title: A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.
abstract: BACKGROUND
  This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity.
  
  
  METHODS
  A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle.
  
  
  RESULTS
  Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%).
  
  
  CONCLUSIONS
  This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.
authors.affiliation: South Texas Accelerated Research Therapeutics LLC, San Antonio. Electronic address: atolcher@start.stoh.com.
authors.forename: A W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville.
authors.forename: J C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: South Texas Accelerated Research Therapeutics LLC, San Antonio.
authors.forename: K P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville.
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: South Texas Accelerated Research Therapeutics LLC, San Antonio.
authors.forename: A
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville.
authors.forename: S F
authors.initials: SF
authors.lastname: Jones
authors.affiliation: South Texas Accelerated Research Therapeutics LLC, San Antonio.
authors.forename: D
authors.initials: D
authors.lastname: Rasco
authors.affiliation: GlaxoSmithKline, Collegeville.
authors.forename: D S
authors.initials: DS
authors.lastname: Cox
authors.affiliation: GlaxoSmithKline, Collegeville.
authors.forename: M
authors.initials: M
authors.lastname: Durante
authors.affiliation: Pharmaceutical Companies of Johnson and Johnson, Greater Philadelphia Area.
authors.forename: K M
authors.initials: KM
authors.lastname: Bellew
authors.affiliation: GlaxoSmithKline, Collegeville.
authors.forename: J
authors.initials: J
authors.lastname: Park
authors.affiliation: Novartis, East Hanover, USA.
authors.forename: N T
authors.initials: NT
authors.lastname: Le
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville.
authors.forename: J R
authors.initials: JR
authors.lastname: Infante
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011728:Pyridones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D000068338:Everolimus; C482128:MAP2K2 protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020123:Sirolimus
keywords: MEK inhibitor; advanced solid tumors; everolimus; mTOR inhibitor; pancreatic cancer; trametinib