Study Title: Peri-operative Immuno-Chemotherapy in Operable Oesophageal and Gastric Cancer (ICONIC Trial)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 44
- 试验地点
- 1
- 主要终点
- Pathological complete response rate of combination FLOT-A
研究概览
简要总结
A single centre phase II trial of peri-operative chemo-immunotherapy in operable gastro-oesophageal adenocarcinoma (GOA). This trial is designed to evaluate the safety and efficacy of administering Avelumab, an anti-PD-L1 monoclonal antibody, with cytotoxic FLOT chemotherapy for patients with operable GOA treated according to a peri-operative protocol.
This trial is in 2 stages: the first stage will establish the safe and tolerated maximum administered dose (MAD) of Avelumab in combination with FLOT and the second stage will assess the efficacy of this combination therapy in achieving pathological complete response (pCR) and peri-operative safety.
详细描述
Patients will receive chemo-immunotherapy consisting of FLOT chemotherapy (Folinic acid 200mg/m2 iv infusion day 1, Oxaliplatin 85mg/m2 iv infusion day 1, Docetaxel 50mg/m2 iv day 1, Fluorouracil 2600mg/m2 over 24 hours iv) and the PD-L1 inhibiting monoclonal antibody Avelumab. The safe dose of Avelumab in combination with FLOT will be established in a safety run-in phase with a standard 3+3 design, starting with the recommended dose of 10mg/kg iv Avelumab (dose level 0) in which a dose reduction to 7mg/kg iv (dose level -1) may occur. Four cycles of two-weekly chemo-immunotherapy will be administered before surgery and four further cycles post-operatively in patients who are fit enough to receive further chemo-immunotherapy after surgery. Resectional surgery will take place 4-8 weeks following the last dose of chemo-immunotherapy in patients who remain fit.
Study Objectives:
To evaluate the safety, efficacy and toxicities and to explore biomarkers of peri-operative chemo-immunotherapy with Avelumab and FLOT.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male/female patients aged ≥18 years
- •Histologically confirmed gastric, gastro-oesophageal junction or oesophageal adenocarcinoma (referred to as gastro-oesophageal adenocarcinoma (GOA) in this protocol).
- •Oesophageal and gastric tumours should be TNM7 stage T1-4 and N0-N2, with no evidence of distant metastases (M0) where the MDT believes that an R0 resection can be achieved after pre-operative chemotherapy.
- •Absence of distant metastases on CT scan and PET scan and staging laparoscopy (where indicated) prior to study entry
- •No prior therapy for GOA
- •Considered fit for surgery by surgical/anaesthetic team
- •Adequate bone marrow function:
- •Absolute neutrophil count (ANC) >1.5x10-9/L
- •White blood count >3x10-9/L
- •Platelets ≥100x10-9/L
- •Haemoglobin (Hb) >9g/dL (can be post-transfusion)
- •Adequate renal function: Creatinine Clearance of >50ml/min or measured EDTA Clearance of ≥50ml/min. If the calculated Creatinine Clearance is <60ml/min then a measured EDTA Clearance is required. If available, the EDTA Clearance should always take precedence over the Creatinine Clearance.
- •Adequate liver function
- •Serum bilirubin <22 umol/L
- •ALT/AST ≤2.5x ULN
- •Adequate coagulation profile
- •International Normalised Ratio (INR) < 1.5
- •Activated Prothrombin Time (APTT) < 1.5xULN
- •Patients on oral anticoagulation are advised to change to low molecular weight heparin prior to study entry, to be eligible
- •ECOG performance status 0 or 1
- •Body Mass Index (BMI) ≤30
- •Patient is fit to undergo all protocol investigations and receive all protocol treatment based on the assessment in the surgical and oncology clinics. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrolment.
