Abstract 3901: Nonclinical safety evaluation of CA102N, a hyaluronic acid (HA) and nimesulide (Nim) conjugate, for colorectal cancer treatment

Abstract

Abstract CA102N is a conjugate of the biological polymer hyaluronic acid (HA) and Nimesulide (Nim), a cyclooxygenase-2 (COX-2) inhibitor that represents a promising new approach to addressing cancer treatment. Similar to an antibody-drug conjugate or a pro-drug, CA102N enhances the efficacy of Nim through targeting and binding of HA to CD44 receptors highly expressed in solid tumors. Pharmacological (in vitro and in vivo) studies indicated that CA102N exhibits apoptotic and tumor growth inhibitory activities against colorectal cancer. The MOA of CA102N was demonstrated to be related to apoptosis and disruption of the PI3K/Akt/mTOR pathway in addition to inhibition of the COX-2/PGE2 related pathways. Safety of CA102N was assessed in acute dose range finding and repeat-dose intravenous toxicity studies in rats and beagle dogs. Three dose levels including the Maximum Tolerated Dose (MTD) from DRF study, a middle dose and a low dose equivalent to the proposed clinical dose were administered twice weekly (BID). A 28-day recovery group was also included in the rat study. Overall CA102N was well tolerated in both species. CA102N did not induce any significant effects on the CNS, the cardiovascular and respiratory systems in animal models. Some changes in hematological parameters were observed only in rats at the highest dose (Std 10: ≥ 600 mg/kg/day ), however, most of these observations were reversible. No hERG inhibition (in vitro) was observed suggesting the risk of QT prolongation with CA102N is low. The Highest Non-Severely Toxic Dose (HNSTD) of CA102N in the dog was determined to be 280 mg/kg/day (7.24 mg/kg in Nim equivalents ) and the rat NOAEL was 400 mg/kg/day (10.16 mg/kg in Nim equivalents ). These doses are 2.3 times (rat) and 5.6 times (dog) of nimesulide dose to be evaluated (up to 0.72 mg/kg of nimesulide) in the proposed phase 1 study. On the basis of the mechanism of action and the nonclinical safety profiles, toxicity associated risks to patients appear to be low at the proposed clinical dose levels. A Phase I study of CA102N in patients with locally advanced or metastatic colorectal cancer is ongoing. Citation Format: Eskouhie Tchaparian, Louis Lin, Elin Hsu, Ivy Chen, Albert Wu. Nonclinical safety evaluation of CA102N, a hyaluronic acid (HA) and nimesulide (Nim) conjugate, for colorectal cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3901.