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/m2 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/m2 and 45 mg/m2 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.
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We would like to thank Katherine Stemke Hale, Shrikanth Reddy and Milind Javle for their thoughful review of the manuscript.
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Dr. Said Sebti is a consultant for Vioquest Pharmaceticals.
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Grant Support: Vioquest Pharmaceuticals, CA107078 and 1KG02-33967.
Preliminary data from this study were presented at the 16th AACR-NCI-EORTC: Molecular Targets and Cancer Therapeutics Symposium, 2007, San Francisco, California.
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Garrett, C.R., Coppola, D., Wenham, R.M. et al. 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. Invest New Drugs 29, 1381–1389 (2011). https://doi.org/10.1007/s10637-010-9479-2
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DOI: https://doi.org/10.1007/s10637-010-9479-2