title: Phase I trial of the anti-Lewis Y drug immunoconjugate BR96-doxorubicin in patients with lewis Y-expressing epithelial tumors.
abstract: OBJECTIVE
  We conducted a phase I clinical trial of BR96-Doxorubicin (BR96-Dox), a chimeric anti-Lewis Y (Le(Y)) monoclonal antibody conjugated to doxorubicin, in patients whose tumors expressed the Le(Y) antigen. The study aimed to determine the toxicity, maximum-tolerated dose, pharmacokinetics, and immunogenicity of BR96-Dox.
  
  
  METHODS
  This was a phase I dose escalation study. BR96-Dox was initially administered alone as a 2-hour infusion every 3 weeks. The occurrence of gastrointestinal (GI) toxicity necessitated the administration of BR96-Dox as a continuous infusion over 24 hours and use of antiemetics and antigastritis premedication. Patients experiencing severe GI toxicity underwent GI endoscopy. All patients underwent restaging after two cycles.
  
  
  RESULTS
  A total of 66 patients predominantly with metastatic colon and breast cancer were enrolled onto the study. The most common side effects were GI toxicity, fever, and elevation of pancreatic lipase. At higher doses, BR96-Dox was associated with nausea, vomiting, and endoscopically documented exudative gastritis of the upper GI tract, which was dose-limiting at a maximum dose of 875 mg/m(2) (doxorubicin equivalent, 25 mg/m(2)) administered every 3 weeks. Toxicity was reversible and generally of short duration. Premedication with the antiemetic Kytril (granisetron hydrochloride; SmithKline Beecham, Philadelphia, PA), the antacid omeprazole, and dexamethasone was most effective in ameliorating GI toxicity. A dose of 700 mg/m(2) BR96-Dox (doxorubicin equivalent, 19 mg/m(2)) every 3 weeks was determined to be the optimal phase II dose when administered with antiemetic and antigastritis prophylaxis. BR96-Dox deposition on tumor tissue was documented immunohistochemically and by confocal microscopy. At the 550-mg/m(2) dose, the half-life (mean +/- SD) of BR96 and doxorubicin was 300 +/- 95 hours and 43 +/- 4 hours, respectively. BR96-Dox elicited a weak immune response in 37% of patients. Objective clinical responses were seen in two patients.
  
  
  CONCLUSIONS
  BR96-Dox provides a unique strategy to deliver doxorubicin to Le(Y)-expressing tumor and was well tolerated at doses of 700 mg/m(2) every 3 weeks. BR96-Dox was not associated with the typical side-effect profile of native doxorubicin and can potentially deliver high doses of doxorubicin to antigen-expressing tumors. A phase II study in doxorubicin-sensitive tumors is warranted.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, 35294-3300, USA. mansoor.saleh@ccc.uab.edu
authors.forename: M N
authors.initials: MN
authors.lastname: Saleh
authors.forename: S
authors.initials: S
authors.lastname: Sugarman
authors.forename: J
authors.initials: J
authors.lastname: Murray
authors.forename: J B
authors.initials: JB
authors.lastname: Ostroff
authors.forename: D
authors.initials: D
authors.lastname: Healey
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: C R
authors.initials: CR
authors.lastname: Daniel
authors.forename: D
authors.initials: D
authors.lastname: LeBherz
authors.forename: H
authors.initials: H
authors.lastname: Brewer
authors.forename: N
authors.initials: N
authors.lastname: Onetto
authors.forename: A F
authors.initials: AF
authors.lastname: LoBuglio
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000922:Immunotoxins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007983:Lewis Blood Group Antigens / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D015295:Antigens, Tumor-Associated, Carbohydrate; D000970:Antineoplastic Agents; C092612:BR96-doxorubicin immunoconjugate; D000922:Immunotoxins; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D004317:Doxorubicin