Phase II Study to Assess the Interest of a Sequential Treatment With Gemcitabine/Nab-paclitaxel (GEMBRAX) and Then FOLFIRINOX Followed by Stereotactic Magnetic Resonance-guided Adaptive Radiotherapy in Patients With Locally Advanced Pancreatic Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 103
- 试验地点
- 18
- 主要终点
- Rate of non-progression at 4 months
研究概览
简要总结
The aim of this study is to demonstrate the efficacy of intensified and sequential chemotherapy (Gabrinox) comprising Gembrax regimen (Gemcitabine-Abraxane) followed by the Folfirinox regimen (5FU, Oxaliplatin and Irinotecan) in patients with locally advanced pancreatic adenocarcinoma.
The study will also demonstrate the feasibility of combining this intensified chemotherapy with MRI-guided stereotactic radiotherapy in non-progressive patients after the chemotherapy by Gabrinox regimen.
详细描述
Pancreatic cancer was the third cause of death by cancer worldwide in 2016, surpassing breast cancer. It is estimated that in 2030, pancreatic cancer will become the second cause of death by cancer after lung cancer.
Its prognosis is very poor, with an overall survival (OS) at 5 years, all stages included, of 5.5%. According to the French cancer registry network (FRANCIM), its incidence has more than doubled in men and women between 1990 and 2018. The world standardized incidence rates for men and women were 5.2% and 2.7% in 1990 and 11% and 7% in 2018, respectively. This means a yearly annual increase of 2.7 for men and of 3.8 for women. The often late diagnosis, in 50% of cases at stage 4, and the limited treatment options explain the very low survival rate at 5 years.
Currently, only surgery associated with adjuvant chemotherapy for 6 months allows doubling this survival rate. However, this situation concerns only 20% of cases. Indeed, 50% of pancreatic cancers are discovered at stage 4, and in 30% of patients cancer is detected when not resectable and non-metastatic (i.e. borderline resectable or locally advanced). To make an unresectable cancer resectable is one of the therapeutic strategies under development. However, treatment of locally advanced pancreatic cancer (LAPC) is not standardized. Chemotherapy is a used strategy, but 30% of cases will progress to metastatic disease. Therefore, the need in LAPC to control not only the local disease but also micro-metastases has led to the development of combined strategies with chemotherapy and optimal radiotherapy.
For LAPC, chemotherapy is based on two drug combinations that are classically used for the first-line treatment of metastatic disease: FOLFIRINOX (FFX) (association of 5FU, Oxaliplatin and Irinotecan) and GEMBRAX (GA) (association of gemcitabine and nab-paclitaxel). Their association has been validated by phase 3 studies showing that compared with gemcitabine alone, they allow increasing the response rate by three times (30%), and almost doubling the median survival and progression-free survival, but with higher grade 3 hematologic and neurological toxicities.
FFX and GA have been assessed also in LAPC. Retrospective studies confirmed the high response rate, 30 to 80% according to the study, and a median survival of 9 to 30 months. Recently, two phase 2 studies, evaluated GA alone and GA followed by FFX, respectively, for LAPC, and confirmed the efficacy, with a response rate of 30% and a secondary resection rate of 15% and 30.6%, respectively. Moreover, in patients who underwent tumour resection after treatment, survival was longer than in those not operated (27.4 vs 14.2 months; Hazard Ratio (HZ) = 0.45; p = 0.0035). Overall Survival (OS) (n= 165 patients) was 17.2 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Patient aged from 18 to 75 years at the date of signature of the consent form
- •Histologically or cytologically proven pancreatic adenocarcinoma
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
- •Non-resectable tumour according to the National Comprehensive Cancer Network (NCCN) 1.2015 recommendations after external review of imaging data by multidisciplinary experts.
