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.

Macitentan, a Dual Endothelin Receptor Antagonist, in Combination with Temozolomide Leads to Glioblastoma Regression and Long-term Survival in Mice

“…This finding may help to explain the disappointing results from clinical trials of single agent endothelin receptor antagonists in cancer patients (21). For example, atrasentan produced only partial responses (8%) in a phase I trial in patients with recurrent glioblastoma (48). Combination studies of type-selective endothelin receptor antagonists with chemotherapy have also failed to demonstrate improved clinical benefit (49).…”

Cerebral Blood Flow, Metabolism, and Head Trauma

“…Atrasentan (ABT-627) is an ETA receptor selective antagonist currently being investigated for new drugs in the arsenal of brain tumor therapy. Atrasentan has shown promising results in its ability to inhibit tumor cell proliferation and angiogenesis (Phuphanich et al 2008 ) . Given that the ET receptors and peptides are known to be expressed throughout much of the brain, further investigation is necessary to explore the potential gain from pharmacological manipulation in the treatment of brain-related diseases.…”

Role of the endothelin axis and its antagonists in the treatment of cancer

“…A Phase I‐II study of atrasentan in combination with paclitaxel and carboplatin in chemotherapy‐naïve patients with stage IIIB and IV NSCLC reported that this combination was well tolerated, and efficacy (Response Evaluation Criteria In Solid Tumors) and median survival were comparable with chemotherapy alone (Chiappori et al ., 2008). Atrasentan has also been investigated in a Phase I safety study in patients with progressive or recurrent malignant glioma (Phuphanich et al ., 2008), and in a Phase II trial of patients with locally recurrent or metastatic kidney cancer, data from which did not support further investigation as monotherapy in this patient population (Manola et al ., 2007).…”