title: Phase I and pharmacokinetic study of trastuzumab emtansine in Japanese patients with HER2-positive metastatic breast cancer.
abstract: OBJECTIVE
  Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in human epidermal growth factor receptor 2-positive metastatic breast cancer patients. This study evaluated the maximum tolerated dose, toxicity and pharmacokinetics of trastuzumab emtansine in Japanese breast cancer patients.
  
  
  METHODS
  Inoperable advanced or recurrent human epidermal growth factor receptor 2-positive breast cancer patients were administered trastuzumab emtansine intravenously at a dose of 1.8, 2.4 or 3.6 mg/kg every 3 weeks. The maximum tolerated dose was estimated using the continual reassessment method.
  
  
  RESULTS
  This study enrolled 10 patients who were administered trastuzumab emtansine for a median of seven cycles. The dose-limiting toxicity was Grade 3 elevation of aspartate aminotransferase/alanine aminotransferase at the 2.4 mg/kg dose level. The maximum tolerated dose was estimated to be 3.6 mg/kg because at the point when dose-limiting toxicity was evaluable in 10 patients, the probability of dose-limiting toxicity estimated using the continual reassessment method was closest to 25% at a dose of 3.6 mg/kg and this was unchanged by the results for patients enrolled after that. The most frequent adverse events were nausea, arthralgia, fever, fatigue and decreased appetite. Adverse events were generally tolerable. The maximum concentration and area under the concentration-time curve increased linearly with the dose.
  
  
  CONCLUSIONS
  Trastuzumab emtansine up to 3.6 mg/kg was well tolerated by Japanese breast cancer patients. Although thrombocytopenia and hepatotoxicity tended to be more severe than was seen in Western patients in previous trastuzumab emtansine trials, those adverse events recovered without special supportive treatment.
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo Department of Medical Oncology and Translational Research Graduate School of Medical Sciences, Kumamoto University, Kumamoto haryamam@ncc.go.jp.
authors.forename: Harukaze
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ando
authors.affiliation: Department of Breast Oncology, Shikoku Cancer Center, Ehime.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Aogi
authors.affiliation: Department of Breast Oncology, Aichi Cancer Center Hospital, Aichi.
authors.forename: Hiroji
authors.initials: H
authors.lastname: Iwata
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo Department of Medical Oncology and Translational Research Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo.
authors.forename: Kan
authors.initials: K
authors.lastname: Yonemori
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo.
authors.forename: Chikako
authors.initials: C
authors.lastname: Shimizu
authors.affiliation: Department of Breast Oncology, Shikoku Cancer Center, Ehime.
authors.forename: Fumikata
authors.initials: F
authors.lastname: Hara
authors.affiliation: Department of Breast Surgery, Kochi Health Science Center, Kochi.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takabatake
authors.affiliation: Department of Breast Oncology, Aichi Cancer Center Hospital, Aichi.
authors.forename: Masaya
authors.initials: M
authors.lastname: Hattori
authors.affiliation: Department of Clinical Research Planning, Chugai Pharmaceutical Co, Ltd, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Asakawa
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujiwara
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000097:blood* / Q000737:chemistry / Q000188:drug therapy*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007008:Hypokalemia / Q000139:chemically induced; D007564:Japan; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000139:chemically induced; D000068878:Trastuzumab
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: HER2-positive; breast cancer; pharmacokinetics; safety; trastuzumab emtansine