ABSTRACT
BACKGROUND: Responses to bevacizumab in glioblastoma (GBM) are not durable. Plasma levels of basic fibroblast growth factor (bFGF) increase at the time of tumor progression. By targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, Src, and FGF receptor pathways, ponatinib may potentially help to overcome some of the putative mechanisms of adaptive resistance. METHODS: We performed a phase II trial of ponatinib in patients with bevacizumab-refractory GBM and variants. Adult patients with Karnofsky performance score (KPS) ≥60, measurable disease, and normal organ and marrow function received 45 mg ponatinib daily. No limit on the number of prior therapies but only one prior bevacizumab-containing regimen was allowed. Primary endpoint was 3-month progression-free survival. Plasma biomarkers of angiogenesis and inflammation were evaluated before and after treatment. RESULTS: The study closed after the first stage. Fifteen patients enrolled: median age 61 [27-74]; median KPS 80 [70-90]; median number of prior relapses 2 [2-4]. Three-month progression-free survival rate was 0, median overall survival was 98 days [95% CI 56, 257], and median PFS was 28 days [95% CI 27, 30]. No responses were seen. The most common grade ≥3 adverse events included fatigue (n = 3), hypertension (2), and lipase elevation (2). Ponatinib treatment significantly increased plasma VEGF, soluble (s)VEGFR1, sVEGFR2, sTIE2, interferon gamma (IFNγ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-8, and IL-10 and decreased sVEGFR2. CONCLUSIONS: Ponatinib was associated with minimal activity in bevacizumab-refractory GBM patients. Circulating biomarker data confirmed pharmacodynamic changes and suggested that resistance to ponatinib may be related to an increase in inflammatory cytokines.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Imidazoles/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyridazines/therapeutic use , Adult , Aged , Biomarkers/blood , Brain Neoplasms/blood , Brain Neoplasms/mortality , Cytokines/blood , Drug Resistance, Neoplasm/drug effects , Female , Glioblastoma/blood , Glioblastoma/mortality , Humans , Imidazoles/adverse effects , Imidazoles/pharmacology , Karnofsky Performance Status , Male , Middle Aged , Progression-Free Survival , Protein Kinase Inhibitors/adverse effects , Pyridazines/adverse effects , Pyridazines/pharmacology , Receptor, TIE-2/blood , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor Receptor-1/blood , Vascular Endothelial Growth Factor Receptor-2/bloodABSTRACT
OBJECTIVES: To review the existing glioma literature and National Comprehensive Cancer Network current standard-of care guidelines for recurrent high-grade glioma, which includes surgery, radiation, and systemic therapies. DATA SOURCES: PubMed, MedlinePlus, Science Direct, National Comprehensive Cancer Network, and Google Scholar were searched. Key words for databases were high-grade glioma, glioblastoma, recurrent, surgery, radiation, and systemic therapy. CONCLUSION: Approved treatments for patients with recurrent high-grade glioma are limited and do not significantly impact progression-free survival rates, nor do they offer long-term benefit in symptom improvement or quality of life. Particular consideration for progression versus pseudoprogression should be evaluated before pursuing recurrent therapies. IMPLICATIONS FOR NURSING PRACTICE: Given the limited availability of standard-of-care treatments, clinical trials should be prioritized to maximize future treatment options. Individual performance status, genetic and molecular profiles, as well as goals of care and quality of life are important considerations in the context of treatment plans.