- •Non-metastatic cancer confirmed by thorax-abdomen-pelvis computerized tomography (CT) scan and liver MRI
- •SMART feasibility confirmed by centralized review
- •Uracilemia < 16 ng/ml
- •Hematological assessment within 14 days before inclusion, defined by:
- •Neutrophils ≥ 2 000/mm3 (2 × 109/L);
- •Platelets ≥ 100 000/mm3 (100 × 109/L);
- •Hemoglobin ≥ 9 g/dl
- •Liver function (within 14 days before inclusion) defined by:
- •ASpartate Transaminase (AST) and ALanine Transaminase (ALT) ≤ 2.5 x Upper Limit of Normal (ULN);
- •Total bilirubin ≤ 1.5 x ULN. Patients with a metallic biliary prosthesis due to biliary obstruction caused by the cancer may be included, if: a CT scan with injection of contrast medium and thin pancreas sections was performed before placing the biliary prosthesis, the bilirubin level after prosthesis fitting decreased to ≤20 mg/L (≤34 μmol/L), and in the absence of cholangitis.
- •Creatininaemia within the reference limits, or calculated clearance ≥50 ml/min for patients with a serum creatinine value above or below the reference values (clearance calculated using the Chronic Kidney Disease EPIdemiology collaboration (CKDEPI formula).
- •Serum calcium AND magnesium AND potassium ≥ Lower Limit Normal (LLN and ≤ 1.2 x Upper Limit Normal (ULN)
- •Cancer Antigen (CA 19.9) <500 IU/mL (without cholestasis). Patients with CA 19.9 between 500 IU/mL and 1000 IU/mL can be included if the Positron Emission Tomography (PET) scan and peritoneal MRI (optional) do not detect any distant fixation, indicative of metastasis. Patients with CA 19.9 ≥ 1000 IU/mL cannot be included.
- •Sexually active patients must use a contraceptive method considered adequate and suitable by the investigator during the entire period of administration of the study treatment and up to 6 months after the treatment end, for female and male patients.
- •Signature of the consent form before any study-specific procedure.
- •Covered by the French health insurance.
排除标准
- •Any previous treatment for pancreatic cancer (e.g. chemotherapy, radiotherapy, surgery, targeted therapy, experimental therapy)
- •Gilbert's syndrome or homozygous Uridine DiPhosphate Glucuronosyl Transferase 1 A1 (UGT1A1 * 28)
- •Other concomitant cancer or history of cancer, except for treated in situ cancer of the cervix , basal cell or squamous cell carcinoma, superficial bladder tumour (Ta, Tis, and T1), or good-prognosis tumour cured without chemotherapy and without signs of disease in the 3 years before inclusion
- •Prior radiotherapy likely to overlap with the planned study radiotherapy area (e.g. previous abdominal irradiation).
- •Patients with high cardiovascular risk, including, but not limited to, coronary stent or myocardial infarction in the past 6 months.
- •Peripheral neuropathy ≥ grade 2
- •ECG with QTcorrected (QTc) interval longer than 450 ms for men and longer than 470 ms for women
- •Contraindication to MRI and MRI-guided radiotherapy
- •History of chronic inflammatory disease of the colon or rectum
- •Any other concomitant and not controlled serious illness or disturbance that may interfere with the patient's participation in the study and safety during the study (e.g. severe liver, kidney, lung, metabolic, or psychiatric disorder)
- •Intolerance or allergy to one of the study drugs (gemcitabine, Nab-paclitaxel, oxaliplatin, irinotecan, 5-FU) or to one of their excipients (e.g. fructose) listed in the Contraindications or Warnings sections and Special precautions of the Summary of Product Characteristics (SmPC) or prescription information
- •Legal incapacity (patient under guardianship or wardship)
- •Pregnant or breastfeeding woman. Fertile women must have a negative pregnancy test (serum β-hCG) performed 72 hours before inclusion
- •Patient using vitamin K antagonists (Coumadin…) (possible modification of the treatment before inclusion)
- •Active and uncontrolled bacterial or fungal infection that requires systemic treatment.
- •Know active HIV infection
- •History of peripheral arterial disease (e.g. lameness, Buerger's disease).
- •Patient who received a attenuated live vaccine in the 10 days before inclusion
- •Patient with history of pulmonary fibrosis or interstitial pneumonia.
- •Inability to attend the follow-up visits due to geographic, social or mental reasons.
- •Participation in another clinical study with a research product during the last 30 days before inclusion.
