A single-dose, crossover, placebo- and moxifloxacin-controlled study to assess the effects of neratinib (HKI-272) on cardiac repolarization in healthy adult subjects.

Abstract

e11070 Background: Neratinib is a potent, orally administered, irreversible pan-ErbB tyrosine kinase inhibitor that has shown antitumor activity in patients with advanced ErbB2+ breast cancer and is in phase III development. This study was conducted to assess the effects of therapeutic and supratherapeutic neratinib concentrations on cardiac repolarization in healthy adults, in accordance with ICH E14 guidelines. Methods: This was a 2-part, randomized, single-dose, double-blind, crossover, placebo- and open- label moxifloxacin-controlled study in healthy subjects. In part 1, subjects received placebo, moxifloxacin 400 mg, and neratinib 240 mg (therapeutic dose) following a high-fat meal. In part 2, following a washout period, subjects received placebo plus ketoconazole 400 mg (a potent inhibitor of neratinib metabolism) and neratinib 240 mg plus ketoconazole (supratherapeutic dose). Triplicate ECG readings were obtained. ANOVA was used to separately compare the baseline adjusted QTc intervals of 1) neratinib to placebo, and 2) neratinib plus ketoconazole to placebo plus ketoconazole. Assay sensitivity was evaluated by comparing moxifloxacin to placebo. The primary endpoint was QTcN (population-specific QT correction). PK/PD analyses and categorical summaries of interval data were performed. Results: Sixty (60) healthy subjects (median age: 36 y; range: 18-57 y) were enrolled in this study. The upper bounds of the 90% CI for QTcN were ≤ 10 ms at all postdose time-points for both the therapeutic and the supratherapeutic neratinib plasma concentrations. No relevant PK/PD relationship was observed between neratinib concentrations and QTc interval. No subjects had a QTcF, QTcI, or QTcN interval > 450 ms or a change from baseline > 30 ms. Moxifloxacin produced a significant increase in QTcN compared with placebo (p < 0.05). Conclusions: Therapeutic and supratherapeutic exposures of neratinib are not associated with QTc prolongation in healthy subjects. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer