title: A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies.
abstract: OBJECTIVE
  Akt plays a key role in the aggressive pathogenesis of HER2+ malignancies, suggesting that Akt-inhibitors may be of therapeutic value in the treatment of HER2+ tumors. Preclinical studies demonstrate synergy between MK-2206, a selective allosteric Akt-inhibitor, with paclitaxel and trastuzumab. We aimed to evaluate the safety of this combination in patients with HER2+ malignancies.
  
  
  METHODS
  We conducted a phase 1b study of weekly MK-2206 in combination with weekly paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg in patients with HER2+ malignancies. Dose escalation was performed using a modified toxicity probability interval method. Molecular profiling of archived tissue samples and limited PK analyses were performed.
  
  
  RESULTS
  16 patients with HER2+ tumors were enrolled (12 breast, 3 gastric, 1 esophageal). 81 and 75 % had received prior trastuzumab and taxane chemotherapy, respectively. MK-2206 135 mg/week was determined to be tolerable. Three dose-limiting toxicities were observed including two grade 3 rashes and 1 grade 3 neutropenia resulting in a > 7 day delay in treatment. Grade 3/4 adverse events include neutropenia (44 %), rash (13 %), peripheral neuropathy (6 %), and depression (6 %). 10 patients (63 %) demonstrated tumor response (3 complete, 7 partial). Median duration of response was 6 months. Exploratory analyses identified STARD3, TM7SF2, and G3BP1 as potential biomarkers of response.
  
  
  CONCLUSIONS
  MK-2206 at a dose of 135 mg/week in combination with weekly paclitaxel and trastuzumab is safe and well tolerated, and is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in patients with HER2+ tumors despite prior HER2-directed therapy.
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA. Jo.chien@ucsf.edu.
authors.forename: Amy Jo
authors.identifier: http://orcid.org/0000-0003-2978-6249
authors.initials: AJ
authors.lastname: Chien
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA.
authors.forename: Alyson
authors.initials: A
authors.lastname: Cockerill
authors.affiliation: Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc, Kenilworth, NJ, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Fancourt
authors.affiliation: Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Emmett
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Moasser
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA.
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Melisko
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Ko
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA.
authors.forename: R Katie
authors.initials: RK
authors.lastname: Kelley
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Korn
authors.affiliation: Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Esserman
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, Sanfrancisco, CA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: van't Veer
authors.affiliation: Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Yau
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, Sanfrancisco, CA, USA.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Wolf
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA.
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Munster
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C548887:MK 2206
keywords: Akt-inhibitor; Breast cancer; HER2+; MK-2206; Trastuzumab resistance