title: A phase I trial of escalating doses of trastuzumab combined with daily subcutaneous interleukin 2: report of cancer and leukemia group B 9661.
abstract: OBJECTIVE
  The purpose of this study was to determine the toxicity of escalating doses of trastuzumab when combined with a fixed dose regimen of interleukin (IL)-2.
  
  
  METHODS
  Eligible patients had nonhematological malignancies for which standard therapy did not exist or was no longer effective and had tumors that overexpressed HER2. IL-2 was initially administered at a dose of 1.25 million IU/m(2) (low dose) s.c. daily except for 3 days every 2 weeks, when it was given at a dose of 15 million IU/m(2) (intermediate dose). These doses were reduced to 1.0 million and 12 million IU/m(2) after the first 18 patients. Trastuzumab was administered i.v. just before the first intermediate IL-2 dose and was escalated in cohorts of six or more patients from 1 mg/kg every 2 weeks to 8 mg/kg weekly. In vitro cytotoxicity testing was performed with patient peripheral blood mononuclear cells and HER2-overexpressing cell lines.
  
  
  RESULTS
  Forty-five patients were treated. Dose-related toxicity from trastuzumab was not observed. IL-2-related toxicities such as fever, chills, and fatigue were less common with the reduced doses of IL-2. There were two grade 3 and three grade 4 pulmonary reactions. Four major responses were observed, all in breast cancer patients treated with trastuzumab doses of at least 4.0 mg/kg. Although IL-2 produced expansion of natural killer cell subsets, there was no correlation between in vitro cytotoxicity and clinical response.
  
  
  CONCLUSIONS
  A regimen of IL-2 combined with trastuzumab is feasible, and response numbers are encouraging. Further testing of this regimen is warranted if the pulmonary toxicity can be ameliorated.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. gfleming@medicine.bsd.uchicago.edu
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Meropol
authors.forename: Gary L
authors.initials: GL
authors.lastname: Rosner
authors.forename: Donna R
authors.initials: DR
authors.lastname: Hollis
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.forename: Michael
authors.initials: M
authors.lastname: Caligiuri
authors.forename: Joanne
authors.initials: J
authors.lastname: Mortimer
authors.forename: Katherine
authors.initials: K
authors.lastname: Tkaczuk
authors.forename: Robin
authors.initials: R
authors.lastname: Parihar
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019002:CD56 Antigen / Q000378:metabolism; D002857:Chromium / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D007376:Interleukin-2 / Q000008:administration & dosage; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019002:CD56 Antigen; D002857:Chromium; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab