Abstract:
Introduction: The rationale for combination therapy in treating cancer is to use drugs with different mechanisms of action. This approach reduces the likelihood that resistant cancer cells will develop. CLX-155A is an oral prodrug conjugate hydrolyzed by intestinal enzymes to yield 5’-DFCR and valproic acid. 5’-DFCR is an intermediate in generating 5-FU, a clinically proven antimetabolite, which produces DNA and RNA damage in cancer cells. Valproic acid is an approved antiseizure medication known to produce antitumor activity due to its epigenetic modulating histone deacetylase (HDAC) inhibitory activity.
CLX-155A differs from capecitabine, an approved oral prodrug of 5-fluorouracil (5-FU), used to treat metastatic breast and colorectal cancer due to these mechanistic and metabolic considerations. In particular, hepatic carboxyl esterases hydrolyze capecitabine to yield intermediate 5’-DFCR, which the tumor will convert to 5-FU. Variability in therapeutic levels of 5-FU and severe neurologic (e.g., hand-foot syndrome), gastrointestinal, and hepatic toxicities have limited the use of capecitabine in treating solid tumors. Unlike capecitabine, CLX-155A yields 5-FU, independent of liver metabolism. Due to the combined activity of 5’-DFCR and valproic acid, CLX-155A can offer the potential for greater potency for anticancer effects.
Methods: This preclinical study aims to address the question about the efficacy of CLX-155A in a human colon cancer xenograft model in nude mice as monotherapy. This investigation 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-155A (300mg/kg daily, 1000mg/kg daily, 150mg/kg BID, and 500mg/kg BID), capecitabine (1000mg/kg daily, 500mg/kg BID). Oral treatment was initially administered for 10 days, followed by 2 doses off for daily groups and 3 doses off for BID groups, and then continued for another 7 days. Investigators recorded tumor volumes thrice weekly and observed clinical signs, mortality, and body weights. The tumor growth inhibition (TGI) percentage analysis involved calculation based on the tumor volume on a given day compared to the vehicle control group.
Results: CLX-155A showed dose-dependent tumor growth inhibition at daily and twice-daily regimens, which were significant from the sham control group (p<0.0001). On Day 18, CLX-155A demonstrated a TGI of 71.0 and 94.2% at 300 and 1000mg/kg/day QD and 50.5% and 98.4% at 150 and 500mg/kg BID, respectively. Capecitabine at 1000mg/kg daily and 500mg/kg BID showed TGI of 91.1% and 97.4%, respectively, on Day 18. Only one animal in the CLX-155A 500 mg/kg BID group expired, whereas two in the 500mg/kg BID group on the capecitabine group died. Animals tolerated CLX-155A well, with small changes in weight loss (-2.6% and -6.9% in 300 and 1000 mg/kg QD, -5.4% and -13.9% at 150 and 500 mg/kg BID, respectively). Also, multiple capecitabine animals presented with a hunchback (3/10) and progressive body weight loss (-24.5% and -16.8% at 1000 mg/kg and 500 mg/kg BID, respectively).
Conclusion: CLX-155A at multiple doses displayed significant antitumor (p<0.0001) activity in human colon cancer cell-derived tumor xenografts. The once-daily dosing schedule of 300mg/kg/day demonstrated numerically better antitumor activity than the twice-daily dosing schedule at 150mg/kg BID. While these initial data indicate that CLX-155A shows activity in this model, there will be the need for additional dose-ranging efficacy in the xenograft model further to characterize the CLX-155A's efficacy and safety profile.
Audience Take Away Notes:
- The audience will be able to use such data to evaluate the candidacy of CLX-155A for phase 1/2 study investigation in solid tumors, such as colon cancer, where clinicians might use capecitabine.
- This research will add knowledge about antimetabolites, capecitabine, and their role in solid tumors, which academics can teach 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 CLX-155 as an antimetabolite alternative and issues with current options such as capecitabine. Such awareness will help clinicians reevaluate the current and future roles of antimetabolites and capecitabine based on their therapeutic benefits and toxicity profiles, which might limit current use, particularly that of capecitabine.
