Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT.

Autor: Garrett CR; Department of Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612-9497, USA. cgarrett@mdanderson.org, Coppola D, Wenham RM, Cubitt CL, Neuger AM, Frost TJ, Lush RM, Sullivan DM, Cheng JQ, Sebti SM
Jazyk: angličtina
Zdroj: Investigational new drugs [Invest New Drugs] 2011 Dec; Vol. 29 (6), pp. 1381-9. Date of Electronic Publication: 2010 Jul 20.
DOI: 10.1007/s10637-010-9479-2
Abstrakt: Purpose: Triciribine phosphate is a potent, small-molecule inhibitor of activation of all three isoforms of AKT in vitro. AKT is an intracellular protein that, when activated, leads to cellular division; it is dysregulated in a large number of malignancies, and constitutively activating AKT mutations are present in a minority of cancers.
Patients and Methods: In this phase I study triciribine phosphate monohydrate (TCN-PM) was administered to subjects whose tumors displayed evidence of increased AKT phosphorylation (p-AKT) as measured by immunohistochemical analysis (IHC). TCN-PM was administered over 30 min on days 1, 8 and 15 of a 28-day cycle. Tumor biopsy specimens, collected before treatment and on day +15, were assessed for p-AKT by IHC and western blot analyses.
Results: Nineteen subjects were enrolled; 13 received at least one cycle of therapy, and a total of 34 complete cycles were delivered. One subject was treated at the 45 mg/m(2) dose before the study was closed due to its primary objective having been met. No dose-limiting toxic effects were observed. Modest decreases in tumor p-AKT following therapy with TCN-PM were observed at the 35 mg/m(2) and 45 mg/m(2) dose levels, although definitive conclusions were limited by the small sample size.
Conclusions: These preliminary data suggest that treatment with TCN-PM inhibits tumor p-AKT at doses that were tolerable. Although single agent activity was not observed in this enriched population, further combination studies of TCN-PM with other signal transduction pathway inhibitors in solid tumors is warranted.
Databáze: MEDLINE
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