Official Title
The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma
Phase
Phase 2Lead Sponsor
British Columbia Cancer AgencyStudy Type
InterventionalStatus
Unknown statusIndication/Condition
Resectable Pancreatic Ductal AdenocarcinomaIntervention/Treatment
sitagliptin ...Study Participants
20This 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.
In the event of any grade 2 toxicities (with the exception of hyperglycemia), metformin will be withheld until improvement to ≤ grade 1, then restarted at a dose of 500 mg daily. In the event of grade ≥ 3 toxicities related to metformin, treatment will be discontinued. Metformin therapy will also be discontinued if serum lactate levels are above normal values.
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.
Inclusion Criteria: 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/mm3. 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 Exclusion Criteria: 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
