1. Dual antiangiogenic inhibition: a phase I dose escalation and expansion trial targeting VEGF-A and VEGFR in patients with advanced solid tumors.
- Author
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Falchook GS, Wheler JJ, Naing A, Piha-Paul SA, Fu S, Tsimberidou AM, Hong DS, Janku F, Zinner R, Jiang Y, Huang M, Lin Q, Parkhurst K, and Kurzrock R
- Subjects
- Adult, Aged, Aged, 80 and over, Angiogenesis Inhibitors administration & dosage, Angiogenesis Inhibitors adverse effects, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bevacizumab, Class I Phosphatidylinositol 3-Kinases, Female, Humans, Male, Middle Aged, Mutation, Neoplasms genetics, Niacinamide administration & dosage, Niacinamide adverse effects, Niacinamide analogs & derivatives, PTEN Phosphohydrolase genetics, PTEN Phosphohydrolase metabolism, Phenylurea Compounds administration & dosage, Phenylurea Compounds adverse effects, Phosphatidylinositol 3-Kinases genetics, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins genetics, Sorafenib, Tumor Suppressor Protein p53 genetics, Vascular Endothelial Growth Factor A genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasms drug therapy, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Vascular Endothelial Growth Factor A antagonists & inhibitors
- Abstract
Purpose: Angiogenesis plays a pivotal role in tumor growth and metastasis. Sorafenib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), combined with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF-A), would vertically inhibit VEGF/VEGFR signaling. A phase I trial was performed to assess safety, maximum tolerated dose (MTD), and clinical correlates., Experimental Design: Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received sorafenib daily for 28 days and bevacizumab every two weeks. Clinical correlates included VEGF polymorphisms. Expansion cohorts of responding tumor types were enrolled., Results: One hundred fifteen patients were treated, and the MTD was identified as 200 mg twice daily sorafenib and 5 mg/kg bevacizumab every two weeks. Median number of prior therapies was four. Twenty-nine patients (25 %) achieved stable disease ≥6 months; six patients (5 %) achieved a partial response (total SD ≥ 6 months/PR=35 (30 %)). 76 patients (66 %) experienced adverse events of grade 2 or higher, most commonly hand and foot syndrome (n = 27, 24 %) and hypertension (n = 24, 21 %). Dose-limiting toxicity occurred in eight patients (7 %), and 45 patients (39 %) required dose reduction for toxicity. Grade 3 and 4 hypertension was associated with longer time to treatment failure, overall survival, and higher response rate., Conclusions: Combination sorafenib and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced solid tumors.
- Published
- 2015
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