SYHA-1813

SYHA1813 is a potent multikinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs)/colony-stimulating factor 1 receptor (CSF1R). This study aimed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of escalating doses of SYHA1813 in patients with recurrent high-grade gliomas (HGGs) or advanced solid tumors. This study adopted a combination of accelerated titration and a 3 + 3 design for dose escalation, with a starting dose of 5 mg once daily. The dose escalation continued at successive dose levels until the maximum tolerated dose (MTD) was determined. A total of 14 patients were enrolled and treated, including 13 with WHO grade III or IV gliomas and 1 with colorectal cancer. Two patients experienced dose-limiting toxicities (grade 4 hypertension and grade 3 mucositis oral) at 30 mg SYHA1813. The MTD was defined as 15 mg once daily. Hypertension (n = 6, 42.9%) was the most frequent treatment-related adverse event. Among evaluable patients (n = 10), 2 (20%) patients achieved partial response, and 7 (70%) had stable disease. The exposure increased with increasing doses within the studied dose range of 5 to 30 mg. Biomarker assessments demonstrated significant reductions in the levels of soluble VEGFR2 (P = .0023) and increases in the levels of VEGFA (P = .0092) and placental growth factor (P = .0484). The toxicities of SYHA1813 were manageable, and encouraging antitumor efficacy was observed in patients with recurrent malignant glioma. This study is registered with the Chinese Clinical Trial Registry (www.chictr.org.cn/index.aspx; identifier ChiCTR2100045380).

Recurrent high‐grade gliomas have a poor prognosis and limited therapeutic options. This study aimed to evaluate the safety and efficacy of SYHA1813, a dual inhibitor of VEGFR and CSF1R, in patients with recurrent high‐grade gliomas.

Eligible patients (aged ≥ 18) with histologically or cytologically confirmed recurrent high‐grade gliomas were included. Patients were administered different doses of SYHA1813 daily to assess its safety and initial efficacy.

Sixty‐four individuals with high‐grade gliomas were enrolled. Treatment‐related adverse events (TRAEs) were reported in 92.2% of the patients, with 40.6% experiencing grade 3 or higher TRAEs. No grade 5 TRAE was reported. The overall objective response rate (ORR) and disease control rate (DCR) were 18.8% (95% confidence interval [CI], 10.1–30.5) and 51.6% (95% CI, 38.7–64.3), respectively. With a median follow‐up duration of 9.5 months, the median progression‐free survival (PFS) was 2.8 months (95% CI, 2.3–4.2) with PFS‐6 of 22.5% (95% CI, 11.8–35.4) and the median OS was 15.1 months (95% CI, 10.2–NE) with OS‐12 of 63.3% (95% CI, 49.3–74.4). Among the 38 patients with glioblastoma, the ORR was 18.4% (95% CI, 7.7–34.3), with a DCR of 52.6% (95% CI, 35.8–69.0). The median PFS and OS were 4.1 months (95% CI, 2.3–5.3) and 13.0 months (95% CI, 9.1–NE), respectively. SYHA1813 was detected in cerebrospinal fluid samples and the drug concentration to plasma free drug concentration ratio was 0.30–1.27.

SYHA1813 exhibits encouraging anti‐tumor activity with a manageable safety profile for the treatment of recurrent high‐grade gliomas, especially glioblastoma.

chictr.org.cn (ChiCTR2100045380)