Phase I trial of single-agent recombinant human anti-vascular endothelial growth factor (GB222) followed a combination therapy of GB222 and temozolomide in patients with recurrent WHO grade III and IV glioma
Authors: Kang Xun , Ma Wenbin , Li Weiping , Qi Songtao , Xu Chongyuan , Yang Xuejun , Wang Liming , Gao Chao , Chen Feng , Wang Ce , Kang Zhuang , Jiang Chuanlu , Li Wenbin 
Published: July 2022

Abstract
Background
Treatment options for malignant and aggressive glioma are limited. Vascular endothelial growth factor (VEGF) antibodies are angiogenesis inhibitors that prevent the growth of neoplasms by inhibiting the expansion of the vascular tissue that supports them. We designed this phase I trial to assess the safety and establish the maximum tolerable dose (MTD) of GB222, a recombinant human anti-VEGF monoclonal, for patients with recurrent malignant glioma.

Methods
Eligible patients were those who were diagnosed with WHO grade III and IV glioma and progressed after initial treatment including surgery, radiotherapy, and temozolomide. GB222 was initiated at 3 mg/kg (Cohort 1) intravenously once every four weeks (Q4W), then escalated in a 3 + 3 design at 5 mg/kg (Cohort 2, Q4W), 5 mg/kg (Cohort 3, Q2W), 7.5 mg/kg (Cohort 4, Q2W), and 10 mg/kg (Cohort 5, Q2W). The initial 28 days of each dose level cohort was the observation period for dose-limiting toxicity (DLT). After that, patients continued the treatment with the same dose of GB222 in combination of temozolomide if patients were considered to have benefited from the treatment. Our study also evaluated anti-tumor efficacy including objective response rate (ORR), progress free survival (PFS), and overall survival (OS), as well as pharmacokinetic parameters of GB222.

Findings
Sixteen patients were enrolled: 4 in Cohort 1, 3 each in Cohort 2, 3, 4, and 5. In the 28 days with GB222 alone, no DLT events were observed in all dose cohorts, and MTD was not reached. Among 16 patients, 14 (87.5%) received the combined treatment of GB222 and temozolomide after the DLT observation period. Two patients stopped the treatment after the DLT observation period due to disease progression. All patients (100%) reported experiencing at least one adverse event (AE) among patients who either received GB222 alone or the combination therapy of both GB222 and temozolomide. Four patients experienced grade 3/4 AE (one in Cohort 1, one in Cohort 2, and two in Cohort 3), including status epilepticus, herpes zoster, bone marrow failure, and hematological laboratory abnormalities. None of them was determined to be GB222 related. No death and treatment termination occurred due to AEs. Among these 16 patients, 81.3% (13/16) had treatment-related adverse events (TRAE). The common TRAE included decreased neutrophil count, decreased leukocyte count, increased alanine aminotransferase, hypertension, and rash. Pharmacokinetics (PK) studies showed drug exposure of GB222 had a linear relationship with the dose administrated. The overall objective response rate among 16 patients was 31.3% (95% CI: 11.02%, 58.66%) with 0% in Cohort 1, 66.7% in Cohort 2 (1 CR and 1 PR), 33.3% in Cohort 3 (1PR), 0% in Cohort 4, and 66.7% in Cohort 4 (2 PR). The median PFS was 4.44 months [95% confidence interval (CL) 2.76–6.60 months]. The median OS was 8.38 months (95% Cl: 4.24-not reached).

Interpretation
GB222 alone or combined with temozolomide had manageable safety profiles and encouraging anti-tumour activity in treating patients with recurrent HGG.