title: Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: a phase II trial (CTEP 7190/Mel47).
abstract: OBJECTIVE
  A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma.
  
  
  METHODS
  Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mg weekly and bevacizumab 10 mg every 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood.
  
  
  RESULTS
  Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0-39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAF(WT) tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P < 0.001), and decreased mitotic rate (Ki67(+)) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4(+)FoxP3(+) cells.
  
  
  CONCLUSIONS
  These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAF(wt) melanoma. Mixed effects on immunologic function also support combination with immune therapies.
authors.affiliation: University of Virginia, Charlottesville, VA 22908, USA. cls8h@virginia.edu
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
authors.forename: Gina R
authors.initials: GR
authors.lastname: Petroni
authors.forename: Kerrington R
authors.initials: KR
authors.lastname: Molhoek
authors.forename: David L
authors.initials: DL
authors.lastname: Brautigan
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Chianese-Bullock
authors.forename: Amber L
authors.initials: AL
authors.lastname: Shada
authors.forename: Mark E
authors.initials: ME
authors.lastname: Smolkin
authors.forename: Walter C
authors.initials: WC
authors.lastname: Olson
authors.forename: Alison
authors.initials: A
authors.lastname: Gaucher
authors.forename: Cheryl Murphy
authors.initials: CM
authors.lastname: Chase
authors.forename: William W
authors.initials: WW
authors.lastname: Grosh
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Weiss
authors.forename: Aubrey G
authors.initials: AG
authors.lastname: Wagenseller
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Olszanski
authors.forename: Lainie
authors.initials: L
authors.lastname: Martin
authors.forename: Sofia M
authors.initials: SM
authors.lastname: Shea
authors.forename: Gulsun
authors.initials: G
authors.lastname: Erdag
authors.forename: Prahlad
authors.initials: P
authors.lastname: Ram
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weber
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D001706:Biopsy; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010750:Phosphoproteins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D010750:Phosphoproteins; D000068258:Bevacizumab; C401859:temsirolimus; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D020123:Sirolimus