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

Maryam Fouladi; John P. Perentesis; Christine L. Phillips; Sarah Leary; Joel M. Reid; Renee M. Mcgovern; Ashish M. Ingle; Charlotte H. Ahern; Matthew M. Ames; Peter Houghton; L. Austin Doyle; Brenda Weigel; Susan M. Blaney

doi:10.1002/pbc.25023

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

Maryam Fouladi, John P. Perentesis, Christine L. Phillips, Sarah Leary, Joel M. Reid, Renee M. Mcgovern, Ashish M. Ingle, Charlotte H. Ahern, Matthew M. Ames, Peter Houghton, L. Austin Doyle, Brenda Weigel, Susan M. Blaney

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Abstract

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.

Original language	English (US)
Pages (from-to)	1246-1251
Number of pages	6
Journal	Pediatric Blood and Cancer
Volume	61
Issue number	7
DOIs	https://doi.org/10.1002/pbc.25023
State	Published - Jul 2014

Keywords

AKT inhibitor
MK-2206
Pediatric
Phase I trial
Relapsed solid tumors

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/pbc.25023

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Fouladi, M., Perentesis, J. P., Phillips, C. L., Leary, S., Reid, J. M., Mcgovern, R. M., Ingle, A. M., Ahern, C. H., Ames, M. M., Houghton, P., Doyle, L. A., Weigel, B., & Blaney, S. M. (2014). A phase I trial of MK-2206 in children with refractory malignancies: A Children's Oncology Group study. Pediatric Blood and Cancer, 61(7), 1246-1251. https://doi.org/10.1002/pbc.25023

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

abstract = "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.",

keywords = "AKT inhibitor, MK-2206, Pediatric, Phase I trial, Relapsed solid tumors",

author = "Maryam Fouladi and Perentesis, {John P.} and Phillips, {Christine L.} and Sarah Leary and Reid, {Joel M.} and Mcgovern, {Renee M.} and Ingle, {Ashish M.} and Ahern, {Charlotte H.} and Ames, {Matthew M.} and Peter Houghton and Doyle, {L. Austin} and Brenda Weigel and Blaney, {Susan M.}",

year = "2014",

month = jul,

doi = "10.1002/pbc.25023",

language = "English (US)",

volume = "61",

pages = "1246--1251",

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T1 - A phase I trial of MK-2206 in children with refractory malignancies

T2 - A Children's Oncology Group study

AU - Fouladi, Maryam

AU - Perentesis, John P.

AU - Phillips, Christine L.

AU - Leary, Sarah

AU - Reid, Joel M.

AU - Mcgovern, Renee M.

AU - Ingle, Ashish M.

AU - Ahern, Charlotte H.

AU - Ames, Matthew M.

AU - Houghton, Peter

AU - Doyle, L. Austin

AU - Weigel, Brenda

AU - Blaney, Susan M.

PY - 2014/7

Y1 - 2014/7

N2 - 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.

AB - 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.

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KW - MK-2206

KW - Pediatric

KW - Phase I trial

KW - Relapsed solid tumors

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

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