Patient eligibility
Eligible patients were ≥ 18 years of age with recurrent or advanced solid tumors confirmed by histology or cytology, such as HGG, brain metastases, kidney cancer, colorectal cancer, thyroid cancer, lung cancer, gastric cancer, and tendon sheath giant cell tumor. At least one measurable lesion during the baseline period (primary central nervous system tumors were assessed as per the Response Assessment in Neuro-Oncology [RANO] criteria; other solid tumors were assessed as per the Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). The time interval between the end of the last anti-tumor treatment and the first administration of SYHA1813 was ≥ four weeks for cytotoxic drugs, immunotherapy, macromolecular targeted drugs, and biological therapy; ≥ two weeks or five half-lives (whichever is longer) for oral small-molecule targeted drug therapy, anti-cancer traditional Chinese medicine or proprietary Chinese medicine; ≥ four weeks for radiotherapy (≥ two weeks for palliative local radiotherapy for symptom relief). Other inclusion criteria included a Karnofsky Performance Status (KPS) of 60 or more for patients with central nervous system tumors, an Eastern Cooperative Oncology Group (ECOG) physical performance status of 0 to 2 for patients with other solid tumors; and a life expectancy of 12 weeks.
Exclusion criteria included participation in other interventional clinical studies within four weeks, major surgery within four weeks, use of glucocorticoid with an equivalent dose of more than 5 mg dexamethasone within five days for glioma or brain metastases, or bevacizumab, ramucirumab, and other anti-VEGF/VEGFR antibodies within three months for glioma or brain metastases. Patients were also excluded if they had impaired cardiac function or clinically significant cardiovascular and cerebrovascular diseases, including but not limited to: a history of myocardial infarction, congestive heart failure, and unstable angina pectoris within six months; cerebrovascular accident occurred within six months (transient ischemic attack, lacunar infarction with no clinical significance can be enrolled); hypertension that cannot be controlled after medication (repeated blood pressure measurement at least 1 hour apart, and blood pressure value 150/90 mmHg for two consecutive times); uncontrolled arrhythmia requiring medical treatment; electrocardiogram (ECG) examination, QTc interval > 470 ms; left ventricular ejection fraction < 50%.
Study design
This was a phase Ⅰa, multicenter, open-label, dose-escalation study of SYHA1813. The overall study design is presented in Supplementary Fig. S1. The primary endpoints were the safety and tolerability of SYHA1813, including the occurrence of dose-limiting toxicities (DLT) and the establishment of the maximum tolerated dose (MTD). Secondary endpoints included the PK profile, preliminary anti-tumor activity consisting of objective response rate (ORR), and disease control rate (DCR), as well as the exploration of the potential biomarkers of SYHA1813. The study has been approved by the National Medical Products Administration (NMPA) for clinical trials. We conducted the study according to the ethical principles of the Declaration of Helsinki and Good Clinical Practices guidelines. The study was approved by an institutional review board
at each participating site. All patients provided written informed consent. The study was registered on chictr.org.cn (Trial registration ID: ChiCTR2100045380).
Safety assessments and definition of DLT
DLT was defined as the occurrence of the following AEs that the investigator judged to be related to SYHA1813 within 28 days of the first dose during the dose-escalation period (Supplementary Table S1). The MTD was defined as the maximum dose for which the probability of a DLT was ≤ 33%.
The maximum recommended starting dose (referenced body weight 60 kg) of 11 mg was estimated based on 1/6 of the highest non-severely toxic dose in the beagle dog study. For further safety considerations, 5 mg was selected as the starting dose in human subjects. In the dose-escalation study, patients were enrolled sequentially to receive SYHA1813 orally at prespecified doses of 5, 15, 30, 60, 100, 150, and 200 mg once daily and then were offered to continue the treatment (3 weeks/cycle) if the treatment was well tolerated and beneficial.
An accelerated titration design with one patient enrolled was utilized for the first two dose levels (5 and 15 mg). Then, a 3 + 3 dose-escalation design was conducted starting from the third dose level (30 mg). If grade 3 or above adverse events (AEs, non-DLT) occurred in one patient at the first two doses, two more patients should be enrolled for further observation. If DLT was observed in one of 3 patients, up to 3 more patients were enrolled at the same level. If 2 or more out of 3 to 6 patients experience DLT at a dose level, the dose should be decreased to the previous dose group. When decreasing to the previous dose group, if there were only 3 patients in this dose group, 3 more patients should be added; if there were already 6 patients, the dose escalation ended, and this dose was the MTD. A patient who was withdrawn from the study before the completion of the DLT observation period due to a reason other than a DLT should be replaced. A dose de-escalation or reduction was permitted if safety re-evaluation was deemed necessary.
Safety analyses were conducted for all patients who received at least one dose of SYHA1813. AEs were assessed throughout the study using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The health status assessment of the patients included a physical examination (vital signs, weight, PS score, etc.), a hematologic and biochemical profile, a routine urine and stool test, and an electrocardiogram performed at screening and throughout the study.
PK evaluation
Blood samples for the assessment of PK parameters were collected at predefined time points during DLT observation period as follows: Cycle 0 Day 1 (predose; 0.5-, 1-, 2-, 4-, 8-, and 12-hr postdose), Day 2 (24-hr postdose), and Day 3 (48-hr postdose); Cycle 1 Day 1 (predose), Day 8 (predose), Day 15 (predose), Day 21 (predose; 0.5-, 1-, 2-, 4-, 8-, and 12-hr postdose), Day 22 (24-hr postdose), Day 23 (48-hr postdose), and Day 24 (72-hr postdose). Plasma SYHA1813 levels were measured using a validated high-performance liquid chromatography-mass spectrometry method.
Single- and multiple-dose PK parameters of SYHA1813 were estimated using non-compartmental analysis, including maximum observed plasma concentration (Cmax), Cmax/dose, time to Cmax (Tmax), the area under curve extrapolated to infinity (AUCinf), AUCinf/dose, the volume of distribution (Vz/F), terminal elimination half-life (t1/2), and oral clearance (CL/F) after the first dose. PK parameters at steady-state (ss), including Cmax, ss, Cmax, ss/dose, minimum observed plasma concentration (Cmin, ss), AUCinf, AUCinf/dose, Tmax, ss, Vss, t1/2, CLss/F after multiple doses, and accumulation index (Rac).
Efficacy assessment
Radiographic assessments were conducted at screening, at the end of the DLT observation period, and repeated every six weeks during the extended treatment period until disease progression, intolerable toxicity, or withdrawal of consent (whichever came first). The patients with central nervous system tumors were evaluated for responses according to the RANO criteria by enhanced magnetic resonance imaging (MRI) scan. Patients with other solid tumors were measured by computed tomography (CT) or MRI scan according to RECIST criteria version 1.1. Categories of the evaluation of the response to treatment included complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). ORR and DCR were defined as CR + PR and CR + PR + SD respectively.
Exploratory biomarker analysis
Samples for biomarkers were collected on Cycle 1, Day 1 (predose), Cycle 1, Day 24 (72-hr post-dose), and 14-day after the end of treatment. Soluble VEGFR2, VEGF, and CSF1 were measured using multiplex enzyme-link immunosorbent assay (ELISA) plates from R&D System (Minneapolis, MN), as well as for placental growth factor (PlGF) using electrochemiluminescence immunoassay (ECLIA) kit from Roche Diagnostics (Mannheim, Germany).
Statistical analysis
All statistical analyses were performed using SAS® 9.4 (SAS Institute, Inc., Cary, NC, USA) except for the calculation of PK parameters using Phoenix® WinNonlin 8.1 (Pharsight Corp., Certara, Princeton, NJ, USA). Exploratory biomarker analyses were done by a two-tailed paired t-test using GraphPad Prism 9.3 (GraphPad Software, Inc., CA, USA).