| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically confirmed, resectable advanced gastric cancer GC and adenocarcinoma of the esophago-gastric junction |
| Histologisch bestätigter, operierbarer, fortgeschrittener Magenkrebs und Adenokarzinom des ösophagogastralen Übergangs |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced cancer of the stomach and adenocarcinoma of aesophagus, microscopical confirmed |
| Fortgeschrittener Magenkrebs und Drüsenkrebs der Speiseröhre, mikroskopisch bestätigt |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017758 |
| E.1.2 | Term | Gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10030151 |
| E.1.2 | Term | Oesophageal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056267 |
| E.1.2 | Term | Gastroesophageal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
Ziel dieser Studie ist es, die Rate der pathologischen Komplettremissionen (pCR) in den zwei Behandlungsarmen zu bestimmen. Basierend auf den Ergebnissen der FLOT4-Studie wird eine pCR-Rate von 15% unter neoadjuvanter FLOT-Chemotherapie als historische Kontrolle genutzt. Eine Erhöhung auf 35% in den Behandlungsarmen wird als klinisch relevant angenommen.
|
|
| E.2.2 | Secondary objectives of the trial |
•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:
|
•Pathologischen Ansprechrate (komplette oder subtotale Remssion pCR/pSR) nach den Becker-Kriterien
•R0 Resektionsrate
•Krankheitsfreie Überlebensrate nach 3 Jahren, gemäß RECIST 1.1
•Allgemeine Überlebensrate nach 3 Jahren
•Sicherheit und Verträglichkeit
•Perioperative Morbidität und Mortalität
•Durchführbarkeit der perioperativen Immuntherapie und Immunochemotherapie, Vollständigkeit der prä- und postoperativen Therapie
•Ergebnisse der Patientenbefragung zur Lebensqualität (Quality of Life, QoL-Fragebogen)
•Translationale Endpunkte: Tumorproben, Durchflusszytometrie, HLA-Typisierung, Mikrobiom-Analysen der Magenflüssigkeit und des Stuhls
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 < 50 mL/min (using Cockroft-Gault formula)
o Bilirubin ≤ 1.5 x ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN, alkaline phosphatase ≤ 6 x ULN, 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
- Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures
- Optional, if further IO combination will be added per amendment: positive Biomarker expression (i.e. LAG-3) if data from previous clinical trials support the use of IO combination in selected patients
|
•Histologisch bestätigtes, resezierbares MK oder AEG (AEG I-III) (uT2, uT3, uT4, jede N Kategorie, M0), oder jeder T N+ M0 Patient, mit den folgenden Spezifikationen:
o Ausschluss von Fernmetastasen durch CT oder MRT von Bauch, Becken und Thorax, Knochenszintigrafie oder MRT (bei Verdacht auf Knochenmetastasen aufgrund klinischer Anzeichen). Ausschluss einer Infiltration benachbarter Organe oder Strukturen durch CT oder MRT
o Messbare Zielläsion mit Hilfe von Standard-Bildgebungsverfahren oder klinischer Auswertung und signifikanter FDG-Aufnahme in der PET
•Weibliche und männliche Patienten ≥ 18 Jahre: Patienten im reproduktiven Alter müssen bereit sein, während der Studie und für 33 Wochen nach Behandlungsende (Männer) und für 24 Wochen nach der Behandlung (Frauen) eine angemessene Verhütung anzuwenden. Gebärfähige Frauen müssen innerhalb von 24 Stunden vor Beginn der Studie einen negativen Serum- oder Urin-Schwangerschaftstest (Mindestsensitivität 25 IU/L oder gleichwertige Einheiten von HCG) aufweisen
•ECOG ≤ 1
•Adäquate hämatologische, hepatische und renale Funktionsparameter:
o Leukozyten ≥ 2000/mm³, Thrombozyten ≥ 100,000/mm³, absolute Zahl der Neutrophilen Granulozyten (ANC) ≥1500/µL, Hämoglobin ≥9 g/dL (5.58 mmol/L),
o Adäquate Gerinnungsfunktion mit einer International Normalized Ratio (INR) ≤ 1.5, und einer partiellen Thromboplastinzeit (PTT) ≤ 5 Sekunden über der oberen Normgrenze (außer bei Antikoaglutationstherapie). Patienten, die Warfarin/Phenprocoumon erhalten, müssen auf niedermolekulares Heparin umgestellt werden und vor der Randomisierung ein stabiles Gerinnungsprofil erreicht haben.
