title: Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.
abstract: BACKGROUND
  MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS1402 (formerly R1550) is a humanized IgG1k monoclonal antibody that binds to PDTR sequences within this tandem repeat that are not exposed in normal cells. AS1402 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), specifically against MUC1-expressing tumor cells. The objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) characteristics of AS1402 monotherapy in patients with locally advanced or metastatic MUC1-positive breast cancer that had progressed after anthracyclines- and taxane-based therapy.
  
  
  METHODS
  Patients received AS1402 over a 1- to 3-hour intravenous (i.v.) infusion at doses between 1 and 16 mg/kg, with repeated dosing every 1 to 3 weeks (based on patient-individualized PK assessment) until disease progression. Serum AS1402 levels were measured at multiple times after i.v. administration. Human anti-human antibody (HAHA) responses were measured to determine the immunogenicity of AS1402. Noncompartmental pharmacokinetic parameters were determined and were used to assess dose dependency across the dose range studied.
  
  
  RESULTS
  Twenty-six patients were treated. AS1402 was generally well tolerated. Two grade 3/4 drug-related adverse events were reported, both at the 3-mg/kg dose. Neither was observed in expanded or subsequent dosing cohorts. No anti-human antibodies were detected. Plasma concentrations of AS1402 appeared to be proportional to dose within the 1- to 16-mg/kg dose range assessed, with a mean terminal half-life of 115.4 +/- 37.1 hours.
  
  
  CONCLUSIONS
  Repeated iv administration of AS1402 was well tolerated, with a maximum tolerated dose (MTD) exceeding 16 mg/kg, the highest dose administered in this study. The half-life and exposure of AS1402 were such that weekly dosing could achieve plasma concentrations corresponding to the maximal ADCC activity observed in vitro. A phase II study is ongoing to evaluate the clinical activity of AS1402 in patients with advanced breast cancer.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT00096057.
authors.affiliation: Division of Hematology/Oncology, University of Miami Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Avenue; Suite 3400 (D8-4), Miami, FL 33136, USA. mpegram@med.miami.edu
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pegram
authors.forename: Virginia F
authors.initials: VF
authors.lastname: Borges
authors.forename: Nuhad
authors.initials: N
authors.lastname: Ibrahim
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Fuloria
authors.forename: Charles
authors.initials: C
authors.lastname: Shapiro
authors.forename: Susan
authors.initials: S
authors.lastname: Perez
authors.forename: Karen
authors.initials: K
authors.lastname: Wang
authors.forename: Franziska
authors.initials: F
authors.lastname: Schaedli Stark
authors.forename: Nigel
authors.initials: N
authors.lastname: Courtenay Luck
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D001943:Breast Neoplasms / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D015331:Cohort Studies; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D008875:Middle Aged; D018396:Mucin-1 / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018396:Mucin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; C060192:MUC1 protein, human; C547393:epitumomab; C508053:ERBB2 protein, human