title: Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study.
abstract: OBJECTIVE
  To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) directed to CanAg, intravenously (i.v.) once every 3 weeks and to seek evidence of antitumor activity.
  
  
  METHODS
  Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered i.v. every 3 weeks. The pharmacokinetic parameters of cantuzumab mertansine, the presence of plasma-shed CanAg, and the development of both human antihuman and human anti-DM1 conjugate antibodies also were characterized.
  
  
  RESULTS
  Thirty-seven patients received 110 courses of cantuzumab mertansine at doses ranging from 22 to 295 mg/m2. Acute, transient, and reversible elevations of hepatic transaminases were the principal toxic effects. Nausea, vomiting, fatigue, and diarrhea were common but rarely severe at the highest dose levels. Dose, peak concentration, and area under the concentration-time curve correlated with the severity of transaminase elevation. The mean (+/- SD) clearance and terminal elimination half-life values for cantuzumab mertansine averaged 39.5 (+/-13.1) mL/h/m2 and 41.1 (+/-16.1) hours, respectively. Strong expression (3+) of CanAg was documented in 68% of patients. Two patients with chemotherapy-refractory colorectal carcinoma had minor regressions, and four patients had persistently stable disease for more than six courses.
  
  
  CONCLUSIONS
  The recommended dose for cantuzumab mertansine is 235 mg/m2 i.v. every 3 weeks. The absence of severe hematologic toxic effects, preliminary evidence of cantuzumab mertansine tumor localization, and encouraging biologic activity in chemotherapy-refractory patients warrant further broad clinical development of this immunoconjugate in CanAg-expressing tumors.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. atolcher@saci.org
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Leonel
authors.initials: L
authors.lastname: Ochoa
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hammond
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Tam
authors.initials: T
authors.lastname: Edwards
authors.forename: Chris
authors.initials: C
authors.lastname: Takimoto
authors.forename: Lon
authors.initials: L
authors.lastname: Smith
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.forename: Garry
authors.initials: G
authors.lastname: Schwartz
authors.forename: Theresa
authors.initials: T
authors.lastname: Mays
authors.forename: Zdenka L
authors.initials: ZL
authors.lastname: Jonak
authors.forename: Randall
authors.initials: R
authors.lastname: Johnson
authors.forename: Mark
authors.initials: M
authors.lastname: DeWitte
authors.forename: Helen
authors.initials: H
authors.lastname: Martino
authors.forename: Charlene
authors.initials: C
authors.lastname: Audette
authors.forename: Kate
authors.initials: K
authors.lastname: Maes
authors.forename: Ravi V J
authors.initials: RV
authors.lastname: Chari
authors.forename: John M
authors.initials: JM
authors.lastname: Lambert
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D018796:Immunoconjugates; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000493:pharmacokinetics* / Q000494:pharmacology; D008875:Middle Aged; D018396:Mucin-1 / Q000276:immunology; D009369:Neoplasms / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D018796:Immunoconjugates; D018396:Mucin-1; D008453:Maytansine