- •Willingness and ability to comply with the protocol for the duration of the study including scheduled visits, examinations, investigations and treatment plans
- •Exclusion Criteria
- •Patients are not eligible for the trial if any of the exclusion criteria below are met:
- •Any contraindication or known hypersensitivity reaction to any of the study drugs, or components of Folinic acid, Oxaliplatin, 5FU or Docetaxel
- •Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE v 4.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of partially controlled asthma)
- •If known dihydropyrimidine dehydrogenase (DPD) deficiency, patients must be deemed safe to receive appropriate dose-adjusted 5-FU according to the identified mutation.
- •Patients who have received anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
- •Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
- •Patients recommended to have radiotherapy as part of routine management for their GOA are ineligible
- •Any immunodeficiency disorder
- •Any active autoimmune disease that has required systemic treatment in the past 2 years (i.e, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) or is expected to deteriorate when receiving avelumab, with the following exceptions:
- •Patients only receiving hormone replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy (doses ≤10mg - or equivalent - of prednisolone per day) for adrenal or pituitary insufficiency) are eligible.
- •Patients with vitiligo or psoriasis not requiring immunosuppressive treatment are eligible
- •Patients requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement
- •Administration of steroids through a route known to result in minimal systemic exposure (topical, intranasal intra-ocular, or inhalation) are acceptable. Steroids as pre-medication for hypersensitivity reactions e.g. CT contrast are also acceptable
- •Prior organ transplantation, including allogeneic stem-cell transplantation
- •History of inflammatory bowel disease with the following exception:
- •Patients with a history of ulcerative colitis who have had a colectomy are eligible
- •Patients with a history of interstitial lung disease or radiological evidence of pulmonary fibrosis
- •Cerebrovascular disease (including transient ischaemic attacks (TIA) and strokes) within the previous year
- •Cardiovascular diseases as follows:
- •Myocardial infarction within the previous year
- •Serious cardiac arrhythmia requiring medication (for example, ventricular tachycardia, supraventricular tachycardia or atrial fibrillation with a resting heart rate > 110bpm)
- •Unstable angina
- •Congestive cardiac arrhythmia (New York Heart Association Classification Class II or above)
- •Other severe acute or chronic medical conditions or psychiatric conditions including recent (within the past year) active suicidal ideation or behaviour
- •Current signs or symptoms of any other severe progressive or uncontrolled hepatic, haematologic, gastrointestinal, endocrine, respiratory or cardiac disease other than directly related to gastrooesophageal adenocarcinoma, which in the opinion of the investigator,might impair the subject's tolerance of trial treatment or procedures.
- •Major surgery, major trauma or open biopsy within 28 days prior to registration (not including staging laparoscopy)
- 另有 8 项未显示
排除标准
- 未提供
研究组 & 干预措施
FLOT plus Avelumab (FLOT-A)
Avelumab 10mg/kg (or Maximum Administered Dose established in safety run-in) iv infusion over 1 hour.
Followed by FLOT: Oxaliplatin 85mg/m2 iv infusion day 1 over 2 hours, Folinic acid 200mg/m2 iv infusion day 1 over 2 hours, Docetaxel 50mg/m2 iv day 1 over 1 hour, Fluorouracil 2600mg/m2 over 24 hours iv
干预措施: FLOT-A (Drug)
结局指标
主要结局
Pathological complete response rate of combination FLOT-A
时间窗: Within 2 years of study opening
The primary objective is to assess the efficacy of FLOT-A in the peri-operative setting in patients with operable GOAs. We aim to increase the pCR rate after peri-operative treatment from 10% (minimum expected path CR rate for peri-operative FLOT chemotherapy), to a superior pCR rate of \>25%, by adding Avelumab to FLOT. Complete histopathologic response is defined by no vital tumour cells neither in the oesophagus, the stomach nor in the regional lymph nodes. In cases of residual tumour, the response assessment will follow criteria described by Mandard et al.
次要结局
- Number of participants with grade 3 or 4 treatment-related adverse events as assessed by CTCAE v4.0(Within 2 years)
- Radiological response rate using RECIST 1.1 criteria(Within 3 years)
- Median progression free survival by Kaplan Meir method(Within 5 years)
- Median overall survival by Kaplan Meir method(Within 5 years)