A First-in-Human Study of ATM Inhibitor Lartesertib as Monotherapy in Patients with Advanced Solid Tumors
Lillian L Siu1, Timothy A Yap2, Sofia Genta1,3
1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
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.
Insights
The first-in-human study of lartesertib, an ataxia-telangiectasia mutated (ATM) kinase inhibitor, found it safe and well-tolerated up to 300 mg daily. Lartesertib achieved target engagement with promising molecular responses in patients with advanced solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Ataxia-telangiectasia mutated (ATM) kinase is a key regulator of DNA damage response.
- Targeting ATM is a promising strategy for cancer therapy.
- Lartesertib is a novel, potent, and selective oral ATM kinase inhibitor.
Purpose of the Study:
- Evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and maximum tolerated dose (MTD) of lartesertib in a first-in-human Phase 1 study.
- Assess the anti-tumor activity of lartesertib in patients with advanced solid tumors.
Main Methods:
- Open-label, dose-escalation study of oral lartesertib (100-400 mg QD) in 22 patients with advanced solid tumors.
- Dose escalation guided by Bayesian logistic regression model using PK, PD, and safety data.
- Molecular responses (MRs) assessed via circulating tumor DNA; PD markers included γ-H2AX levels.
Main Results:
- Lartesertib was administered at doses up to 400 mg QD, with MTD determined as 300 mg QD.
- Maculopapular rash was the most frequent dose-limiting toxicity; Grade ≥3 treatment-emergent adverse events included anemia and hypersensitivity.
- Lartesertib achieved dose-related exposure, with mean half-life of 5-7 hours and target engagement (80%-100% γ-H2AX inhibition).
- Molecular responses observed in 4/21 evaluable patients; best overall response was stable disease.
Conclusions:
- Lartesertib demonstrated target exposure and engagement with an acceptable safety profile, with no significant hematological toxicity.
- The MTD was established at 300 mg QD.
- Further clinical evaluation of lartesertib, particularly in combination therapy, is warranted.
More Related Videos
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
06:25Author Spotlight: Assessing the Potential of Circulating Tumor Cells in Leptomeningeal Disease Research
Published on: March 29, 2024
