A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer Journal Article


Authors: Beeram, M.; Krop, I. E.; Burris, H. A.; Girish, S. R.; Yu, W.; Lu, M. W.; Holden, S. N.; Modi, S.
Article Title: A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer
Abstract: BACKGROUND: We conducted a phase 1, multicenter, open-label, dose-escalation study (TDM3569g) to assess the safety, tolerability, and pharmacokinetics of single-agent trastuzumab emtansine (T-DM1) administered weekly and once every 3 weeks in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab. The weekly dose results are described here. METHODS: Patients were administered escalating doses of T-DM1 weekly, starting at 1.2 mg/kg. Additional patients were enrolled at the maximum tolerated dose (MTD) to better characterize tolerability and pharmacokinetics. RESULTS: Twenty-eight patients received weekly T-DM1, and the MTD was determined to be 2.4 mg/kg. In general, T-DM1 was well tolerated, requiring few dose modifications or discontinuations because of adverse events (AEs). Grade ≥3 AEs were reported in 19 patients (67.9%); treatment-related AEs occurred in 25 (89.3%) patients. Exposure to weekly T-DM1 was dose-proportional at ≥1.2 mg/kg, and accumulation of T-DM1 and total trastuzumab was observed. Objective partial tumor responses were reported in 13 (46.4%) patients; the median duration of response was 18.6 months, and the 6-month clinical benefit rate was 57.1%. CONCLUSION: The results suggest that a weekly dose of T-DM1 2.4 mg/kg has antitumor activity and is well tolerated in patients with HER2-positive metastatic breast cancer. © 2012 American Cancer Society.
Keywords: epidermal growth factor; adult; controlled study; treatment response; aged; middle aged; unclassified drug; constipation; drug tolerability; fatigue; neutropenia; area under the curve; diarrhea; drug safety; drug withdrawal; hepatic encephalopathy; side effect; treatment duration; antineoplastic agents; liver dysfunction; anorexia; neutrophil count; pain; sensory neuropathy; breast cancer; anemia; steady state; bleeding; leukopenia; lung disease; nausea; thrombocytopenia; vomiting; peripheral neuropathy; calcium blood level; antineoplastic activity; breast neoplasms; arthralgia; chill; drug dose escalation; drug fever; dyspnea; pneumonia; lung embolism; confusion; drug induced headache; gastrointestinal toxicity; drug distribution; multicenter study; immunogenicity; xerostomia; drug clearance; glucose blood level; open study; receptor, erbb-2; alkaline phosphatase blood level; maximum plasma concentration; metastasis potential; eye disease; liver function test; maximum tolerated dose; phase 1 clinical trial; drug half life; dry eye; sodium blood level; influenza; epistaxis; uric acid blood level; maytansine; dysgeusia; cellulitis; osteomyelitis; immunotoxins; her2-positive; trastuzumab emtansine; potassium blood level; antibodies, monoclonal, humanized; antibody-drug conjugate; t-dm1; epidermal growth factor 2
Journal Title: Cancer
Volume: 118
Issue: 23
ISSN: 0008-543X
Publisher: Wiley Blackwell  
Date Published: 2012-12-01
Start Page: 5733
End Page: 5740
Language: English
DOI: 10.1002/cncr.27622
PROVIDER: scopus
PUBMED: 22648179
DOI/URL:
Notes: --- - "Export Date: 3 December 2012" - "CODEN: CANCA" - "Source: Scopus"
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  1. Shanu Modi
    171 Modi