Phase I safety and pharmacokinetic study of cipatinib, an original dual tyrosine kinase inhibitor

Background: Cipatinib is a novel tyrosine kinase inhibitor against both EGFR and HER2/neu. This phase I trial was conducted to assess the safety, dose-limiting toxicities (DLTs), and maximum-tolerated dose of cipatinib in HER2-positive patients with advanced breast cancer. Methods: Eligible adults with advanced breast cancer were administered cipatinib 200 mg/day (n = 3) as an initial dose, with escalating dosages of 400 mg (n = 4), 800 mg (n = 2), 1200 mg (n = 3), 1400 mg (n = 3), 1600 mg (n = 3), and 1800 mg (n = 2) in 21 day cycles. DLTs were monitored until the end of cycle 2. Physical examinations, vital signs, blood sampling for hematology, clinical chemistry, and pharmacokinetics were performed throughout the trial. Results: Of the 26 subjects enrolled, 23 completed the trial. A total of 143 adverse events (AEs) were reported, of which 87 were associated with cipatinib treatment and comprised: neutropenia (38%), hypertriglyceridemia (15%), fatigue (15%), nausea (12%), fever (19%), and myocardial ischemia (19%). Six AEs were graded 3–4 (neutropenia, increases in aspartate aminotransferase, and total bilirubin, fatigue, dizziness and nodal tachycardia), but none of the AEs observed were considered to be DLTs. Conclusion: This tolerability study revealed that despite a mild toxicity profile, cipatinib was well tolerated up to the anticipated maximum dosage of 1800 mg/m ² . Further clinical trials are warranted.