A phase I trial of MK‐2206 in children with refractory malignancies: A Children's Oncology Group study. Issue 7 (24th March 2014)

• Record Type: Journal Article
• Authors: Fouladi, Maryam; Perentesis, John P.; Phillips, Christine L.; Leary, Sarah; Reid, Joel M.; McGovern, Renee M.; Ingle, Ashish M.; Ahern, Charlotte H.; Ames, Matthew M.; Houghton, Peter; Doyle, L. Austin; Weigel, Brenda; Blaney, Susan M.
• Is Part Of: Pediatric blood & cancer. Volume 61:Issue 7(2014:Jul.)
• Page Start: 1246
• Page End: 1251
• Publication Date: 2014-03-24
• Subjects: Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.25023
• Languages: English
• ISSNs: 1545-5009

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="pbc25023-sec-0001" sec-type="section"> <title>Background</title> <p>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.</p> </sec> <sec id="pbc25023-sec-0002" sec-type="section"> <title>Procedure</title> <p>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.</p> </sec> <sec id="pbc25023-sec-0003" sec-type="section"> <title>Results</title> <p>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 28 mg/m<sup>2</sup>; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m<sup>2</sup>; and grade 3 rash in 3/6 patients at dose level 4 (58 mg/m<sup>2</sup>). Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m<sup>2</sup>; grade 3 rash in 1/6 patients at 120 mg/m<sup>2</sup>; and grade 3 rash in 2/6 patients at 155 mg/m<sup>2</sup>.</p> </sec> <sec id="pbc25023-sec-0004" sec-type="section"> <title>Conclusions</title> <p>The recommended pediatric phase 2 dose of MK‐2206 is 45 mg/m<sup>2</sup>/dose every other day or 120 mg/m<sup>2</sup>/dose weekly. PK appeared linear over the dose range studied. Pediatr Blood Cancer 2014;61:1246–1251. © 2014 Wiley Periodicals, Inc.</p> </sec> </abstract>