title: Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma.
abstract: CD44v6 is a tumor associated antigen abundantly expressed in head and neck squamous cell carcinomas (HNSCC) and in normal squamous epithelium. The immunoconjugate bivatuzumab mertansine (BIWI 1) consists of a highly potent antimicrotubule agent coupled to a monoclonal antibody against CD44v6. The maximum tolerated dose (MTD), safety and efficacy of BIWI 1 administered IV in patients with HNSCC has not been determined. In a clinical phase I trial, adult patients with recurrent or metastatic HNSCC were treated intravenously with BIWI 1. Starting with 25mg/m(2), the dose was escalated in steps of 25mg/m(2) until dose limiting toxicity was observed. Six women and 25 men were included. The MTD was 300 mg/m(2). Twelve patients were treated with at least the MTD. The principal toxic effects were maculopapular rashes, focal blister formation and skin exfoliation. Three patients had partial responses at doses of 200, 275 and 325 mg/m(2). The concept that bivatuzumab can direct mertansine activity to CD44v6 expressing tumors was confirmed. Although CD44v6 was abundantly expressed in all tumors, the response to BIWI 1 was variable. Binding to CD44v6 on skin keratinocytes mediated serious skin toxicity with a fatal outcome in a parallel trial, which led to the termination of the development program of bivatuzumab mertansine and the present study.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Ulm, Frauensteige 12, 89075 Ulm, Germany. Herbert.riechelmann@uniklinik-ulm.de
authors.forename: Herbert
authors.initials: H
authors.lastname: Riechelmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Sauter
authors.forename: Wolfram
authors.initials: W
authors.lastname: Golze
authors.forename: Gertraud
authors.initials: G
authors.lastname: Hanft
authors.forename: Carsten
authors.initials: C
authors.lastname: Schroen
authors.forename: Karl
authors.initials: K
authors.lastname: Hoermann
authors.forename: Thomas
authors.initials: T
authors.lastname: Erhardt
authors.forename: Silke
authors.initials: S
authors.lastname: Gronau
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006258:Head and Neck Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D008875:Middle Aged; D018579:Patient Selection; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C112697:CD44v6 antigen; D018960:Hyaluronan Receptors; D018796:Immunoconjugates; C519271:bivatuzumab mertansine; D008453:Maytansine