A First-in-Human Study of ATM Inhibitor Lartesertib as Monotherapy in Patients with Advanced Solid Tumors.

purposeThis 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

methodsPatients 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.

resultsTwenty-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.

conclusionsLartesertib achieved target exposure and engagement without significant hematological toxicity. Further clinical evaluation of lartesertib in combination therapy is ongoing.