Final results of a phase I trial with the novel anthracycline derivative RTA 744 in patients with primary brain tumors

Abstract

2062 Background: RTA 744 is an anthracycline derivative that was shown preclinically to cross the blood-brain barrier, not be a substrate for P-gp or MRP, and improve survival in an orthotopic murine model of glioblastoma. A trial of RTA 744 was conducted in patients with progressive high-grade gliomas. Methods: RTA 744 was administered as a 2-hour intravenous infusion on each of the first 3 days of a 21-day cycle. Five dose levels were tested until an MTD was reached. Pharmacokinetic samples were taken at multiple time points on days 1–5 of cycle 1. Tumor activity was assessed according to the MacDonald criteria. Results: As of December 2006, RTA 744 has been administered to 20 patients at doses ranging from 1.2 to 9.6 mg/m2/day. The MTD was determined as 7.5 mg/m2/day, and the DLTs were neutropenia and thrombocytopenia. No neurotoxicity, cardiotoxicity, alopecia, or drug-related nausea and vomiting were reported. The pharmacokinetic profile indicates dose proportionality, with a mean plasma half-life of 35 hours. Clear evidence of anti-tumor activity has been reported in 7 of 20 patients. A Complete Response was observed in a patient with GBM after seven cycles at 2.4 mg/m2/day, the patient continues greater than 5 months post-RTA744 treatment. Additionally, a Partial Response (81% tumor reduction) has been observed in a patient with AO after two cycles at 7.5 mg/m2/day who continues on treatment at this time. A Minor Response was observed at 2.4 mg/m2/day, and several patients have experienced Stable Disease of several months duration. Two patients with stable disease have shown radiographic evidence of necrosis. Median time to tumor progression was 6 weeks (range 2 to >50). Median number of cycles was 2 (range 1 to 7). The study is now enrolling additional patients at the MTD to further profile the drug’s safety and activity. Additionally, a once-weekly dosing schedule is being tested in a satellite cohort. Conclusions: RTA 744 is well tolerated when administered at doses up to and including 7.5 mg/m2/day for the first three days of a 21-day cycle. Based on clear evidence of drug activity, pivotal trials of RTA 744 in high-grade gliomas are planned as well as trials in patients with brain metastases. [Table: see text]