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

January 16, 2018 updated by: British Columbia Cancer Agency

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.

Study Overview

Study Type

Interventional

Enrollment (Anticipated)

20

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 4E6
        • BC Cancer Agency - Vancouver Cancer Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / 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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
R0 resection rates in patients undergoing curative PDAC resection
Time Frame: 6 months
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)
Time Frame: 6 months
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)
Time Frame: 6 months
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)
Time Frame: 6 months
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
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 months
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.
6 months
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.

6 months
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.

6 months
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.

6 months
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.

6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ANTICIPATED)

January 1, 2019

Primary Completion (ANTICIPATED)

June 1, 2020

Study Completion (ANTICIPATED)

January 1, 2021

Study Registration Dates

First Submitted

November 2, 2016

First Submitted That Met QC Criteria

November 28, 2016

First Posted (ESTIMATE)

December 1, 2016

Study Record Updates

Last Update Posted (ACTUAL)

January 18, 2018

Last Update Submitted That Met QC Criteria

January 16, 2018

Last Verified

January 1, 2018

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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