A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors

Ann Oncol. 2015 Jan;26(1):58-64. doi: 10.1093/annonc/mdu482. Epub 2014 Oct 24.

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.

Patients and 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.

Trial registration: ClinicalTrials.gov NCT00955773.

Keywords: MEK inhibitor; advanced solid tumors; everolimus; mTOR inhibitor; pancreatic cancer; trametinib.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Drug Administration Schedule
  • Everolimus
  • Female
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 2 / antagonists & inhibitors
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyridones / adverse effects
  • Pyridones / pharmacokinetics
  • Pyridones / therapeutic use*
  • Pyrimidinones / adverse effects
  • Pyrimidinones / pharmacokinetics
  • Pyrimidinones / therapeutic use*
  • Sirolimus / adverse effects
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacokinetics
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Treatment Outcome
  • Young Adult

Substances

  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • trametinib
  • Everolimus
  • MAP2K2 protein, human
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Sirolimus

Associated data

  • ClinicalTrials.gov/NCT00955773