Phase I Trial and Pharmacokinetic Study of Berubicin (RTA 744) in Patients with Recurrent or Refractory High-Grade Gliomas

Abstract Background This multi-institutional phase I trial aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary antitumor activity of berubicin (WP744 or RTA744), designed to cross the blood-brain barrier, in patients with primary brain cancers. Methods Thirty-five patients with recurrent or refractory primary brain cancers, including glioblastoma multiforme (GBM), received berubicin infusions over 2 hours for 3 consecutive days (one course) every 21 days. Daily doses escalated from 1.2 to 9.6 mg/m2 using an accelerated titration design. Plasma levels of berubicin were measured via high-performance liquid chromatography-tandem mass spectrometry to estimate pharmacokinetic parameters. Results The daily MTD was determined to be 7.5 mg/m2. Nonhematological toxicities were minimal; no cardiotoxicity was observed. In the intention-to-treat population (n = 35), one patient had a durable complete response, one had a partial response, and nine had stable disease, corresponding to an objective response rate of 5.7% and a disease control rate of 31.4%. In the response-evaluable subset (n = 25), the corresponding rates were 8% and 44%, respectively; these secondary estimates should be interpreted with caution as patients who discontinued early were excluded. Pharmacokinetic analysis determined a mean half-life of 32.8 hours. The area under the curve increased proportionally with dose. Conclusions The tolerability and efficacy of berubicin, including one durable complete response, warrant continued development of the molecule. Berubicin shows activity over a range of doses, including a durable response at 2.4 mg/m2. The recommended phase II dose is 7.5 mg/m2 infusions over 2 hours for 3 days every 3 weeks. Trial registration NCT00526812