Phase I and Pharmacodynamic Study of Arsenic Trioxide plus Radiotherapy in Patients with Newly Diagnosed Glioblastoma

Abstract

When Arsenic trioxide (ATO) was combined with radiation for treatment of transplanted murine gliomas in the brain, tumor response improved with disrupted tumor blood flow and survival was significantly prolonged. Total of 31 patients with newly diagnosed glioblastoma were accrued to a multi-institutional, NCI-funded, Phase I study to determine the maximum tolerated dose (MTD) of ATO administered with radiation. Secondary objectives were survival and pharmacodynamic changes in perfusion on magnetic resonance imaging (MRI). Patients (unknown MGMT and IDH status) received ATO either once or twice weekly during radiation without concurrent or adjuvant temozolomide. Median age: 54.9 years, male: 68%, KPS >90: 77%, debulking surgery: 77%. Treatments were well-tolerated: 81% of patients received all the planned ATO doses. Dose-limiting toxicities included elevated liver function tests, hypokalemia, and edema. The MTD on the weekly schedule was 0.4mg/kg and on the biweekly was 0.3mg/kg. The median survival (mOS) for all patients was 17.7 months. Survival on the biweekly schedule (22.8 months) was longer than on the weekly schedule (12.1 months) (P=0.039) as was progression free survival (p=0.004). Similarly, cerebral blood flow was significantly reduced in patients treated on the biweekly schedule (p=0.007). ATO with standard radiation is well tolerated in patients with newly diagnosed glioblastoma. Even without temozolomide or adjuvant therapy, the overall survival of all patients (17.7 months) and especially patients who received biweekly ATO (22.8 months) is surprising and accompanied by pharmacodynamic changes on MRI. Further studies of this regimen are warranted.