Quantitative characterization of platelet count and alanine aminotransferase dynamics to inform personalized dosing in the first-in-human LP-184 trial.

Abstract

Purpose: Safety evaluation in first-in-human (FIH) Phase 1 oncology trials is largely descriptive and provides limited quantitative insights. This study characterized the dynamics of platelet count (PLT) and alanine aminotransferase (ALT) concentration in the LP-184 FIH study and explored statistical modeling to support personalized dosing strategies.

Methods: PLT and ALT data were analyzed to characterize temporal trends, inter-patient variability, and correlations with baseline characteristics and exposure. Firth logistic regression was fitted to identify potential contributors to clinically relevant PLT abnormalities.

Results: PLT nadir predominantly occurred in cycle 2, with baseline PLT and total single-infusion dose as critical contributors. Patients with baseline PLT below 200 K/µL were at high risk of developing grade ≥ 2 PLT decreased adverse events. ALT levels mostly peaked in cycle 1, with a moderate association with dose and no evident relationship to baseline liver metastases. Patients with glioblastoma exhibited a higher probability of experiencing ALT increased events at grade ≥ 2. A single infusion dose above 40 mg was associated with increased occurrence of high-grade PLT decreased and ALT increased events. A personalized dose recommendation strategy is proposed.

Conclusion: Integration of in-depth data analytics in FIH studies facilitates earlier safety signal detection and informs safety monitoring and dose selection in later studies.

Registry: ClinicalTrials.gov, TRN: NCT05933265, Registration date: 23 June 2023.