title: A dose-escalation study of aerosolized sargramostim in the treatment of metastatic melanoma: an NCCTG Study.
abstract: OBJECTIVE
  Early testing of aerosolized sargramostim therapy demonstrated anecdotal clinical responses in patients with metastatic melanoma associated with emergence of systemic antitumor immunity. To improve the clinical and immunologic efficacy of therapy without compromising patient safety, we performed a further dose escalation trial in patients with metastatic melanoma.
  
  
  METHODS
  We conducted a dose-escalation clinical trial of HLA-A2 patients with metastatic melanoma to the lung treated with aerosolized granulocyte macrophage colony stimulating factor (GM-CSF) (500-2000 microg/dose, with increments of 250 microg/dose/cohort) twice/d on days 1 to 7 and 15 to 21 every 28 days until progression or severe toxicity to find a dose where a majority of patients develop antitumor immunity. Five patients were treated per each dose level. Clinical, immune, and safety parameters were examined.
  
  
  RESULTS
  The study accrued 40 patients. Toxicity was acceptable. All doses levels were exhausted without identifying a dose of GM-CSF at which a majority of patients (> or =3 of 5) demonstrated significant up-regulation of antitumor immunity. Three of 16 patients who were tetramer positive for at least one melanoma antigen (eg, MART-1) pretreatment developed an immune response (IR) to different tumor antigens. Two of 9 patients who were tetramer negative to all melanoma antigens pretreatment developed an IR against gp100. The greatest changes in antitumor immunity occurred at the highest dose levels.
  
  
  CONCLUSIONS
  A dose of aerosolized GM-CSF capable of inducing antitumor immunity in the majority of patients was not reached. All tested doses were well tolerated. The greatest increase in antitumor T cell IRs was achieved at the highest doses of GM-CSF.
authors.affiliation: Melanoma Study Group, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. markovic.svetomir@mayo.edu
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Nevala
authors.forename: Louis
authors.initials: L
authors.lastname: Geeraerts
authors.forename: Edward T
authors.initials: ET
authors.lastname: Creagan
authors.forename: Lori A
authors.initials: LA
authors.lastname: Erickson
authors.forename: Kendrith M
authors.initials: KM
authors.lastname: Rowland
authors.forename: Roscoe F
authors.initials: RF
authors.lastname: Morton
authors.forename: William L
authors.initials: WL
authors.lastname: Horvath
authors.forename: Mark R
authors.initials: MR
authors.lastname: Pittelkow
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000336:Aerosols; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D016130:Immunophenotyping; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D058965:MART-1 Antigen; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000336:Aerosols; D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D007155:Immunologic Factors; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C081222:sargramostim; D016178:Granulocyte-Macrophage Colony-Stimulating Factor