Search

e12109 Background: The PAM (PI3K/Akt/mTOR) signaling pathway has been implicated in the oncogenesis of multiple solid malignancies, including breast cancer (BC). Our aim is to characterize the TIM in a series of patients with operable stage I-III BC treated with MK-2206, an allosteric Akt inhibitor within a presurgical trial. In NCT01319539 , patients received 2 doses of MK-2206 with first dose at day -9 and second at day -2 from surgery. Methods: mIHC was performed using immune biomarkers (DAPI, CD3, CD8, CD4, FOXP3, CD68, Pancytokeratin) on full section (4uM) tissue slides from core biopsy specimens and postsurgical specimens of 10 patients - 5 treated with MK-2206, 5 paired controls. Images were taken using Vectra, a novel pathology workstation and analyzed using inForm software to perform cell classification and phenotyping. T- tests were used to compare biomarker changes before and after MK-2206. Results: Our preliminary analysis demonstrates that patients treated with MK-2206 exhibited an increase in median cytotoxic T-cells (CD3CD8+) density, as compared to the control population , which was statistically significant (87% vs.0.2%, p < 0.05). We did not identify a change in macrophage (CD68) or T helper/T reg (CD4/CD4FOXP3+) density following MK-2206 treatment in this small cohort. We are currently expanding our myeloid panel as well as performing additional tissue analysis to validate our findings. As data is exploratory no correction was made for multiple comparisons. Conclusions: Tumor infiltrating lymphocytes (TILs) are both prognostic of overall survival as well as predictive of response to neoadjuvant chemotherapy in BC. At present, there are currently both FDA approved therapies, as well as agents in clinical development that exert antineoplastic activity through the PAM pathway. Investigations that endeavour to understand the impact of these therapies on the tumor immune microenvironment may lead to both an increased understanding of the bioactivity of these agents and potentially identify aspects of the immune response which can be exploited in future therapeutics.

9 Background: Men with PSA recurrence and fast PSA doubling time (PSADT) are at high risk of progression. While castration effectively decreases PSA and delays metastases, it compromises heath and quality of life without clear survival benefit. E2809 tested whether blocking Akt with MK alone or together with the AR using Bic, would be more effective than Bic alone to suppress AR activity without castration. Methods: 108 PSA-recurrent N0 M0, non-castrate PC patients (pts) with PSADT2ng/mL; were randomized 1:1 to 11, 4-week (wk) treatment (tx) cycles (cy), up to18cy: arms (A) cy1-3, observation, cy 4-11, Bic 50 mg daily; (B) cy1-3 MK 200 mg once wk orally, cy 4-11 MK+Bic. Endpoints: Primary: proportion of pts with PSA 7 81/81%; >T2b 98/86%; prostatectomy, 81/75%; radiation, 30/31%; previous castration, 43/46%; testosterone, 302/333 ng/dL; PS 0, 94/93%; mPSA 5.1/6.1ng/dL; PSADT

4119 Background: Over 90% of pancreatic cancers (PC) have mutant KRAS that is at present not druggable. Activating mutations lead to signaling through RAF/MEK/ERK and PI3K/AKT/mTOR pathways leading...

6039 Background: Recurrent/metastatic adenoid cystic carcinoma (ACC) is a rare, incurable disease with no standard treatments. MYB is an oncogenic driver in ACC that is often overexpressed via a t(...

524 Background: A key node of growth and survival signaling pathways is the Akt serine/threonine kinase that activates mTOR and downstream effectors. I-SPY 2 is a randomized neoadjuvant trial to te...

2613 Background: The PI3K/Akt signaling pathway is an important signaling pathway in breast cancer (BC). MK-2206 is the first allosteric Akt inhibitor in clinical development. The purpose of this p...

e19013 Background: The PI3K/AKT pathway is one of the key pathways of EGFR signaling in NSCLC. We hypothesize that combination of gefitinib with MK-2206, an allosteric oral AKT inhibitor, will over...

TPS2640 Background: AKT is a frequently hyperactivated oncogenic kinase in human cancers (Degenhardt 2006). Inhibition of AKT activates autophagy, promoting tumor survival, and hence AKT inhibitors...

