Resectable Pancreatic Ductal Adenocarcinoma
Conditions
Keywords
Resectable pancreatic ductal adenocarcinoma, PDAC, Metformin
Brief summary
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.
Interventions
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.
Sponsors
Pancreatic Cancer Canada
BC Cancer Foundation
British Columbia Cancer Agency
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The effect of neoadjuvant metformin treatment on tumour cell proliferation in PDAC tumours | 6 months | Assessment of Ki-67 fraction as assessed by IHC of pre- and post-metformin tumour samples. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting GGT (mmol/L) | 6 months | The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared. |
| The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting glucose (mmol/L) | 6 months | The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared. |
| The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting insulin (mU/L) | 6 months | The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared. |
| The effect of metformin on glucose and insulin metabolism as assessed by serum marker, HOMA index | 6 months | HOMA index is calculated from serum glucose and insulin. The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared. |
| R0 resection rates in patients undergoing curative PDAC resection | 6 months | Proportion of patients with R0 resections. |
| The effect of metformin on metabolomic profile of pre- and post-metformin samples | 6 months | Serum and urine metabolomic profile. Comparison of metabolite levels in pre-and post-metformin samples. |
| Transcriptome sequencing (RNAseq) of pre- and post-treatment tumour samples. | 6 months | To investigate the molecular signatures associated with metformin response Comparison of gene expression in pre-metformin biopsy samples and post-metformin resected tumour samples. Expression of altered genes to be validated by IHC in tumour sections. |
| Plasma ctDNA, measured as percentage of mutant to total DNA fragments in plasma | 6 months | To assess the presence of ctDNA in resectable PDAC, and dynamic changes following treatment with metformin and surgical resection Proportion of patients with detectable plasma ctDNA at baseline. Comparison of values pre- and post-metformin and 4-10 weeks after surgery. |
| Correlation between imaging and pathologic parameters | 6 months | To explore the correlation between apparent diffusion coefficient (ADC) on MRI and pathologic findings. ADC values will be individually compared to tumour differentiation and Ki-67 fraction on pathologic examination. |
| The effect of metformin on glucose and insulin metabolism as assessed by clinical marker, weight (kg) | 6 months | The clinical marker will be reported with pre- and post-metformin values compared. |
Countries
Canada
Contacts
Primary ContactDaniel J Renouf, MD
Backup ContactHui-li Wong, MD
Outcome results
None listed