Discussion
tumor, DLTs, toxicities, HGG, Hypertension, hypertension
TUMOR, SINUS BRADYCARDIA, HYPERTENSION, HYPERTENSION, MALIGNANT GLIOMAS
This trial was the first to investigate the safety, PK profile, and preliminary antitumor activity of single and multiple doses of SYHA1813. The MTD of SYHA1813 was defined as 15 mg once daily.While most patients experienced at least one TRAE, most treatment-related toxicities were mild and included hypertension, platelet count decreased, and sinus bradycardia. Doses up to 15 mg per day were considered tolerable. Two patients in the 30-mg group experienced DLTs. Hypertension and platelet count decreased were the most frequently reported grade 3–4 AEs. The occurrence of hypertension was likely the result of effective inhibition of the VEGF signaling pathway, consistent with the observations of increased incidence of hypertension in other clinical studies with small-molecule VEGF TKIs[When administered as a single dose, the exposure (CSYHA1813 administration resulted in a significant decrease in the level of sVEGFR2 from baseline, consistent with previous clinical findings with other VEGFR inhibitors, such as cediranib and pazopanib. Previous preclinical studies suggested that changes in the level of sVEGFR2 could be a pharmacodynamic marker of systemic exposure to drug, not a predictive marker of tumor response or clinical benefit. Similar to a previous study of the CSF1R inhibitor pexidartinib, we also observed an increased plasma concentration of CSF1 following multiple-dose administration [SYHA1813 has promising antitumor activity in recurrent HGG. A sustained tumor response was observed in HGG. Similar to the results of the phase II studies of cediranib (ORR of 56.7%) and pazopanib (ORR of 5.9%) in patients with recurrent malignant gliomas, SYHA1813 monotherapy showed encouraging antitumor activity (ORR of 20%) [In conclusion, oral administration of SYHA1813 at 15 mg daily demonstrated acceptable tolerability and preliminary antitumor activity in recurrent HGG. The subsequent dose-expansion cohort and phase Ib clinical trials of SYHA1813 should include HGG as a focus.