A phase I clinical trial investigating the safety, tolerability, and pharmacokinetics of HX301 (narazaciclib), a novel multi-kinase inhibitor targeting CSF1R, CDK 4/6, and ARK5, in patients with advanced solid tumors.
Authors: Wang Jiani , Shi Yehui , Luo Suxia , Li Qing , Zhang Faming , Zhang Lei , Sun Peng , Mo Yunlong , Yu Ting , Xu Binghe 
Published: June 2024

e15106 Background: HX301 (narazaciclib) is a promising novel multi-kinase inhibitor with potent activity against Colony Stimulating Factor 1 Receptor (CSF1R), Cyclin-Dependent Kinase 4/6 (CDK4/6), and Aurora Kinase 5 (ARK5), with a half-maximal inhibitory concentration (IC50) values in 0.29-4.95 nM range. It is an oral bioavailable agent and has the ability to cross blood-brain barrier. Preclinical data have showed significant antitumor activities, warranting further clinical trials to evaluate the safety, and potential efficacy in human subjects. Methods: Utilizing the standard 3+3 design, the study aimed to evaluate the safety, tolerability and pharmacokinetics of ascending doses of HX301. Patients with heavily pretreated advanced solid tumors received HX301single agent via oral administration, with doses ranging from 40mg to 200mg once daily for the first 21 days of each 28-day cycle. Results: As of December 27, 2023, a total of 20 patients (5 males, 15 females) were enrolled in the study, with varying doses of HX301 administered: 40 mg (n=3), 80 mg (n=3), 120 mg (n=4), 160 mg (n=3), and 200 mg (n=7). The median age of the patients was 55 years, ranging from 30 to 71. Notably, 15 patients (75%) had metastatic breast cancers. Dose-limiting toxicities (DLTs) were observed in 2 patients in the 200 mg group. These included a Grade 4 increase in alanine aminotransferase (ALT) and a Grade 3 decrease in platelet counts with associated epistaxis, both of which resolved after discontinuation of treatment. The most common treatment-related adverse events (AEs) observed were elevated aspartate aminotransferase (AST) (65.0%), decreased white blood cell count (50%), decreased neutrophil count (50%), elevated ALT (45%), elevated creatine kinase (45%), and elevated creatinine (35%). Additionally, 4 patients experienced Grade 3 or higher treatment-related AEs, including 1 patient in the 160 mg group with Grade 3 elevated γ-glutamyl transferase and alkaline phosphatase, and 3 patients in the 200 mg group with Grade 4 elevated ALT and Grade 3 elevated AST and Dyspepsia, Grade 3 decreased neutrophil and platelet counts, and Grade 3 hyperglycemia. Notably, no AEs led to death. Among the 20 patients evaluable for tumor assessment using RECIST 1.1 by Investigators, 4 obtained stable disease, including 2 patients in the 200 mg group, 1 in the 120 mg group, and 1 in the 80 mg group. Furthermore, 1 patient with HR+ breast cancer in the 200 mg group received study drug for over a year and achieved prolonged stable disease for more than 12 months, highlighting a notable clinical outcome. Conclusions: HX301 at dose levels ranging from 40mg to 160mg was tolerable with a manageable toxicity profile. Further clinical studies are needed to explore the drug's anti-tumor activity, particularly in combination settings. Clinical trial information: NCT05731934 .