Threshold Pharmaceuticals Inc. (THLD) announced preliminary data from an ongoing dose-escalation Phase 1/2 clinical trial of its investigational hypoxia-targeted drug TH-302 in combination with bevacizumab in patients with recurrent glioblastoma.
The company said that the vo dose-limiting toxicity has been reported to date in the first two dose cohorts (240 mg/m2 TH-302 plus bevacizumab and 340 mg/m2 TH-302 plus bevacizumab); dose escalation is ongoing.
Preliminary results in six patients show a median time to progression (worsening of disease) of 128 days compared with a median time to progression of 89.5 days these same patients experienced while taking single-agent bevacizumab prior to study enrollment.
Glioblastoma remains an incurable malignancy with poor survival despite aggressive surgery and chemoradiation therapy. When glioblastoma recurs, a standard salvage therapy is bevacizumab, a biologic antibody designed to interfere with the tumor blood supply by directly binding to a protein called VEGF.
The company stated that preclinical data suggest that antiangiogenic agents, such as bevacizumab, may increase tumor hypoxia, which supports the rationale for combining TH-302 -- a drug designed to target and kill cells in hypoxic regions of the tumor -- with bevacizumab in treating glioblastoma.
The company said that the study is enrolling patients with recurrent glioblastoma whose disease has progressed following initial treatment with bevacizumab and who are scheduled for debulking craniotomy (brain surgery to remove tumor tissue). Patients are randomized to treatment with a single dose of TH-302 (575 mg/m2) or placebo prior to surgery, followed by postoperative combination therapy of bevacizumab (10 mg/m2 every two weeks) and TH-302 dose-escalated 240-480 mg/m2 every 2 weeks (4 week cycle) until disease progression.
According to the company, no dose limiting toxicity has been reported to date. There were no Grade 3 or 4 adverse events observed with 240 mg/m2 TH-302. One Grade 3 adverse event (skin ulceration) and no Grade 4 adverse events have been observed thus far in the second cohort at 340 mg/m2 TH-302.
Data from the first six patients treated with TH-302 plus bevacizumab in the first two dose cohorts were presented at the ESMO 2012 Congress. Examination of surgical specimens revealed extensive areas of hypoxia.
Five patients had stable disease including one patient with a target lesion best response by Response Assessment in Neuro-Oncology (RANO) criteria. One patient had progressive disease.
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