Banoxantrone (AQ4N), tissue CYP 450 targeted prodrug: The results of a phase I study using an accelerated dose escalation

2011 Background: AQ4N was rationally designed to have anti-tumor activity following bioreduction by tissue cytochrome P450 to AQ4, an active DNA topoisomerase II inhibitor. Preclinical studies demonstrated AQ4N selectively targets lymphoid tissues and hypoxic tumor tissues. This study assessed the maximum tolerated dose (MTD), pharmacokinetic (PK), and pharmacodynamic (PD) of repeated weekly dosing of AQ4N in patients (pts) with advanced cancers. Methods: AQ4N was administered IV on Days 1, 8, and 15 of a 28-day cycle in the following dose cohorts 12, 24, 48, 96, 192, 384, 768, and 1200 mg/m2. Accelerated titration design 2B was employed and the MTD was defined by ≤ 33% of 6 pts with a drug-related dose limiting toxicity (DLT). Response was assessed every 8 weeks by RECIST. Results: 16 pts were enrolled. A single pt per cohort was treated up to 384 mg/m2. At 1200 mg/m2, 2 of 5 pts experienced a DLT (Grade 5 respiratory distress and Grade 3 fatigue). A total of 5 pts were treated without toxicity at the 76...