Phase 2 study evaluating the addition of immune-sensitizing radiotherapy and biomarker-driven low-dose nivolumab in locally advanced resectable gastroesophageal junction/gastric cancers
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 127
- 试验地点
- 1
- 主要终点
- The primary outcome and endpoint of the study is assessment of pathological complete response PCR rates in surgical specimens post neoadjuvant chemotherapyimmunotherapy and immunesensitizing RT. Patients will be undergoing surgical resection after neoadjuvant therapy. Resection specimens graded as TRG1 at primary site and nodes will be considered as having pathological complete response PCR. The proportion of patients achieving PCR will be evaluated for measurement of primary endpoint of study.
研究概览
简要总结
A validated biomarker in G slash GEJ is a Combined positive score ie CPS. A large trial evaluating the addition of nivolumab to chemotherapy in advanced G slashGEJ carcinomas suggested improvement in survival when a CPS cut-off of greater than 5 was used, with even better outcomes when CPS greater than 10. We are using similar cutoffs in the proposed study. Trials utilizing only ICIs with NACT have shown an improvement in PCR rates. PCR is an accepted surrogate endpoint in G slashGEJ cancers, and improving PCR can translate into improvements in survival. The combination of low-dose ICIs (which has significant preclinical rationale) with RT with standard chemotherapy in resectable G slashGEJ is novel with biological rationale. The use of specialized immuno-sensitizing types of radiotherapy with low-dose ICIs is cost-effective and takes advantage of the synergistic activity between both.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 盲法
- None
入排标准
- 年龄范围
- 18.00 Year(s) 至 90.00 Year(s)（—）
- 性别
- All
入选标准
- •Histologically confirmed esophagogastric adenocarcinomas with the following features Radiologically stage T2 or higher with nodal positivity cN plus or both and no clinical evidence of distant metastases.
- •No evidence of peritoneal disease including peritoneal cytology positivity or other sites of metastases on staging laparoscopy preferably.
- •No evidence of clinical or radiological gastric outlet obstruction including no findings on upper gastrointestinal endoscopy.
- •No evidence of acute bleeding tumor such as melena or hematemesis.
- •Age greater than 18 years.
- •ECOG performance status of 0 to
- •The patient must be able to provide informed consent for the study.
- •The patient must not have any contraindications to receiving FLOT chemotherapy nivolumab or radiotherapy.
- •A combined positive score CPS of at least
- •The CPS is calculated using the following formula on biopsy specimens CPS equals the number of PDL1 stained cells tumor cells macrophages lymphocytes multiplied by 100 and then divided by the total number of viable tumor cells.
- •Antibodies used will either be 28 8 on the Dako platform or SP263 on the Ventana platform.
- •The patient must be able to undergo radiation therapy as planned as detailed in the protocol.
- •Adequate hematological hepatic and renal end-organ function.
- •Normal cardiac ejection fraction and cardiac function as assessed by echocardiography and ECG.
- •Women of childbearing age must have a negative pregnancy test at the time of randomization and be willing to use adequate contraception during the treatment phase of the trial.
排除标准
- •Squamous cell cancers of the oesophagus and stomach Patients undergoing upfront resection for G or GEJ adenocarcinomas Radiologically or endoscopically T1b or T2 N0 cancers Known hypersensitivity or contraindications to docetaxel oxaliplatin, 5-FU or nivolumab Contraindication to receive radiotherapy Uncontrolled comorbidities or infections Significant or uncontrolled autoimmune conditions precluding use of Nivolumab Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix Baseline neuropathy greater than NCI Grade I Subject is pregnant, breastfeeding, or planning to become pregnant within 6 months after the end of treatment.
结局指标
主要结局
The primary outcome and endpoint of the study is assessment of pathological complete response PCR rates in surgical specimens post neoadjuvant chemotherapyimmunotherapy and immunesensitizing RT. Patients will be undergoing surgical resection after neoadjuvant therapy. Resection specimens graded as TRG1 at primary site and nodes will be considered as having pathological complete response PCR. The proportion of patients achieving PCR will be evaluated for measurement of primary endpoint of study.
时间窗: In Arm A The combination of mFLOT and Nivolumab will be given for 4 cycles following which there will be an assessment for surgery. Surgery will be considered approximately 2 to 6 weeks post 4th cycle of chemoimmunotherapy. In Arm B patient will receive Three doses of RT, 1st dose prior to starting mFLOT plus Nivolumab and then one dose each between Cycle 1 and Cycle 2 of mFLOT+Nivolumab and Cycle 2 and Cycle 3 of mFLOT plus Nivolumab.
次要结局
- Secondary endpoints(Progression free survival (PFS) will be defined as the time from randomization to the time of disease progression or lost to follow up whichever is earlier.)
研究者
Dr Anant Ramaswamy
Tata Memorial Hospital