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.

Abstract

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.

• Authors: Christopher R Garrett, Domenico Coppola, Robert M Wenham, Christopher L Cubitt, Anthony M Neuger, Timothy J Frost, Richard M Lush, Daniel M Sullivan, Jin Q Cheng, Saïd M Sebti
• Journal: Investigational new drugs (Invest New Drugs) Vol. 29 Issue 6 Pg. 1381-9 (Dec 2011) ISSN: 1573-0646 [Electronic] United States
• PMID: 20644979 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acenaphthenes
• Ribonucleotides
• triciribine phosphate
• Proto-Oncogene Proteins c-akt

Topics

• Acenaphthenes (adverse effects, pharmacokinetics, pharmacology)
• Adult
• Biopsy
• Dose-Response Relationship, Drug
• Humans
• Mutation
• Neoplasms (drug therapy, pathology)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Ribonucleotides (adverse effects, pharmacokinetics, pharmacology)
• Treatment Outcome