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

Abstract

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 768 mg/m2, and established this dose as MTD. One pt in the 1200 mg/m2 cohort died during the trial from acute complications of metastatic soft tissue sarcoma and respiratory distress. The most common adverse events (AE) observed were fatigue (63%), anorexia (38%), nausea (38%), vomiting (38%), peripheral edema (25%), and diarrhea (25%). 6 pts experienced 8 serious AEs. Anticipated blue coloration of skin and body fluids was observed. One pt (48 mg/m2) with renal cancer has had stable disease for > 12 months. The PK was linear over all doses studied. At 768 mg/m2 (n=4), the Day 1 AQ4N Cmax was 99.8 ± 27.0 μg/mL, AUC0-∞ was 259.5 ± 67.8 μg·h/mL, and T1/2 was 3.9 ± 0.7 h (range 3.1–4.8 h). A predictable dose-related and exposure related decrease in lymphocytes and neutrophils were observed. Conclusions: AQ4N is well tolerated when administered on a weekly schedule. AQ4N levels sufficient for anti-neoplastic activity in pre-clinical models are achieved with weekly dosing at 768 mg/m2. AQ4N monotherapy and combination trials with chemo- and radiation therapy are planned. [Table: see text]