OT3-01-03: Pre-Surgical Evaluation of the AKT Inhibitor MK-2206 in Patients with Operable Invasive Breast Cancer: New York Cancer Consortium Trial P8740.
Authors: Kalinsky K , Sparano JA , Kim M , Crew KD , Maurer MA , Taback B , Feldman SM , Hibshoosh H , Wiechmann LS , Adelson KB , Hershman DL 
Published: June 2012

Abstract
Background: To serve as a bridge between pre-clinical and early clinical testing, pre-surgical studies are being designed to expose patients to a limited duration of an anti-cancer agent before launching a lengthy clinical trial program. In this model, modulation of predictive tissue and serum biomarkers are assessed. At Columbia University, we have completed 3 pre-surgical studies. The PI3K/Akt signaling pathway is an important signaling pathway in breast cancer (BC). The first allosteric Akt inhibitor to enter clinical development, MK-2206 is well-tolerated and has demonstrated anti-cancer properties in pre-clinical and early-phase clinical studies. The purpose of this study (NCI P8740) is to determine the effects of MK-2206 on women with newly diagnosed BC between breast biopsy and surgery. Trial Design: Patients (n=30) will receive 2 doses of weekly MK-2206 (200 mg): first dose at day −9 and second at day −2 from surgery. This drug administration consistency will decrease the potential for noise in detecting true biomarker response. This time period was selected based upon the pharmacokinetic profile of weekly MK-2206. The main eligibility criteria for this open-label pre-surgical trial include operable, clinical stage I (at least T1c) to IIIC invasive BC. Patients not considered for neoadjuvant chemotherapy are eligible. Specific Aims: Our hypothesis is that MK-2206 will decrease phospho-AktSer473 in tumor tissue after 2 weekly doses. To maintain sample quality and ensure that phospho-Akt evaluated on formalin-fixed paraffin-embedded (FFPE) tissue is comparable across samples (given the 20 minute half life of AKT), all samples will be processed rapidly by a standardized protocol. Secondary objectives include the following in FFPE: modulation of downstream PI3K/Akt pathway signaling [immunohistochemistry and reverse phase-protein microarray analysis (RPPA)]; change in tumor proliferation (Ki-67 staining); and exploration of whether PI3K/Akt signaling change depends upon tumor genetics (PIK3CA mutation or PTEN loss) or expression (Hormone Receptor/HER2 status). Pre- and post-MK-2206 blood will be collected for phospho-expression analysis in peripheral blood mononuclear cells (RPPA and western blotting). Statistical Methods: With the expectation that 20% of the matched pre- and post-treatment tissue samples will not be analyzable, we will enroll 30 patients to ensure that matched tumor samples from 24 patients are available for our primary analysis. A sample size of 24 patients will yield greater than 90% power to detect a difference in the mean score between pre-and-post treatment samples of 60 units, paired t-test (2-sided, 0.05 significance level). This trial was recently activated by the NCI and currently ready to accrue patients. Patients will be enrolled and treated at affiliated institutions in the New York Cancer Consortium.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-03.