Phase I dose escalation and pharmacokinetic study of oral enzastaurin (LY317615) in advanced solid tumors

Enzastaurin is an oral serine/threonine kinase inhibitor that targets the protein kinase C (PKC) and phosphoinositide 3‐kinase/AKT pathways to induce apoptosis and suppress proliferation of various cancer cell lines. This phase I study evaluated the tolerability and pharmacokinetics of enzastaurin in Japanese patients with advanced solid tumors and determined the recommended dose for phase II. Eligible patients had advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 0–2. Patients received enzastaurin orally once daily until disease progression (PD) or unacceptable toxicity occurred. Enzastaurin was started at 250 mg/day followed by stepwise dose increases based on the incidence of dose‐limiting toxicities (DLT). Twenty‐three patients (seven patients: 250 mg; six patients: 375 mg; six patients: 500 mg; four patients: 750 mg) were enrolled and received enzastaurin. The major tumor types were non‐small‐cell lung cancer ( n  = 5) and breast cancer ( n  = 3). No DLT was reported at doses of 500 mg or less. Because two DLT (grade 2 QTc prolongation lasting for a week) were observed at 750 mg enzastaurin, this was determined as the maximum tolerated dose. Multiple daily doses at 500 mg achieved the target plasma concentration to inhibit PKC activity (1400 nmol/L). Enzastaurin was well tolerated up to 500 mg in Japanese patients with advanced solid tumors. The recommended dose for phase II was determined to be 500 mg daily for a 28‐day cycle on the basis of safety and plasma exposures. ( Cancer Sci 2010);