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
Presenter Richard Zuniga
Authors R.M. Zuniga1, J. Sun2, J.R. Floyd3, S.R. Yerragudi3, C. Hart2, C. Eng4, A.J. Brenner3
  • 1University of Texas Health Sceince Center at San Antonio, 78229 - San Antonio/US
  • 2Clinical Operations, Threshold Pharmaceuticals, 94080 - South San Francisco/US
  • 3Cancer Therapy And Research Center, University of Texas Health Sceince Center at San Antonio, 78229 - San Antonio/US
  • 4Clinical Development, Threshold Pharmaceuticals, 94080 - South San Francisco/US

Abstract

Introduction

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.