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.

Trial registration: ClinicalTrials.gov NCT00642031.

Keywords: AML; Akt; Nucleoside analog; Phase I clinical trial; Triciribine.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Fig. 1

Detection of TCN-P in AML blasts and dose-dependent accumulation of TCN-P in leukemia cell lines and AML blasts. A, Blood samples were obtained before therapy, after which normal nucleotides were extracted using perchloric acid. A known amount of TCN-PM was added to these cell extracts, and then normal and analog nucleotides were separated by HPLC to locate the peak for TCN-P. B and C, HPLC profiles from a representative patient before (B) and 24 hours after (C) TCN-PM therapy, demonstrating presence of a discrete TCN-P peak following therapy. AU, Arbitrary units. D, Ml-1 and OCI-AML3 cells were exposed to 0.05, 0.1, 0.2, 0.5, 1, 3, and 10 μM TCN for 3 hours before nucleotides were extracted and amounts of TCN-P were calculated. E, AML blasts were isolated at 2 or 24 hours after TCN therapy at dose levels of 15, 25, 35, and 65 mg/m2, after which nucleotides were extracted and levels of TCN-P were quantitated.

Fig. 2

Action of TCN-P on pSer473Akt levels and on cell death in OCI-AML3 cells. A and B, OCI-AML3 cells were exposed to 1 or 10 μM TCN for varying times, after which levels of pSer473Akt and total Akt were assayed as described under Materials and Methods. C, Percentage of annexin-positive cells.

Fig. 3

Effect of TCN-PM therapy on pSer473Akt and pSer112Bad levels. A, pSer473Akt levels in lymphocytes of normal donors and AML blasts. B and C, pSer473Akt (B) and pSer112Bad (C) levels in AML blasts during therapy.