A Randomized Controlled Clinical Trial of Temozolomide Plus Apatinib in Newly Diagnosed High-grade Glioma
试验速览
- 阶段
- 2 期
- 入组人数
- 211
- 试验地点
- 1
- 主要终点
- Progression Free Survival（PFS）
研究概览
简要总结
Glioma is the most common primary malignant Brain Tumor. Although the traditional treatment (surgery, radiotherapy and chemotherapy) has been actively carried out, the curative effect of High grade glioma (HGG) is still poor.On the basis of a lot of exploration, the union medication has become a hot spot. Malignant glioma has obvious neovascularization and inhibiting angiogenesis can inhibit tumor proliferation and invasion.Studies have found that inhibiting VEGFR-2 can can reduce neovascularization and inhibit tumor growth. NCCN clinical practice guidelines recommend bevacizumab(BEV) for the treatment of recurrent malignant gliomas. AVAglio＆RTOG 0825 subgroup analysis showed that TMZ combined with antiangiogenic drugs may have advantages in the first-line treatment of patients with IDH1 wild-type high grade glioma.However, some studies have shown that bevacizumab can lead to rapid deterioration due to hypoxia or phenotypic changes. So it is urgent to find new antiangiogenic drugs. Apatinib is an oral small molecule antiangiogenic targeted drug. Apatinib plus temozolomide has been shown to be effective and tolerable in recurrent glioma. So the investigators aimed to evaluate the efficacy and safety of temozolomide combined with apatinib in the new diagnosis of high-grade glioma，and to explore the new first-line treatment of HGG, especially to TMZ insensitivity patients(MGMT gene promoter unmethylated) and poor prognosis (IDH1 wild type) population. And Find out the benefit groups of the two drugs.
详细描述
Glioma is the most common primary malignant Brain Tumor.High grade glioma (HGG) has the characteristics of high morbidity, high relapse and high incidence of causing disability.Despite the progress in the combined treatment of surgery, radiotherapy and chemotherapy, the 2-year survival rate and 2-year non-progression survival rate were only 27.2% and 11.2%, respectively.
TMZ is the standard first-line chemotherapy, which can prolong the overall survival time and the progression-free survival time. Although TMZ has achieved satisfactory therapeutic effect since its application, the overall response rate of TMZ alone is still low which related to the methylation level of MGMT promoter.
On the basis of a lot of exploration, the union medication has become a hot spot. Malignant glioma has obvious neovascularization and inhibiting angiogenesis can inhibit tumor proliferation and invasion.
In recent years, antiangiogenic drugs have become a new treatment for malignant glioma. In recent years, studies have found that inhibiting VEGFR-2 can improve the sensitivity of glioma to TMZ chemotherapy. NCCN clinical practice guidelines recommend bevacizumab(BEV) for the treatment of recurrent malignant gliomas. Numerous clinical trials have studied the role of bevacizumab on glioma, and proved that bevacizumab can effectively prolong PFS without significant benefit to OS. AVAglio＆RTOG 0825 subgroup analysis showed that TMZ combined with antiangiogenic drugs may have advantages in the first-line treatment of patients with IDH1 wild-type high grade glioma.
However, some studies have shown that bevacizumab can lead to rapid deterioration due to hypoxia or phenotypic changes. So it is urgent to find new antiangiogenic drugs. Apatinib is an oral small molecule antiangiogenic targeted drug developed in China. As a specific vegfr-2 receptor inhibitor, apatinib plus temozolomide has been shown to be effective and tolerable in patients with recurrent glioma, but high-level evidence is still lacking. So the investigators conducted this clinical trial aimed to explore the new first-line treatment of high-grade glioma. The combination of TMZ and apatinib may have synergistic effect especially to TMZ insensitivity patients(MGMT gene promoter unmethylated) and poor prognosis (IDH1 wild type) population, as the high-level evidence is imminent.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years;
- •Pathological or cytological diagnosis of glioma (WHO Ⅲ or Ⅳ);
- •KPS score ≥ 60;
- •The expected survival period is ≥ 3 months;
- •Blood routine examination is basically normal: a. HB ≥ 90 G /L; b. the ANC ≥ 1.5 x 10^9/L; c. PLT≥ 80 x 10^9/L (without blood transfusion within 2 weeks, or G-CSF and other hematopoietic stimulator correction) ;
- •Normal liver and kidney function.
排除标准
- •Pregnant or lactating women;
- •Second primary malignancy;
- •Severe lung infection;
- •with high blood pressure although treated with medication;
- •Patients with myocardial ischemia or myocardial infarction, arrhythmia (including QT interval > 440 ms) or grade II cardiac insufficiency;
- •Conditions that significantly affect oral drug absorption, such as inability to swallow, chronic diarrhea, and intestinal obstruction;
- •Abnormal coagulation function （INR>1.5 or PT>ULN+4s or APTT >1.5 ULN);
- •Haemorrhagic tendencies or being treated with thrombolysis or anticoagulation;
- •≥CTCAE level 2 Pulmonary hemorrhage or ≥CTCAE level 3 other organ hemorrhage occurred within 4 weeks before the first administration of the study drug;
- •Arteriovenous thrombosis in 6 months prior to first administration, Such as cerebrovascular accident (including temporary ischemic attack), deep vein thrombosis and pulmonary embolism;
- •Small doses of warfarin(1mg/day) or heparin(80-100mg/day) is permitted unless INR ≤1.5;
- •Serious heart, lung and bone marrow impairment;
- •History of severe hypertension or cerebral hemorrhage
研究组 & 干预措施
Temozolomide
Patients were treated with postoperative concurrent chemoradiation.Then Temozolomide alone chemotherapy 6 cycles(first cycle 150mg/m2/d d1-5, later 200mg/m2/d d1-5 q28d).
干预措施: Temozolomide (Drug)
Temozolomide and apatinib
Patients have treated with postoperative concurrent chemoradiation. Then Temozolomide (150mg/m2/d d1-5 in the first cycle, followed by 200mg/m2/d d1-5 q28d) + apatinib (500mg/d QD).
After 6 cycles,apatinib single drug maintained until progress.
干预措施: apatinib (Drug)
Temozolomide and apatinib
Patients have treated with postoperative concurrent chemoradiation. Then Temozolomide (150mg/m2/d d1-5 in the first cycle, followed by 200mg/m2/d d1-5 q28d) + apatinib (500mg/d QD).
After 6 cycles,apatinib single drug maintained until progress.
干预措施: Temozolomide (Drug)
结局指标
主要结局
Progression Free Survival（PFS）
时间窗: 1 year
Record the time from the start of enrollment to the progression of disease or death.
次要结局
- rate of 2-year Overall survival（OS）(2 years)
- Incidence of Treatment-Emergent Adverse Events(every month)
研究者
Xue Xiaoying
Director of Radiotherapy
The Second Hospital of Hebei Medical University