Phase I clinical trial of CX-3543, a protein-rDNA quadruplex inhibitor

3585 Background: CX-3543 inhibits over-expressed ribosomal RNA synthesis in cancer cells by disrupting an essential protein-rDNA quadruplex complex, thereby inducing selective apoptosis. A phase I clinical trial for CX-3543 was undertaken to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK) of this agent. Methods: Eligible patients with advanced solid tumors received CX-3543 in successive dose cohorts at: 10, 20, 40, 80, 160, 240, 360 and 480 mg/m 2 . Drug is administered by daily intravenous infusion on the first five consecutive days of a three week cycle, and the infusion duration has varied from one hour to six hours. Response by RECIST is determined after every 2 cycles. Results: Thirty-three patients (M/F:19/14; median age 69, range 44–83) with advanced solid tumors were treated with intravenous CX-3543. No drug related serious adverse events (SAEs) were encountered. DLTs of infusion-related cough and headache were identified at 480 mg/m 2 (The MTD was 360 mg/m 2 ). These adverse events were fully and rapidly reversible upon slowing or interrupting the infusion. Other drug-related adverse events were of mild to moderate intensity. Four patients had stable disease for longer than 4 months and one patient, with stable disease for over one year, currently continues on study. CX-3543 demonstrated an increasing plasma terminal half life at the higher dose levels due to a ‘reservoir‘ effect from CX-3543 reversibly binding to blood cells. Conclusions: CX-3543 administered as a 6 hour infusion for five consecutive days of a three week cycle is well tolerated and has stabilized disease in a number of patients enrolled in this phase I study. This trial is now in an expanded enrollment phase at 360 mg/m 2 and pharmacodynamic measures, specifically FDG-PET scans and circulating tumor cells, have been included to detect biological activity at this dose level. No significant financial relationships to disclose.