title: PACMEL: a phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel.
abstract: BACKGROUND
  We sought to determine the maximal tolerated dose of the MEK inhibitor trametinib with weekly paclitaxel, with a view to exploring the combination's activity in melanoma lacking a BRAF V600 mutation.
  
  
  METHODS
  In this phase 1 study we used a fixed dose of paclitaxel (80 mg/m2 intravenous (IV) on days 1, 8 and 15 of each 4 week cycle) and escalated the dose of trametinib (to a maximum 2mg orally (PO) daily), following a 3+3 design. Eligible patients had advanced melanoma and could have received up to two previous lines of treatment for metastatic disease.
  
  
  RESULTS
  15 patients were enrolled, all but one of whose melanoma was wild type for BRAF at codon 600. The maximal monotherapy dose of trametinib proved tolerable with weekly paclitaxel. The most frequent adverse events observed were rash and fatigue. Six (40%) partial responses were reported, including four of eight patients with NRAS mutations. Median progression free survival was 5.5 months (95% confidence interval (CI) 1.8-7.8 months) and overall survival, 14.1 months (95% CI 4.6-not reached).
  
  
  CONCLUSIONS
  Trametinib can safely be given with weekly paclitaxel at the full monotherapy dose. In this small group promising progression free and overall survival were observed in patients with melanoma lacking a V600 BRAF mutation.
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Coupe
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Pippa
authors.initials: P
authors.lastname: Corrie
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Mirela
authors.initials: M
authors.lastname: Hategan
authors.affiliation: The Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.affiliation: The Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Avinash
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Oncology Clinical Trials Office, University of Oxford, UK.
authors.forename: Adelyn
authors.initials: A
authors.lastname: Wise
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Suter
authors.affiliation: Center for Statistics in Medicine, University of Oxford, UK.
authors.forename: Cristian
authors.initials: C
authors.lastname: Ciria
authors.affiliation: Center for Statistics in Medicine, University of Oxford, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Love
authors.affiliation: Oncology Clinical Trials Office, University of Oxford, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Collins
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000009:adverse effects; D012878:Skin Neoplasms / Q000188:drug therapy*
chemical_list: D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D017239:Paclitaxel
keywords: BRAF; MEK; Melanoma; Phase 1; Trametinib; Trial