A Phase II Randomized Controlled Trial of Apatinib Monotherapy Versus Apatinib Combined With Camrelizumab in Third-line or Later-line Treatment of Advanced Gastric Adenocarcinoma
试验速览
- 阶段
- 2 期
- 入组人数
- 102
- 试验地点
- 1
- 主要终点
- PFS
研究概览
简要总结
This open, single-center, randomized phase II study was to evaluate the clinical benefit of apatinib plus camrelizumab which is an anti-Programmed cell death-1 (PD-1) monoclonal antibody, versus apatinib in patients with metastatic gastric cancer refractory to two or more lines of treatment, fully evaluating the efficacy and safety of the combined regimen.
详细描述
Gastric cancer is one of the most common malignant tumors with the highest mortality in the world. Post-line treatment options for metastatic gastric cancer (mGC) are limited. Monoclonal antibodies targeting Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) and small molecule tyrosine kinase inhibitors (TKIs) have shown benefits on progression free survival (PFS) and overall survival (OS) in second-line or third-line treatment of mGC. Following a phase III randomized clinical trial, apatinib, an oral small-molecule drug targeted with VEGFR-2, has been proved to significantly prolong patients' OS in the third-line or later-line treatment of mGC, thus becoming the standard third-line or later-line regimen for gastric cancer in China. In immunotherapy of mGC, pembrolizumab has been approved for third-line treatment of programmed cell death-Ligand 1 (PD-L1) positive advanced gastric cancer, and nivolumab also become the standard third-line treatment regimen. What is the best option for third-line treatment of metastatic gastric cancer remains unclear. Analysis from the subgroup of the Attraction 2 study showed that patients who had previously been treated with anti-VEGFR targeted drug ramucizumab had significantly higher PFS and OS than those who had not. The REGONIVO study also showed that the anti-angiogenic TKI regorafenib combined with nivolumab achieved a good objective response rate after the failure of standard treatment in gastric cancer. Therefore, it is worth exploring whether apatinib combined with anti-PD-1 monoclonal antibody could bring improvements in PFS and OS while compared with apatinib monotherapy. This open, single-center, randomized phase II study was to evaluate the clinical benefit of apatinib plus camrelizumab which is an anti-PD-1 monoclonal antibody, versus apatinib in patients with metastatic gastric cancer refractory to two or more lines of treatment, fully evaluating the efficacy and safety of the combined regimen. A total of 102 patients were planned for enrollment in this study. This trial was expected to start in March 2021, and the end of recruitment will be approximately on March 2024, and the end of follow-up will be approximately on October 2023. The control group would take apatinib monotherapy regimen, with 500mg oral apatinib every day, and the experimental group would take apatinib plus camrelizumab regimen, with 250 mg oral apatinib every day continuously and 200mg intravenous camrelizumab every 14 days. Patients would be assessed every 8 weeks and those patients with disease control would be received the treatment until progressive disease (PD) or intolerable toxicity. The maximum treatment duration of camrelizumab was 2 years.
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
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Locally advanced or recurrent/metastatic gastric or gastroesophageal junction adenocarcinoma confirmed by histopathological examination;
- •Standard treatment failure of no less than two lines of systematic treatment (treatment failure is defined as intolerance of toxic and side effects, disease progression during treatment or recurrence after treatment);
- •With one or more measurable lesions, the longest diameter measured by spiral CT scan should be at least 10 mm, and the longest diameter measured by conventional CT scan should be at least 20 mm (RECIST standard, version 1.1);
- •ECOG score was 0-2;
- •Life expectancy ≥12 weeks;
- •The patient has recovered from damage caused by other anti-tumor therapy, received cytotoxic drugs, radiotherapy or surgery for ≥4 weeks, and the wound has completely healed;
- •Bone marrow capacity and liver and kidney function were sufficiently reserved 7 days before screening: absolute neutrophil (ANC) count ≥1.5x109 /L; Hemoglobin ≥ 8.0g/ dL; Platelet count ≥80 x109 /L; Total bilirubin < 1.5 times upper normal limit (ULN); ALT and AST< 2.5x ULN (with liver metastasis <5x ULN); Serum creatinine ≤1 x ULN, the clearance rate of endogenous creatinine >50ml/min;
- •Women of childbearing age should take effective contraceptive measures;
- •Subjects voluntarily joined the study and signed informed consent with good compliance and follow-up.
