Adding simvastatin to nivolumab and oxaliplatin-based chemotherapy for ARID1A‑mutated advanced gastroesophageal cancer

Randomized Phase 2 Study of Simvastatin in Patients With ARID1A Mutated Advanced Gastrooesophageal Carcinoma Treated With Nivolumab and Oxaliplatin- Based Chemotherapy as First-line Treatment (The ARES Trial)

This trial will test whether adding daily simvastatin to nivolumab plus oxaliplatin-based chemotherapy helps people with HER2-negative, ARID1A-mutated advanced gastroesophageal cancer stay progression-free longer.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 84 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: National Cancer Institute, Naples (Academic / other)
• Drugs / interventions: nivolumab, chemotherapy, radiation, immunotherapy
• Locations: 1 site (Naples, Italia)
• Trial ID: NCT07213557 on ClinicalTrials.gov

What this trial studies

This is a randomized, open-label phase 2 study enrolling patients with HER2-negative, ARID1A-mutated advanced or metastatic gastroesophageal carcinoma who are candidates for first-line nivolumab plus oxaliplatin-based chemotherapy (CPS ≥ 5). Participants are randomized 1:1 to receive standard nivolumab with XELOX or mFOLFOX6 chemotherapy with or without oral simvastatin 40 mg daily. Treatment continues until disease progression, unacceptable toxicity, or other discontinuation criteria, with maintenance fluoropyrimidine after 24 weeks for those without progression. Correlative tissue and blood studies are planned to track tumor evolutionary dynamics and explore mechanisms of response to the combination approach.

Who should consider this trial

Good fit: Adults with HER2-negative, ARID1A-mutated advanced or metastatic gastroesophageal carcinoma who are treatment-naive for advanced disease, have PD-L1 CPS ≥ 5, ECOG 0–1, measurable disease, and available tumor tissue are ideal candidates.

Not a fit: Patients without an ARID1A mutation, with HER2-positive tumors, prior systemic therapy for advanced disease, poor performance status (ECOG >1), or relevant contraindications are unlikely to benefit from this study.

Why it matters

Potential benefit: If successful, adding simvastatin could extend progression-free survival compared with immunotherapy and chemotherapy alone in this molecularly defined patient group.

How similar studies have performed: Preclinical work and retrospective analyses suggest statins may enhance anti-tumor immunity, but randomized trials combining simvastatin with chemoimmunotherapy in ARID1A-mutated gastroesophageal cancer are novel and unproven.

Eligibility criteria

Inclusion Criteria:

1. Written informed consent to study procedures and to correlative studies.
2. Aged ≥ 18.
3. Histologically proven of gastrooesophageal carcinoma
4. Diagnosis of advanced not operable or metastatic disease.
5. HER2 negative and ARID1A mutated status at initial diagnosis.
6. Available tumor tissue sample.
7. No prior treatments (chemotherapy, radiation or surgery) for aGEC. Surgery for primary GEC tumor before starting treatment is allowed.
8. Patient candidate to standard treatment with nivolumab and oxaliplatin-based chemotherapy as clinical practice (combined positive score ≥ 5).
9. Eastern Cooperative Oncology Group (ECOG) Performance Status

   ≤ 1 at study entry.
10. Imaging-documented measurable disease, according to RECIST 1.1 criteria.
11. Estimated life expectancy of more than 12 weeks.
12. 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.
13. 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.
14. 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).
15. Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory. The same criteria, except for the status of ARID1A, will be followed to select the 28 consecutive HER2-negative and ARID1A non mutated aGEC patients of observational cohort.

Exclusion Criteria:

1. 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.
2. Prior chemotherapy or any other medical treatment for aGEC (previous adjuvant chemotherapy is allowed if terminated \> 12 months previously).
3. Any contraindication to Nivolumab, simvastatin or oxaliplatin-based chemotherapy.
4. Patients who have treatment with statins or fibrates or any medication for hypercholesterolemia.
5. Major surgical intervention within 4 weeks prior to enrollment.
6. Pregnancy and breast-feeding.
7. Any brain metastasis.
8. 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.
9. 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.
10. Participation in any interventional drug or medical device study within 30 days prior to treatment start.
11. 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.
12. Hypesensitivity to simvastatin.
13. Acute hepatitis or chronic hepatitis.
14. Personal or familial anamnesis of severe hepatopathy.
15. Known coagulation disorders. The same criteria will be followed to select the 28 consecutive HER2-negative and ARID1A non mutated aGEC patients of observational cohort.

Where this trial is running

Naples, Italia

• Istituto Nazionale Tumori Fondazione G. Pascale — Naples, Italia, Italy (Recruiting)

Study contacts

• Study coordinator: Antonio Avallone, MD

Conditions Advanced or Metastatic Gastrooesophageal Carcinoma; HER2 negative; ARID1A mutated; Simvastatin; gastrooesophageal carcinoma; liquid biopsy