This study is a multicentric open label academic non comparative randomized phase-2 study.
Before starting study treatment, at the time of enrollment, patients, with aGEC HER2 negative with ARID1A mutation in tumors candidates for immunotherapy (CPS ≥ 5), will be randomized electronically 1:1 to one of the two arms:
* ARM A, standard treatment with nivolumab + oxaliplatin- based chemotherapy (mFOLFOX6 or XELOX regimen)
* ARM B, experimental treatment with simvastatin oral daily at a fixed dosage of 40 mg, in addition to standard treatment with nivolumab + oxaliplatin-based chemotherapy (mFOLFOX6 or XELOX regimen).
Nivolumab will be administered as flat dose of 360 mg every 3 weeks or 240 mg every 2 weeks with investigator's choice of oxaliplatin-based chemotherapy regimen:
* XELOX (oxaliplatin 130 mg/m2 on day 1 and capecitabine 1,000 mg/m2 orally twice daily on days 1-14 administered every 3 weeks) or
* mFOLFOX6 (oxaliplatin 85 mg/m2 on day 1 followed by lederfolin 200 mg m2 on day 1, fluorouracil 400 mg m2 on day 1 and 2,400 mg m2 continuous infusion over 46 hours every 2 weeks) Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria.
Patients who are progression free after 8 cycles (24 weeks) of XELOX or 12 cycles (24 weeks) of mFOLFOX6 treatment will continue maintenance with fluorouracile (lederfolin 200 mg m2 on day 1, fluorouracil 400 mg m2 on day 1 and 2,400 mg m2 continuous infusion over 46 hours every 2 weeks) or capecitabine (capecitabine 1,250 mg/m2 orally twice daily on days 1-14 administered every 3 weeks), as previously assigned until treatment failure as reported above.
28 aGEC HER2 negative and ARID1A mutated patients will be required along to other 28 aGEC HER2 negative and ARID1A mutated patients as calibration arm, for a total of 56 subjects.
All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected.
An initial safety run-in phase involves a safety evaluation after the first 6 patients are randomly assigned to Arm B. Enrollment will be paused after the first 6 patients randomly assigned to Arm B complete 2 cycles of treatment. The enrollment will be interrupted if the treatment combination will be judged not feasible and major safety concerns will arise. A safety review will be conducted, and recommendations will be made by the Steering Committee. The study will continue if there are 2 or fewer adverse events (AEs) of grade 3 or higher deemed related to the addition of simvastatin to the standard treatment with nivolumab + oxaliplatin-based chemotherapy.
All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 12 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed every 12 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 12 weeks until progressive disease or study withdrawal.
Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0.
Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 12 weeks until disease progression or, treatment failure.
HER2-negative aGEC patients with ARID1A non mutated tumors of observational cohort who are candidates for immunotherapy (ARM C) will be treated with standard treatment with nivolumab and oxaliplatin-based chemotherapy in the same way as the patients in ARM A (28 patients)
