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.
OBJECTIVE
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.


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.
Garrett
Christopher R
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
Domenico
D
Wenham
Robert M
RM
Cubitt
Christopher L
CL
Neuger
Anthony M
AM
Frost
Timothy J
TJ
Lush
Richard M
RM
Sullivan
Daniel M
DM
Cheng
Jin Q
JQ
Sebti
Saïd M
SM
D000073:Acenaphthenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012265:Ribonucleotides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D016896:Treatment Outcome
D000073:Acenaphthenes; D012265:Ribonucleotides; C014205:triciribine phosphate; D051057:Proto-Oncogene Proteins c-akt