title: Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
authors.affiliation: Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. Division of Clinical Studies, The Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, Texas.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: CR-UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.
authors.forename: Nina
authors.initials: N
authors.lastname: Tunariu
authors.affiliation: Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. Division of Clinical Studies, The Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondo
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Ivy
authors.initials: I
authors.lastname: Fearen
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, Texas.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. Division of Clinical Studies, The Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.affiliation: Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. Division of Clinical Studies, The Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Baird
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Liliana
authors.initials: L
authors.lastname: Delgado
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Ernestina
authors.initials: E
authors.lastname: Tetteh
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Beckman
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lupinacci
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Riisnaes
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: Shaun
authors.initials: S
authors.lastname: Decordova
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Heaton
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Swales
authors.affiliation: CR-UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.
authors.forename: Nandita M
authors.initials: NM
authors.lastname: deSouza
authors.affiliation: CR-UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leach
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Garrett
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.affiliation: Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. Division of Clinical Studies, The Institute of Cancer Research, Surrey, United Kingdom. johann.de-bono@icr.ac.uk.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, Texas.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D003952:Diagnostic Imaging; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt