Phase 0 clinical chemoprevention trial of the Akt inhibitor SR13668

Joel M. Reid, Chad A. Walden, Rui Qin, Katie L. Allen Ziegler, John L. Haslam, Roger A. Rajewski, Roger Warndahl, Cindy L. Fitting, Daniel Boring, Eva Szabo, James Crowell, Marjorie Perloff, Ling Jong, Brent A. Bauer, Sumithra J. Mandrekar, Matthew M. Ames, Paul J. Limburg

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

SR13668, an orally active Akt pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability. Healthy adult volunteers were randomly assigned to receive a single, 38-mg oral dose of SR13668 in one of five different formulations, with or without food. On the basis of existing animal data, SR13668 in a PEG400/Labrasol oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration-time curve (AUC 0-∞) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size. Participants (n = 20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC 0-∞ values were highest in the fed state (range = 122-439 ng/mL x hours) and were statistically significantly different across formulations (P = 0.007), with Solutol HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2-6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation-dependent. Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development.

Original languageEnglish (US)
Pages (from-to)347-353
Number of pages7
JournalCancer Prevention Research
Volume4
Issue number3
DOIs
StatePublished - Mar 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Reid, J. M., Walden, C. A., Qin, R., Allen Ziegler, K. L., Haslam, J. L., Rajewski, R. A., Warndahl, R., Fitting, C. L., Boring, D., Szabo, E., Crowell, J., Perloff, M., Jong, L., Bauer, B. A., Mandrekar, S. J., Ames, M. M., & Limburg, P. J. (2011). Phase 0 clinical chemoprevention trial of the Akt inhibitor SR13668. Cancer Prevention Research, 4(3), 347-353. https://doi.org/10.1158/1940-6207.CAPR-10-0313