A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full-dose cetuximab in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy
| Autor: | Linda M. Velasquez, Anthony B. El-Khoueiry, Lillian L. Siu, Christopher R. Garrett, Georgia Kollia, Giuseppe Giaccone, P. He, D. Feltquate, John L. Marshall, Patricia LoRusso |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Cetuximab biology business.industry medicine.drug_class VEGF receptors Prodrug Pharmacology Tyrosine-kinase inhibitor chemistry.chemical_compound Brivanib alaninate Prior Therapy Oncology chemistry Fibroblast growth factor receptor medicine biology.protein business Tyrosine kinase medicine.drug |
| Zdroj: | Journal of Clinical Oncology. 25:14018-14018 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2007.25.18_suppl.14018 |
| Popis: | 14018 Background: Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Prior studies have validated both VEGF and EGF signaling pathways as targets in AGM. The MTD of single-agent brivanib is 800 mg qd (ASCO #3051, 2006). Methods: An open-label Phase I dose-escalation study of brivanib in combination with cetuximab was conducted in pts with AGM who failed prior therapy. Brivanib was given po Day 1 and qd from Day 8, starting at 320 mg. Cetuximab was given IV Day 8 (400 mg/m2) then weekly (250 mg/m2). Dose escalation of brivanib continued to 800 mg qd, when an expansion cohort for pts with colorectal cancer (CRC) was opened for additional safety and efficacy. Fresh tissue and blood sampling for biomarker and pharmacokinetic (PK) analysis was performed. FDG-PET was obtained at Baseline X 2, Days 15 and 56. Tumor response (modified WHO) was evaluated q 8 weeks. Results: 18 pts (15 CRC, 2 esophageal, 1 other) were treated with 320, 600 or 800 mg qd of brivanib in combination with cetuximab for a median of 8 weeks (range 1 - 20+). A single DLT, bilateral pulmonary emboli, occurred at 320 mg qd. Few treatment-related AEs occurred across the 3 cohorts (Table). PK/biomarker data is pending. Available FDG-PET results from measurements in 8 pts with 2–3 target lesions showed good baseline reproducibility in SUVpeak, SUVmean and SUVmax, with intra-subject CV of 3.6%, 7.2% and 9.3%, respectively. Conclusions: Brivanib in combination with full-dose cetuximab was well tolerated at ≤800 mg qd and did not result in enhancement of cetuximab associated AEs. Pre-treatment FDG-PET is a highly reproducible imaging modality. [Table: see text] [Table: see text] |
| Databáze: | OpenAIRE |
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