Harukaze Yamamoto1, Masashi Ando2, Kenjiro Aogi3, Hiroji Iwata4, Kenji Tamura5, Kan Yonemori6, Chikako Shimizu6, Fumikata Hara3, Daisuke Takabatake7, Masaya Hattori4, Takashi Asakawa8, Yasuhiro Fujiwara6. 1. 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. 2. Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi. 3. Department of Breast Oncology, Shikoku Cancer Center, Ehime. 4. Department of Breast Oncology, Aichi Cancer Center Hospital, Aichi. 5. 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. 6. Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo. 7. Department of Breast Surgery, Kochi Health Science Center, Kochi. 8. Department of Clinical Research Planning, Chugai Pharmaceutical Co, Ltd, Tokyo, Japan.
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.
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 humanepidermal growth factor receptor 2-positive metastatic breast cancerpatients. This study evaluated the maximum tolerated dose, toxicity and pharmacokinetics of trastuzumab emtansine in Japanese breast cancerpatients. METHODS: Inoperable advanced or recurrent humanepidermal growth factor receptor 2-positive breast cancerpatients 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 cancerpatients. 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: William D Hedrich; Tamer E Fandy; Hossam M Ashour; Hongbing Wang; Hazem E Hassan Journal: Clin Pharmacokinet Date: 2018-06 Impact factor: 6.447