title: A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors.
abstract: BACKGROUND
  Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling.
  
  
  METHODS
  Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule.
  
  
  RESULTS
  A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206.
  
  
  CONCLUSIONS
  Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation.
  
  
  BACKGROUND
  ClinicalTrials.gov; identifier: NCT00963547.
authors.forename: Clifford
authors.initials: C
authors.lastname: Hudis
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
authors.forename: Yelena Y
authors.initials: YY
authors.lastname: Janjigian
authors.forename: Ray
authors.initials: R
authors.lastname: Lee
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sutherland
authors.forename: Robert
authors.initials: R
authors.lastname: Lehman
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.forename: Nicola
authors.initials: N
authors.lastname: Hamilton
authors.forename: Devika
authors.initials: D
authors.lastname: Gajria
authors.forename: James
authors.initials: J
authors.lastname: Knowles
authors.forename: Jigna
authors.initials: J
authors.lastname: Shah
authors.forename: Keith
authors.initials: K
authors.lastname: Shannon
authors.forename: Ernestina
authors.initials: E
authors.lastname: Tetteh
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.forename: Carolina
authors.initials: C
authors.lastname: Moreno
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.forename: Hyo Sook
authors.initials: HS
authors.lastname: Han
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000188:drug therapy; D058534:Class I Phosphatidylinositol 3-Kinases; D004334:Drug Administration Schedule; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058534:Class I Phosphatidylinositol 3-Kinases; D006575:Heterocyclic Compounds, 3-Ring; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C548887:MK 2206; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human