Simvastatin Efficacy in ARID1A Mutated Advanced gastroESophageal Carcinoma Treated With Immunotherapy

NCT07213557 | Recruiting Phase 2

• 2 other identifiers: ARES2024-519591-39-00
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators hypothesize that simvastatin (SIM) may improve the efficacy of first- line Nivolumab and Oxaliplatin-based chemotherapy, extending progression-free survival (PFS) as compared with Nivolumab and chemotherapy alone in patients with HER2 negative and ARID1A mutated advanced gastrooesophageal carcinoma (aGEC). Correlative mechanistic studies on tissue and blood samples, could help understanding the evolutionary dynamics of tumors in response to therapy thus optimizing the treatment approach and adding new insight into the antitumor mechanism of the combination approach.

Conditions

Advanced or Metastatic Gastrooesophageal Carcinoma

Keywords

HER2 negative; ARID1A mutated; Simvastatin; gastrooesophageal carcinoma; liquid biopsy

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival rate at 1-year (PFS 1-year)

  Progression Free Survival rate at 1-year (PFS 1-year) PFS 1-year is defined as the rate of assessable patients alive and not progressed after 1 year 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, as previously defined, at 1 year.

  up to 1 year to randomization

Secondary Outcomes (6)

• Objective Tumor Response Rate (ORR)

  up to 1 year last patients randomized

• Disease Control Rate (DCR)

  up to 1 year to randomization

• Progression-free survival (PFS)

  up to 1 year to randomization

• Overall survival (OS)

  up to 1 year to randomization

• Safety evaluated as adverse events graded according to NCI CTCAE v 5.0.

  From the start of the first treatment cycle until the end of active treatment

Study Arms (3)

ARM A - standard

ACTIVE COMPARATOR

Patients with HER2 negative aGEC eligible for the standard treatment with nivolumab and oxaliplatin- based chemotherapy (CPS ≥ 5) will be evaluated for ARID1A expression by immunohistochemistry on tumor tissue. Patients with ARID1A mutated will be randomized to receive standard nivolumab and oxaliplatin- based chemotherapy (standard arm, ARM A) or simvastatin in combination with standard nivolumab and oxaliplatin-based chemotherapy (experimental arm, ARM B)

Drug: standard nivolumab and oxaliplatin- based chemotherapy

ARM B

EXPERIMENTAL

Patients with HER2 negative aGEC eligible for the standard treatment with nivolumab and oxaliplatin- based chemotherapy (CPS ≥ 5) will be evaluated for ARID1A expression by immunohistochemistry on tumor tissue. Patients with ARID1A mutated will be randomized to receive standard nivolumab and oxaliplatin- based chemotherapy (standard arm, ARM A) or simvastatin in combination with standard nivolumab and oxaliplatin-based chemotherapy (experimental arm, ARM B)

Drug: simvastatin in combination with standard nivolumab and oxaliplatin-based chemotherapy

ARM C

OTHER

Observational Cohort: patients with ARID1A not mutated of observational cohort (ARM C) will be treated with standard treatment with nivolumab and oxaliplatin-based chemotherapy and compared with standard ARM A as exploratory comparison to evaluate the predictive value for immunotherapy of ARID1A.

Drug: standard nivolumab and oxaliplatin- based chemotherapy

Interventions

standard nivolumab and oxaliplatin- based chemotherapy DRUG

Nivolumab will be administered as 30 minutes intravenous infusion at the dosage of 360 mg every 3 weeks or 240 mg every 2 weeks as flat dose followed by 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)

ARM A - standard; ARM C

simvastatin in combination with standard nivolumab and oxaliplatin-based chemotherapy DRUG

Nivolumab will be administered as 30 minutes intravenous infusion at the dosage of 360 mg every 3 weeks or 240 mg every 2 weeks as flat dose followed by 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) * SIM will be administered per os daily at a fixed dosage of 40 mg that represents the recommended dose as cholesterol lowering agents.

ARM B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent to study procedures and to correlative studies.
• Aged ≥ 18.
• Histologically proven of gastrooesophageal carcinoma
• Diagnosis of advanced not operable or metastatic disease.
• HER2 negative and ARID1A mutated status at initial diagnosis.
• Available tumor tissue sample.
• No prior treatments (chemotherapy, radiation or surgery) for aGEC. Surgery for primary GEC tumor before starting treatment is allowed.
• Patient candidate to standard treatment with nivolumab and oxaliplatin-based chemotherapy as clinical practice (combined positive score ≥ 5).
• Eastern Cooperative Oncology Group (ECOG) Performance Status
• ≤ 1 at study entry.
• Imaging-documented measurable disease, according to RECIST 1.1 criteria.
• Estimated life expectancy of more than 12 weeks.
• 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.
• 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.
• 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).

You may not qualify if:

• 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.
• Prior chemotherapy or any other medical treatment for aGEC (previous adjuvant chemotherapy is allowed if terminated \> 12 months previously).
• Any contraindication to Nivolumab, simvastatin or oxaliplatin-based chemotherapy.
• Patients who have treatment with statins or fibrates or any medication for hypercholesterolemia.
• Major surgical intervention within 4 weeks prior to enrollment.
• Pregnancy and breast-feeding.
• Any brain metastasis.
• 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.
• 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.
• Participation in any interventional drug or medical device study within 30 days prior to treatment start.
• 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.
• Hypesensitivity to simvastatin.
• Acute hepatitis or chronic hepatitis.
• Personal or familial anamnesis of severe hepatopathy.
• 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.

Sponsors & Collaborators

• National Cancer Institute, Naples: lead

Study Sites (1)

Istituto Nazionale Tumori Fondazione G. Pascale

Naples, Italia, 80131, Italy

RECRUITING

MeSH Terms

Interventions

Simvastatin

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Central Study Contacts

Antonio Avallone, MD

CONTACT

08117770357; a.avallone@istitutotumori.na.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2025
• First Posted: October 9, 2025
• Study Start: March 13, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): May 1, 2028
• Last Updated: April 14, 2026

Record last verified: 2026-04

Locations

IT (1)