A pediatric phase I trial and pharmacokinetic study of MLN8237, an oral selective small molecule inhibitor of aurora a kinase: A Children's Oncology Group Phase I Consortium study.

Abstract

9529 Background: MLN8237, a selective small molecule inhibitor of Aurora A Kinase, has activity in a broad range of in vitro and in vivo preclinical models of pediatric cancer. We performed a phase I trial to determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MLN8237 in children with refractory solid tumors. Methods: MLN8237 was administered orally either once daily (part A1) or divided twice daily (part A2) for 7 days, every 21 days. Using the rolling-six design, four dose levels (45, 60, 80, 100 mg/m2/d) were evaluated on the once daily regimen, and subsequently two dose levels (60 and 80 mg/m2/d) on the twice-daily regimen. Pharmacokinetic studies were performed with the initial dose, with trough drug concentrations also being obtained at steady-state. Results: 37 patients were enrolled, 32 were fully evaluable for toxicity [median (range) age 12.5 yrs (4.8 - 21.6)]: 21 on part A1 and 11 on part A2. In part A1, 1/6 pts developed DLT (grade 3 mucositis) at 45 mg/m2 and 1/6 developed DLT (grade 4 mood alteration) at 80 mg/m2. At 100 mg/m2, 3/4 patients developed DLT (neutropenia –thrombocytopenia), thus exceeding the MTD. In part A2, 2/6 patients developed dose limiting myelosuppression at 80 mg/m2; one of whom also experienced grade 3 mucositis. 1/5 patient experienced DLT (grade 3 alkaline phosphatase) at 60 mg/m2. Of note, 5/11 patients experienced hand-foot-skin syndrome (grade 1 - 3) on the bid schedule versus 1/21 (grade 2) on qd schedule. A high degree of inter- patient variability in systemic exposure was observed. Average trough concentrations exceeded 1 μ M, the efficacious concentration in preclinical studies. The mean (±SD) steady state MLN8237 trough concentrations at the 45, 60, 80 and 100 mg/m2/d dose levels were 5.1 ± 5.7, 4.9 ± 6.3, 3.7 ± 3.8, and 5.5 ± 4.9 μ M, respectively. Conclusions: Although the divided dose regimen appears to be well tolerated in adults, children experienced more myelosuppression and hand-foot-skin syndrome with divided versus once daily dosing. Therefore the recommended pediatric phase 2 dose and schedule of MLN8237 is 80 mg/m2/d administered once daily for 7 days. No significant financial relationships to disclose.