Combination of metronomic oral pazopanib and topotecan for recurrent glioblastoma with and without previous bevacizumab: Results from a phase 2 clinical trial

Abstract Background Glioblastoma has limited effective salvage therapy options. The combination of the Type 1B topoisomerase/HIF1α inhibitor topotecan and the tyrosine kinase inhibitor pazopanib has shown promise in solid tumors and may be effective in recurrent glioblastoma. Methods Patients with recurrent glioblastoma who were bevacizumab-naïve (Group A, 9 patients) or had previous bevacizumab (Group B, 22 patients) started daily oral pazopanib (600 mg) and topotecan (0.25 mg). The primary objective was progression-free survival (PFS) at 6 months for Group A and 3 months for Group B patients. Secondary objectives included median progression-free and overall survival (OS), safety, tolerability, and toxicity as measured by patient -reported outcomes (PROs) and adverse event documentation. Results Group A enrolled 9 evaluable patients and closed to accrual early when interim primary objectives were not met (PFS-6 11%). Group B enrolled 22 evaluable patients and narrowly met its primary objective (PFS-3 18%). Median PFS and OS endpoints demonstrated equivalent to slight improvement upon historical metrics, respectively. The regimen was tolerable and safe save for high frequency of hypertension, with PROs data showing stability or worsening in parallel with tumor stability or progression, respectively. Conclusions These findings suggest the regimen is safe and tolerable to glioblastoma patients. The regimen was ineffective in bevacizumab-naïve patients and only narrowly met its pre-determined endpoint in patients with prior bevacizumab. These results do not support the combination regimen as tested in this protocol for further investigation in glioblastoma. Trials Registration ClinicalTrials.gov identifier: NCT01931098