Randomized Phase 3 Trial Comparing FOLFOX to Gemcitabine in Metastatic First-line in Patients With Pancreatic Adenocarcinoma and Non-fit for FOLFIRINOX
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 400
- 试验地点
- 1
- 主要终点
- Overall survival (OS) at 24 months
研究概览
简要总结
Pancreatic adenocarcinoma (PAC) incidence increases regularly in Western countries and it is expected to become the second leading cause of cancer-related mortality in 2020. The prognosis of this disease remains very poor with an overall 5-year survival rate less than 5%.
The FOLFIRINOX regimen (5-fluorouracil [5-FU], folinic acid, irinotecan, and oxaliplatin) and the combination of nab-paclitaxel with gemcitabine demonstrated to be more effective than gemcitabine alone, and are both validated as standard first-line treatment options for metastatic PAC. However, the use of FOLFIRINOX is limited to patients with ECOG performance status (PS) 0-1 and aged less than 75 years. Nab-paclitaxel is currently not reimbursed in France.
详细描述
This trial is an open label, multicenter, randomized phase III trial comparing gemcitabine vs FOLFOX in patients with metastatic pancreatic adenocarcinoma and non-fit for FOLFIRINOX. Adults fulfilling inclusion criteria and non-inclusion criteria will be randomized between a FOLFOX arm and a gemcitabine arm. The primary endpoint is the overall survival (OS) at 24 months. The secondary objectives are : objective response rate and disease control rate (RECIST v1.1, in case of evaluable lesion), duration of response, duration of disease control, progression free survival (PFS), the evolution of biomarkers Ca 19-9 and CEA under treatment, the toxicities according to International Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, the safety of both arms, the quality of life, the dose intensity (DI) of each protocol, the Quality-Adjusted Survival, and the rate and type of second-line / third-line regimens chemotherapy. With an expected median survival time in the control group of 5 months, an accrual period of 3 years and a minimum follow-up period of 2 years, a total of 199 patients per group are required to detect a hazard ratio of 0.75 based on a 5% two-sided type I error rate and a power of 80%, leading to a total number of 400 patients to include.
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
- •Signed and dated informed consent, and willing and able to comply with protocol requirements,
- •Histologically or cytologically proven adenocarcinoma of the pancreas,
- •In absence of histologically or cytologically proven adenocarcinoma, a cluster of clinical, biological and radiological arguments consistent with the diagnosis: among these, a hypodense pancreatic tumor at CT and a Ca 19-9 greater than 500 UI/ml are essential prerequisites,
- •Metastatic disease confirmed (stage IV),
- •No prior therapy for metastatic disease (in case of previous adjuvant therapy, interval from end of chemotherapy and relapse must be >12 months),
- •Age ≥18 years ,
- •Patient non-fit for FOLFIRINOX,
- •For patients with ECOG performance status (PS ) ≥2, an albuminemia level >25 g/l is required,
- •Haematological status: neutrophils (ANC) >2x109/L; platelets >100x109/L; haemoglobin ≥9g/dL,
- •Adequate renal function: serum creatinine level <150μM, and estimated creatinine clearance >30ml/min,
- •Adequate liver function: AST (SGOT) and ALT (SGPT) ≤2.5xULN (≤5xULN in case of liver metastases),
- •Total bilirubin ≤3 x ULN,
- •QT / QTc interval at baseline ECG (performed within 1 month before randomization) < than 450 msec for men and < than 470 msec for women,
- •Baseline evaluations performed before randomization: clinical and blood evaluations no more than 2 weeks (14 days) prior to randomization, tumor assessment (CT-scan or MRI, evaluation of non-measurable lesions) no more than 3 weeks (21 days) prior to randomization,
- •Female patients must be surgically sterile, or be postmenopausal, or must commit to using reliable and appropriate methods of contraception during the study and during at least six months after the end of study treatment (when applicable). All female patients with reproductive potential must have a negative pregnancy test (β HCG) within 7 days prior to starting protocol treatment. Breastfeeding is not allowed.