结局指标
主要结局
Rate of non-progression at 4 months
时间窗: 4 months
(Sequence 1 success = chemotherapy) according to the RECIST v1.1 criteria
Acute gastrointestinal non-toxicity rate
时间窗: 90 days
Absence of toxicity of grade ≥3 related to radiotherapy within 90 days, evaluated using the NCI-CTCAE v5.0 classification (sequence 2 success = radiotherapy)
次要结局
- Assessment of adverse events due to chemotherapy by using the NCI-CTCAE version 5.0 scale(36 months)
- Assessment of adverse events due to radiotherapy by using the NCI-CTCAE version 5.0(36 months)
- Healthy margin resection rate (R0)(From the end of radiotherapy (3 months) through 6 months post-radiotherapy)
- Correlation of planning target volume (PTV) coverage and dose received by the gross tumor volume (GTV) with overall survival(An average of 9 months after the beginning of treatment (chemotherapy then radiotherapy))
- Correlation of the dose received by organs at risk (duodenum, small intestine, stomach, colon) with the appearance of gastrointestinal toxicities(An average of 9 months after the beginning of treatment (chemotherapy then radiotherapy))
- Prognostic impact of CA 19-9 changes on survival(Through study completion, an average of 36 months)
- Quality of life by using the quality of life questionnaire score (QLQ-C30)(Through study completion, an average of 60 months)
- Quality of life by using the quality of life questionnaire score (QLQ-PAN26)(Through study completion, an average of 60 months)
- Correlation of planning target volume (PTV) coverage and dose received by the gross tumor volume (GTV) with progression free survival(An average of 9 months after the beginning of treatment (chemotherapy then radiotherapy))
- Assessment of adverse events due to chemotherapy by using the NCI-CTCAE version 5.0 scale(36 months)
- Assessment of adverse events due to radiotherapy by using the NCI-CTCAE version 5.0(36 months)
- Collection of dosimetric results regarding dose/volume from the planned dosimetry, such as coverage of the planning targeted volume (PTV) by the prescription dose in the accumulated dose(An average of 9 months after the beginning of treatment (chemotherapy then radiotherapy))
- Collection of dosimetric results regarding dose/volume from the planned dosimetry, such as dose received by the gross total volume(An average of 9 months after the beginning of treatment (chemotherapy then radiotherapy))
- Collection and Summation of the dosimetric results in terms of dose/volume for the adaptive radiotherapy sessions and comparison with the predicted dosimetry(An average of 9 months after the beginning of treatment (chemotherapy then radiotherapy))
- Correlation of the dose received by organs at risk (duodenum, small intestine, stomach, colon) with the appearance of gastrointestinal toxicities(An average of 9 months after the beginning of treatment (chemotherapy then radiotherapy))
- Correlation of planning target volume (PTV) coverage and dose received by the gross tumor volume (GTV) with progression free survival(An average of 9 months after the beginning of treatment (chemotherapy then radiotherapy))
- Correlation of planning target volume (PTV) coverage and dose received by the gross tumor volume (GTV) with overall survival(An average of 9 months after the beginning of treatment (chemotherapy then radiotherapy))
- Progression-free Survival (PFS) of the radiotherapy(Through study completion, an average of 68 months)
- Overall Survival (OS) of the radiotherapy(Through study completion, an average of 72 months)
- Local disease control of the radiotherapy(Through study completion, an average of 68 months)
- Progression-free Survival (PFS) of the whole treatement(Through study completion, an average of 72 months)
- Overall Survival (OS) of the whole treatement(Through study completion, an average of 72 months)
- Assessment of adverse events due to the whole treatement(Through study completion, an average of 36 months)
- Healthy margin resection rate (R0)(From the end of radiotherapy (3 months) through 6 months post-radiotherapy)
- Histological response rate(From the end of radiotherapy (3 months) through 6 months post-radiotherapy)
- Prognostic impact of CA 19-9 changes on survival(Through study completion, an average of 36 months)
- Quality of life by using the quality of life questionnaire score (QLQ-C30)(Through study completion, an average of 60 months)
- Quality of life by using the quality of life questionnaire score (QLQ-PAN26)(Through study completion, an average of 60 months)
- Resection rate(From the end of radiotherapy (3 months) through 6 months post-radiotherapy)