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

Purpose: This first-in-human Phase 1, 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 (ATM) kinase inhibitor lartesertib.

Patients And Methods: Patients with advanced solid tumors received oral doses of lartesertib for a dose range of 100-400 mg once daily (QD). Dose-escalation was based on PK, PD, and safety data guided by a Bayesian 2-parameter logistic regression model. Molecular responses (MRs) were assessed in circulating tumor DNA 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) QD. Maculopapular rash was the most common dose-limiting toxicity (4 events in 4 patients). The MTD was 300 mg QD. Most common Grade ≥3 treatment-emergent adverse event was anemia (4 patients). Five patients experienced ≥1 treatment‑related adverse event 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 1-2 hours and mean elimination half‑life from 5-7 hours across the dose range. PD analysis showed a trend of reduction of γ-H2AX levels, with highest target inhibition of 80%-100%. Best overall response was stable disease in 2 patients. MRs 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.