Histologically confirmed, resectable advanced gastric cancer GC and adenocarcinoma of the esophago-gastric junction MedDRA version: 21.1 Level: PT Classification code 10017758 Term: Gastric cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: LLT Classification code 10030151 Term: Oesophageal cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version:
Conditions
Interventions
Trade Name: OPDIVO® (100mg/10ml)
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Nivolumab
Other descriptive name: NIVOLUMAB
Concentration unit: mg/ml milligram(s)/mill
Sponsors
University Hospital Essen
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Histologically confirmed, resectable GC or AEG (AEG I-III) (uT2, uT3, uT4, any N category, M0), or any T N+ M0 patient, with the following specifications: - Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax, bone scan or MRI (if bone metastases are suspected due to clinical signs). Exclusion of the infiltration of any adjacent organs or structures by CT or MRI - Measurable target tumors using standard imaging techniques or clinical evaluation and significant FDG-uptake in PET - Female and male patients = 18. Patients in reproductive age must be willing to use adequate contraception during the study and for 6 months after the end of treatment. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. - Eastern Cooperation Oncology Group (ECOG) = 1 - Adequate hematological, hepatic and renal function parameters: o Leukocytes = 2000/mm³, platelets = 100,000/mm³, absolute neutrophil count (ANC) =1500/µL, hemoglobin =9 g/dL (5.58 mmol/L), o Adequate coagulation function as defined by International Normalized Ratio (INR) = 1.5, and a partial thromboplastin time (PTT) = 5 seconds above the upper limit of normal (ULN) (unless receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to randomization. o Serum creatinine = 1.5 x ULN of normal or calculated creatine clearance of =65 years) yes F.1.3.1 Number of subjects for this age range 22
Exclusion criteria
Exclusion criteria: 1. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis with the following exceptions: -- Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study. -- Patients with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. -- Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic immunosuppressive treatment, in particular corticosteroids are permitted to enroll 2. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration 3. Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: o Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent o Uncontrolled angina within the 3 months prior to consent o Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) o QTc prolongation > 480 msec o History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, deep venous thrombosis, etc ) o Cardiovascular disease-related requirement for daily supplemental oxygen o History of two or more MIs OR two or more coronary revascularization procedures o Subjects with history of myocarditis, regardless of etiology o Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Subjects with TnT or TnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are 1 x ULN. 4. Active malignancy or a prior malignancy within the past 3 years o Patients with completely resected basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and patients with isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer are eligible for the study. 5. Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally. 6. Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV RNA negative). 7. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications 8. Peripheral polyneuropathy = NCI Grade II 9. Confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent 10. History of gastric perforation or fistulae in past 6 months 11. Serious or non-healing
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary endpoint is the rate of pathological complete responses (pCR) as determined by pathological examination of the resected tumor following preoperative systemic therapy. A pCR rate of 15% is expected serves as historical control, which could be achieved with the standard FLOT chemotherapy based on the results of the FLOT4 trial. An increase to 35% in Arm B or D is assumed to be clinically relevant. ;Secondary Objective: •Determination of pathological response rate (complete or subtotal response pCR/pSR) according to the Becker criteria •Curative (R0) resection rate •Assessment of disease-free Survival (DFS) rate at 3 years per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 •Evaluation of overall survival (OS) rate at 3 years •Assessment of safety and tolerability •Perioperative morbidity and mortality •Feasibility of perioperative immunotherapy and immunochemotherapy, completeness of pre- and postoperative therapy •Patient reported Quality of Life •Translational endpoints for investigation of immunomodulatory agents alone and in combination with cytotoxic agents: ;Primary end point(s): Primary endpoint is the rate of pCR as determined by pathological examination of the resected tumor following preoperative systemic therapy. ;Timepoint(s) of evaluation of this end point: Pathological examination of the resected tumor. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Pathological response rate (complete or subtotal response pCR/pSR) according to the Becker criteria • R0 resection rate • Disease-free survival rate at 3 years per RECIST 1.1 • Overall survival rate at 3 years • Safety and tolerability • Perioperative morbidity and mortality • Feasibility of perioperative immunotherapy and immunochemotherapy, completeness of pre- and postoperative therapy • Patient reported outcomes assessed by Quality of Life questionnaire • Translational endpoints: tumor sample, flow cytometry, microbiome analysis of gastric fluid and stool ;Timepoint(s) of evaluation of this end point: Evaluations will be done after reaching the corresponding end points. | — |
Countries
Germany
Contacts
Public ContactProjektmanager, Medical Consulting
GWT-TUD GmbH
Outcome results
None listed