title: Phase I study of dasatinib (BMS-354825) in Japanese patients with solid tumors.
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 200 mg/day. Sixteen patients were treated with dasatinib in the following doses: 100 mg (nine patients), 150 mg (three patients) and 200 mg (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 200 mg. Therefore, 150 mg 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 6 months. In this study population, the safety profile of dasatinib was generally acceptable and 150 mg of dasatinib administered once daily was determined to be the MTD.
authors.affiliation: The Cancer Institute Hospital of JFCR, Medical Oncology, Tokyo, Japan. stakahas@jfcr.or.jp
authors.forename: Shunji
authors.initials: S
authors.lastname: Takahashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ito
authors.forename: Kyoji
authors.initials: K
authors.lastname: Ueda
authors.forename: Taku
authors.initials: T
authors.lastname: Seriu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
mesh_terms: D000368:Aged; D000855:Anorexia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D001862:Bone Resorption / Q000188:drug therapy; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007564:Japan; D008274:Magnesium / Q000097:blood; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010010:Osteoclasts / Q000187:drug effects; D010996:Pleural Effusion / Q000139:chemically induced; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016879:Salvage Therapy; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D019061:src-Family Kinases; D008274:Magnesium; D000069439:Dasatinib