Phase Ⅱ Study of PD-1 Inhibitor Combined With FOLFOX Neoadjuvant Therapy for Resectable Gastric and Gastroesophageal Junctional Adenocarcinoma
试验速览
- 阶段
- 2 期
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- R0 resection rate
研究概览
简要总结
The aim of this study is to observe the efficacy, safety, postoperative pathological response rate and survival benefit of immume checkpoint inhibitor PD-1 SHR1210 combined with chemotherapy in neoadjuvant therapy of locally advanced resectable gastric and gastroesophageal junction adenocarcinoma. In addition ，the investigators will explore the relationship between the immunophenotype of gastric cancer and the efficacy and drug resistance of immunotherapy combined with chemotherapy, and screen out biomarkers that can predict the efficacy of immunotherapy.
详细描述
Neoadjuvant chemotherapy and neoadjuvant radiotherapy and chemotherapy can not only improve the surgical resection rate and postoperative pathological remission rate, but also prolong the postoperative recurrence-free survival and benefit patients.Recent studies have confirmed that immume point inhibitors PD-1 and CTLA-4 monoclonal antibody have a certain effect in advanced gastric and gastroesophageal junction adenocarcinoma which had experienced multi-line treatment. Furthermore，the FOLFOX protocol is recommended as a new adjuvant treatment for locally advanced gastric cancer.In order to further improve the surgical resection rate and survival rate by improving the efficacy of neoadjuvant therapy for locally advanced gastric and gastroesophageal junction adenocarcinoma, the investigators selected PD-1 monoclonal antibody combined with FOLFOX neoadjuvant therapy for locally advanced gastric and gastroesophageal junctions Adenocarcinoma.The aim of this study is to observe the efficacy, safety, postoperative pathological response rate and survival benefit of immume checkpoint inhibitor PD-1 SHR1210 combined with chemotherapy in neoadjuvant therapy of locally advanced resectable gastric and gastroesophageal junction adenocarcinoma. In addition ，the investigators will explore the relationship between the immunophenotype of gastric cancer and the efficacy and drug resistance of immunotherapy combined with chemotherapy, and screen out biomarkers that can predict the efficacy of immunotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 73 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •18-73 years old; male or female
- •confirmed gastric and gastroesophageal junction adenocarcinoma by Gastroscopic biopsy histopathological examination
- •Imaging (CT/MRI) and ultrasound gastroscopy confirmed: cT ≥ T2 and / or regional lymph node positive (N +);
- •ECOG score: 0~2 points;
- •Expected survival period ≥ 12 weeks;
- •A histological specimen can be provided for secondary testing;
- •The main organ function meets the following criteria within 7 days before treatment:
- •Blood routine examination criteria (without blood transfusion within 14 days):
- •Hemoglobin (HB) ≥ 90g / L; The absolute value of neutrophils (ANC) ≥ 1.5 × 109 / L; Platelet (PLT) ≥ 80 × 109 / L (2) Biochemical examinations must meet the following criteria: Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) ≤ 2.5 * ULN; serum creatinine (Cr) ≤ 1.5 * ULN or creatinine clearance (CCr) ≥ 60ml / min; (3) Doppler ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ normal low limit (50%).
- •Women of childbearing age should agree to use contraceptives (such as intrauterine devices, contraceptives or condoms) during the study period and within 6 months after the end of the study; negative serum or urine pregnancy test within 7 days prior to study enrollment and must be non-lactating patients; men should agree to patients who must use contraception during the study period and within 6 months after the end of the study period.
- •The patient volunteered to participate in the study and signed an informed consent form;
排除标准
- •Exceeding or currently suffering from other malignant tumors within 5 years, except for cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (in situ carcinoma) And T1 (tumor infiltrating basement membrane)];
- •Patients with a high risk of bleeding or fistula due to the apparent invasion of adjacent organs (aorta or trachea);
- •Before starting treatment， subject administrated corticosteroids (day> 10 mg equivalent dose prednisone), or other immunosuppressive drugs for systemic treatment of a disease within 14 days . In the absence of active autoimmune disease, >10 mg of daily prednisone equivalent dose of inhaled or topical steroid and adrenal replacement steroid doses are permitted;
- •Anyone who has received any anti-tumor treatment in the past;
- •Significantly malnourished patients. Exclusion is performed if the patient is receiving intravenous fluids or is required to be hospitalized for continuous infusion therapy. Patients with good nutrition control ≥ 28 days can be enrolled before randomization;
- •Participants who received live/attenuated vaccine within 30 days of the first treatment;
- •Unresolved toxicity due to any previous treatment above CTC AE4.0 Level 2, excluding neurotoxicity of ≤2 caused by hair loss and oxaliplatin;
- •Allergic reactions and adverse drug reactions:
- •a history of allergies to the ingredients of the study drug;
- •contraindications to any study drug (fluorouracil or oxaliplatin) in the chemotherapy regimen.
