Abstract 3945: CBT-102, an oral multi-kinase small molecule, demonstrates favorable activity in human hepatocellular carcinoma animal models and cardiac safety in rabbit Purkinje and beagle dogs compared to sorafenib

Abstract

Abstract Background: Cancer is a complex disease involving disruption of more than one receptor or signaling pathway. Inhibiting multiple oncogenic targets have been shown to be an important strategy in managing relapse and resistance. CBT-102 is an oral mTKI inhibiting several key oncogenic drivers including angiogenesis via VEGFR and PDGFR, MAPK pathway via B-RAF and C-RAF, in addition to inhibiting RET, CSF1R, c-KIT, and FLT3. Antitumor activity of CBT-102 was compared to sorafenib in two human primary HCC carcinoma xenografts in nude mice (LIMsh050 and PLCPRF5) and cardiac safety was evaluated in rabbit heart Purkinje fibers and in conscious telemeterized beagle dogs. Methods: Female BALB/c nude mice were inoculated with LIMsh050 and PLCPRF5 tumors to establish the tumor models. In the LIMsh050 model, CBT-102 was administered orally QD x 21 days at 4, 10, and 25 mg/kg and sorafenib at 10 mg/kg (n=8/group). In the PLCPRF5 model, CBT-102 was administered orally QD x 14 days at 3, 8, and 20 mg/kg vs. 8 and 20 mg/kg sorafenib group (n=7/group). In both experiments, in addition to tumor volume, body weight and mortality were monitored. For the cardiac safety studies, rabbit Purkinje fibers were isolated from adult rabbit right heart perfused for 10 minutes with vehicle control, CBT-102 groups (1, 3, and 10 µM) or sorafenib and changes in action potentials were measured. In the second study, ECG parameters were measured after single oral administration of CBT-102 at 15, 45, and 67.5 mg/kg to beagle dogs (n=6/group) via telemetry for 24 h. Results: In both the LIMsh050 and PLCPRF5 models, CBT-102 and sorafenib doses were well tolerated with no suspension of dosing due to weight loss or deaths. CBT-102 demonstrated inhibition of tumor growth in both models, to a significantly greater extent than sorafenib at comparable doses. In the PLCPRF5 model, CBT-102 demonstrated an ED50 of 2.5 mg/kg vs. 16.8 mg/kg of sorafenib. Importantly, unlike sorafenib, CBT-102 did not show a cardiac liability: there were no changes in action potential duration in rabbit Purkinje fibers nor any changes in cardiac conduction parameters (HR, QTc, RR, PR, and QRS intervals) in beagle dogs. Conclusions: CBT-102 demonstrated improved efficacy in HCC xenografts models compared to sorafenib and does not appear to have the cardiac liability observed with sorafenib. CBT-102 will advance into GLP toxicology studies with a potential IND filing in 2H 2018. Citation Format: Sarath Kanekal, Xiquan Zhang, Yanrui Song, Tan Wenmiao, Juan Zhang, Deyi Zhang, Henry Li, Mamatha Reddy, Gavin Choy, Sanjeev Redkar. CBT-102, an oral multi-kinase small molecule, demonstrates favorable activity in human hepatocellular carcinoma animal models and cardiac safety in rabbit Purkinje and beagle dogs compared to sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3945.