4041 Background: The PI3K/AKT/MTOR pathway is frequently activated in gastric/GEJ cancers. This study evaluated the activity of single agent MK-2206 at the dose of 60 mg every other day in this tumor type. Methods: Eligible patients (pts) had gastric /GEJ adenocarcinoma with measurable disease, who had had progression after first-line treatment, or recurrence within six months after adjuvant therapy. Other pertinent eligibility criteria included a Zubrod performance status of 0-1, a fasting serum glucose ≤150 mg/dL, and < Grade 2 malabsorption or chronic diarrhea. Adequate hematologic, renal, hepatic, and cardiac function were required. Prior treatment with a PI3, AKT, or mTOR inhibitor was not allowed. MK-2206 (60 mg every other day) was given until progression or intolerable toxicity. Primary endpoint was overall survival (OS), secondary endpoints were safety, progression free survival (PFS) and response rate (RR). The study required 60 evaluable pts and a median OS of 6.5 months (mo) (power of 89%, sig...

5515 Background: Although PTEN mutations or loss of PTEN expression are uncommon in endometrial serous carcinomas, approximately half of these tumors harbor PIK3CA mutations and/or amplification of...

8015 Background: Preclinical modeling in NSCLC cell lines shows that in some E-sensitive cells (whether epidermal growth factor receptor [EGFR] mutated or wild type), stimulation with HGF reverses the cytostatic and cytotoxic effects of E. Inhibitors of AKT signaling mitigated this HGF-mediated resistance, partially restoring E activity. We conducted a phase II trial of E plus MK2206, a highly selective inhibitor of AKT, in NSCLC pts previously benefiting from E. Methods: Eligible pts must have had progression (PD) following prior benefit from E [response or stable disease > 12 weeks]. Treatment consisted of E 150 mg po QD + MK-2206 45 mg po QOD on a 28-day cycle. Pts were accrued into 2 strata: 1) presence of EGFR activating mutation; and 2) EGFR wild type. Primary endpoints: RECIST response rate (RR) > 30% (stratum 1) and disease control rate (DCR) > 20% at 12 weeks (stratum 2). Up to 41 pts per stratum were planned in a two-stage design. Results: Eighty pts were enrolled with median age 64 years (range...

e15133 Background: Up-regulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with poor prognosis in NET cell lines. In patients treated with mTOR inhibitors, up-regulation of AKT may be a key driver in development of resistance. We hypothesized that blockade of AKT in patients with refractory NETs would result in eliminating one of the key drivers of tumor growth and prolong PFS. We evaluated the safety and efficacy of MK-2206, an orally active, allosteric Akt inhibitor of human Akt1, Akt2, and Akt3 as monotherapy in metastatic well differentiated progressive neuroendocrine patients. Methods: A phase II study was performed in which patients received MK-2206 at a dose of 200 mg PO once weekly. Archived pretreatment tumor tissue was obtained for putative biomarkers. Results: The study terminated early on the basis of a business decision by the sponsor. Eight patients were treated (6 carcinoid, 2 pNET); female, 25%; median age, 58.5 years, range 66-25). There were no complete or partial responses. 1 patient (atypical thymic carcinoid with brain metastases refractory to all standard therapies including mTOR and VEGF inhibitors) experienced a 17% decrease in tumor size (SD) for over 10 months and an additional 3 patients had SD for 12 weeks or longer by RECIST 1.0 (4/8, 50%; range 4.2-10.2 months). The most common grade 3 adverse events potentially related to MK-2206 were hyperglycemia (3 pts, 37.5%), elevated liver function tests (3 pts, 37.5%), and rash (3 pts, 37.5%). There were no serious adverse events (SAEs) related to MK-2206. Tumor from the patient with greatest radiographic response was evaluated by next generation sequencing, which failed to identify mutations in the AKT pathway (i.e., PTEN, AKT, and PI3KCA). Conclusions: MK-2206 alone was well tolerated, except for hyperglycemia, transaminitis, and rash, all of which were manageable. Although the study was incomplete, evidence of antitumor response in a refractory carcinoid tumor is of interest. Further evaluation of agents targeting AKT and/or PI3K are warranted in NETS. Preclinical studies are ongoing to better define a potential targeted population. Clinical trial information: NCT01169649.

