Phase I and pharmacokinetic study of trastuzumab emtansine in Japanese patients with HER 2-positive metastatic breast cancer

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 whowere 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 thiswas 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 bemore severe than was seen in Japanese Journal of Clinical Oncology, 2015, 45(1) 12–18 doi: 10.1093/jjco/hyu160 Advance Access Publication Date: 20 October 2014