title: A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors.
abstract: The RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors.
  
  
  
  This study was a phase I, open-label, multicenter study in patients aged ≥18 years with advanced solid tumors who were candidates for docetaxel or dacarbazine treatment. Part A of the study (dose escalation) evaluated safety, tolerability, PK, and maximum tolerated dose (MTD) of selumetinib twice daily (BID) with docetaxel 75 mg/m2or dacarbazine 1000 mg/m2administered every 21 days. Patients receiving docetaxel could be administered primary prophylactic granulocyte-colony stimulating factor according to standard guidelines. Part B of the study (dose expansion) further evaluated safety, tolerability, and PK in 12 additional patients at the MTD combinations determined in part A.
  
  
  
  A total of 35 patients received selumetinib plus docetaxel, and 25 received selumetinib plus dacarbazine. The MTD of selumetinib was 75 mg BID in combination with either docetaxel (two dose-limiting toxicity [DLT] events: neutropenia with fever, and thrombocytopenia) or dacarbazine (one DLT event: thrombocytopenia). Common adverse events occurring with each treatment combination were diarrhea, peripheral/periorbital edema, fatigue, and nausea. PK parameters for selumetinib and docetaxel or dacarbazine were similar when administered alone or in combination. Partial responses were reported in 6/35 patients receiving selumetinib plus docetaxel and 4/25 patients receiving selumetinib plus dacarbazine.
  
  
  
  The combinations of selumetinib plus docetaxel and selumetinib plus dacarbazine demonstrated manageable safety and tolerability profiles and preliminary signs of clinical activity in patients with advanced solid tumors.
  
  
  
  ClinicalTrials.gov NCT00600496; registered 8 July 2009.
authors.affiliation: Yale Cancer Center, PO Box 208028, New Haven, CT, 06520-8028, USA. patricia.lorusso@yale.edu.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.|Tennessee Oncology PLLC, Nashville, TN, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: California Pacific Medical Center, San Francisco, CA, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.|Tennessee Oncology PLLC, Nashville, TN, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: AstraZeneca, Wilmington, DE, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Curt
authors.affiliation: AstraZeneca, Wilmington, DE, USA.
authors.forename: Ugochi
authors.initials: U
authors.lastname: Emeribe
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Delyth
authors.initials: D
authors.lastname: Clemett
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Tomkinson
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001562:Benzimidazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003606:Dacarbazine / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D061214:Patient Safety; D043823:Taxoids / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D043823:Taxoids; D000077143:Docetaxel; D003606:Dacarbazine
keywords: Advanced solid tumors; Dacarbazine; Docetaxel; Dose-escalation; Selumetinib