排除标准
- •A history of other malignant tumors within 5 years, except cured cervical carcinoma in situ or basal cell carcinoma of the skin;
- •Patients with hypertension that could not be controlled by antihypertensive medication (systolic blood pressure >140mmHg, diastolic blood pressure >90mmHg), coronary heart disease of grade I or above, arrhythmia of grade I or above (including prolonged QTc interval > 450ms in males and > 470 ms in females) and cardiac dysfunction of grade I or above;
- •Symptomatic brain or meningeal metastases (unless the patient was treated for >6 months, imaging results were negative within 4 weeks prior to study entry, and tumor-related clinical symptoms were stable at study entry);
- •with a history of uncontrolled epileptic seizures, central nervous system dysfunction, or mental disorders;
- •Uncontrolled pleural or abdominal effusion;
- •Undergoing kidney dialysis;
- •severe or uncontrolled infection;
- •pregnant or lactating women who are fertile but have not taken adequate contraceptive measures;
- •Multiple factors affecting oral medication (inability to swallow, chronic diarrhea and intestinal obstruction);
- •Abnormal coagulation function (PT>16s, APTT>43s, TT>21s, Fbg< 2G /L), bleeding tendency or receiving thrombolytic or anticoagulant treatment;
- •patients with gastrointestinal bleeding risk should not be enrolled, including the following conditions :(1) active peptic ulcer lesions and fecal occult blood (++); (2) patients with history of black stools and hematemesis within 3 months;
- •Prior exposure to any anti-PD-1 or anti-PD-L1, PD-L2, CD137, CTLA-4 antibody therapy, or any other antibody or drug that specifically targets T-cell costimulation or immune checkpoint pathways.
- •Participated in clinical trials of other drugs within four weeks
- •Urine routine examination indicated urine protein > 2+
- •Received systemic systemic therapy with anti-tumor indications of Chinese herbal medicine or immunomodulatory drugs (including thymosin, interferon, interleukin, etc.) within 2 weeks before the first administration;
- •Use of immunosuppressive agents within 4 weeks prior to the first dose of study therapy, excluding nasal, inhaled, or other topical or physiological doses of systemic glucocorticoids (i.e., no more than 10 mg/ d of prednisone or equivalent doses of other glucocorticoids), or hormone use for the prevention of contrast agent allergy.
- •Residual liver volume is less than 50% of the total liver volume.
研究组 & 干预措施
apatinib monotherapy
Apatinib，500 mg，po., qd, q2w
干预措施: Apatinib Mesylate (Drug)
Apatinib Combined With Camrelizumab
Apatnib，250 mg，po., qd，q2w; Camrelizumab，200mg， ivgtt，d1, q2w
干预措施: Apatinib Mesylate (Drug)
Apatinib Combined With Camrelizumab
Apatnib，250 mg，po., qd，q2w; Camrelizumab，200mg， ivgtt，d1, q2w
干预措施: Camrelizumab (Drug)
结局指标
主要结局
PFS
时间窗: Time Frame: from the time signing of ICF until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
progression free survival
次要结局
- OS(from the time signing of ICF until the date of death from any cause, assessed up to 36 months)
- DCR(the rate of patients with CR, PR and SD, through study completion, an average of 1 year)
- ORR(the rate of patients with CR and PR, through study completion, an average of 1 year)
- DoR(the time between the first tumor evaluation for CR or PR and the first evaluation for PD(Progressive Disease) or death from any cause, assessed up to 36 months)
- AEs(the adverse events rate and types of all enrolled patients, through study completion, an average of 1 year)