Literature DB >> 25239610

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

Timothy A Yap1, Li Yan2, Amita Patnaik3, Nina Tunariu4, Andrea Biondo1, Ivy Fearen2, Kyriakos P Papadopoulos3, David Olmos1, Richard Baird1, Liliana Delgado2, Ernestina Tetteh2, Robert A Beckman2, Lisa Lupinacci2, Ruth Riisnaes5, Shaun Decordova5, Simon P Heaton5, Karen Swales5, Nandita M deSouza4, Martin O Leach4, Michelle D Garrett5, Daniel M Sullivan6, Johann S de Bono7, Anthony W Tolcher3.   

Abstract

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). ©2014 American Association for Cancer Research.

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Year:  2014        PMID： 25239610      PMCID： PMC4233149          DOI： 10.1158/1078-0432.CCR-14-0868

Source DB:  PubMed          Journal:  Clin Cancer Res        ISSN： 1078-0432            Impact factor:   12.531


  35 in total

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Journal:  Cancer Biol Ther       Date:  2006-07-26       Impact factor: 4.742

2.  The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice.

Authors:  Mei-Ling Chen; Pei-Zhang Xu; Xiao-ding Peng; William S Chen; Grace Guzman; Ximing Yang; Antonio Di Cristofano; Pier Paolo Pandolfi; Nissim Hay
Journal:  Genes Dev       Date:  2006-06-15       Impact factor: 11.361

3.  Frequent mutation of the PIK3CA gene in ovarian and breast cancers.

Authors:  Douglas A Levine; Faina Bogomolniy; Cindy J Yee; Alex Lash; Richard R Barakat; Patrick I Borgen; Jeff Boyd
Journal:  Clin Cancer Res       Date:  2005-04-15       Impact factor: 12.531

4.  Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group.

Authors:  G J Bubley; M Carducci; W Dahut; N Dawson; D Daliani; M Eisenberger; W D Figg; B Freidlin; S Halabi; G Hudes; M Hussain; R Kaplan; C Myers; W Oh; D P Petrylak; E Reed; B Roth; O Sartor; H Scher; J Simons; V Sinibaldi; E J Small; M R Smith; D L Trump; G Wilding
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Authors:  Kevin D Courtney; Ryan B Corcoran; Jeffrey A Engelman
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Authors:  Anwar R Padhani; Guoying Liu; Dow Mu Koh; Thomas L Chenevert; Harriet C Thoeny; Taro Takahara; Andrew Dzik-Jurasz; Brian D Ross; Marc Van Cauteren; David Collins; Dima A Hammoud; Gordon J S Rustin; Bachir Taouli; Peter L Choyke
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7.  Murine cell lines derived from Pten null prostate cancer show the critical role of PTEN in hormone refractory prostate cancer development.

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Authors:  Ming-Chih Crouthamel; Jason A Kahana; Susan Korenchuk; Shu-Yun Zhang; Gobalakrishnan Sundaresan; Derek J Eberwein; Kathleen K Brown; Rakesh Kumar
Journal:  Clin Cancer Res       Date:  2009-01-01       Impact factor: 12.531

9.  Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

Authors:  M O Leach; B Morgan; P S Tofts; D L Buckley; W Huang; M A Horsfield; T L Chenevert; D J Collins; A Jackson; D Lomas; B Whitcher; L Clarke; R Plummer; I Judson; R Jones; R Alonzi; T Brunner; D M Koh; P Murphy; J C Waterton; G Parker; M J Graves; T W J Scheenen; T W Redpath; M Orton; G Karczmar; H Huisman; J Barentsz; A Padhani
Journal:  Eur Radiol       Date:  2012-05-07       Impact factor: 5.315

Review 10.  DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents.

Authors:  J P B O'Connor; A Jackson; G J M Parker; G C Jayson
Journal:  Br J Cancer       Date:  2007-01-09       Impact factor: 7.640
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4.  AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma.

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Review 5.  Hyperglycemia Associated With Targeted Oncologic Treatment: Mechanisms and Management.

Authors:  Jonathan W Goldman; Melody A Mendenhall; Sarah R Rettinger
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6.  A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors.

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7.  A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer.

Authors:  Cynthia X Ma; Cesar Sanchez; Feng Gao; Robert Crowder; Michael Naughton; Timothy Pluard; Allison Creekmore; Zhanfang Guo; Jeremy Hoog; A Craig Lockhart; Austin Doyle; Charles Erlichman; Matthew J Ellis
Journal:  Clin Cancer Res       Date:  2016-01-18       Impact factor: 12.531

Review 8.  Targeting the PI3K pathway in cancer: are we making headway?

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9.  Novel pharmacodynamic biomarkers for MYCN protein and PI3K/AKT/mTOR pathway signaling in children with neuroblastoma.

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10.  A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors.

Authors:  Carol Aghajanian; Katherine M Bell-McGuinn; Howard A Burris; Lillian L Siu; Lee-Ann Stayner; Jennifer J Wheler; David S Hong; Carla Kurkjian; Shubham Pant; Ademi Santiago-Walker; Jennifer L Gauvin; Joyce M Antal; Joanna B Opalinska; Shannon R Morris; Jeffrey R Infante
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