title: Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer.
abstract: OBJECTIVE
  Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer.
  
  
  METHODS
  Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods.
  
  
  RESULTS
  Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade < or = 2 thrombocytopenia, elevated transaminases, fatigue, nausea, and anemia. No grade > 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clinical benefit rate (objective response plus stable disease at 6 months) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%.
  
  
  CONCLUSIONS
  At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.
authors.affiliation: Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Ian_krop@dfci.harvard.edu
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.forename: Shanu
authors.initials: S
authors.lastname: Modi
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Scott N
authors.initials: SN
authors.lastname: Holden
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
authors.forename: Jay
authors.initials: J
authors.lastname: Tibbitts
authors.forename: Joo-Hee
authors.initials: JH
authors.lastname: Yi
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
authors.forename: Fred
authors.initials: F
authors.lastname: Jacobson
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Lutzker
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D001707:Biopsy, Needle; D001859:Bone Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006207:Half-Life; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008875:Middle Aged; D009367:Neoplasm Staging; D018579:Patient Selection; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D018570:Risk Assessment; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab