patients. Molecular responses were observed in four patients of 21 evaluable patients. CONCLUSIONS: Lartesertib achieved target exposure and engagement without significant hematological toxicity. Further clinical evaluation of lartesertib in combination therapy is ongoing.