title: A phase 1b study of trametinib, an oral Mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours.
abstract: OBJECTIVE
  This phase 1b study determined the safety, tolerability, and recommended phase 2 dose (RP2D) and schedule of trametinib in combination with gemcitabine. Secondary objectives included assessment of clinical activity and steady-state pharmacokinetics.
  
  
  METHODS
  Adults with advanced solid tumours, adequate organ function and Eastern Co-operative Oncology Group performance status (ECOG PS) ⩽ 1 were eligible. Once-daily oral trametinib (1mg, 2mg, 2.5mg) was escalated in a 3+3 design with standard gemcitabine dosing (1000 mg/m(2) IV Days 1, 8, and 15 of 28-day cycles). During expansion, trametinib 2mg was combined with gemcitabine. Pharmacokinetics samples were collected on Day 15 pre-dose and 1, 2, 4 and 6h post-dose; tumour assessments were repeated every two cycles.
  
  
  RESULTS
  Between 8/2009 and 11/2010, 31 patients (pancreas = 11, breast = 6, non-small cell lung cancer (NSCLC) = 4, other = 10) were treated. Dose-limiting toxicities (DLTs) occurred in each cohort, and included febrile neutropenia, transaminase elevation and uveitis. The RP2D was declared as trametinib 2mg daily with standard gemcitabine dosing. Common grade 3/4 toxicities at the RP2D included: neutropenia (38%), thrombocytopenia (19%) and transaminase elevation (14%). Of 10 patients with measurable pancreatic cancer, three partial responses (30%) were documented; two additional patients achieved objective responses (breast, complete response (CR); salivary glands, partial response (PR)). Pharmacokinetics suggested no change in exposures of either drug in combination.
  
  
  CONCLUSIONS
  Administration of trametinib at its full monotherapy dose of 2mg daily in combination with standard gemcitabine dosing (1000 mg/m(2) IV Days 1, 8, and 15 every 28 days) was feasible. Though most toxicities were manageable, the addition of trametinib may increase gemcitabine-associated myelosuppression. Future studies of this combination will require monitoring to maintain dose and schedule.
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA. Electronic address: jinfante@tnonc.com.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
authors.forename: Drew
authors.initials: D
authors.lastname: Rasco
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
authors.forename: Lon
authors.initials: L
authors.lastname: Smith
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Cox
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Durante
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Bellew
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Joohyun Jennifer
authors.initials: JJ
authors.lastname: Park
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Ngocdiep T
authors.initials: NT
authors.lastname: Le
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D011728:Pyridones; D011744:Pyrimidinones; D003841:Deoxycytidine; C560077:trametinib; D000093542:Gemcitabine