- •Patients with any severe and/or uncontrolled disease, including:
- •patients with hypertension who are not well controlled by antihypertensive drug (systolic blood pressure ≥150 mmHg, diastolic blood pressure ≥100 mmHg);
- •with grade I or higher myocardial ischemia or myocardial infarction, arrhythmia (including QTc ≥ 480ms) and ≥ grade 2 congestive heart failure (New York Heart Association (NYHA) classification);
- •Severe or uncontrolled disease or active infection (≥CTCAE grade 2 infection), which the investigator believes may increase the risk associated with study participation, study drug administration, or affect the subject's ability to receive study medication;
- •Renal failure requires hemodialysis or peritoneal dialysis;
- •a history of immunodeficiency, including HIV-positive or other acquired, congenital immunodeficiency disease, or a history of organ transplantation;
- •Patients with diabetes who have poor glycemic control (fasting blood glucose (FBG) > 10 mmol/L); subjects with active, known or suspected autoimmune diseases. Subjects with type 1 diabetes, residual hypothyroidism caused by autoimmune thyroiditis requiring hormone replacement therapy, and skin diseases that do not require systemic treatment (such as vitiligo, psoriasis or alopecia) can be enrolled;
- •patients with seizures and requiring treatment;
- •The subject has an interstitial lung disease that is symptomatic or may interfere with the discovery or management of suspected drug-related lung toxicity; previous and current subjects with a history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-associated pneumonia, severe impaired lung function, etc. that may interfere with the detection and management of suspected drug-related lung toxicity;
- •Patients with gastrointestinal diseases such as intestinal obstruction (including incomplete intestinal obstruction) or those who may have caused gastrointestinal bleeding, perforation or obstruction;
- •Patients who underwent surgical treatment, incisional biopsy or significant traumatic injury within 28 days prior to enrollment;
- •In the 4 weeks prior to enrollment, patients with any bleeding event ≥ CTCAE 3 have unhealed wounds, ulcers or fractures;
- •Overactive/venous thrombosis events within 3 months, such as cerebrovascular accidents (including transient ischemic attacks), deep static Pulmonary thrombosis and pulmonary embolism;
- •Prepare or accept previous allogeneic or allogeneic bone marrow transplantation, including liver transplantation;
- •According to the investigator's judgment, there is a concomitant disease that seriously harms the patient's safety or affects the patient's completion of the study;
- •Cannot perform biopsy to provide histological specimens;
- •those who have a history of psychotropic substance abuse and are unable to quit or have a mental disorder; Prepare or accept previous allogeneic or allogeneic bone marrow transplants, including liver transplants;
- •Urine routine showed urinary protein ≥ 2+ and confirmed 24-hour urine protein quantitation > 1.0 g;
- •Patients with brain metastases;
- •Patients who have participated in other clinical trials of anti-tumor drugs within four weeks.
研究组 & 干预措施
treatment group
Neoadjuvant therapy:SHR1210 combined with FOLFOX repeat every 14 days for a total of 4 cycles.
Adjuvant therapy:SHR1210 combined with chemotherapy (the specific regimen will be chosen at the discretion of the investigator), every 14 days for a total of 4 cycles. After that, the patients will receive camrelizumab monotherapy for up to 1 year (from the first SHR1210 treatment).
干预措施: SHR1210 combined with FOLFOX (Drug)
结局指标
主要结局
R0 resection rate
时间窗: Up to approximately 16 weeks
The percentage of patients who have no residual cancer cells (gross or microscopically) at the resection margins.
pathological complete response (pCR) rate
时间窗: Up to approximately 16 weeks
The percentage of patients with no residual cancer cells at the primary cancer site and N(-) per histological evaluation.
次要结局
- Near pathological complete response (near-pCR) rate(Up to approximately 16 weeks)
- Overall survival(OS)(From randomization to the date of death (up to approximately 4 years))
- Progression-free survival(PFS)(up to 2 years)
- Disease-free survival (DFS)(From randomization to the date of recurrence or death (up to approximately 4 years))
- Percentage of Participants Who Experience One or More Adverse Events (AEs)(up to approximately 1 years)