Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer Journal Article


Authors: Krop, I. E.; Beeram, M.; Modi, S.; Jones, S. F.; Holden, S. N.; Yu, W.; Girish, S.; Tibbitts, J.; Yi, J. H.; Sliwkowski, M. X.; Jacobson, F.; Lutzker, S. G.; Burris, H. A.
Article 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: 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 <= 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. J Clin Oncol 28:2698-2704. (C) 2010 by American Society of Clinical Oncology
Keywords: survival; inhibitor; oncogene; therapy; resistance; maytansine; cells; mechanism; growth; monoclonal-antibody
Journal Title: Journal of Clinical Oncology
Volume: 28
Issue: 16
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2010-06-01
Start Page: 2698
End Page: 2704
Language: English
ACCESSION: ISI:000278108800008
DOI: 10.1200/jco.2009.26.2071
PROVIDER: wos
PUBMED: 20421541
Notes: --- - Article - "Source: Wos"
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  1. Shanu Modi
    171 Modi