title: Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors.
abstract: BACKGROUND
  Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies.
  
  
  METHODS
  Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m2 (arm 1), docetaxel 75 mg/m2 (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested.
  
  
  RESULTS
  MTD of MK-2206 (N = 72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ≥6 months.
  
  
  CONCLUSIONS
  MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity.
authors.affiliation: Drug Development Unit, The Institute of Cancer Research/The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. rhoda.molife@icr.ac.uk.
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.forename: Joanna
authors.initials: J
authors.lastname: Vitfell-Rasmussen
authors.forename: Adriane M
authors.initials: AM
authors.lastname: Zernhelt
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Cassier
authors.forename: Eric
authors.initials: E
authors.lastname: Chen
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondo
authors.forename: Ernestina
authors.initials: E
authors.lastname: Tetteh
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Susan
authors.initials: S
authors.lastname: Minton
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride; D005076:Exanthema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D064147:Febrile Neutropenia / Q000139:chemically induced; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D013280:Stomatitis / Q000139:chemically induced; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D014012:Tinnitus / Q000139:chemically induced; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D016190:Carboplatin; D000069347:Erlotinib Hydrochloride; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel