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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).

Phase 2
Not yet recruiting
Conditions
advanced or metastatic gastrooesophageal carcinoma HER2 negative and ARID1A mutated
Registration Number
2024-519591-39-00
Lead Sponsor
IRCCS Istituto Nazionale Tumori Fondazione Pascale
Brief Summary

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

Detailed Description

Not available

Recruitment & Eligibility

Status
Authorised, recruitment pending
Sex
Not specified
Target Recruitment
84
Inclusion Criteria

Written informed consent to study procedures and to correlative studies

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)

Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory.

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.

Exclusion Criteria

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.

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

Prior chemotherapy or any other medical treatment for aGEC (previous adjuvant chemotherapy is allowed if terminated > 12 months previously).

Any contraindication to Nivolumab 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

Study & Design

Study Type
Not specified
Study Design
Not specified
Primary Outcome Measures
NameTimeMethod
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

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 Outcome Measures
NameTimeMethod
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.

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.

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.

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.

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.

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.

Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response

Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response

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

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

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.

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.

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.

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.

Trial Locations

Locations (4)

Azienda Ospedaliera Dei Colli

🇮🇹

Naples, Italy

Azienda Ospedaliera Universitaria Universita' Degli Studi Della Campania Luigi Vanvitelli

🇮🇹

Naples, Italy

Azienda Ospedaliera Di Rilievo Nazionale Antonio Cardarelli

🇮🇹

Naples, Italy

IRCCS Istituto Nazionale Tumori Fondazione Pascale

🇮🇹

Naples, Italy

Azienda Ospedaliera Dei Colli
🇮🇹Naples, Italy
Vincenzo Montesarchio
Site contact
0817065286
vincenzo.montesarchio@ospedalideicolli.it

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