Pharmacokinetic findings from the phase I study of Quarfloxin (CX-3543): a protein-rDNA quadruplex inhibitor, in patients with advanced solid tumors.

B93

Background: Ribosomal RNA (rRNA) biosynthesis and subsequent ribosome assembly determine the proliferative state of cells, and these processes are highly amplified in cancer due to mutations in regulatory signaling pathways that control rRNA biogenesis. Quarfloxin, a novel fluoroquinolones derivative, directly inhibits aberrant rRNA biogenesis in cancer cells by disrupting an essential protein-ribosomal DNA interaction that is over-expressed, thereby selectively triggering apoptotic cell death in tumor cells but not in normal cells. A phase I study of quarfloxin has been completed in patients with solid tumors, including an elucidation of this agent’s pharmacokinetic attributes. Material and Methods: This phase I study was designed to identify the maximum tolerated dose (MTD), the dose limiting toxicities and the pharmacokinetic profile of quarfloxin when administered as an IV infusion for 5 consecutive days every 21 days, to patients with advanced solid tumors. Serial blood samples were collected for analysis on Day 1 and Day 5 of dosing during the first cycle of drug administration. A twelve hour urine sample was also collected with Day 1 drug administration to determine urinary clearance of quarfloxin. Results: A total of 48 patients from 8 escalating dose cohorts of quarfloxin had samples collected for pharmacokinetic analysis. Twenty of these patients were dosed at the maximum tolerated dose level (360 mg/m²). Area under the plasma concentration versus time curve generally increased in proportion with each dose level escalation. Urinary clearance was noted to be consistent throughout all dose levels. Plasma terminal half life was observed to be longer on Day 5 when compared with Day 1, and a trend of increasing plasma terminal half life with each subsequent dose escalation was also evident. The increase in plasma terminal half lives did not result in significant plasma quarfloxin accumulation, and were thought unlikely to be due to saturated elimination. In vitro tests using human whole blood revealed that quarfloxin associates reversibly with blood cells, and that whole blood concentration could be up to five fold more than plasma quarfloxin concentration. The pharmacokinetic analysis protocol was amended to include assessments of whole blood and plasma concentration in ten phase I patients at the MTD level of 360 mg/m². At the MTD, Day 5 quarfloxin plasma and whole blood terminal half lives are 75.1 hours and 28.3 hours, respectively. Conclusions: Thereversible association of quarfloxin with blood cells creates a “reservoir” of drug that is gradually released into plasma, thus extending the plasma terminal half life. This attribute supports drug administration on a weekly basis, and a phase I study of weekly quarfloxin administration is in progress.