title: Phase I trial of subcutaneous recombinant macrophage colony-stimulating factor: clinical and immunomodulatory effects.
abstract: OBJECTIVE
  Recombinant human macrophage colony-stimulating factor (rM-CSF) has been demonstrated to control the growth, differentiation, and function of mononuclear phagocytes. Preclinical studies have indicated antitumor effects, and therefore a phase I trial of rM-CSF in patients with malignancy was initiated. The toxicity and hematologic and immunologic effects were investigated.
  
  
  METHODS
  rM-CSF was administered as a subcutaneous injection on days 1 through 5 and 8 through 12. Cycles were repeated every 28 days. Cohorts of four to seven patients received rM-CSF at dose levels from 0.1 to 25.6 mg/m2/d. Forty-two patients received 88 cycles of rM-CSF. All patients had metastatic solid tumors refractory to standard therapy.
  
  
  RESULTS
  The toxicity of rM-CSF was mild. Dose-limiting toxicity included thrombocytopenia (two patients) and iritis (one patient) occurring at a dose of 25.6 mg/m2/d. Hematologic studies demonstrated dose-related monocytosis occurring routinely at doses > or = 3.2 mg/m2/d, and thrombocytopenia. Immunologic studies demonstrated enhanced secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) by monocytes after in vitro stimulation with lipopolysaccharide, and increased expression of TNF-alpha mRNA at higher rM-CSF dose levels. Pharmacokinetic studies demonstrated that the systemic clearance rate of M-CSF increases during week 1 of therapy, resulting in lower blood levels of M-CSF during the second week of therapy.
  
  
  CONCLUSIONS
  rM-CSF can be safely administered to patients, and has biologic activity on peripheral-blood monocytes.
authors.affiliation: Department of Hematology and Medical Oncology, Cleveland Clinic Foundation, OH.
authors.forename: R M
authors.initials: RM
authors.lastname: Bukowski
authors.forename: G T
authors.initials: GT
authors.lastname: Budd
authors.forename: J A
authors.initials: JA
authors.lastname: Gibbons
authors.forename: R J
authors.initials: RJ
authors.lastname: Bauer
authors.forename: A
authors.initials: A
authors.lastname: Childs
authors.forename: J
authors.initials: J
authors.lastname: Antal
authors.forename: J
authors.initials: J
authors.lastname: Finke
authors.forename: L
authors.initials: L
authors.lastname: Tuason
authors.forename: V
authors.initials: V
authors.lastname: Lorenzi
authors.forename: D
authors.initials: D
authors.lastname: McLain
mesh_terms: D000328:Adult; D000368:Aged; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007279:Injections, Subcutaneous; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor