Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.

PURPOSE: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. EXPERIMENTAL DESIGN: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. RESULTS: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. CONCLUSIONS: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488).This study was supported by Merck & Co., Inc. The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a program grant from Cancer Research U.K. Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research), the National Institute for Health Research (NIHR) Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research), the NIHR Clinical Research Facility (to the Royal Marsden NHS Foundation Trust) and the Cancer Research UK and EPSRC Cancer Imaging Centre. T.A. Yap is the recipient of the 2011 Rebecca and Nathan Milikowsky – PCF Young Investigator Award and is supported by the NIHR. M.O. Leach is an NIHR Senior Investigator.This is the accepted manuscript. The final version is available from AACR at http://clincancerres.aacrjournals.org/content/early/2014/09/19/1078-0432.CCR-14-0868

Long-Term Follow-Up of Trauma Patients with a Vena Caval Filter.

BACKGROUND: Venous thromboembolism (VTE) is an important complication in blunt trauma patients. At our Level I trauma center, we had a deep venous thrombosis (DVT) rate of 3.2% from 1993 to 1997 despite an aggressive VTE prophylaxis program. During this time period, we placed vena caval filters (VCF) for both traditional and prophylactic indications. This project was developed to establish a VCF registry for trauma patients to determine the long-term complications of VCF placement. METHODS: A letter was sent to all trauma patients who had a VCF placed from 1993 through 1997. Patients were asked to return for a history and physical examination to detect signs and symptoms related to VTE, a duplex ultrasound of the inferior vena cava, and a plain abdominal radiograph to determine filter migration. RESULTS: There were 191 VCFs inserted in our trauma population from 1993 to 1997. There were 105 patients (75 male and 30 female) available for evaluation, with a mean follow-up of 28.9 months. Forty-one VCFs were placed in patients with DVT or pulmonary embolism, and 64 were placed in patients for prophylactic indications as per the guidelines developed by the Eastern Association for the Surgery of Trauma. There were no clinically identifiable complications related to insertion of the VCF. There were no pulmonary embolisms detected after VCF insertion. In follow-up, only one filter (0.95%) migrated, and this was minimal (1 cm cephalad). One (0.95%) vena cava was occluded, based on duplex ultrasonography, and 11 patients (10.4%) had signs or symptoms of leg swelling after hospital discharge. Twenty eight (44%) of the 64 patients with prophylactic VCFs developed a DVT after filter placement. CONCLUSION: VCFs placed in trauma patients have acceptable short- and long-term complication rates. Consideration should be given to prophylactic VCF placement in patients at high risk for VTE. Randomized controlled trials are needed to evaluate whether VCF insertion increases the risk for subsequent DVT