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).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06], Diseases [C] - Neoplasms [C04]

Trial duration

11 Nov 2025 → ongoing

Decision date (initial)

2025-06-04

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To evaluate the efficacy of SIM in patients with HER2 negative and ARID1a mutated aGEC candidate to standard first-line treatment with nivolumab plus oxaliplatin-based chemotherapy (administered until progressive disease, unacceptable toxicity, physician’s decision, pregnancy or patient choice to discontinue), measured as progression-free survival rate at 1-year

Secondary objectives 2

1. To assess the activity, safety, tolerability and quality of life of the addition of SIM to the first line of treatment in HER2 negative and ARID1A mutated aGEC patients. Specifically, objective tumor response rate, disease control rate, progression-free survival, overall survival, safety and quality of life will be evaluated
2. Exploratory: To explore the potential predictive value for immunotherapy of ARID1A mutation in HER2 negative aGEC patients treated with standard first-line combination of nivolumab and oxaliplatin-based chemotherapy regimen with progression-free survival and overall survival as endpoints.

Conditions and MedDRA coding

advanced or metastatic gastrooesophageal carcinoma HER2 negative and ARID1A mutated

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

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.

Exclusion criteria 15

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 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 7

1. 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.
2. 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.
3. 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.
4. Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response
5. 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
6. 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.
7. 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Sponsor organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Address

Via Mariano Semmola 52

City

Naples

Postcode

80131

Country

Italy

Scientific contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Antonio Avallone

Public contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Antonio Avallone

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications