435TiP - A dual phase I/II study of TH-302 and bevacizumab in resectable recurrent glioblastoma following bevacizumab failure
|Date||30 September 2012|
|Event||ESMO Congress 2012|
|Session||Poster presentation II|
|Topics|| Drug Development
Central Nervous System Malignancies
R.M. Zuniga1, J. Sun2, J.R. Floyd3, S.R. Yerragudi3, C. Hart2, C. Eng4, A.J. Brenner3
Bevacizumab, a recombinant human monoclonal anti-VEGF antibody, exhibits anti-tumor activity in recurrent glioblastoma; however, the median progression free survival (PFS) of patients who progress on bevacizumab and are subsequently started on a non-bevacizumab containing regimen is only 1.6 months. Pre-clinical studies have shown that anti-angiogenic treatment leads to an increase in hypoxia in the tumor microenvironment leading to increased invasiveness. Hypoxia upregulates survival mechanisms, inhibits apoptosis, and stimulates invasiveness. TH-302 is a hypoxia-activated prodrug that once activated releases the alkylating agent Br-IPM. This drug has shown to potentiate, in vivo, the anti-tumor efficacy of other anti-angiogenic agents. This dual phase I/II study enrolled subjects with recurrent glioblastoma following bevacizumab failure that were planned for repeat craniotomy.Methods
Single center, dose-escalation, prospective study with TH-302 single dose at 575 mg/m2 or placebo administered pre-operatively, followed by postoperative combination therapy of bevacizumab at 10 mg/kg every 2 weeks and TH-302 dose escalated 240–480 mg/m2 every 2 weeks (4 week cycle) until disease progression. Resected tumor tissue was evaluated for hypoxia induced pimonidazole adducts, endogenous CAIX staining, double-strand DNA damage by gamma-H2AX and MGMT expression.Results
Five patients underwent craniotomy and initiated TH-302 plus bevacizumab. No dose limiting toxicity was reported. There were no grade 3 or 4 adverse events (AEs) observed at 240mg/m2, and one grade 3 (skin ulceration) and no grade 4 AEs observed thus far in the second cohort at 340mg/m2. Of the initial 5 patients treated, one patient had a partial response (PR) and 3 patients had stable disease (SD) per RANO criteria. Histological assessment of resected tumors demonstrated extensive areas of hypoxia as measured by pimonidazole and a heterogeneous distribution of gamma-H2AX staining.Conclusions
TH-302 demonstrates good tolerability when combined with bevacizumab. The MTD has not been reached and only one grade 3/4 toxicity was observed. Dose escalation is ongoing, with planned expansion at the MTD.Disclosure
J. Sun: The author is an employee of pharmaceutical industry with a financial interest in the drug which is the subject of this abstract.
C. Hart: The author is an employee of pharmaceutical industry with a financial interest in the drug which is the subject of this abstract.
C. Eng: The author is an employee of pharmaceutical industry with a financial interest in the drug which is the subject of this abstract.
All other authors have declared no conflicts of interest.