NIVOLUMAB for Advanced gastroesophageal carcinoma (HER2-negative, ARID1A-mutated)

Inclusion criteria

• {"criterion_text":"- Written informed consent to study procedures and to correlative studies\n- Imaging-documented measurable disease, according to RECIST 1.1 criteria.\n- Estimated life expectancy of more than 12 weeks.\n- Adequate bone marrow hematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL.\n- Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 2 (in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5 X ULN\n- Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula)\n- Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory.\n- Aged ≥ 18\n- Histologically proven of gastrooesophageal carcinoma\n- Diagnosis of advanced not operable or metastatic disease\n- HER2 negative and ARID1A mutated status at initial diagnosis.\n- Available tumor tissue sample\n- No prior treatments (chemotherapy, radiation or surgery) for aGEC. Surgery for primary GEC tumor before starting treatment is allowed.\n- Patient candidate to standard treatment with nivolumab and oxaliplatin-based chemotherapy as clinical practice (combined positive score ≥ 5).\n- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry."}

Exclusion criteria

• {"criterion_text":"- Prior malignancy within five years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.\n- Participation in any interventional drug or medical device study within 30 days prior to treatment start.\n- Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment\n- Hypesensitivity to simvastatin\n- Acute hepatitis or chronic hepatitis\n- Personal or familial anamnesis of severe hepatopathy\n- Known coagulation disorders\n- Prior chemotherapy or any other medical treatment for aGEC (previous adjuvant chemotherapy is allowed if terminated > 12 months previously).\n- Any contraindication to Nivolumab or oxaliplatin-based chemotherapy.\n- Patients who have treatment with statins or fibrates or any medication for hypercholesterolemia\n- Major surgical intervention within 4 weeks prior to enrollment.\n- Pregnancy and breast-feeding\n- Any brain metastasis\n- Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study\n- History of poor co-operation, non-compliance with medical treatment, unreliability or any condition that may impair the patient's understanding of the Informed consent form"}

Primary endpoints

• {"endpoint_text":"- PFS 1-year is measured as the time from initiation of study(i.e randomization)to the first documentation of objective disease progression by RECIST 1.1 criteria,including deterioration of clinical conditions preventing radiological restaging, treatment interruption due to AEs followed by initiation of an alternative antineoplastic treatment, or death due to any cause, whichever occurs first in one year.It will be measured as the rate of assessable patients alive and without disease progression","definition_or_measurement_approach":"Progression-free survival at 1 year measured from randomization to first documentation of objective disease progression by RECIST 1.1, or treatment interruption due to AEs followed by alternative antineoplastic treatment, or death; reported as the rate of assessable patients alive and without disease progression at 1 year."}

Secondary endpoints

• {"endpoint_text":"- Progression free survival (PFS) calculated as the time from randomization until the date of death from any cause until the date of the first observation of disease progression or death due to any cause, as previously defined, whichever occurs first. PFS will be censored at the time of the last available tumor assessment documenting absence of progressive disease for patients alive at the time of analysis.\n- Overall survival (OS) calculated as the time from randomization until the date of death from any cause. OS will be censored at the last date the patient was known to be alive for patients alive at the time of analysis.\n- Objective Tumor Response Rate (ORR) assessed according to RECIST criteria 1.1, as the proportion of patients achieving complete or partial response relative to total enrolled patients.\n- Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response\n- Overall Toxicity rate defined as adverse events graded according to NCI CTCAE v 5.0. as the proportion of patients experiencing any grade AE accordingly to the NCI Common Terminology Criteria of Adverse Events (NCI CTC-AE) Version 5, relative to the total of patients receiving at least one cycle of treatment.AE will be listed individually by the patient and summarized overall (severity grades 1-4) and for grade ≥3 by treatment received\n- Quality of life (QoL) investigated through the EORTC QOL-C30 questionnaire at baseline (prior to treatment start, once eligibility is confirmed) and every 12 weeks until disease progression, treatment failure or death.\n- Exploratory Endpoint: For the exploratory objective, we will compare PFS and OS of the standard ARM A with PFS and OS calculated in observational cohort of 28 consecutive aGEC HER2 negative and ARID1A non mutated patients (ARM C) treated with standard first-line combination of nivolumab and oxaliplatin-based chemotherapy regimen.","definition_or_measurement_approach":"PFS and OS measured from randomization to progression or death; ORR and DCR assessed per RECIST 1.1; toxicity graded by NCI CTCAE v5.0 and reported as proportions; QoL assessed with EORTC QLQ-C30 at baseline and every 12 weeks; exploratory comparison versus observational cohort of 28 patients for PFS and OS."}

Italy

Earliest CTIS Part Ii Submission Date

28-04-2025

Latest Decision Or Authorization Date

04-06-2025

Processing Time Days

37

Number Of Sites

4

Number Of Participants

84

Primary sponsor

Full Name

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Italy