e13532 Background: Though there have been many advances in the treatment of HNSCC, the 5-year survival rate remains at 50%. This is partly due to molecular alterations such as the activation of the PI3k-AKT pathway in HNSCC, which has been associated with treatment failure. We stained human tissue samples and saw increased expression of p-AKT and pS6 in HNSCC compared to normal and dysplasia. This led us to investigate the role of the AKT inhibitor MK-2206 in combination with an already established chemotherapeutic agent, paclitaxel. Methods: Cell viability and Combination index were used to determine synergy in 4 HNSCC cell lines. PI exclusion and Annexin/PI staining were used to determine cell death and apoptosis, respectively. Autophagy was measured through changes in LC3BII protein levels using western blot analysis and a stably transfected GFP-LC3BII cell line was used to detect changes in protein localization under confocal microscopy. Results: All cell lines were sensitive to paclitaxel while only some were sensitive to MK-2206. However, there was effective synergy to the combination treatment in all cell lines. Apoptotic synergy was observed in some cell lines indicating that the combination stimulates cell death in the appropriate context. In one autophagy competent cell line, MK-2206 induced robust autophagy while paclitaxel blocked a latter step in the pathway leading to an accumulation of autophagosomes prior to induction of apoptosis. Conclusions: Paclitaxel and MK-2206 appears to be an effective combination in HNSCC possibly through their effect on autophagy trafficking, leading to an accumulation of autophagosomes and eventual apoptosis. Clinical trials examining this combination are warranted.

2607 Background: The AKT protein kinase is a key mediator of signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. Lapatinib is an oral tyrosine kinase inhibitor of HER2. MK-2206 is an oral selective inhibitor of AKT with a maximum tolerated dose (MTD) of 60mg qod. Both agents cause rash and diarrhea. This study was designed to determine the MTD, dose limiting toxicities (DLTs), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods: This phase I study evaluated the safety of MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. Because of the continuous nature of therapy, protocol-specified intolerable grade 2 AEs were considered DLTs during cycle 1. Results: 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. The most common malignancies were colorectal (8 pts), lung (4 pts), and breast (3 pts). 4 pts were unevaluable per protocol; 19 evaluable pts were on study a median of 8 weeks (range 3-35). 3 pts experienced DLTs. At dose level one, 1 pt had grade (gr) 3 hyponatremia and fatigue. At dose level four, 1 pt had gr 4 hyponatremia, gr 3 rash and hypocalcemia and 1 pt had intolerable gr 2 mucositis with delivery of

5524 Background: EC has high rates of PI3K pathway alteration including PTEN mutation (50%) or IHC loss (>50%), PIK3CA mutation (25-40%) and PIK3R1 (20%) mutation. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized that pts whose tumors harbored PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. Methods: Pts had recurrent or advanced EC; all histologies except MMMT were eligible. Up to 2 prior chemo lines were permitted; excluding prior treatment with PI3K/MTOR inhibitors. The first 19 pts were treated with MK-2206 200mg QW; due to initial skin toxicity rates, the starting dose was amended to 135mg QW. Co-primary endpoints were objective response and 6 mo PFS. The first 37 pts were stratified retrospectively. PIK3CA MT included R88Q, K111N, E110K, E418K, C420R, E453K, E542K/V,E545K, Q546R, H701P, M1043V, H1047R/L/Y changes. Independent Simon 2-stage tests were planned within PIK3CA MT and WT stratum: for MT, n1=15 and n2=10 pts would allow discrimination of RR25% or 6moPFS>35%; for WT, n1=31 and n2=24 pts would discriminate RR20% or 6moPFS>25%. Results: 37 pts were enrolled (1 ineligible) before accrual was stopped as timely CLIA-compliant prospective mutation analysis was not feasible. By PIK3CA mutation analysis, 9 pts were MT: 1 pt had both PR and 6moPFS. 27 pts were WT: 1 pt had PR and 3 pts had 6moPFS. 2 pts with 6moPFS were treated at 200mg; 2 pts with 6moPFS were treated at 135mg. Each group had 1 PR. The most common toxicity was grade 3 rash (19%). Grade 3 and 4 toxicities occurred in 50% and 8% of pts. Exploratory analysis of histology found all pts with 6moPFS were classified as serous (4 of 8) as compared to all other histologies (0 of 28, p=.001). Targeted exome sequencing and copy number analysis of the PI3K pathway and PTEN IHC are underway. Associative studies will be reported. Conclusions: There is limited single agent activity of MK-2206 in both PIK3CA MT and PIK3CA WT EC populations. Activity was detected in pts with serous histology tumors and warrants further study. Clinical trial information: NCT01307631. [Table: see text]

TPS4145 Background: Pancreatic cancer remains a deadly disease and despite advances in chemotherapy treatment, survival for most patients is still less than one year. Over 80% of pancreatic cancers are KRAS mutant which activates the PI3K/AKT pathway and signals downstream to mTOR leading to cell growth, proliferation and survival. Recent data has shown that blocking both the PI3K/AKT and MEK pathways simultaneously is effective in KRASmutant tumors. Our trial is a novel, molecular targeted treatment approach for patients with metastatic pancreatic cancer that has the potential to establish a new treatment paradigm. Methods: S1115 was activated in SWOG in August 2012 and is currently IRB approved at 130 institutions within SWOG and the Clinical Trials Support Unit (CTSU). Patients (performance status 0 or 1) with metastatic pancreatic cancer failing standard gemcitabine chemotherapy are randomized to MK-2206 135 mg orally weekly plus selumetinib 100 mg orally daily or mFOLFOX IV every 2 weeks. Eligibility criteria allow metastatic patients who have progressed within 6 months of receiving adjuvant gemcitabine. Patients receiving prior 5-fluorouracil (excluding radiation-sensitizing doses), capecitabine, oxaliplatin, MEK or PI3K/AKT inhibitors are not eligible. Stratification factors include duration of prior systemic therapy and presence of liver metastases. The primary endpoint of this study is overall survival (OS) in patients treated with the combination of MK-2206 and selumetinib compared with those treated with mFOLFOX. Based on previous studies, median OS in the control group is approximately 6 months. Assuming a one-sided type 1 error of 10%, 80% power, approximately 2 years of accrual and 1.5 years of follow-up, 120 eligible patients will be accrued to detect an improvement in median survival from 6 to 9 months (corresponding to a 1.5 hazard ratio). Prospective tumoral tissue collection will be undertaken. ClinicalTrials.gov Identifier: NCT01658943. Support: NCI grants CA32102 & CA38926 Clinical trial information: NCT01658943.

e13599 Background: Simultaneous inhibition of both the PI3K-Akt and RAF/MEK/ERK pathways may yield greater benefits than inhibiting either pathway alone. This phase I study (NCT01021748) examined the safety, pharmacokinetics (PK), pharmacodynamics (PD), maximal tolerated dose (MTD), and preliminary antitumor activity of the combination of a MEKi (selumetinib) and AKTi (MK-2206). Methods: Eligible patients (pts) with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered either once daily (QD) or twice daily (BID). Results: 51 pts with advanced solid tumors (15 colon, 8 NSCLC, 6 ovarian, 5 pancreatic, 3 breast and 14 others) were treated across 9 dose levels. There were 2 confirmed partial response (PR) (1 NSCLC, ongoing > 52 wks; 1 ovarian, on treatment for 47 weeks; both KRAS mutation positive), 1 unconfirmed PR (pancreatic, on treatment 20 wks), and 24 pts with stable disease (ranged from 6 to 47 wks). Preliminary assessment of PK data suggested no apparent drug-drug interactions with unaltered PK profiles of each drug when administered in combination. Conclusions: In combination the maximum tolerated doses of MK-2206 and selumetinib are 135 mg QW and 100 mg QD, respectively. This combination of investigational agents demonstrated preliminary antitumor activity in pts with advanced cancer. [Table: see text]

9581 Background: AKT, a serine threonine protein kinase, is activated downstream of phosphatidylinositol 3-kinase (PI3K) which transmits signals from cytokines, growth factors and oncoproteins to multiple targets. Activated AKT regulates survival, proliferation, and growth. The PI3K/AKT pathway is downstream of most of the common growth factor tyrosine kinase receptors in cancer, e.g., EGFR, HER2, IGFR, etc., and is a driver of tumor progression in many cancers. AKT protein kinase is activated in many pediatric solid tumors, including glioblastoma, malignant rhabdoid tumors, neuroblastoma, synovial sarcoma, rhabdomyosarcoma and medulloblastoma. MK2206, an oral allosteric AKT1, 2,3 inhibitor, has demonstrated antitumor activity in in vitro and in vivo cancer models.A phase I trial evaluating MK2206 was conducted in children with refractory solid tumors. Methods: Using a rolling-6 design, MK2206 was administered either once every 7 days (schedule 1), or once every other day (schedule 2) in a 28-day cycle. Serial PK studies were obtained on day 1, cycle 1 and trough samples were obtained on days 7, 14, 21 and 28. Biological studies included analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. Results: Forty-five patients [23 males, median age 13.6 years (range 3.1-21.9)] with malignant glioma (14), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2) or other tumors (22) were enrolled; 34 were fully evaluable for toxicity (schedule 1 n=17; schedule 2 n=17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m2; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m2. There were no DLTs at 35 mg/m2 and dose level 4 (58 mg/m2) is currently open for patient accrual with one enrollment. Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m2; grade 3 rash in 1/6 patients at 120 mg/m2), and grade 3 rash in 2/6 patients at 155 mg/m2. Conclusions: The recommended pediatric phase II dose of weekly MK2206 is 120 mg/m2 and the last cohort of patients to the every other day dosing schedule of MMK206 is enrolling. PK and PD data are currently being analyzed and will be presented.

3529 Background: The RAF/MEK/ERK and PI3K/AKT signaling pathways are commonly deregulated in CRC. Each can serve as a compensatory mechanism mediating resistance to single pathway blockade. Combined inhibition with MK-2206 and selumetinib (AZD6244) could enhance antitumor activity. Tolerable doses for the combination in solid tumors (ASCO 2011, abstr 3004) are less than single agent MTDs. We conducted a biomarker driven trial of MK-2206 and selumetinib at the established combination doses to determine extent of pERK and pAKT inhibition in tumor biopsies (bx), using new, clinically validated immunoassays for pERK and pAKT. Methods: Patients (pts) with advanced CRC, refractory to standard therapy, ECOG ≤ 2, adequate organ function, and disease amenable to bx were treated with oral MK-2206, 90 mg QW and selumetinib, 75 mg daily, stratified for KRAS mutation status (+ or WT). For each strata, pAKT and pERK levels from paired tumor bx, baseline and 3-6 hrs post-dose in 3 pts each on C1D1 or C1D22, were measured using a quantitative, chemiluminescence immunoassay (dilution linearity R2 = 0.985 pERK, 0.995 pAKT; % CV at 0 < 6). 70% inhibition was considered biologically significant based on levels observed in preclinical models that demonstrated antitumor activity. Results: 11 pts enrolled to date (KRAS +, 6 pts; WT, 5 pts). 2/9 pts had SD after 2 cycles. Gr 1/ 2 toxicities: rash, reversible retinal detachment, liver abnormalities, hypoalbuminemia, lymphopenia. Target protein inhibition data are available for 8 paired bx samples (Table). Conclusions: Although 4/8 pts demonstrated biologically significant inhibition in one marker, at the MTD for this combination no pt had ≥ 70% inhibition of both targets. If repeated dosing does not produce the desired inhibition of pERK and pAKT, we will conclude that the dose reductions for each agent necessitated by the toxicity of the agents used in combination preclude the possibility of providing adequate dual pathway inhibition. Loss of PTEN and DNA mutation analyses (KRAS, BRAF, PIK3Ca, AKT) are planned. [Table: see text]

TPS192 Background: Up-regulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with poor prognosis in patients with renal cell carcinoma (RCC). Our data show that metastat...

3037^ Background: AKT is a key regulator of cellular proliferation, apoptosis and growth. A range of cancers have genetic aberrations that involve the PI3K/AKT pathway, leading to abnormal AKT hype...

7573 Background: Mechanisms of acquired resistance to erlotinib (E) in NSCLC include aberrant activation of alternative receptor tyrosine kinases and/or their downstream signal transduction cascade...

