Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma

Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if du...

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Published in:PloS one 2016-05, Vol.11 (5), p.e0156369
Main Authors: Brown, Nicholas, McBain, Catherine, Nash, Stephen, Hopkins, Kirsten, Sanghera, Paul, Saran, Frank, Phillips, Mark, Dungey, Fiona, Clifton-Hadley, Laura, Wanek, Katharina, Krell, Daniel, Jeffries, Sarah, Khan, Iftekhar, Smith, Paul, Mulholland, Paul
Format: Article
Language:English
Subjects:
Adult
Aged
Analysis
Angiogenesis
Antineoplastic Agents - adverse effects
Antineoplastic Agents - therapeutic use
Binding sites
Biology and Life Sciences
Brain cancer
Cancer therapies
Care and treatment
Cell cycle
Chemoradiotherapy
Chemotherapy
Clinical trials
Disease Progression
Dosage and administration
Enzyme inhibitors
Epidermal growth factor
Epidermal growth factor receptors
Epidermal growth factors
ErbB Receptors - metabolism
Female
Gefitinib
Glioblastoma
Glioblastoma - drug therapy
Glioblastoma - metabolism
Glioblastoma - pathology
Glioblastomas
Humans
Hypoxia
Inhibitor drugs
Inhibitors
Kinases
Ligands
Male
Medical research
Medicine and Health Sciences
Middle Aged
Molecular Targeted Therapy
Mutation
Oncology
Patients
Placebos
Protein-tyrosine kinase receptors
Quality of Life
Quinazolines - adverse effects
Quinazolines - therapeutic use
Radiation therapy
Randomization
Recurrence
Research and Analysis Methods
Rodents
Safety
Surgery
Survival
Tumors
Tyrosine
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - metabolism
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Summary:Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. ClinicalTrials.gov NCT01310855.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0156369