Despite the success of anti-angiogenic therapy in multiple treatment settings, a fraction of patients are refractory to vascular endothelial growth factor (VEGF) inhibitor treatment while the majority of patients will eventually develop evasive resistance and exhibit disease progression while on therapy. It is proposed that mesenchymal-epithelial transition factor (c-MET) and its ligand hepatocyte growth factor (HGF or scatter factor) contribute significantly to VEGF inhibitor resistance such that combining a c-MET inhibitor with a VEGF inhibitor will provide additional clinical activity compared to VEGF inhibitor alone. This hypothesis will be tested using the cMET/ALK inhibitor, crizotinib, in combination with individual VEGF inhibitors. Three combinations will be prioritized, namely crizotinib plus axitinib, crizotinib plus sunitinib and crizotinib plus bevacizumab, with a fourth combination, crizotinib plus sorafenib to be tested only if crizotinib does not combine with either axitinib and/or sunitinib.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Three combinations will be prioritized, namely crizotinib plus axitinib, crizotinib plus sunitinib and crizotinib plus bevacizumab, with a fourth combination, crizotinib plus sorafenib to be tested only if crizotinib does not combine with either axitinib and/or sunitinib. All study drugs are tablets or capsules except for bevacizumab which is parenteral (intravenous). Dosage, frequency and duration to be determined.
Study drugs are tablets or capsules; dosage, frequency and duration to be determined.
Study drugs are tablets or capsules; dosage, frequency and duration to be determined.
Study drugs are tablets or capsules; dosage, frequency and duration to be determined.
Study drugs are tablets or capsules; dosage, frequency and duration to be determined.
Study drugs are tablets or capsules except for bevacizumab which is parenteral (intravenous). Dosage, frequency and duration to be determined.
Study drugs are tablets or capsules; dosage, frequency and duration to be determined.
Dose Limiting Toxicities (DLTs).
Time frame: 12 months
Duration of Response (DR)
Time frame: 24 months
Progression free survival (PFS)
Time frame: 24 months
Area under the plasma concentration versus time curve (AUC) of crizotinib and each VEGF inhibitor
Time frame: 24 months
Best overall response, as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 or , in the case of GBM (glioblastoma multiforme , RANO (Response Assessment in Neuro-Oncology) criteria.
Time frame: 24 months
Overall survival (OS) up to 12 months
Time frame: 24 months
Pre- and post-dose levels of soluble peripheral blood biomarkers.
Time frame: 24 months
Tumor tissue biomarkers.
Time frame: 18 months
6-month progression free survival proportion (PFS6) for glioblastoma patients
Time frame: 24 months
Peak plasma concentration (Cmax) of crizotinib and each VEGF inhibitor
Time frame: 24 months
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