A phase I, first-in-human, dose-escalation and dose-expansion study of the multitarget kinase inhibitor TT-00420 in patients with advanced solid tumors.

Sarina Anne Piha-Paul The University of Texas MD Anderson Cancer Center, Houston, TX info_outline Sarina Anne Piha-Paul, Qunfang Wan, Wendy Xiong, Peng Peng, Xiaoju Yang, Henry Wu, Brenda Ngo, Frank Wu

Authors Sarina Anne Piha-Paul The University of Texas MD Anderson Cancer Center, Houston, TX info_outline Sarina Anne Piha-Paul, Qunfang Wan, Wendy Xiong, Peng Peng, Xiaoju Yang, Henry Wu, Brenda Ngo, Frank Wu Organizations The University of Texas MD Anderson Cancer Center, Houston, TX, Nanjing TransThera Biosciences Co. Ltd., Nanjing, China, Nanjing CR Medicon Pharmaceutical Technology Co., Ltd., Nanjing, China, CRC Oncology LLC, San Diego, CA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Multi-target kinase inhibitors have gained increasing attention in the past few years due to their capabilities of simultaneously targeting several hallmarks of cancer. Triple negative breast cancer (TNBC), the most aggressive type of breast cancer, is a highly heterogeneous disease composed of several subtypes with distinct genomic profiles and activating pathways. TT-00420 is a multi-target kinase inhibitor that targets Aurora A/B, receptor tyrosine kinases (RTKs) involved in angiogenesis, and other kinases involved in tumor-associated inflammation and immune escape. Preclinical studies have established signs of efficacy for TT-00420 in TNBC. Targets inhibited by TT-00420 are among the key dysregulated pathways directly involved in the tumorigenesis of TNBC. TT-00420 is efficacious against most subtypes of TNBC cell lines. This anti-TNBC activity is confirmed in both cell line derived xenograft (CDX) and patient derived xenograft (PDX) TNBC model in vivo , in which TT-00420 is active both as first-line and second-line treatment. TT-00420 demonstrated good oral bioavailability and pharmacokinetic properties in mice, rats and dogs, and revealed mechanism-related but manageable toxicities. The IND approval of TT-00420 was granted by the FDA on Sept. 27, 2018. Methods: TT420X2101 is an open-label, first-in-human, multicenter, phase I study including a dose escalation portion in adult patients with advanced solid tumors, followed by dose expansion in two parallel cohorts, TNBC cohort (N=22) and selected advanced tumor (SAT) cohort (N=22). Adverse events will be evaluated per CTCAE v5.0 criteria, and tumor responses will be evaluated per RECIST v1.1 criteria. Patients aged 18-75 with measurable target lesion(s) at baseline and ECOG status of 0 or 1 will be enrolled. Patients are treated with a single daily oral administration of TT-00420 continuously for a 28-day cycle. Dose escalation is driven by Bayesian modeling with over-dose control. Approximately 66 patients are expected to be enrolled and treated in this study. Primary endpoint is to evaluate dose limiting toxicity (DLT) and identify maximum tolerate dose (MTD), if feasible, or establish recommended dose for Dose Expansion. Preliminary efficacy and PK profile will be evaluated as well. Enrollment is currently ongoing. Clinical trial information: NCT03654547