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A phase I study of BMS-690514 in Japanese patients with advanced or metastatic solid tumors
Hiroshi Nokihara1, Noboru Yamamoto, Yasuhide Yamada
1Internal Medicine and Thoracic Oncology, Division of Internal Medicine, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
Purpose:
BMS-690514 is a novel oral tyrosine kinase inhibitor of ErbB and vascular endothelial growth factor receptor. This open-label phase I dose-escalation study (ClinicalTrials.gov Identifier: NCT00516451) aimed to assess the safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics of BMS-690514 in Japanese patients with advanced or metastatic solid tumors.
Methods:
Patients with advanced or metastatic solid tumors received oral BMS-690514 once daily continuously until disease progression or intolerable toxicity occurred. Dose-limiting toxicity (DLT) was evaluated from the first dose to Day 29. Dose levels at 100 and 200 mg were investigated. Assessments included adverse events, tumor response, pharmacokinetics, pharmacodynamics, 2 [18F] fluoro-2-deoxyglucose positron-emitting tomography, and epidermal growth factor receptor and K-ras mutations.
Results:
BMS-690514 at the dose of 100 mg (n = 3) or 200 mg (n = 3) was administered once daily to totally nine patients and was well tolerated up to 200 mg. No treatment-related serious adverse events or DLTs were reported. Frequently observed treatment-related AEs were acne, diarrhea, dry skin, hypertension, stomatitis, blood fibrinogen increased, hemoglobin decreased, pruritus, and hypoalbuminemia. These were generally reported as Grade 1 and 2. Five of 9 patients (56 %) had stable disease. Plasma concentrations of BMS-690514 reached Cmax within 3 h and declined with an effective half-life of approximately 10 and 12 h at 100 and 200 mg, respectively.
Conclusions:
Oral BMS-690514 was well tolerated in Japanese patients with advanced or metastatic solid tumors up to 200 mg.
Insights
This study found that oral BMS-690514, a tyrosine kinase inhibitor, was well tolerated in Japanese patients with advanced solid tumors up to 200 mg, showing preliminary efficacy and favorable pharmacokinetics.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- BMS-690514 is a novel oral tyrosine kinase inhibitor targeting ErbB and vascular endothelial growth factor receptor.
- Advanced or metastatic solid tumors represent a significant unmet medical need.
Purpose of the Study:
- To assess the safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics of BMS-690514 in Japanese patients.
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of BMS-690514.
Main Methods:
- Open-label, phase I, dose-escalation study (NCT00516451) in Japanese patients with advanced/metastatic solid tumors.
- Oral BMS-690514 administered daily at 100 mg and 200 mg doses.
- Safety, tumor response, pharmacokinetics, pharmacodynamics, and exploratory biomarkers (PET, EGFR/K-ras mutations) were assessed.
Main Results:
- BMS-690514 was well tolerated up to 200 mg daily in nine patients; no serious adverse events or DLTs were reported.
- Common adverse events (Grade 1-2) included acne, diarrhea, dry skin, and hypertension.
- Five of nine patients (56%) achieved stable disease; pharmacokinetic analysis showed a half-life of 10-12 hours.
Conclusions:
- Oral BMS-690514 demonstrated good tolerability and preliminary efficacy in Japanese patients with advanced solid tumors.
- The maximum tolerated dose was determined to be at least 200 mg daily.
- Further investigation in larger trials is warranted.
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