The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma
试验速览
- 阶段
- 2 期
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- The effect of neoadjuvant metformin treatment on tumour cell proliferation in PDAC tumours
研究概览
简要总结
This is a single arm, non-randomized phase II study of neoadjuvant metformin in resectable PDAC. Twenty patients will be enrolled and treated with metformin 500 mg BD for a minimum of 7 days, until 2 days prior to surgery. Patients will undergo laboratory investigations at baseline, prior to surgery and 4-10 weeks after surgery. Patients eligible for and consented to the optional MRI substudy will undergo diffusion-weighted MRI 1 to 14 days before surgery.
At surgery, resected tumour and normal tissue will be collected and banked. FFPE specimens will be used for sectioning, histological analysis and IHC for Ki67 (cell proliferation marker), pAMPK, ACC targets, p53 and mTOR targets, apoptotic markers (Bax, Bcl-2, caspases 3, 8 and 9). Fresh frozen tumour and matched normal tissue samples will be used for western blot analysis of insulin and IGF receptors, total and activated ERK and Akt, and RNAseq analysis. Pre-metformin biopsy samples will be retrieved for molecular analysis.
Fasting blood samples at baseline and before surgery will be analyzed for glucose and insulin levels. Plasma and whole blood will also be processed and banked for circulating tumour DNA analysis. Urine samples will be sent for metabolomic profiling.
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
- •Age greater than or equal to 18 years on the day of study consent
- •Pathologic diagnosis of PDAC where 2 pre-treatment core biopsy samples are available for analysis. Patients with suspected PDAC without a pathologic diagnosis must undergo confirmatory biopsy under endoscopic ultrasound guidance.
- •Resectable disease based on standard imaging criteria
- •Surgery planned ≥ 2 weeks after study entry
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Adequate hematologic, renal, and hepatic function as measured by the following laboratory assessments conducted within 7 days prior to the initiation of study treatment:
- •Total bilirubin < 1.5 times the upper limit of normal (ULN)
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 times the ULN
- •Lipase < 1.5 times the ULN
- •Serum creatinine < 1.5 times the ULN
- •Glomerular filtration rate > 30 mL/min/1.73 m2 according to the modified diet in renal disease abbreviated formula
- •International normalized ratio (INR) or prothrombin time (PT; PT-INR) and partial thromboplastin time (PTT) < 1.5 times the ULN
- •Platelet count > 100000 /mm3, hemoglobin (> 9 g/dL, absolute neutrophil count > 1500/mm
- •Baseline fasting glucose <13.9 mmol/L
- •No prior chemotherapy or radiotherapy for PDAC
- •Serum lactate levels within normal range assessed within 7 days prior to the initiation of study treatment
- •MRI sub-study:
- •Signed informed consent for the optional MRI substudy
- •No contraindications to MRI
排除标准
- •Presence of locally unresectable disease or distant metastases
- •Treatment with metformin or any other anti-hyperglycemic agent within the previous 6 months
- •Known allergy or contraindication to metformin
- •Not fit for surgery
- •Planned for, or received, neoadjuvant treatment of any type
研究组 & 干预措施
Metformin
All patients will receive metformin 500 mg per oral twice daily with food for at least 7 days, until 2 days prior to surgery. Metformin therapy should be discontinued 2 days before surgery to reduce the risk of lactic acidosis associated with fasting.
干预措施: Metformin Hydrochloride 500Mg Tablet (Drug)
结局指标
主要结局
The effect of neoadjuvant metformin treatment on tumour cell proliferation in PDAC tumours
时间窗: 6 months
Assessment of Ki-67 fraction as assessed by IHC of pre- and post-metformin tumour samples.
次要结局
- The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting GGT (mmol/L)(6 months)
- R0 resection rates in patients undergoing curative PDAC resection(6 months)
- The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting glucose (mmol/L)(6 months)
- Transcriptome sequencing (RNAseq) of pre- and post-treatment tumour samples.(6 months)
- Plasma ctDNA, measured as percentage of mutant to total DNA fragments in plasma(6 months)
- The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting insulin (mU/L)(6 months)
- The effect of metformin on glucose and insulin metabolism as assessed by clinical marker, weight (kg)(6 months)
- Correlation between imaging and pathologic parameters(6 months)
- The effect of metformin on metabolomic profile of pre- and post-metformin samples(6 months)
- The effect of metformin on glucose and insulin metabolism as assessed by serum marker, HOMA index(6 months)