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

Abstract

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/m2. 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/m2 (The MTD was 360 mg/m2). 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/m2 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.

G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

“…After so many years only one promising in vivo G4-ligand, Quarfloxin, has reached phase II clinical trials for treating neuroendocrine tumors and carcinoid tumors. 30 Upon its binding with the G-quadruplex structure in the ribosomal DNA (rDNA) template, the interaction between nucleolin protein and rDNA is disrupted, resulting in the inhibition of rRNA biogenesis and ribosome synthesis in cancer cells. Similar ribosomal DNA G4-targeted metal complexes have not been reported.…”

“…28,29 The representative member is a first-in-class in vivo G4-ligand, named as CX3543 (also known as Quarfloxin), which has reached phase II clinical trials for treating neuroendocrine tumors and carcinoid tumors. 30 Besides purely organic G4-ligands, metal complexes acting as small molecule G4-ligands have recently attracted a lot of interest, as they interact strongly and selectively with quadruplex nucleic acids. 28,31 Compared with organic molecules, metal complexes possess characteristic structural features, various charges, and additional electromagnetic properties providing advantages for the construction of G4-ligands.…”

Health‐promoting phytochemicals of Italian common wheat varieties grown under low‐input agricultural management

“…Small molecules that can facilitate the formation of or stabilize the G‐quadruplex structures have the potential for the arrest of cancer‐cell growth through disruption of telomere maintenance or alteration of oncogene expression levels, and may be potentially valuable as antitumor drugs 5–7. A good case in point is the compound quarfloxin (CX‐3543), which targets the parallel/mixed class of quadruplexes that are overexpressed in the ribosomal RNA (rRNA) gene during rRNA biogenesis in cancer cells and is currently in clinical trials as an antitumor agent 8–10. There is thus a considerable interest in discovering G‐quadruplex ligands that could ultimately be used against cancer cells 11.…”

Four-stranded DNA: cancer, gene regulation and drug development

“…One such compound has already completed phase I clinical trials as an anticancer agent. Quarfloxacin, as it is called (originally CX-3543; Papadopoulos et al 2007), was developed by Cylene Pharmaceuticals, Inc., and was intended to bind to the c-myc promoter. Instead, it appears to bind ribosomal quadruplexes, interfering with the binding of the protein nucleolin, which normally binds to quadruplex structures, leading to cell death in cancerous cells.…”