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.

Figures

Fig. 1

Atrasentan (two cycles, 56 days): case 1, partial response in glioblastoma multiforme (GBM). Tumor regression was evidenced by MRI of the brain (axial T1 with gadolinium). A tumor (arrow) showed a partial response.

Fig. 2

Atrasentan (six cycles): case 2, partial response in glioblastoma (GBM). Atrasentan-induced response in a patient with recurrent GBM after radiation and temozolomide by MRI of the brain (saggital T1 with gadolinium).

Fig. 3

Kaplan-Meier survival curves for all patients enrolled in the phase I study. Survival was measured from the time of entry into the study. Abbreviations: OS, overall survival; PFS, progression-free survival.