PMID- 20421541
OWN - NLM
STAT- MEDLINE
DCOM- 20100721
LR  - 20220317
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Linking)
VI  - 28
IP  - 16
DP  - 2010 Jun 1
TI  - Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 
      weeks to patients with HER2-positive metastatic breast cancer.
PG  - 2698-704
LID - 10.1200/JCO.2009.26.2071 [doi]
AB  - PURPOSE: 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. PATIENTS AND 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%. CONCLUSION: 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.
FAU - Krop, Ian E
AU  - Krop IE
AD  - Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. 
      Ian_krop@dfci.harvard.edu
FAU - Beeram, Muralidhar
AU  - Beeram M
FAU - Modi, Shanu
AU  - Modi S
FAU - Jones, Suzanne F
AU  - Jones SF
FAU - Holden, Scott N
AU  - Holden SN
FAU - Yu, Wei
AU  - Yu W
FAU - Girish, Sandhya
AU  - Girish S
FAU - Tibbitts, Jay
AU  - Tibbitts J
FAU - Yi, Joo-Hee
AU  - Yi JH
FAU - Sliwkowski, Mark X
AU  - Sliwkowski MX
FAU - Jacobson, Fred
AU  - Jacobson F
FAU - Lutzker, Stuart G
AU  - Lutzker SG
FAU - Burris, Howard A
AU  - Burris HA
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20100426
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Immunoconjugates)
RN  - 14083FR882 (Maytansine)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P188ANX8CK (Trastuzumab)
RN  - SE2KH7T06F (Ado-Trastuzumab Emtansine)
SB  - IM
MH  - Ado-Trastuzumab Emtansine
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal/*administration & dosage/adverse effects/pharmacokinetics
MH  - Antibodies, Monoclonal, Humanized
MH  - Biopsy, Needle
MH  - Bone Neoplasms/secondary
MH  - Breast Neoplasms/*drug therapy/*metabolism/mortality/pathology
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Female
MH  - Follow-Up Studies
MH  - Half-Life
MH  - Humans
MH  - Immunoconjugates/*administration & dosage/adverse effects
MH  - Immunohistochemistry
MH  - Liver Neoplasms/secondary
MH  - Lung Neoplasms/secondary
MH  - Maximum Tolerated Dose
MH  - Maytansine/administration & dosage/*analogs & derivatives/pharmacokinetics
MH  - Middle Aged
MH  - Neoplasm Staging
MH  - Patient Selection
MH  - Receptor, ErbB-2/drug effects/*metabolism
MH  - Risk Assessment
MH  - Survival Analysis
MH  - Thrombocytopenia/chemically induced
MH  - Trastuzumab
MH  - Treatment Outcome
EDAT- 2010/04/28 06:00
MHDA- 2010/07/22 06:00
CRDT- 2010/04/28 06:00
PHST- 2010/04/28 06:00 [entrez]
PHST- 2010/04/28 06:00 [pubmed]
PHST- 2010/07/22 06:00 [medline]
AID - JCO.2009.26.2071 [pii]
AID - 10.1200/JCO.2009.26.2071 [doi]
PST - ppublish
SO  - J Clin Oncol. 2010 Jun 1;28(16):2698-704. doi: 10.1200/JCO.2009.26.2071. Epub 
      2010 Apr 26.