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Phase I safety study of escalating doses of atrasentan in adults with recurrent malignant glioma
Cedars-Sinai Medical Center, Los Angeles, CA (S.P.); Brain Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD (K.A.C., S.A.G., S.D., J.D.F.); Wake Forest University, Comprehensive Cancer Center, Winston-Salem, NC (G.L.); Emory University, Atlanta, GA (J.O.); Henry Ford Hospital, Detroit, MI (T.M.); USA
Address correspondence to Joy D. Fisher, Nabtt Central Office, Johns Hopkins University, The David H. Koch Cancer Research Building, Suite 1M 16, 1550 Orleans St., Baltimore, MD 21231, USA (Jfisher{at}jhmi.edu). Address reprint requests to Surasak Phuphanich, Cedars-Sinai Medical Center, Suite 410 E., 8631 W. Third St., Los Angeles, CA 90048, USA (Phuphanich{at}cshs.org).
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Abstract |
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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 chemo therapy 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.
Keywords: anaplastic astrocytoma, antiangiogenesis, atrasentan, endothelin receptor antagonist, glioblastoma multiforme, malignant glioma
Received May 11, 2007; Accepted January 14, 2008