title: Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma.
abstract: OBJECTIVE
  High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2-restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial.
  
  
  METHODS
  In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment.
  
  
  RESULTS
  From 1998 to 2003, 131 patients with HLA-A2-positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at >or= 30 months. Immune studies including assays of CD3-zeta expression and numbers of CD4(+)/CD25(+)/FoxP3(+) regulatory T cells, CD15(+)/CD11b(+)/CD14(-) immature myeloid-derived cells, and CD8(+)gp100 tetramer-positive cells in the blood did not correlate with clinical benefit.
  
  
  CONCLUSIONS
  The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.
authors.affiliation: Vanderbilt-Ingram Cancer Center Vanderbilt, University Medical Center, Section of Hematology/Oncology, 777 Preston Research Bldg, Nashville, TN 37232-6307, USA. jeff.sosman@vanderbilt.edu
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Carole
authors.initials: C
authors.lastname: Carrillo
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Urba
authors.forename: Lawrence
authors.initials: L
authors.lastname: Flaherty
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Clark
authors.forename: Janet
authors.initials: J
authors.lastname: Dutcher
authors.forename: Kim A
authors.initials: KA
authors.lastname: Margolin
authors.forename: James
authors.initials: J
authors.lastname: Mier
authors.forename: Jarod
authors.initials: J
authors.lastname: Gollob
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: David J
authors.initials: DJ
authors.lastname: Panka
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Crosby
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Boyle
authors.forename: Bonnie
authors.initials: B
authors.lastname: LaFleur
authors.forename: Marc S
authors.initials: MS
authors.lastname: Ernstoff
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage; D015789:HLA-A2 Antigen / Q000096:biosynthesis* / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008353:Mannitol / Q000008:administration & dosage / Q000031:analogs & derivatives; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009829:Oleic Acids / Q000008:administration & dosage; D058951:gp100 Melanoma Antigen
chemical_list: D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D009829:Oleic Acids; C548637:PMEL protein, human; D058951:gp100 Melanoma Antigen; C477385:montanide ISA 51; D008353:Mannitol; D005620:Freund's Adjuvant