Abstract
Dasatinib is a potent oral inhibitor of tyrosine kinases including the SRC family kinases, which are activated in tumors, and implicated in invasion and bone metastasis. This phase I dose-escalation study assessed safety, tolerability, maximum tolerated dose (MTD), antitumor activity, pharmacokinetics and pharmacodynamics in Japanese patients with refractory, advanced solid tumors. Dasatinib was administered once daily at 100, 150 and 200mg/day. Sixteen patients were treated with dasatinib in the following doses: 100mg (nine patients), 150mg (three patients) and 200mg (four patients). The most frequent adverse events (AE; ≥50%) were anorexia, fatigue, pleural effusion, anemia, constipation, diarrhea, vomiting and increased aspartate aminotransferase (AST). The most frequent AE of grade ≥3 (≥10%) were anemia, decreased lymphocyte count, fatigue and increased blood magnesium. Dose-limiting toxicities were observed in two patients: grade 2 pleural effusion and bronchial wall thickening at the 100-mg level and grade 3 dyspnea at the 200-mg level. In addition, grade 2 pleural effusion was observed in all four patients treated with 200mg. Therefore, 150mg was determined to be the MTD. The pharmacokinetic parameters were comparable among the dose levels. As a pharmacodynamic study, markers of bone metabolism were assessed. Bone resorption markers, NTx and TRACP-5b, showed a decrease of 46.3% and 22.2%, respectively. No objective responses were observed, but three patients had stable disease that lasted for over 6months. In this study population, the safety profile of dasatinib was generally acceptable and 150mg of dasatinib administered once daily was determined to be the MTD.
| Original language | English |
|---|---|
| Pages (from-to) | 2058-2064 |
| Number of pages | 7 |
| Journal | Cancer Science |
| Volume | 102 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 1 2011 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
Cite this
Phase I study of dasatinib (BMS-354825) in Japanese patients with solid tumors. / Takahashi, Shunji; Miyazaki, Masaki; Okamoto, Isamu; Ito, Yoshinori; Ueda, Kyoji; Seriu, Taku; Nakagawa, Kazuhiko; Hatake, Kiyohiko.
In: Cancer Science, Vol. 102, No. 11, 01.11.2011, p. 2058-2064.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phase I study of dasatinib (BMS-354825) in Japanese patients with solid tumors
AU - Takahashi, Shunji
AU - Miyazaki, Masaki
AU - Okamoto, Isamu
AU - Ito, Yoshinori
AU - Ueda, Kyoji
AU - Seriu, Taku
AU - Nakagawa, Kazuhiko
AU - Hatake, Kiyohiko
PY - 2011/11/1
Y1 - 2011/11/1
N2 - Dasatinib is a potent oral inhibitor of tyrosine kinases including the SRC family kinases, which are activated in tumors, and implicated in invasion and bone metastasis. This phase I dose-escalation study assessed safety, tolerability, maximum tolerated dose (MTD), antitumor activity, pharmacokinetics and pharmacodynamics in Japanese patients with refractory, advanced solid tumors. Dasatinib was administered once daily at 100, 150 and 200mg/day. Sixteen patients were treated with dasatinib in the following doses: 100mg (nine patients), 150mg (three patients) and 200mg (four patients). The most frequent adverse events (AE; ≥50%) were anorexia, fatigue, pleural effusion, anemia, constipation, diarrhea, vomiting and increased aspartate aminotransferase (AST). The most frequent AE of grade ≥3 (≥10%) were anemia, decreased lymphocyte count, fatigue and increased blood magnesium. Dose-limiting toxicities were observed in two patients: grade 2 pleural effusion and bronchial wall thickening at the 100-mg level and grade 3 dyspnea at the 200-mg level. In addition, grade 2 pleural effusion was observed in all four patients treated with 200mg. Therefore, 150mg was determined to be the MTD. The pharmacokinetic parameters were comparable among the dose levels. As a pharmacodynamic study, markers of bone metabolism were assessed. Bone resorption markers, NTx and TRACP-5b, showed a decrease of 46.3% and 22.2%, respectively. No objective responses were observed, but three patients had stable disease that lasted for over 6months. In this study population, the safety profile of dasatinib was generally acceptable and 150mg of dasatinib administered once daily was determined to be the MTD.
AB - Dasatinib is a potent oral inhibitor of tyrosine kinases including the SRC family kinases, which are activated in tumors, and implicated in invasion and bone metastasis. This phase I dose-escalation study assessed safety, tolerability, maximum tolerated dose (MTD), antitumor activity, pharmacokinetics and pharmacodynamics in Japanese patients with refractory, advanced solid tumors. Dasatinib was administered once daily at 100, 150 and 200mg/day. Sixteen patients were treated with dasatinib in the following doses: 100mg (nine patients), 150mg (three patients) and 200mg (four patients). The most frequent adverse events (AE; ≥50%) were anorexia, fatigue, pleural effusion, anemia, constipation, diarrhea, vomiting and increased aspartate aminotransferase (AST). The most frequent AE of grade ≥3 (≥10%) were anemia, decreased lymphocyte count, fatigue and increased blood magnesium. Dose-limiting toxicities were observed in two patients: grade 2 pleural effusion and bronchial wall thickening at the 100-mg level and grade 3 dyspnea at the 200-mg level. In addition, grade 2 pleural effusion was observed in all four patients treated with 200mg. Therefore, 150mg was determined to be the MTD. The pharmacokinetic parameters were comparable among the dose levels. As a pharmacodynamic study, markers of bone metabolism were assessed. Bone resorption markers, NTx and TRACP-5b, showed a decrease of 46.3% and 22.2%, respectively. No objective responses were observed, but three patients had stable disease that lasted for over 6months. In this study population, the safety profile of dasatinib was generally acceptable and 150mg of dasatinib administered once daily was determined to be the MTD.
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UR - http://www.scopus.com/inward/citedby.url?scp=80054999429&partnerID=8YFLogxK
U2 - 10.1111/j.1349-7006.2011.02041.x
DO - 10.1111/j.1349-7006.2011.02041.x
M3 - Article
C2 - 21781226
AN - SCOPUS:80054999429
VL - 102
SP - 2058
EP - 2064
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 11
ER -