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Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma
- Source :
- Cancer Chemotherapy and Pharmacology. 74:77-84
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
Abstract
- Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for enhanced antitumor efficacy.Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two-stage design, after 14 of planned 21 subjects were enrolled.Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) ≥16 weeks was observed in 57 % patients, including three patients with SD lasting ≥1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug-related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (300 pg/ml) experienced longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance.Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration.
- Subjects :
- Male
Niacinamide
Oncology
Sorafenib
Cancer Research
medicine.medical_specialty
Bevacizumab
Phases of clinical research
Angiogenesis Inhibitors
Antibodies, Monoclonal, Humanized
Toxicology
Severity of Illness Index
chemistry.chemical_compound
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Pharmacology (medical)
Melanoma
Protein Kinase Inhibitors
Neoplasm Staging
Pharmacology
Proteinuria
Vascular Endothelial Growth Factors
business.industry
Phenylurea Compounds
Middle Aged
medicine.disease
Vascular endothelial growth factor
Kinetics
Receptors, Vascular Endothelial Growth Factor
Tolerability
chemistry
Tumor progression
Early Termination of Clinical Trials
Hypertension
Disease Progression
Feasibility Studies
Female
Hand-Foot Syndrome
Drug Monitoring
medicine.symptom
business
Biomarkers
medicine.drug
Subjects
Details
- ISSN :
- 14320843 and 03445704
- Volume :
- 74
- Database :
- OpenAIRE
- Journal :
- Cancer Chemotherapy and Pharmacology
- Accession number :
- edsair.doi.dedup.....d559015c483040a7d4333fe3d57018cf