Abstract
Evofosfamide (Evo or TH302) is a hypoxia-activated prodrug which is reduced leading to the release of alkylating agent bromo-isophosphoramide mustard, which has shown safety and signals of efficacy in a prior phase 1 study in recurrent glioblastoma. We performed a dual center single-arm Phase II study to expand on the safety and efficacy of Evo plus bevacizumab in bevacizumab refractory glioblastoma. 33 patients with bevacizumab refractory GBM received Evo 670 mg/m2 in combination with Bevacizumab 10 mg/kg IV every 2 weeks. Assessments included adverse events, response, and survival. Median age of patients was 47 (range 19–76) and 24 (69%) were male. At the time of study entry, 9 (26%) had ongoing corticosteroid use. ECOG performance status was 0 or 1 in 83% of patients. Patients were mostly heavily pretreated with 77% have three or more prior regimens. A total of 12 patients (36%) suffered grade 3–4 drug associated adverse event (AE); no grade 5 AE were reported. Of the 33 evaluable patients, best response was PR in 3 (9%), SD in 14 (43%), and PD in 16 (48%) with responses confirmed by a second reviewer. Median time to progression of disease was 53 days (95% CI 42–113) and Median time to death was 129 days (95% CI 86–199 days). Progression free survival at 4 months (PFS-4) on Evo-Bev was 31%, which was a statistically significant improvement over the historical rate of 3%. The median overall survival of patients receiving Evo-Bevacizumab was 4.6 months (95% CI 2.9–6.6). The progression free survival of patients on Evo-Bevacizumab met the primary endpoint of progression free survival at 4 months of 31%, although the clinical significance of this may be limited. Given the patient population and Phase II design, these clinical outcomes will need further validation.
Highlights
Glioblastoma (GBM, Grade IV astrocytoma) is the most common primary malignant brain tumors in adults
Given the hypoxic nature of GBM, and the tendency of antiangiogenics to exacerbate tumoral hypoxia, we hypothesized that Evo may be active in recurrent glioblastoma following bevacizumab failure
Once patients progress on Bev, survival remains very poor even if treated on a second Bevacizumab containing regimen with a historical OS of 3 m onths[20]
Summary
Glioblastoma (GBM, Grade IV astrocytoma) is the most common primary malignant brain tumors in adults. While bevacizumab has become a standard part of salvage therapy for recurrent GBM, multiple studies have shown it does not improve s urvival[9,10,11,12]. Increasing evidence points to the root cause of angiogenesis, hypoxia, as a driving force for resistance to Bevacizumab[13]. This is supported by biomarker studies in which surrogates of hypoxia such as carbonic anhydrase (CAIX), hypoxia-inducible factor 1α (HIF-1α), hypoxia-inducible factor. Given the hypoxic nature of GBM, and the tendency of antiangiogenics to exacerbate tumoral hypoxia, we hypothesized that Evo may be active in recurrent glioblastoma following bevacizumab failure. In order to further evaluate the activity and safety of Evo in bevacizumab refractory GBM, we undertook an open label, single-arm, dual center, Phase II study of Evo with Bev after Bevacizumab failure
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