Abstract:
Introduction: Capecitabine is an oral prodrug of antimetabolite 5-fluorouracil (5-FU), used to treat metastatic breast and colorectal cancer. Variability in therapeutic levels of 5-FU and severe neurologic (e.g., hand-foot syndrome), gastrointestinal, and hepatic toxicities have limited this agent’s use. The development of CLX-155 arose from the need to address these clinical issues. This novel oral 5-FU prodrug differs from capecitabine. Unlike capecitabine, CLX-155 design involves 5’-DFCR, an intermediate in generating 5-FU, independent of liver metabolism. CLX-155 can offer the potential for greater potency for anticancer effects at a lower dose, with less variability. Hence, this preclinical work addresses the research question – what is the relative efficacy of CLX-155 in a human colon cancer xenograft model in nude mice?
Methods: This study involved Foxn1 athymic nude female mice (7-8 weeks) implanted subcutaneously with HCT116 human colon cancer (5 million cells/site) in the dorsal right flank. The study randomized these animals into different treatment groups (N=10 per group) as vehicle control, CLX-155 (125, 250, and 500 mg/kg/day), or capecitabine (1000 mg/kg/day). Animals underwent treatment for three consecutive weeks (5 days/week; 2 days off). Investigators recorded tumor volumes thrice weekly and observed clinical signs of toxicity, mortality, and body weights. Analysis of tumor growth inhibition (TGI) percentage involved calculation based on the tumor volume on a given day compared to Day 1.
Results: CLX-155 demonstrated statistically significant, dose-dependent tumor growth inhibition at all doses compared to vehicle control (p<0.05). The tumor growth inhibition on Day 15 was 57.8, 70.4, and 90.6% at 125, 250, and 500 mg/kg/day, respectively. Two animals experienced complete tumor regressions at 500 mg/kg/day. Capecitabine at 1000 mg/kg/day showed 87.7% TGI, but no complete responders were in the capecitabine group. There were no clinical signs of toxicity at any CLX-155 dose levels, whereas 2 of 10 animals in the capecitabine group showed hunched back and scaly skin. All CLX-155 treated animals survived, whereas 2 of 10 capecitabine animals expired at 1000 mg/kg/day."
Conclusion: CLX-155 is expected to provide an additional therapeutic option with the potential for better efficacy and improved tolerability due to the potential reduction in dosing and non-requirement of liver carboxylesterase for producing the active drug. Such characteristics offer new opportunities for clinical investigators to engage in Phase 1 and 2a studies for managing colorectal cancer. Moreover, the preclinical and clinical efficacy and tolerability of CLX-155 in breast cancer treatment are to be investigated.
Audience Take Away Notes:
- The audience will be able to use such data to evaluate the candidacy of CLX-155 for phase 1/2 study investigation in solid tumors, such as breast and colon cancer, where capecitabine might be used
- This research will add knowledge about antimetabolites, capecitabine, and their role in solid tumors. Such can be taught in both pharmacology and therapeutics class settings
- This research offers an avenue to examine drug design strategies to improve the therapeutic window of newer antimetabolite candidates for use in solid tumors
- This effort creates awareness about the antimetabolite and capecitabine alternatives. Such will help clinicians reevaluate the current and future roles of antimetabolites and capecitabine based on the therapeutic benefit and toxicity profiles, which might limit current use, particularly that of capecitabine