o Serumkreatinin ≤ 1.5 x der oberen Normgrenze oder kalkulierte Kreatinin Clearance < 50 mL/min mittels Cockroft-Gault Formel
o Bilirubin ≤ 1.5 x der oberen Normgrenze, AST und ALT ≤ 3.0 x der oberen Normgrenze, alkalische Phosphatase ≤ 6 x der oberen Normgrenze, Serumalbumin ≥ 2.8 g/dL
o Adäquate linksventrikuläre Ejektionsfraktion (LVEF) mit dokumentierter LVEF ≥50% entweder durch transthorakale Echokardiographie (TTE) oder MUGA ( multiple update gated acquisition, TTE ist die bevorzugte Methode), innerhalb von 6 Monaten vor der ersten Gabe der Studienmedikation
•Der Patient ist in der Lage und willens, eine schriftliche Einwilligung nach Aufklärung zu erteilen und das Studienprotokoll sowie die geplanten chirurgischen Eingriffe einzuhalten
•Optional, wenn eine weitere IO-Kombination durch Prüfplan-änderung hinzugefügt wird: positive Biomarker-Expression (z.B. LAG-3), wenn Daten aus früheren klinischen Studien die Verwendung der IO-Kombination bei ausgewählten Patienten unterstützen.
|
|
| E.4 | Principal 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 wound, ulcer, or bone fracture within 28 days prior to enrollment.
12. The patient has undergone major surgery within 28 days prior to enrollment except staging laparoscopy or implantation of a venous port-system.
13. Patients in a closed institution according to an authority or court decision
14. Any other concurrent antineoplastic treatment including irradiation
15. 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)
16. Patients with active neurological diseases
17. Prior treatment with LAG-3 targeted agents
18. Breastfeeding women
19. Women of childbearing potential unless safe practice of contraception is guaranteed
20. Men of sexual activity with women of childbearing potential who are not willing to use an effective barrier method of contraception
21. History of allergy or hypersensitivity against one of the active substances or any of the excipients.
22. DPD-Deficiency*
23. Treatment with plasmapheresis within 4 weeks prior to randomization.
24. 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint is the rate of pCR as determined by pathological examination of the resected tumor following preoperative systemic therapy.
|
| Der primäre Endpunkt ist die Rate der pCR determiniert durch die pathologische Untersuchung des resezierten Tumors im Anschluss an die prä-operative Therapie |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Pathological examination of the resected tumor. |
| Pathologische Untersuchung des resezierten Tumors |
|
| E.5.2 | 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
|
•Pathologischen Ansprechrate (komplette oder subtotale Remssion pCR/pSR) nach den Becker-Kriterien
•R0 Resektionsrate
•Krankheitsfreie Überlebensrate nach 3 Jahren, gemäß RECIST 1.1
•Allgemeine Überlebensrate nach 3 Jahren
•Sicherheit und Verträglichkeit
•Perioperative Morbidität und Mortalität
•Durchführbarkeit der perioperativen Immuntherapie und Immunochemotherapie, Vollständigkeit der prä- und postoperativen Therapie
•Ergebnisse der Patientenbefragung zur Lebensqualität (Quality of Life, QoL-Fragebogen)
•Translationale Endpunkte: Tumorproben, Durchflusszytometrie, Mikrobiom-Analysen der Magenflüssigkeit und des Stuhls
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Evaluations will be done after reaching the corresponding end points. |
| Die Evaluierungen werden bei Erreichen der jeweiligen Endpunkte durchgeführt. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| As for this study, the primary outcome will be analyzed after the last patient was resected, the end of the study as a whole will be the date of last patient last visit (LPLV) at follow-up / clean database. Therapy will be continued after end of the study if medically indicated. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
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