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

¹ Cedars-Sinai Medical Center, Los Angeles, CA, USA
² Brain Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
³ Wake Forest University, Comprehensive Cancer Center, Winston-Salem, NC, USA
⁴ Emory University, Atlanta, GA, USA
⁵ Henry Ford Hospital, Detroit, MI, USA

^* To whom correspondence should be addressed. E-mail: Jfisher{at}jhmi.edu.

	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 oli­ogodendroglioma; 24 patients had received one prior chemo­therapy regimen before being enrolled in the study. The most common atrasentan-related toxicities 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.

Key Words: anaplastic astrocytoma, antiangiogenesis, atrasentan, endothelin receptor antagonist, glioblastoma multiforme, malignant glioma