A phase I trial of MK-2206 in children with refractory malignancies: A Children's Oncology Group study

Background: We report results of a phase I trial designed to estimate the maximum tolerated dose (MTD), describe dose-limiting toxicities (DLT), and characterize the pharmacokinetic profile of MK-2206, an AKT inhibitor, in children with refractory or recurrent malignancies. Procedure: MK-2206 was administered either every other day (Schedule 1), or once a week (Schedule 2) in a 28-day cycle. Dose escalations in increments of ~30% were independently made in each part using the rolling-six design. Serial pharmacokinetic (PK) studies were obtained. Biological studies include analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. Results: Fifty patients (26 males, median age 12.6 years [range, 3.1-21.9]) with malignant glioma (16), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2), or other tumors (22) were enrolled; 40 were fully evaluable for toxicity (Schedule 1, n=23; Schedule 2, n=17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28mg/m²; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45mg/m²; and grade 3 rash in 3/6 patients at dose level 4 (58mg/m²). Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90mg/m²; grade 3 rash in 1/6 patients at 120mg/m²; and grade 3 rash in 2/6 patients at 155mg/m². Conclusions: The recommended pediatric phase 2 dose of MK-2206 is 45mg/m²/dose every other day or 120mg/m²/dose weekly. PK appeared linear over the dose range studied. Pediatr Blood Cancer 2014;61:1246-1251.