3001^ Background: MK-2206 is a novel allosteric inhibitor of all 3 isoforms of AKT, which are targets implicated in malignant progression. Methods: The investigational agent MK-2206 was given orally QOD to patients (pt) with advanced solid tumors. PD studies of AKT and downstream protein phosphorylation (p) were carried out in tumor biopsies and platelet-rich plasma with MesoScale Discovery (MSD) ELISA, and hair follicles with immunofluorescence. Tumor biopsies were sequenced with Sequenom Oncocarta panel for putative predictive biomarkers and stained with IHC for PTEN expression. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), MR spectroscopy (MRS) and diffusion weighted imaging (DWI) were conducted. Results: 71 pt (37 M; median age 59y; ECOG PS 0/1: 22/49) received MK-2206 at 30, 60, 75, 90 mg QOD. G3 rash (n=6) was dose limiting at 75-90 mg QOD, establishing MTD at 60mg QOD. Four MTD expansion cohorts were then undertaken: paired tumor biopsies (n=14), functional imaging (n=13), ovarian...

3028 Background: Trastuzumab (T) is effective in HER2 overexpressing breast and gastric cancer, but patients eventually develop clinical resistance. Lapatinib (L) with chemotherapy is active after progression on T. Preclinical data suggest that signaling downstream of HER2 via PI3K-AKT pathway may be one mechanism of resistance. MK-2206, an investigational allosteric AKT inhibitor, should inhibit this compensatory signaling. As a single agent, DLTs of MK-2206 are rash and diarrhea. Combined with either T or T/L, MK-2206 could provide more effective HER-family signaling blockade in HER2 positive disease. Methods: Patients with HER2+ treatment-refractory breast and gastroesophageal cancer with adequate organ function were enrolled. In part 1, patients were treated with standard doses of IV T (8 mg/kg load, followed by 6 mg/kg Q3W), and escalating dose levels of PO MK-2206 using either a QOD or QW schedule. In part 2, patients are treated with MK-2206 at the MTD dose derived from part 1 with standard T and e...

3503 Background: Akt facilitates cell proliferation/survival and is a suspected driver of progression in ST. MK-2206, a highly selective non-ATP competitive allosteric Akti, has nM IC50 and broad preclinical antitumor activity. Methods: Safety and tolerability of MK-2206 administered QOD in 28-day cycles (cy) was assessed. Doses evaluated: 30, 60, 90 mg, and 75 mg. Main eligibility criteria: ≥18 yo, evaluable advanced ST, ECOG ≤1, HbA1c ≤8% or fasting glucose ≤110% upper limit of normal. PK and phosphorylated Akt (pAkt) in whole blood by meso-scale ELISA were measured. Sequential tumor biopsies were performed in a subset of pts. Results: Dose escalation occurred in 19 pts (8 female/11 male; median age 57 yo; ECOG 0/1: 5/14) and 37 cy of therapy with no DLTs at 30 and 60 mg. CTCAE G3/4 skin rash and CTCAE G3 mucositis were observed at 90 mg in 4/7 pts. After further accrual at 60 mg confirmed safety at this dose, 75 mg was explored; however, 2/3 pts experienced DLT of rash. Dose escalation is complete; the MTD of MK-2206 is 60 mg QOD. Common drug-related AEs included skin (47.1%), gastrointestinal (41.2%), and general disorders (29.4%). AUC0–48hr and Cmax were dose proportional up to 60 mg. Median Tmax is 6 hrs and mean t1/2 ranged from 63 to 76 hr. MK-2206 concentrations exceeding a preliminary, statistically determined PK target of approximately 50–65 nM for significant pAkti in blood were maintained over the entire dosing interval in all patients in the 60 mg cohort. Evidence of PD activity included decreases in whole blood pAkt at all dose levels, reversible CTCAE G1/2 hyperglycemia and CTCAE G1 insulin c-peptide elevations. RECIST stable disease following 2 cycles of therapy was observed in 1 pt at 30 mg and 5 pts at 60 mg. Observed clinical activity included: central tumor necrosis, decreased ascites and peripheral edema, reduction in index lesions, normalization of LFTs, and decreased CA-125. Conclusions: MK-2206 is generally well tolerated at doses up to 60 mg QOD with plasma concentrations that portend activity in preclinical models. PK/PD data suggest a substantial and maintained target inhibition at 60 mg. [Table: see text]