title: Phase I safety study of escalating doses of atrasentan in adults with recurrent malignant glioma.
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 >or=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.
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Phuphanich@cshs.org
authors.forename: Surasak
authors.initials: S
authors.lastname: Phuphanich
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Carson
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
authors.forename: Glenn
authors.initials: G
authors.lastname: Lesser
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Olson
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Serena
authors.initials: S
authors.lastname: Desideri
authors.forename: Joy D
authors.initials: JD
authors.lastname: Fisher
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000077868:Atrasentan; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D011759:Pyrrolidines; D000077868:Atrasentan