title: A phase I and pharmacodynamic evaluation of polyethylene glycol-conjugated L-asparaginase in patients with advanced solid tumors.
abstract: OBJECTIVE
  To evaluate the in vitro activity of polyethylene glycol-conjugated L-asparaginase (PEG-Lasparaginase) against fresh human tumor specimens, using the human tumor clonogenic assay (HTCA), and to perform a phase I dose-escalation clinical trial of PEG-L-asparaginase. The goal of the clinical study was to determine the toxicity and optimum biologic dose of PEG-L-asparaginase based on depletion of serum L-asparagine in patients with advanced solid tumors.
  
  
  METHODS
  A modified method for determination of serum L-asparagine is described. PEG-L-asparaginase was administered by intramuscular injection every 2 weeks to 28 patients with various types of advanced solid tumor malignancies. At least 3 patients were evaluated at each dose level: 250 IU/m2, 500 IU/m2, 1,000 IU/m2, 1,500 IU/m2, 2,000 IU/m2.
  
  
  RESULTS
  The in vitro HTCA studies suggested good antitumor activity against malignant melanoma and multiple myeloma. Serum L-asparagine was most consistently and profoundly depleted (up to 4 weeks) in patients treated with 2,000 IU/m2. Patients receiving this dose level also showed more frequent grade 1, grade 2, and occasional grade 3 toxicities of fatigue/weakness, nausea/vomiting, and anorexia/ weight loss. Three patients developed hypersensitivity reactions, but these were not dose related. Two patients developed deep vein thromboses. We saw no episodes of clinical pancreatitis, but there were minor fluctuations of serum amylase and lipase. We saw no partial or complete responses in patients treated in this study, including 11 patients with malignant melanoma.
  
  
  CONCLUSIONS
  We conclude that PEG-L-asparaginase is generally well tolerated in patients with advanced solid tumors, and a dosage of 2,000 IU/m2 by intramuscular injection every 2 weeks results in significant depletion of serum L-asparagine.
authors.affiliation: The University of Arizona, Tucson 85724, USA. ctaylor@azcc.arizona.edu
authors.forename: C W
authors.initials: CW
authors.lastname: Taylor
authors.forename: R T
authors.initials: RT
authors.lastname: Dorr
authors.forename: P
authors.initials: P
authors.lastname: Fanta
authors.forename: E M
authors.initials: EM
authors.lastname: Hersh
authors.forename: S E
authors.initials: SE
authors.lastname: Salmon
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001216:Asparagine / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005972:Glutaminase / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D009363:Neoplasm Proteins / Q000097:blood; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; C022324:polyethylene glycol-glutaminase-asparaginase; D011092:Polyethylene Glycols; D001216:Asparagine; D001215:Asparaginase; D005972:Glutaminase