A phase I evaluation of the safety of escalating doses of atrasentan in adults with recurrent malignant glioma (MG)

Abstract

1526 Background: Atrasentan is a highly potent and selective endothelin (ET) receptor antagonist that may inhibit cell proliferation by blocking the ET receptor that regulates angiogenesis of glioma growth. This dose-finding study evaluates the safety and toxicity, and seeks preliminary evidence of efficacy, of Atrasentan in the treatment of MG. Methods: Patients (pts) with MG with prior radiation and < 1 chemotherapy were eligible. Planned dose levels were: 10 and 20 mg/day (cohorts of size 2), then 30 and incrementing by 20 mg/day up to a dose of 150 (cohorts of size 3), until a dose-limiting toxicity (DLT) is observed. The maximum tolerated dose (MTD) is defined as the maximum dose that causes no DLT in an expanded cohort of 10 pts. The cycle length was 28 days and intra-pt dose escalation was not allowed. Patients remained on study until progression. Results: Twenty-five pts, 16 (64%) males, median age = 53 years (range: 25–70); median KPS = 90% (range: 60–100) were enrolled. 22 (88%) had GBM and only 1 patient had no prior chemotherapy. Thirteen pts were on enzyme-inducing anti-epileptic drugs, and 12 were not. Only 23 pts were evaluable for toxicity because two pts developed early progression (1 each in the 30 and 70 mg/day cohorts). One pt had a DLT of grade 3 hypoxia and peripheral edema after 18 days of dosing with Atrasentan at 90 mg/day. The 70 mg/day cohort was expanded to 10 patients with no observed DLT and was declared the MTD. The most common adverse events were rhinitis, headache, and peripheral edema. These events were reported as grade 1/2 and were probably related to Atrasentan. There were no events of myelosuppression. One GBM pt (90 mg/day) had a partial response (4% response rate) and 4 GBM pts had stable disease before progressing. To date, 18/25 (72%) pts have died. Kaplan-Meier median survival was 6.0 m (95% confidence interval, 4.2–9.5 m) and 6-month progression free survival was 13% (95% confidence interval, 3–32%). Conclusions: Chronic oral dosing of Atrasentan is safe in pts with recurrent malignant gliomas, and the MTD is 70 mg/day. Pharmacokinetic data are currently being analyzed. Further study of Atrasentan with radiation therapy in newly diagnosed malignant gliomas is planned. No significant financial relationships to disclose.