- •Male patients must agree to use effective contraception in addition to having their partner use a contraceptive method as well during the trial and during at least six months after the end of the study treatment
- •Affiliation to a French social security system (recipient or assign).
排除标准
- •History or evidence upon physical examination of CNS metastasis unless adequately treated (e.g. non irradiated CNS metastasis, seizure not controlled with standard medical therapy),
- •Local or locally advanced disease (stage I to III),
- •Patient uses warfarin,
- •Patient receiving concomitant radiotherapy,
- •Electrolytic report uncontrolled: hypercalcemia and/or hypokalemia and/or hypomagnesemia,
- •Pre-existing permanent neuropathy (NCI grade ≥2 ),
- •Poor nutritional status
- •Known dihydropyrimidine dehydrogenase (DPD) total or partial deficiency (DPD activity dosage at inclusion visit),
- •Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),
- •Treatment with any other investigational medicinal product within 28 days prior to study entry,
- •Other serious and uncontrolled non-malignant disease (eg. active infection requiring systemic therapy, coronary stenting or myocardial infarction or stroke in the past 6 months),
- •Known or historical active infection with HIV, or known active infection untreated with hepatitis B or hepatitis C ,
- •Known uncontrolled bacterial infection
- •History or active interstitial lung disease (ILD),
- •Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >5 years,
- •Patients with known allergy to active substance or any excipient of study drugs,
- •Allergy to iodinated contrast product
- •Concomitant administration of live, attenuated virus vaccine and concomitant administration of prophylactic phenytoin.
- •Patients under legal protection or unable to consent
- •Participation in another interventional research
研究组 & 干预措施
Group I
Gemcitabine at 1000 mg/m²
干预措施: Gemcitabine (Drug)
Group II
Oxaliplatin at 85 mg/m² ; Folinic acid 400 mg/m² (racemic form) or 200 mg/m² (L-form) and 5-FU 2400 mg/m²
干预措施: FOLFOX (Drug)
结局指标
主要结局
Overall survival (OS) at 24 months
时间窗: At 24 months after inclusion
OS will be defined as the delay between the date of inclusion and the date of death (whatever the cause) or the date of last news if the patient is alive.
次要结局
- Objective response rate(At 24 months after inclusion)
- Duration of response(Tumor assessment will be done every 2 cycles (1cycle = 28 days), assessed up to 24 months after inclusion)
- Disease control rate(At 24 months after inclusion)
- Duration of disease control(Tumor assessment will be done every 2 cycles (1 cycle = 28 days), assessed up to 24 months after inclusion)
- Carbohydrate antigen 19-9 (CA-19-9) and carcinoembryonic antigen (CEA) levels(At baseline (at selection or inclusion visit before starting treatment) and then each 2 cycles (every 8 weeks) until end of treatment, up to 24 months)
- Dose intensity of each protocol(During the entire treatment period, up to 24 months)
- Progression Free Survival (PFS)(From inclusion to the date of first event (progression or death) or date of last news if the patient is alive without progression, assessed up to 60 months)
- Toxicities: Type, frequency and severity of adverse events and serious adverse events(From inclusion to end of treatment, up to 24 months)
- Safety: Rate of serious adverse events, grade 3-4 toxicities (hematologic and non-hematologic)(From inclusion to end of treatment, up to 24 months)
- Quality-adjust Time Without Symptoms of disease or Toxicities (Q-TWiST)(During the entire treatment period, up to 24 months)
- Rate of second and third line(From end of study treatment to patient death, assessed up to 60 months.)
- inLongitudinal changes in Quality of life (EORTC QLQ C-30 questionnaire and a consensual geriatric minimum data set (SOFOG) for patients ≥75 years)(At inclusion, before starting treatment, and then Day 1 of each cycle (every 4 weeks, 1 cycle = 28 days) until end of treatment, up to 24 months)