Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies

Deepa Sampath; Asifa Malik; William Plunkett; Billie Nowak; Betsy Williams; Michelle Burton; Srdan Verstovsek; Stefan Faderl; Guillermo Garcia-Manero; Alan F. List; Said Sebti; Hagop M. Kantarjian; Farhad Ravandi; Jeffrey E. Lancet

doi:10.1016/j.leukres.2013.07.034

Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies

Deepa Sampath, Asifa Malik, William Plunkett, Billie Nowak, Betsy Williams, Michelle Burton, Srdan Verstovsek, Stefan Faderl, Guillermo Garcia-Manero, Alan F. List, Said Sebti, Hagop M. Kantarjian, Farhad Ravandi, Jeffrey E. Lancet

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Abstract

Akt, a serine/threonine protein kinase, is constitutively phosphorylated and hyperactivated in multiple cancers, including acute myeloid leukemia. High levels are linked to poor survival and inferior responses to chemotherapy, making Akt inhibition an attractive therapeutic target. In this phase I/II study of TCN-PM, a small-molecule Akt inhibitor, TCN-PM therapy was well tolerated in patients with advanced hematological malignancies, and reduced levels of phosphorylation of Akt and its substrate Bad were shown, consistent with inhibition of this survival pathway and induction of cell death. Further investigation of TCN-PM alone or in combination in patients with high Akt levels is warranted.

Original language	English (US)
Pages (from-to)	1461-1467
Number of pages	7
Journal	Leukemia Research
Volume	37
Issue number	11
DOIs	https://doi.org/10.1016/j.leukres.2013.07.034
State	Published - Nov 2013

Keywords

AML
Akt
Nucleoside analog
Phase I clinical trial
Triciribine

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

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Sampath, D., Malik, A., Plunkett, W., Nowak, B., Williams, B., Burton, M., Verstovsek, S., Faderl, S., Garcia-Manero, G., List, A. F., Sebti, S., Kantarjian, H. M., Ravandi, F., & Lancet, J. E. (2013). Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies. Leukemia Research, 37(11), 1461-1467. https://doi.org/10.1016/j.leukres.2013.07.034

Sampath, D, Malik, A, Plunkett, W, Nowak, B, Williams, B, Burton, M, Verstovsek, S, Faderl, S, Garcia-Manero, G, List, AF, Sebti, S, Kantarjian, HM , Ravandi, F & Lancet, JE 2013, 'Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies', Leukemia Research, vol. 37, no. 11, pp. 1461-1467. https://doi.org/10.1016/j.leukres.2013.07.034

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title = "Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies",

abstract = "Akt, a serine/threonine protein kinase, is constitutively phosphorylated and hyperactivated in multiple cancers, including acute myeloid leukemia. High levels are linked to poor survival and inferior responses to chemotherapy, making Akt inhibition an attractive therapeutic target. In this phase I/II study of TCN-PM, a small-molecule Akt inhibitor, TCN-PM therapy was well tolerated in patients with advanced hematological malignancies, and reduced levels of phosphorylation of Akt and its substrate Bad were shown, consistent with inhibition of this survival pathway and induction of cell death. Further investigation of TCN-PM alone or in combination in patients with high Akt levels is warranted.",

keywords = "AML, Akt, Nucleoside analog, Phase I clinical trial, Triciribine",

author = "Deepa Sampath and Asifa Malik and William Plunkett and Billie Nowak and Betsy Williams and Michelle Burton and Srdan Verstovsek and Stefan Faderl and Guillermo Garcia-Manero and List, {Alan F.} and Said Sebti and Kantarjian, {Hagop M.} and Farhad Ravandi and Lancet, {Jeffrey E.}",

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doi = "10.1016/j.leukres.2013.07.034",

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AU - Sampath, Deepa

AU - Malik, Asifa

AU - Plunkett, William

AU - Nowak, Billie

AU - Williams, Betsy

AU - Burton, Michelle

AU - Verstovsek, Srdan

AU - Faderl, Stefan

AU - Garcia-Manero, Guillermo

AU - List, Alan F.

AU - Sebti, Said

AU - Kantarjian, Hagop M.

AU - Ravandi, Farhad

AU - Lancet, Jeffrey E.

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AB - Akt, a serine/threonine protein kinase, is constitutively phosphorylated and hyperactivated in multiple cancers, including acute myeloid leukemia. High levels are linked to poor survival and inferior responses to chemotherapy, making Akt inhibition an attractive therapeutic target. In this phase I/II study of TCN-PM, a small-molecule Akt inhibitor, TCN-PM therapy was well tolerated in patients with advanced hematological malignancies, and reduced levels of phosphorylation of Akt and its substrate Bad were shown, consistent with inhibition of this survival pathway and induction of cell death. Further investigation of TCN-PM alone or in combination in patients with high Akt levels is warranted.

KW - AML

KW - Akt

KW - Nucleoside analog

KW - Phase I clinical trial

KW - Triciribine

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Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies

Abstract

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