Perioperative Immunotherapy vs. Chemo-immunotherapy Stratified by Early Response Evaluation in Patients With Advanced Gastric Cancer (GC) and Adenocarcinoma of the Esophago-gastric Junction (AEG)
Perioperative Immunotherapy vs. Chemo-immunotherapy Stratified by Early Response Evaluation in Patients With Advanced Gastric Cancer (GC) and Adenocarcinoma of the Esophago-gastric Junction (AEG)
IMAGINE is a Phase II, randomized, two-arm, chemotherapy controlled modular trial in subjects with histologically confirmed, resectable gastric cancer (GC) or adenocarcinoma of the gastroesophageal junction (AEG). Up to 22 patients will be included in each arm of the trial.
This study will determine 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 with neoadjuvant FLOT chemotherapy. An increase to 35% is estimated to be clinically relevant when patients are treated with either nivolumab in combination with chemotherapy (Arm B) or nivolumab and another immuno-oncology (IO) agent (relatlimab) in Arm D. Additional objectives include resection rate, diseasefree survival (DFS), median overall survival (OS), patient's quality of life (QoL), and safety and tolerability of the treatment. Furthermore, translational endpoints will be investigated.
Inclusion Criteria:
- Histologically confirmed, resectable GC or AEG (AEG I-III) (classified per TNM staging system as uT2, uT3, uT4, any N category, M0), or any T N+ M0 Patient (classified per TNM staging system), 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 (defined as [18F]-FDG-uptake of primary tumor in baseline >1.35 x liver-SUV + 2 x standard deviation of liver-SUV)
Leukocytes ≥ 2000/mm³, platelets ≥ 100,000/mm³, absolute neutrophil count (ANC) ≥ 1500/µL, hemoglobin ≥ 9 g/dL (5.58 mmol/L)
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
Serum creatinine ≤ 1.5 x upper limit of normal or calculated creatine clearance of > 50 mL/min (using Cockroft-Gault formula)
Bilirubin ≤ 1.5 x upper limit of normal, AST and ALT ≤ 3.0 x upper limit of normal, alkaline phosphatase ≤ 6 x upper limit of normal, Serum albumin ≥ 2.8 g/dL
Left ventricular ejection fraction (LVEF) assessment with documented LVEF ≥ 50% by either trans-thoracic echocardiography (TTE) or multigated acquisition (MUGA) (TTE preferred test) within 6 months from first study drug administration
Exclusion criteria:
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:
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. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:
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.
Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Testing for HIV must be performed at sites where mandated locally.
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).
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
Peripheral polyneuropathy ≥ NCI Grade II
Confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
History of gastric perforation or fistulae in past 6 months
Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to enrollment.
The patient has undergone major surgery within 28 days prior to enrollment except staging laparoscopy or implantation of a venous port-system.
Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
Any other concurrent antineoplastic treatment including irradiation
Subjects with history of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways)
Patients with active neurological diseases
Prior treatment with LAG-3 targeted agents
Breastfeeding women
Women of childbearing potential unless women who meet the following criteria:
Men of sexual activity with women of childbearing potential who are not willing to use an effective barrier method of contraception such as condoms during and up to 33 weeks after the end of therapy
History of allergy or hypersensitivity against one of the active substances (IMPs) or any of the excipients
DPD deficiency*
Treatment with plasmapheresis within 4 weeks prior to randomization.
Subjects who have received a live /attenuated vaccine within 30 days of first treatment.
(*) patients with complete DPD deficiency must be excluded as 5-FU treatment is contraindicated. For patients with partial DPD deficiency a stepwise increase of the 5-FU dose is specified in section 6.9.1.1.
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