Phase I safety study of escalating doses of atrasentan in adults with recurrent malignant glioma

Surasak Phuphanich, Kathryn A. Carson, Stuart A. Grossman, Glenn Lesser, Jeffrey Olson, Tom Mikkelsen, Serena Desideri, Joy D. Fisher

Research output: Contribution to journalArticle

Abstract

Atrasentan is an oral selective endothelin-A receptor antagonist that may inhibit cell proliferation and interfere with angiogenesis during glioma growth. We conducted a dose-finding study to assess atrasentan's safety and toxicity and to gather preliminary evidence of efficacy. Patients with recurrent malignant glioma received oral atrasentan at ≥10 mg/day. We increased the dose among cohorts until the maximum tolerated dose (MTD) was defined. Patients were evaluated for response every 8 weeks and remained on the study until the tumor progressed or toxicities occurred. Twenty-five patients were enrolled, with a median age of 53 years (range, 25 - 70) and a median KPS of 90% (range, 60 - 100%). Twenty- two patients had glioblastoma multiforme (GBM), 2 had anaplastic astrocytoma, and 1 had an anaplastic oli- ogodendroglioma; 24 patients had received one prior chemotherapy regimen before being enrolled in the study. The most common atrasentan-related toxici- ties were grade 1 or 2 rhinitis, fatigue, and edema. One patient developed grade 3 hypoxia and peripheral edema at a dose of 90 mg/day. We observed no dose-limiting toxicities in an expanded cohort of 10 patients at 70 mg/day, which was declared the MTD. Two partial responses (8%) were seen in patients with GBM at the 70- and 90-mg/day dose levels, and 4 patients had stable disease before progressing. Nineteen patients have died, and median survival was 6.0 months (95% confidence interval, 4.2 - 9.5 months). We conclude that the MTD of daily oral atrasentan in patients with recurrent malignant glioma is 70 mg/day. Further study of atrasentan with radiation therapy and temozolomide in newly diagnosed GBM is warranted to evaluate the efficacy of this novel agent.

Original languageEnglish (US)
Pages (from-to)617-623
Number of pages7
JournalNeuro-oncology
Volume10
Issue number4
DOIs
StatePublished - Aug 1 2008

Keywords

  • Anaplastic astrocytoma
  • Antiangiogenesis
  • Atrasentan
  • Endothelin receptor antagonist
  • Glioblastoma multiforme
  • Malignant glioma

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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