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

• Published in: Investigational new drugs 2011-12, Vol.29 (6), p.1381-1389
• Main Authors: Garrett, Christopher R., Coppola, Domenico, Wenham, Robert M., Cubitt, Christopher L., Neuger, Anthony M., Frost, Timothy J., Lush, Richard M., Sullivan, Daniel M., Cheng, Jin Q., Sebti, Saïd M.
• Format: Article
• Language: English
• Subjects: Acenaphthenes - adverse effects; Acenaphthenes - pharmacokinetics; Acenaphthenes - pharmacology; Adult; Biopsy; Cancer therapies; Cell cycle; Clinical trials; Dose-Response Relationship, Drug; Drug dosages; Humans; Hypocalcemia; Inhibitor drugs; Kinases; Medical prognosis; Medicine; Medicine & Public Health; Mutation; Neoplasms - drug therapy; Neoplasms - pathology; Oncology; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Phosphorylation; Phosphorylation - drug effects; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Research centers; Ribonucleotides - adverse effects; Ribonucleotides - pharmacokinetics; Ribonucleotides - pharmacology; Signal transduction; Studies; Thyroid gland; Toxicity; Treatment Outcome; Tumors
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-010-9479-2

Summary 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.