title: Study design and rationale for a randomised, placebo-controlled, double-blind study to assess the efficacy of selumetinib (AZD6244; ARRY-142886) in combination with dacarbazine in patients with metastatic uveal melanoma (SUMIT).
abstract: BACKGROUND
  Uveal melanoma is characterised by mutations in GNAQ and GNA11, resulting in Ras/Raf/MEK/ERK pathway activation. Treatment with selumetinib (AZD6244, ARRY-142886), a MEK1/2 inhibitor, results in antitumour effects in uveal melanoma pre-clinical models. A randomised phase II trial demonstrated improved progression-free survival (PFS) and response rate (RR) with selumetinib monotherapy versus chemotherapy with temozolomide or dacarbazine in patients with metastatic uveal melanoma. Pre-clinically, selumetinib in combination with alkylating agents enhanced antitumour activity compared with chemotherapy alone. We hypothesise that selumetinib in combination with dacarbazine will result in improved clinical outcomes in patients with metastatic uveal melanoma versus dacarbazine alone.
  
  
  METHODS
  SUMIT is a randomised, international, double-blind, placebo-controlled, phase III study assessing the efficacy and safety of selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma who have not received prior systemic therapy. Primary endpoint is PFS. Secondary endpoints include objective RR, duration of response, change in tumour size at Week 6, overall survival, safety and tolerability. Exploratory endpoints include efficacy in tumours with GNAQ or GNA11 mutations. Eligible patients must have: ≥1 lesion that can be accurately measured at baseline, and is suitable for accurate repeated measurements; ECOG performance status 0-1; life expectancy>12 weeks. Mutation status for GNAQ/GNA11 will be assessed retrospectively. An estimated 128 patients from approximately 50 sites globally will be randomised (3:1) to selumetinib 75 mg twice daily or placebo in combination with dacarbazine 1000 mg/m(2) on Day 1 of every 21-day cycle until objective disease progression, intolerable toxicity or occurrence of another discontinuation criterion. Randomisation will be stratified by the presence/absence of liver metastases. Tumours will be evaluated by RECIST v1.1 every 6 weeks. All patients have the option of receiving selumetinib with or without dacarbazine at disease progression. Study enrolment began in April 2014 and is expected to complete in early 2015.
  
  
  CONCLUSIONS
  Treatment of patients with metastatic uveal melanoma represents an area of high unmet medical need. This study evaluating selumetinib in combination with dacarbazine was designed with input from the US FDA, and is the first potential registration trial to be conducted in patients with metastatic uveal melanoma.
  
  
  BACKGROUND
  Clinicaltrials.gov (Date of registration, October 10, 2013) REGISTRATION NUMBER: NCT01974752 Trial abbreviation: SUMIT.
authors.affiliation: Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, 10032, USA. rdc2150@cumc.columbia.edu.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.affiliation: Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, 10032, USA. gks2123@cumc.columbia.edu.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.affiliation: AstraZeneca, Macclesfield, UK. Helen.Mann@astrazeneca.com.
authors.forename: Helen
authors.initials: H
authors.lastname: Mann
authors.affiliation: AstraZeneca, Macclesfield, UK. smithic@mac.com.
authors.forename: Ian
authors.initials: I
authors.lastname: Smith
authors.affiliation: Mt Vernon Cancer Centre, Northwood, UK. nathan.pd@gmail.com.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Nathan
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001562:Benzimidazoles / Q000008:administration & dosage*; D003606:Dacarbazine / Q000008:administration & dosage*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000098943:Uveal Melanoma
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D003606:Dacarbazine