title: A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas.
abstract: BACKGROUND
  The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.
  
  
  METHODS
  Seventy-one adults with advanced STS who received ⩽ 2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).
  
  
  RESULTS
  There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N = 11) over single agent (N = 10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P = 0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).
  
  
  CONCLUSIONS
  While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.
authors.affiliation: City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Eroglu
authors.affiliation: University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Tawbi
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hu
authors.affiliation: City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Guan
authors.affiliation: City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: P H
authors.initials: PH
authors.lastname: Frankel
authors.affiliation: City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Ruel
authors.affiliation: City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wilczynski
authors.affiliation: University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Christensen
authors.affiliation: University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Chow
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C401859:temsirolimus; D020123:Sirolimus