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The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma (Metformin 001)

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ClinicalTrials.gov Identifier: NCT02978547
Recruitment Status : Not yet recruiting
First Posted : December 1, 2016
Last Update Posted : January 18, 2018
Sponsor:
Collaborators:
Pancreatic Cancer Canada
BC Cancer Foundation
Information provided by (Responsible Party):
British Columbia Cancer Agency

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.


Condition or disease Intervention/treatment Phase
Resectable Pancreatic Ductal Adenocarcinoma Drug: Metformin Hydrochloride 500Mg Tablet Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma
Estimated Study Start Date : January 2019
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
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.




Primary Outcome Measures :
  1. The effect of neoadjuvant metformin treatment on tumour cell proliferation in PDAC tumours [ Time Frame: 6 months ]
    Assessment of Ki-67 fraction as assessed by IHC of pre- and post-metformin tumour samples.


Secondary Outcome Measures :
  1. R0 resection rates in patients undergoing curative PDAC resection [ Time Frame: 6 months ]
    Proportion of patients with R0 resections.

  2. The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting GGT (mmol/L) [ Time Frame: 6 months ]
    The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.

  3. The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting glucose (mmol/L) [ Time Frame: 6 months ]
    The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.

  4. The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting insulin (mU/L) [ Time Frame: 6 months ]
    The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.

  5. The effect of metformin on glucose and insulin metabolism as assessed by serum marker, HOMA index [ Time Frame: 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.

  6. The effect of metformin on glucose and insulin metabolism as assessed by clinical marker, weight (kg) [ Time Frame: 6 months ]
    The clinical marker will be reported with pre- and post-metformin values compared.

  7. The effect of metformin on metabolomic profile of pre- and post-metformin samples [ Time Frame: 6 months ]

    Serum and urine metabolomic profile.

    Comparison of metabolite levels in pre-and post-metformin samples.


  8. Transcriptome sequencing (RNAseq) of pre- and post-treatment tumour samples. [ Time Frame: 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.


  9. Plasma ctDNA, measured as percentage of mutant to total DNA fragments in plasma [ Time Frame: 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.


  10. Correlation between imaging and pathologic parameters [ Time Frame: 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.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02978547


Contacts
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Contact: Daniel J Renouf, MD 6048776000 ext 2445 drenouf@bccancer.bc.ca
Contact: Hui-li Wong, MD 6048776000 ext 2445 HuiLi.Wong@bccancer.bc.ca

Locations
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Canada, British Columbia
BC Cancer Agency - Vancouver Cancer Centre
Vancouver, British Columbia, Canada, V5Z 4E6
Sponsors and Collaborators
British Columbia Cancer Agency
Pancreatic Cancer Canada
BC Cancer Foundation
Investigators
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Principal Investigator: Daniel J Renouf, MD British Columbia Cancer Agency

Publications:
Canadian Cancer Society's Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2015. Toronto, ON: Canadian Cancer Society. 2015.
AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010.
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.

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Responsible Party: British Columbia Cancer Agency
ClinicalTrials.gov Identifier: NCT02978547     History of Changes
Other Study ID Numbers: H16-02566
First Posted: December 1, 2016    Key Record Dates
Last Update Posted: January 18, 2018
Last Verified: January 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by British Columbia Cancer Agency:
Resectable pancreatic ductal adenocarcinoma
PDAC
Metformin

Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs