DLTs and MTD
anaplastic astrocytoma, bradycardia, DLTs, non-DLT, mucositis, glioblastoma, hypertension
GLIOBLASTOMA, ANAPLASTIC ASTROCYTOMA, HYPERTENSION, MUCOSITIS
According to the accelerated titration design, two patients successively completed the DLT observation period (28 days) of treatment at 5 and 15 mg. However, the patient treated with 15 mg experienced grade 3 hypertension (non-DLT), and another two patients were enrolled at 15 mg based on the study design. Of those patients, one patient discontinued the treatment due to grade 2 bradycardia, which the investigator considered not related to the treatment. As a result, one more patient was enrolled at 15 mg for safety evaluation, and no more than grade 3 AEs were reported. In the 30 mg group, two out of five patients experienced DLTs (grade 3 mucositis oral and grade 4 hypertension), and the drug administration to the sixth patient in the 30 mg group was stopped according to the investigator’s decision to protect the safety and welfare of patients. Hence, for safety re-evaluation, four additional patients were enrolled in the lower dose level of 15 mg (one patient withdrew consent and was replaced), and no DLTs occurred. The dose-escalation process is shown in Supplementary Fig. S3.Two patients in the dose escalation had DLTs. The first patient with WHO grade III anaplastic astrocytoma in the 30-mg group had a DLT (grade 3 mucositis oral) on Cycle 1 Day 18, which lasted 5 days. The second patient with WHO grade IV glioblastoma in the 30-mg group had a DLT (grade 4 hypertension) on Cycle 1 Day 15, which lasted 8 days. No DLT was observed at doses of 15 mg and lower. Based on protocol-defined criteria, the MTD for SYHA1813 was determined to be 15 mg once daily.