Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: A phase I surgical study

Andrew Brenner, Richard Zuniga, Jessica D. Sun, John R Floyd, Charles P. Hart, Stew Kroll, Lisa Fichtel, David Cavazos, Laura Caflisch, Aleksandra Gruslova, Shiliang Huang, Yichu Liu, Alessia Lodi, Stefano Tiziani

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background: Anti-angiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced, leading to the release of the alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev-refractory GBM. Methods: Twenty-eight patients with Bev-refractory GBM were enrolled in a dose escalation study receiving from 240 mg/m2 (cohort 1) to 670 mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev. Patients deemed surgical candidates underwent a single dose of Evo or placebo with pimonidazole immediately prior to surgery for biomarker evaluation, followed by dose escalation upon recovery. Assessments included adverse events, response, and survival. Results: Evo plus Bev was well tolerated up to and including the maximum dose of 670 mg/m2, which was determined to be the recommended phase II dose. Overall response rate was 17.4%, with disease control (complete response, partial response, and stable disease) observed in 14 (60.9%) of the 23 patients.The ratio of enhancement to non-enhancement was significant on log-rank analysis with time to progression (P = 0.023), with patients having a ratio of less than 0.37 showing a median progression-free survival of 98 days versus 56 days for those with more enhancement. Conclusions: Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation.

Original languageEnglish (US)
Pages (from-to)1231-1239
Number of pages9
JournalNeuro-Oncology
Volume20
Issue number9
DOIs
StatePublished - Jan 1 2018

Keywords

  • Bevacizumab
  • Evofosfamide
  • Glioblastoma
  • Hypoxia
  • Recurrence

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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    Brenner, A., Zuniga, R., Sun, J. D., Floyd, J. R., Hart, C. P., Kroll, S., Fichtel, L., Cavazos, D., Caflisch, L., Gruslova, A., Huang, S., Liu, Y., Lodi, A., & Tiziani, S. (2018). Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: A phase I surgical study. Neuro-Oncology, 20(9), 1231-1239. https://doi.org/10.1093/neuonc/noy015