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)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 84
- 试验地点
- 1
- 主要终点
- Progression Free Survival rate at 1-year (PFS 1-year)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent to study procedures and to correlative studies.
- •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).
- •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.
排除标准
- •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.
研究组 & 干预措施
ARM A - standard
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)
干预措施: standard nivolumab and oxaliplatin- based chemotherapy (Drug)
ARM B
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)
干预措施: simvastatin in combination with standard nivolumab and oxaliplatin-based chemotherapy (Drug)
ARM C
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.
干预措施: standard nivolumab and oxaliplatin- based chemotherapy (Drug)
结局指标
主要结局
Progression Free Survival rate at 1-year (PFS 1-year)
时间窗: up to 1 year to randomization
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.
次要结局
- 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)
- Quality of life (QoL)(at baseline and every 12 weeks until disease progression.)