Operable oesophageal and gastric cancer MedDRA version: 19.1 Level: PT Classification code 10062878 Term: Gastrooesophageal cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Avelumab
Product Name: Avelumab
Product Code: N/A
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN:
Sponsors
The Royal Marsden NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: i. Histologically confirmed gastric, gastro-oesophageal junction or oesophageal adenocarcinoma (referred to as gastro-oesophageal adenocarcinoma (GOA) in this protocol). ii. Oesophageal and gastric tumours should be TNM7 stage T1-3 and N0-N2, with no evidence of distant metastases (M0) where the MDT believes that an R0 resection can be achieved at the outset. T4 tumours will be excluded due to the variable need to prolong pre-operative chemotherapy or chemo-radiotherapy as part of locally advanced protocol to reduce margin involvement and improve resectability. iii. Absence of distant metastases on CT scan and PET scan and staging laparoscopy (where indicated) prior to study entry iv. No prior therapy for GOA v. Adequate cardio-pulmonary reserve as assessed by: Supervised Incremental Shuttle Walk threshold > 350 metres, or formal CPET testing with an anaerobic threshold =9 mls/min/kg. vi. 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) viii. Adequate renal function: glomerular filtration rate (GFR) =30ml/min calculated (as per local practice) or measured. If the calculated GFR is =65 years) yes F.1.3.1 Number of subjects for this age range 30
Exclusion criteria
Exclusion criteria: Patients are not eligible for the trial if any of the exclusion criteria below are met: i. Any contraindication or known hypersensitivity reaction to any of the study drugs, or components of Folinic acid, Oxaliplatin, or 5FU ii. 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) iii. Known dihydropyrimidine dehydrogenase (DPD) deficiency iv. Patients who have received chemotherapy, radiotherapy or immunotherapy for a previous malignancy v. Any previous malignancy, with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer vi. Patients recommended to have radiotherapy as part of routine management for their GOA are ineligible vii. Any immunodeficiency disorder viii. Any active, known or suspected autoimmune disease that might deteriorate when receiving immunostimulatory agent, with the following exceptions: • Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease 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 and at doses =10mg (or equivalent) of prednisolone per day • Administration of steroids through a route known to result in minimal systemic exposure (topical, intranasal intra-ocular, or inhalation) are acceptable ix. Prior organ transplantation, including allogeneic stem-cell transplantation x. History of inflammatory bowel disease xi. Patients with a history of interstitial lung disease or radiological evidence of pulmonary fibrosis xii. Cerebrovascular disease (including transient ischaemic attacks (TIA) and strokes) within the previous year xiii. 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) xiv. Current signs or symptoms of any other severe progressive or uncontrolled hepatic, haematologic, gastrointestinal, endocrine, respiratory or cardiac disease other than directly related to gastro-oesophageal adenocarcinoma, which in the opinion of the investigator, might impair the subject’s tolerance of trial treatment or procedures. xv. Major surgery, major trauma or open biopsy within 28 days prior to registration (not including staging laparoscopy) xvi. Evidence of bleeding diathesis or coagulopathy xvii. Active non-healing wound, ulcer or bone fracture requiring therapy xviii. Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis A or C virus, acute or chronic active hepatitis B infection xix. Known peripheral neuropathy > grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible) xx. Use of live attenuated vaccine within 28 days of
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: There are two parts to the trial: the first is the 'safety run-in' phase and the second is the 'main phase' or 'efficacy phase'. Each of these has different principal research objectives: - The 'safety run-in' phase will establish the safe and tolerated dose of Avelumab in combination with FOLFOX in the first 6 to 12 patients entered into the trial. This so called 'maximum administered dose' will then be used for all subsequent patients entered into the main phase. -The 'main phase' will assess the efficacy of FOLFOX-A in the peri-operative setting in patients with operable GOAs. We aim to increase the pathologic complete response rate from currently <5% with standard peri-operative chemotherapy to 20% with FOLFOX in combination with Avelumab. This would be an important achievement as patients who achieve a pathologic complete response with peri-operative therapy tend to have a better prognosis and are at much lower risk for subsequent distant disease recurrence. ; Secondary Objective: • To assess the safety and tolerability of peri-operative FOLFOX-A • To assess further efficacy measures including: - pathological regression grading - R0 resection rate (i.e. complete removal of the cancer at the time of surgery) - Progression free survival - Overall survival - Radiological responses in the pre-operative phase • To perform translational research analysis that may identify candidate predictive biomarkers, drug resistance mechanisms and biological rationals for more effective furture therapies ; Primary end point(s): Safety run-in phase: The primary endpoint for the safety run-in phase will be to establish the maximum administered dose (MAD) of Avelumab in combination with FOLFOX that will be recommended for use | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints are: 1) Safety of peri-operative FOLFOX-A in patients with operable gastro-oesophageal adenocarcinoma 2) To assess further efficacy measures including: - Mandard pathological regression grading assessed in the resection specimen - Radiological response rate assessed at the pre-operative scan using RECIST 1.1 criteria, additional radiological response criteria may also be applied - R0 resection rate - PFS - OS - Heterogeneity of regression grading of the primary cancer in comparison to lymph node metastatic cancer ; Timepoint(s) of evaluation of this end point: The following endpoints will be reported after ~2 y, when 38 patients have undergone surgery: -Safety of peri-operative FOLFOX-A in patients with operable gastro-oesophageal adenocarcinoma -Mandard pathological regression grading assessed in the resection specimen -Radiological response rate assessed at the pre-operative scan using RECIST 1.1 criteria, additional radiological response criteria may also be applied -R0 resection rate -Heterogeneity of regression grading of the primary cancer in comparison to lymph node metastatic cancer Survival endpoints will be reported as 1 year and 2 year PFS/OS, approximately 3 and 4 y after study start. Kaplan Meier analysed will be performed once sufficient events have occurred and when the last patient had the last follow visit (~y 7). | — |
Countries
United Kingdom
Contacts
Public ContactGI & Lymphoma Clinical Trials Unit
The Royal Marsden NHS Foundation Trust
Outcome results
None listed