Background: Postoperative with radiotherapy, and concomitant and up to 6 cycles of maintenance temozolomide (TMZ) chemotherapy (STUPP regimen) is now the standard treatment for newly diagnosed GBM, while the effectiveness is limited. Anlotinib is a novel, multi-kinase inhibitor against both tumor angiogenesis and tumor cell proliferation with encouraging findings in preclinical GBM models. Our previous single-arm study (NCT04119674) showed that the addition of anlotinb to STUPP exhibited promising progression-free survival (PFS) in patients with GBM. Therefore, a phase II trial was designed to assessed the efficacy and safety of anlotinib with the STUPP regimen. Methods: This is a multicenter, randomized, controlled, phase II superiority trial. Approximately 150 patients will be randomly assigned 1:1 to receive TMZ-based radiochemotherapy with anlotinib or TMZ-based radiochemotherapy with placebo. All patients will receive radiotherapy (fractionated focal irradiation in daily fractions of 1.8–2.0 Gy given 5 days per week for 6 weeks, for a total of 54–60 Gy) concurrently with TMZ (75 mg/m2 QD) and anlotinib (10 mg QD, d1–14/3wks) or placebo. Anlotinib or placebo is administrated during the 28-day treatment break. Adjuvant therapy start four weeks after radiotherapy completion, including six cycles of TMZ (150–200mg/m2, d1–5/4wks) and eight cycles of anlotinib (10 mg QD, d1–14/3wks) or placebo. Patients who complete adjuvant therapy are administrated anlotinib or placebo continuously until the disease progressed or unacceptable toxic effects developed. Eligibility criteria include histologically confirmed newly diagnosed GBM and a World Health Organization (WHO) performance status ≤ 2. Additional inclusion criteria include patients between 18 and 75 years old with adequate wound healing of craniotomy or biopsy; adequate hematologic, hepatic, and renal function; acceptable blood coagulation levels; and the stable or decreasing usage of glucocorticoid doses within 5 days before randomization. Exclusion criteria include potentially fatal intracranial hemorrhage on magnetic resonance imaging (MRI); tumors located only in the brainstem; prior chemotherapy or radiotherapy administered for GBM; and IDH1/2 mutation. The primary objective of this study is to compare PFS accessed by Independent Review Committee in patients receiving anlotinib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include overall survival (OS), PFS accessed by investigators, overall response rate (ORR), severity and frequency of AEs (CTCAE V5.0), and quality of life (QOL). The disease control rate (DCR) and duration of response (DOR) will also be explored. Clinical trial information: NCT04959500. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.