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

Oncology

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

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

ASJC Scopus subject areas

Pediatrics, Perinatology, and Child Health
Hematology
Oncology

Access to Document

10.1002/pbc.25023

Cite this

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

@article{870eaca5d9c14633b8ac115605d3346a,

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",

journal = "Pediatric Blood and Cancer",

issn = "1545-5009",

publisher = "Wiley-Liss Inc.",

number = "7",

}

TY - JOUR

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.

KW - AKT inhibitor

KW - MK-2206

KW - Pediatric

KW - Phase I trial

KW - Relapsed solid tumors

UR - http://www.scopus.com/inward/record.url?scp=84899685343&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899685343&partnerID=8YFLogxK

U2 - 10.1002/pbc.25023

DO - 10.1002/pbc.25023

M3 - Article

C2 - 24664955

AN - SCOPUS:84899685343

SN - 1545-5009

VL - 61

SP - 1246

EP - 1251

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

IS - 7

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this