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

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.

• Authors: Andrew Brenner, Richard Zuniga, Jessica D Sun, John Floyd, Charles P Hart, Stew Kroll, Lisa Fichtel, David Cavazos, Laura Caflisch, Aleksandra Gruslova, Shiliang Huang, Yichu Liu, Alessia Lodi, Stefano Tiziani
• Journal: Neuro-oncology (Neuro Oncol) Vol. 20 Issue 9 Pg. 1231-1239 (08 02 2018) ISSN: 1523-5866 [Electronic] England
• PMID: 29415215 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Nitroimidazoles
• Phosphoramide Mustards
• TH 302
• Bevacizumab

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab (administration & dosage)
• Brain Neoplasms (drug therapy, pathology, surgery)
• Combined Modality Therapy
• Drug Resistance, Neoplasm
• Female
• Follow-Up Studies
• Glioblastoma (drug therapy, pathology, surgery)
• Humans
• Hypoxia
• Male
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy, pathology, surgery)
• Nitroimidazoles (administration & dosage)
• Phosphoramide Mustards (administration & dosage)
• Prognosis
• Salvage Therapy