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| Name | Class |
|---|---|
| Pancreatic Cancer Canada | OTHER |
| BC Cancer Foundation | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metformin | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin Hydrochloride 500Mg Tablet | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| The effect of neoadjuvant metformin treatment on tumour cell proliferation in PDAC tumours | Assessment of Ki-67 fraction as assessed by IHC of pre- and post-metformin tumour samples. | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| R0 resection rates in patients undergoing curative PDAC resection | Proportion of patients with R0 resections. | 6 months |
| The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting GGT (mmol/L) |
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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:
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:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Daniel J Renouf, MD | Contact | 6048776000 | 2445 | drenouf@bccancer.bc.ca |
| Hui-li Wong, MD | Contact | 6048776000 | 2445 | HuiLi.Wong@bccancer.bc.ca |
| Name | Affiliation | Role |
|---|---|---|
| Daniel J Renouf, MD | British Columbia Cancer Agency | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| BC Cancer Agency - Vancouver Cancer Centre | Vancouver | British Columbia | V5Z 4E6 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | Canadian Cancer Society's Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2015. Toronto, ON: Canadian Cancer Society. 2015. | ||
| 18326920 | Background | Garcea G, Dennison AR, Pattenden CJ, Neal CP, Sutton CD, Berry DP. Survival following curative resection for pancreatic ductal adenocarcinoma. A systematic review of the literature. JOP. 2008 Mar 8;9(2):99-132. | |
| Background | AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010. | ||
| 19396496 |
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|
The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.
| 6 months |
| The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting glucose (mmol/L) | The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared. | 6 months |
| The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting insulin (mU/L) | The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared. | 6 months |
| The effect of metformin on glucose and insulin metabolism as assessed by serum marker, HOMA index | 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. | 6 months |
| The effect of metformin on glucose and insulin metabolism as assessed by clinical marker, weight (kg) | The clinical marker will be reported with pre- and post-metformin values compared. | 6 months |
| The effect of metformin on metabolomic profile of pre- and post-metformin samples | Serum and urine metabolomic profile. Comparison of metabolite levels in pre-and post-metformin samples. | 6 months |
| Transcriptome sequencing (RNAseq) of pre- and post-treatment tumour samples. | 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. | 6 months |
| Plasma ctDNA, measured as percentage of mutant to total DNA fragments in plasma | 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. | 6 months |
| Correlation between imaging and pathologic parameters | 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. | 6 months |
| Background |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| D013607 | Tablets |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
Not provided
Not provided