Evaluation of Tumoral Perfusion Modification by Dynamic Imaging After Neoadjuvant Chemotherapy Combining Gemcitabine and a Hedgehog Inhibitor (Vismodegib) in Patients With Resectable Pancreatic Adenocarcinoma
试验速览
- 阶段
- 早期 1 期
- 入组人数
- 21
- 试验地点
- 2
- 主要终点
- "Dynamic" tumor response rate as defined by a 20% modification of tumoral perfusion and cellular density parameters.
研究概览
简要总结
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all human cancers and is considered as a sanctuary, resistant to most of the drugs used. Identification of new molecular targets involved in its pathogenesis is urgently needed and required both proper and innovative efficacy assessment.
This proof-of-concept trial is studying the "dynamic" tumor response after the administration of a short course (4 weeks) neoadjuvant combination of gemcitabine and a Hedgehog inhibitor (Vismodegib) before surgery in patients with operable pancreatic cancer.
详细描述
Pancreatic cancer is characterized by a high stromal density and is a hypoperfused tumor, precluding cytotoxics delivery to the epithelial tumoral compartment. There is thus a rationale for combining chemotherapy and antistromal drugs like Hedgehog inhibitors. Targeting the resectable primary tumor offers an appropriate setting to (1) evaluate and monitor early treatment effects on the tumor, (2) correlate dynamic imaging changes (perfusion and diffusion coefficient) to pre- and post-therapeutic tissue changes, (3) identify specific predictive biomarkers for the drugs used (i.e. gemcitabine transporters and Hedgehog pathway genes and proteins) and (4) assess if this early "dynamic and biomolecular response" can predict treatment benefit and patient outcome.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histo(cyto)logically proven ductal pancreatic adenocarcinoma
- •Resectable or potentially resectable tumor; resectability assessed during a multidisciplinary meeting with expert surgeon and radiologist
- •First line chemotherapy
- •Age > 18 years
- •WHO performance status (PS) grade 0 or 1;
- •Absolute neutrophil count > 1.5 x 10 9 / L, platelets > 100 x 10 9/ L, creatinine clearance (Cockcroft and Gault formula) > 60 ml/min, haemoglobin level > 10 g/dl (transfusions authorized), bilirubin<1.5 g/dl;
- •Optimal biliary drainage;
- •Women of child-bearing potential (WCBP), defined as a sexually mature woman who has not undergone a hysterectomy or tubal ligation of who has not been naturally postmenopausal for at least 24 consecutive months, must have a negative serum or urine pregnancy test prior to treatment. All WCBP, all sexually active male patients, and all partners of patients must agree to use adequate methods of birth control throughout the study;
- •Signed written informed consent.
排除标准
- •Locally advanced non resectable or metastatic pancreatic adenocarcinoma
- •Previous anticancer therapy for the pancreatic adenocarcinoma
- •Biliary obstruction without endoscopic biliary drainage
- •Any contre-indication for surgery
- •Prior malignancy (except non-melanoma skin cancer, and in situ carcinoma of the uterine cervix treated with a curative intent and any other tumor in complete remission with a disease-free interval > 3 years)
- •Uncontrolled congestive heart failure or angina pectoris, myocardial infarction within 1 year prior to study entry, uncontrolled hypertension (systolic pressure > 160 mm or diastolic pressure > 100 mm under well conducted antihypertensive treatment), QT prolongation
- •Major uncontrolled infection
- •Severe hepatic impairment
- •Any medical, psychological, or social condition, which, in the opinion of the investigator, could hamper patient's compliance to the study protocol and/or assessment/interpretation of the data
- •Pregnant or lactating women, or patients of both genders with procreative potential not using adequate contraceptive methods
- •Patients receiving or having received any investigational treatment within 4 weeks prior to study entry, or participating to another clinical study;Subject previously enrolled into this study.
研究组 & 干预措施
Gemcitabine+Vismodegib
Neoadjuvant chemotherapy combining gemcitabine and Vismodegib during 4 weeks before surgery
干预措施: gemcitabine (Drug)
Gemcitabine+Vismodegib
Neoadjuvant chemotherapy combining gemcitabine and Vismodegib during 4 weeks before surgery
干预措施: Vismodegib (Drug)
Gemcitabine+Vismodegib
Neoadjuvant chemotherapy combining gemcitabine and Vismodegib during 4 weeks before surgery
干预措施: Neoadjuvant chemotherapy (Procedure)
结局指标
主要结局
"Dynamic" tumor response rate as defined by a 20% modification of tumoral perfusion and cellular density parameters.
时间窗: 4 weeks (duration of the neoadjuvant chemotherapy).
In order to detect changes in the tumor microenvironment and to monitor treatment efficacy, Dynamic Contrast-Enhanced-Magnetic Resonance Imaging (DCE-MRI) and Diffusion Weighted-Magnetic Resonance Imaging (DW-MRI) constitute tools more and more used. The acquired data can be analyzed using a pharmacokinetic model to obtain quantitative parameters relative to tissue perfusion and vascular permeability (Ktrans, a volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space; Apparent Diffusion Coefficient as a surrogate marker of tissue cellularity). DCE/DW-MRI will be achieved weekly before each neoadjuvant chemotherapy treatment and before surgery. Each patient will be his/her own control by comparing serial imaging results with those of the baseline MRI.
次要结局
- Number of participants with adverse events as assessed by National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0.(End of study follow-up (up to 2 years).)
研究者
Jean-Luc Van Laethem
MD, PhD
Erasme University Hospital