Leveraging E7386 phase 1 trials for cardiac safety: Gaining concentration-QTc insights to inform early-stage oncology development.

Abstract

e24005 Background: E7386 is a novel oral anticancer agent that inhibits the interaction between β-catenin and CREB-binding protein. Phase 1 studies provide an efficient approach to cardiac safety assessment by using data across a range of doses to model the concentration-QTc (C-QTc) relationship; such modeling enables early detection of cardiac risk. The analysis described herein was conducted to evaluate cardiac safety and assess the potential effect of E7386 on ECG parameters, including the QTcF interval. Methods: C-QTc analyses were performed using E7386 plasma concentrations and continuous Holter ECG data collected on C1D1 and C1D8 (at steady state) from two phase 1 monotherapy studies in patients (pts) with solid tumors: Study 101 (NCT03264664; data available from 25 pts treated with E7386 at doses ranging from 10-120 mg twice daily [BID]) and Study 103 (NCT03833700; data available from 18 pts treated at the E7386 monotherapy RP2D of 120 mg BID). The relationship between E7386 plasma concentrations and change-from-baseline QTcF (ΔQTcF) was investigated using a linear mixed-effects modeling approach. The concentration level at which the upper bound of the 2-sided 90% CI of model-predicted ΔQTcF exceeded 10 ms was determined. Results: E7386 showed no clinically significant impact on cardiac conduction parameters (PR and QRS intervals) or heart rate across the studied dose ranges. Observed changes on heart rate were minimal and unlikely to influence the C-QTc analysis. The absolute slopes of QTcF vs RR were minimal, indicating negligible effect on the C-QTc assessment. Consequently, additional heart rate correction methods were not warranted. Hysteresis was not present. Neither the fixed intercept nor the slope for the E7386 ─ C-QTc relationship were statistically significant. C-QTc analysis showed no clinically meaningful QTc effect (ΔQTcF >10 ms) for E7386 concentrations up to 2650 ng/mL in Study 103. Consistent results were seen in Study 101 with exclusion of a QTc effect up to E7386 concentrations of 2300 ng/mL. Results from the C-QTc analyses in Study 103 and 101 indicate substantial cardiac safety margins of ~5.70 and ~3.36‐fold, respectively, over corresponding clinical C max,ss values reported for the E7386 RP2D of 120 mg BID (Study 103, 464.8 ng/mL; Study 101, 684.0 ng/mL). Conclusions: Phase 1 C-QTc evaluations of E7386 offer critical insights on cardiac safety that inform dose selection and monitoring strategies for further clinical development. The predicted mean ΔQTcF and its 90% CI upper bound remained below 10 ms for concentrations up to 2650 ng/mL, based on C-QTc analysis of two phase 1 studies. No significant cardiac safety concerns were identified at the studied dose levels. Clinical trial information: NCT03264664 , NCT03833700 .