A Randomized Phase III Trial of Short-course Versus Long-course Pre-operative Chemotherapy With mFOLFIRINOX or PAXG Regimen for Stage I-III Pancreatic Ductal Adenocarcinoma (PDAC)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 261
- 试验地点
- 22
- 主要终点
- Event-free survival
研究概览
简要总结
The main aim of this study is to compare the efficacy of short-course versus long-course pre-operative chemotherapy with PAXG or mFOLFIRINOX in patients who receive a diagnosis of pancreatic ductal adenocarcinoma (PDAC) resectable or borderline resectable.
详细描述
Pancreatic cancer is the seventh cause of death in cancer patients and more than 94% of affected patients die of cancer disease. In the majority of cases, the diagnosis is done at an advanced stage and only 10-20% of patients can be treated with a surgical resection. For this neoplasia, a radical resection may be an effective treatment. Nevertheless, results obtained with surgery alone are rather inadequate, showing a median survival of 12-14 months and 2-year survival of almost 20%: it seems evident the necessity to use complementary treatments in order to improve survival rate in this group of patients.
Pancreatic cancer can relapse locally, at the level of tumoral bed, of the regional lymph nodes, on the immediately adjacent peritoneal surface or on contiguous organs. Also, distant metastases are quite frequent, mainly to the liver, at the entire peritoneal surface and, rarely, to the extra-abdominal organs. The rapid appearance of these metastases after surgical resection strongly suggests the presence of subclinical metastatic diffusion at an early phase of the disease.
Currently, combination chemotherapy based on the mFOLFIRINOX regimen is considered the therapeutic standard in the adjuvant setting, in young and fit patients. Unfortunately, mFOLFIRINOX is burdened with strong haematological and extra-haematologic toxicity and just 2/3 of patients are able to complete the treatment. Recently, PAXG regimen [(Cisplatin (P), Abraxane (A), Capecitabine (X), Gemcitabine (G)] when compared to AG in randomized studies, showed an improvement in terms of progression-free survival (PFS) and overall survival in borderline resectable, locally advanced and metastatic patients. To date, several ongoing randomized trials are investigating the efficacy of perioperative or neoadjuvant strategies in early stage PDAC. Only few studies are available regarding neoadjuvant treatment: some are outdated, numerically inconsistent, retrospective, or not randomized. In this scenario, it aims to better investigate pre-operative therapeutic strategy.
For this purpose, two randomizations are planned.
- FIRST RANDOMIZATION. Eligible patients will be randomized (1:1), stratifying by basal CA19.9 level (<5 ULN vs ≥ 5ULN) and centre to receive:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cyto/histological diagnosis of pancreatic ductal adenocarcinoma*;
- •Clinical stage I-III disease according to TNM 8th Ed. 2017 [appendix 1];
- •Resectable or borderline resectable disease, as anatomically defined according to NCCN Guidelines Version 1.2020 - Pancreatic Adenocarcinoma [appendix 2] and biologically defined according to the International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017 (CA 19.9 > 500 IU/ml) (Isaji et al., 2018);
- •Karnofsky Performance Status > 60% [appendix 3];
- •Age > 18 and ≤ 75 years;
- •Adequate bone marrow function (GB ≥ 3500/mm3, neutrophils ≥1500/mm3, platelets ≥ 100000/mm3, Hb ≥10 g/dl);
- •Adequate kidney function (serum creatinine < 1.5 mg/dL);
- •Adequate liver function:
- •ALT and AST < 3 ULN
- •Serum total bilirubin ≤ 1.5 ULN or in subjects with biliary stenting ≤ 2 ULN;
- •No prior treatment (chemotherapy, radiotherapy and/or surgery) for pancreatic cancer;
- •Women must not be on pregnancy or lactation;
- •Patient of child-bearing potential must agree to use two medically acceptable methods of contraception (one for the patient and one for the partner) during the study and for a minimum of the following 6 months; this applies to patients of both sexes. [appendix 4];
- •Patient information and signed written informed consent.
排除标准
- •Other types of non-ductal tumor of the pancreas, including endocrine tumors or acinar cell adenocarcinoma, cystadenocarcinoma and other periampullary malignancies.
- •Prior (within 1 year) or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin
- •Symptomatic duodenal stenosis;
- •Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment
- •Known infection with hepatitis B or C, or history of human immunodeficiency virus (HIV) infection, or subject receiving immunosuppressive or myelosuppressive medications that would in the opinion of the investigator, increase the risk of serious neutropenic complications
- •Clinical stage IV (including ascites or malignant pleural effusion) disease according to TNM 8th Ed. 2017 [appendix 1];
- •Locally advanced disease according to NCCN Guidelines Version 1.2020 - Pancreatic Adenocarcinoma [appendix 2];
- •Serious medical risk factors involving any of the major organ systems, or serious psychiatric disorders, which could compromise the subject's safety or the study data integrity. These include, but are not limited to:
- •History of connective tissue disorders (eg, lupus, scleroderma, arteritis nodosa)
- •History of interstitial lung disease, slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies
- •History of the following within 6 months prior to Cycle 1 Day 1: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or ECG abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder
- •Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
- •Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
- •Any condition that confounds the ability to interpret data from the study
- •Any familiar, sociologic or geographic conditions that can potentially interfere with the adhesion to the protocol or to the follow-up;
- •Pre-existing neuropathy
- •c.1679GG, c.1905+1AA, c.2846TT mutations in homozygous in DPYD gene. Dose modification according to DPYD and UGT1A1 mutations are reported in Table 1 (https://www.aiom.it/wp-content/uploads/2019/10/2019_Racc-analisi-farmacogenetiche.pdf.)
- •Inflammatory disease of the colon or rectum, or occlusion or sub-occlusion of the intestine.
- •Concurrent treatment with other experimental drugs;
- •Fructose intolerance.
研究组 & 干预措施
PAXG Arm A
cisplatin 30 mg/m2 every 2 weeks, nab-paclitaxel 150 mg/m2 every 2 weeks, gemcitabine 800 mg/m2 every 2 weeks, capecitabine 1250 mg/m2/day (for 28 consecutive days) in 28-day cycles administered for 4 cycles (4 months).
干预措施: PAXG (Drug)
mFOLFIRINOX Arm B
irinotecan 150 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, folinic acid at a fixed dose of 400 mg/m2, fluorouracil continuous IV infusion 2.4 g/m2 over 46 hours in 14-day cycles administered for 8 cycles (4 months).
干预措施: mFOLFIRINOX (Drug)
short-course chemotherapy
Allocated by second randomization after 4 months of chemotherapy to receive immediate surgery followed by 2 further months of the same chemotherapy
干预措施: short-course chemotherapy (Drug)
long-course chemotherapy
Allocated by second randomization after 4 months of chemotherapy to receive 2 further months of the same chemotherapy followed by surgery
干预措施: long-course chemotherapy (Drug)
结局指标
主要结局
Event-free survival
时间窗: 12 weeks
to compare in terms of event free survival (EFS) the efficacy of 4 months pre-operative and 2 months postoperative chemotherapy to that of 6 months of pre-operative chemotherapy . EFS is defined as the time from randomization to: RECIST 1.1 progression \[At least a 20 percent increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20 percent, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression\]; CA19.9 failure (defined as 2 consecutive increases of serum level ≥20 percent, separated by at least 4 weeks); recurrence; preoperative or intraoperative unresectability; intraoperative evidence of metastases; death for any cause; whichever occurs first. R1 resections will NOT be considered as events whereas R2 resections will be.
次要结局
- Ca19.9 response rate(4-6 months)
- Quality of life(4-6 months)
- Overall survival(36 months)
- RECIST 1.1 radiological response(4-6 months)
- Surgery outcome(4-6 months after chemotherapy)
- Incidence of Treatment Adverse Events(4-6 months)