The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma

Resectable Pancreatic Ductal Adenocarcinoma Clinical Trial

— Metformin 001  

Official title:

The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02978547
• Other study ID #: H16-02566
• Status: Not yet recruiting
• Phase: Phase 2
• First received: November 2, 2016
• Last updated: January 16, 2018
• Start date: January 2019
• Est. completion date: January 2021

Study information

• Verified date: January 2018
• Source: British Columbia Cancer Agency
• Contact: Daniel J Renouf, MD
• Phone: 6048776000
• Email: drenouf[@]bccancer.bc.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 20
• Est. completion date: January 2021
• Est. primary completion date: June 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Resectable Pancreatic Ductal Adenocarcinoma

Intervention

Drug:
• Metformin Hydrochloride 500Mg Tablet
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.

Locations

Country	Name	City	State
Canada	BC Cancer Agency - Vancouver Cancer Centre	Vancouver	British Columbia

Sponsors (3)

Lead Sponsor	Collaborator
British Columbia Cancer Agency	BC Cancer Foundation, Pancreatic Cancer Canada

Country where clinical trial is conducted

Canada, 

References & Publications (51)

AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010.

Appleman VA, Ahronian LG, Cai J, Klimstra DS, Lewis BC. KRAS(G12D)- and BRAF(V600E)-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling. Mol Cancer Res. 2012 Sep;10(9):1228-39. Epub 2012 Aug 7. — View Citation

Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based appraisal. J Gastrointest Oncol. 2012 Jun;3(2):105-19. doi: 10.3978/j.issn.2078-6891.2011.021. — View Citation

Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008 Jun 5;27(25):3576-86. doi: 10.1038/sj.onc.1211024. Epub 2008 Jan 21. — View Citation

Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther. 2010 May;9(5):1092-9. doi: 10.1158/1535-7163.MCT-09-1186. Epub 2010 May 4. Review. — View Citation

Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011 Jul 1;71(13):4366-72. doi: 10.1158/0008-5472.CAN-10-1769. Epub 2011 May 3. — View Citation

Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih lM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014 Feb 19;6(224):224ra24. doi: 10.1126/scitranslmed.3007094. — View Citation

Blumer I, Hadar E, Hadden DR, Jovanovic L, Mestman JH, Murad MH, Yogev Y. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013 Nov;98(11):4227-49. doi: 10.1210/jc.2013-2465. — View Citation

Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A, Gennari A, Trabacca MS, Galimberti V, Veronesi P, Johansson H, Aristarco V, Bassi F, Luini A, Lazzeroni M, Varricchio C, Viale G, Bruzzi P, Decensi A. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol. 2012 Jul 20;30(21):2593-600. doi: 10.1200/JCO.2011.39.3769. Epub 2012 May 7. — View Citation

Callery MP, Chang KJ, Fishman EK, Talamonti MS, William Traverso L, Linehan DC. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol. 2009 Jul;16(7):1727-33. doi: 10.1245/s10434-009-0408-6. Epub 2009 Apr 24. — View Citation

Canadian Cancer Society's Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2015. Toronto, ON: Canadian Cancer Society. 2015.

Castells A, Puig P, Móra J, Boadas J, Boix L, Urgell E, Solé M, Capellà G, Lluís F, Fernández-Cruz L, Navarro S, Farré A. K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significance. J Clin Oncol. 1999 Feb;17(2):578-84. — View Citation

Cazzaniga M, DeCensi A, Pruneri G, Puntoni M, Bottiglieri L, Varricchio C, Guerrieri-Gonzaga A, Gentilini OD, Pagani G, Dell'Orto P, Lazzeroni M, Serrano D, Viale G, Bonanni B. The effect of metformin on apoptosis in a breast cancer presurgical trial. Br J Cancer. 2013 Nov 26;109(11):2792-7. doi: 10.1038/bjc.2013.657. Epub 2013 Oct 24. — View Citation

Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol. 2004 Jun 15;159(12):1160-7. — View Citation

Cuneo KC, Chenevert TL, Ben-Josef E, Feng MU, Greenson JK, Hussain HK, Simeone DM, Schipper MJ, Anderson MA, Zalupski MM, Al-Hawary M, Galban CJ, Rehemtulla A, Feng FY, Lawrence TS, Ross BD. A pilot study of diffusion-weighted MRI in patients undergoing neoadjuvant chemoradiation for pancreatic cancer. Transl Oncol. 2014 Oct 24;7(5):644-9. doi: 10.1016/j.tranon.2014.07.005. eCollection 2014 Oct. — View Citation

Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, Rosenfeld N. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013 Mar 28;368(13):1199-209. doi: 10.1056/NEJMoa1213261. Epub 2013 Mar 13. — View Citation

Dombrowski F, Mathieu C, Evert M. Hepatocellular neoplasms induced by low-number pancreatic islet transplants in autoimmune diabetic BB/Pfd rats. Cancer Res. 2006 Feb 1;66(3):1833-43. — View Citation

Dowling RJ, Niraula S, Chang MC, Done SJ, Ennis M, McCready DR, Leong WL, Escallon JM, Reedijk M, Goodwin PJ, Stambolic V. Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res. 2015 Mar 3;17:32. doi: 10.1186/s13058-015-0540-0. — View Citation

El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000 Jan 7;275(1):223-8. — View Citation

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. Review. — View Citation

Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010 Apr 20;7(4):e1000267. doi: 10.1371/journal.pmed.1000267. Review. — View Citation

Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009 Oct 1;69(19):7507-11. doi: 10.1158/0008-5472.CAN-09-2994. Epub 2009 Sep 14. Erratum in: Cancer Res. 2009 Nov 15;69(22):8832. — View Citation

Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL, McBurnie W, Fleming S, Alessi DR. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008 Jun 1;412(2):211-21. doi: 10.1042/BJ20080557. — View Citation

Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009 Jul 10;27(20):3297-302. doi: 10.1200/JCO.2009.19.6410. Epub 2009 Jun 1. — View Citation

Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, Kemp BE, Bardeesy N, Dennis P, Schlager JJ, Marette A, Kozma SC, Thomas G. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010 May 5;11(5):390-401. doi: 10.1016/j.cmet.2010.03.014. — View Citation

Kinugasa H, Nouso K, Miyahara K, Morimoto Y, Dohi C, Tsutsumi K, Kato H, Matsubara T, Okada H, Yamamoto K. Detection of K-ras gene mutation by liquid biopsy in patients with pancreatic cancer. Cancer. 2015 Jul 1;121(13):2271-80. doi: 10.1002/cncr.29364. Epub 2015 Mar 30. — View Citation

Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 2009 Aug 15;69(16):6539-45. doi: 10.1158/0008-5472.CAN-09-0418. — View Citation

Kourelis TV, Siegel RD. Metformin and cancer: new applications for an old drug. Med Oncol. 2012 Jun;29(2):1314-27. doi: 10.1007/s12032-011-9846-7. Epub 2011 Feb 8. Review. — View Citation

Kurosawa J, Tawada K, Mikata R, Ishihara T, Tsuyuguchi T, Saito M, Shimofusa R, Yoshitomi H, Ohtsuka M, Miyazaki M, Yokosuka O. Prognostic relevance of apparent diffusion coefficient obtained by diffusion-weighted MRI in pancreatic cancer. J Magn Reson Imaging. 2015 Dec;42(6):1532-7. doi: 10.1002/jmri.24939. Epub 2015 May 6. — View Citation

Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. doi: 10.1002/jso.21527. — View Citation

Lonardo E, Cioffi M, Sancho P, Sanchez-Ripoll Y, Trabulo SM, Dorado J, Balic A, Hidalgo M, Heeschen C. Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PLoS One. 2013 Oct 18;8(10):e76518. doi: 10.1371/journal.pone.0076518. eCollection 2013. — View Citation

Mohammed A, Janakiram NB, Brewer M, Ritchie RL, Marya A, Lightfoot S, Steele VE, Rao CV. Antidiabetic Drug Metformin Prevents Progression of Pancreatic Cancer by Targeting in Part Cancer Stem Cells and mTOR Signaling. Transl Oncol. 2013 Dec 1;6(6):649-59. eCollection 2013 Dec 1. — View Citation

Niraula S, Dowling RJ, Ennis M, Chang MC, Done SJ, Hood N, Escallon J, Leong WL, McCready DR, Reedijk M, Stambolic V, Goodwin PJ. Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat. 2012 Oct;135(3):821-30. doi: 10.1007/s10549-012-2223-1. Epub 2012 Aug 30. — View Citation

Niwa T, Ueno M, Ohkawa S, Yoshida T, Doiuchi T, Ito K, Inoue T. Advanced pancreatic cancer: the use of the apparent diffusion coefficient to predict response to chemotherapy. Br J Radiol. 2009 Jan;82(973):28-34. doi: 10.1259/bjr/43911400. — View Citation

Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000 Jun 15;348 Pt 3:607-14. — View Citation

Palmer DH, Stocken DD, Hewitt H, Markham CE, Hassan AB, Johnson PJ, Buckels JA, Bramhall SR. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol. 2007 Jul;14(7):2088-96. Epub 2007 Apr 24. — View Citation

Pannala R, Basu A, Petersen GM, Chari ST. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009 Jan;10(1):88-95. doi: 10.1016/S1470-2045(08)70337-1. Review. — View Citation

Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008 Dec;8(12):915-28. doi: 10.1038/nrc2536. Review. Erratum in: Nat Rev Cancer. 2009 Mar;9(3):224. — View Citation

Sadeghi N, Abbruzzese JL, Yeung SC, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res. 2012 May 15;18(10):2905-12. doi: 10.1158/1078-0432.CCR-11-2994. Epub 2012 Mar 31. — View Citation

Sah RP, Nagpal SJ, Mukhopadhyay D, Chari ST. New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat Rev Gastroenterol Hepatol. 2013 Jul;10(7):423-33. doi: 10.1038/nrgastro.2013.49. Epub 2013 Mar 26. Review. — View Citation

Schaeffer DF, Owen DR, Lim HJ, Buczkowski AK, Chung SW, Scudamore CH, Huntsman DG, Ng SS, Owen DA. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) overexpression in pancreatic ductal adenocarcinoma correlates with poor survival. BMC Cancer. 2010 Feb 23;10:59. doi: 10.1186/1471-2407-10-59. — View Citation

Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, Adrian TE, Pour PM. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology. 2001 Apr;120(5):1263-70. — View Citation

Sinnett-Smith J, Kisfalvi K, Kui R, Rozengurt E. Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: dependence on glucose concentration and role of AMPK. Biochem Biophys Res Commun. 2013 Jan 4;430(1):352-7. doi: 10.1016/j.bbrc.2012.11.010. Epub 2012 Nov 15. — View Citation

Skinner HD, Crane CH, Garrett CR, Eng C, Chang GJ, Skibber JM, Rodriguez-Bigas MA, Kelly P, Sandulache VC, Delclos ME, Krishnan S, Das P. Metformin use and improved response to therapy in rectal cancer. Cancer Med. 2013 Feb;2(1):99-107. doi: 10.1002/cam4.54. Epub 2013 Feb 3. — View Citation

Skinner HD, McCurdy MR, Echeverria AE, Lin SH, Welsh JW, O'Reilly MS, Hofstetter WL, Ajani JA, Komaki R, Cox JD, Sandulache VC, Myers JN, Guerrero TM. Metformin use and improved response to therapy in esophageal adenocarcinoma. Acta Oncol. 2013 Jun;52(5):1002-9. doi: 10.3109/0284186X.2012.718096. Epub 2012 Sep 5. — View Citation

Tie J, Kinde I, Wang Y, Wong HL, Roebert J, Christie M, Tacey M, Wong R, Singh M, Karapetis CS, Desai J, Tran B, Strausberg RL, Diaz LA Jr, Papadopoulos N, Kinzler KW, Vogelstein B, Gibbs P. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol. 2015 Aug;26(8):1715-22. doi: 10.1093/annonc/mdv177. Epub 2015 Apr 7. — View Citation

Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012 Mar;122(6):253-70. doi: 10.1042/CS20110386. Review. — View Citation

Wang LW, Li ZS, Zou DW, Jin ZD, Gao J, Xu GM. Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol. 2008 Dec 21;14(47):7192-8. — View Citation

Wang Y, Chen ZE, Nikolaidis P, McCarthy RJ, Merrick L, Sternick LA, Horowitz JM, Yaghmai V, Miller FH. Diffusion-weighted magnetic resonance imaging of pancreatic adenocarcinomas: association with histopathology and tumor grade. J Magn Reson Imaging. 2011 Jan;33(1):136-42. doi: 10.1002/jmri.22414. — View Citation

Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol. 2013 Jun;37(3):207-18. doi: 10.1016/j.canep.2012.12.009. Epub 2013 Jan 24. — View Citation

Zhuang Y, Miskimins WK. Metformin induces both caspase-dependent and poly(ADP-ribose) polymerase-dependent cell death in breast cancer cells. Mol Cancer Res. 2011 May;9(5):603-15. doi: 10.1158/1541-7786.MCR-10-0343. Epub 2011 Mar 21. — View Citation

* Note: There are 51 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Secondary	R0 resection rates in patients undergoing curative PDAC resection	Proportion of patients with R0 resections.	6 months
Secondary	The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting GGT (mmol/L)	The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.	6 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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