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

Primary Purpose

Resectable Pancreatic Ductal Adenocarcinoma

Status

Unknown status

Phase

Phase 2

Locations

Canada

Study Type

Interventional

Intervention

Metformin Hydrochloride 500Mg Tablet

About this trial

This is an interventional treatment trial for Resectable Pancreatic Ductal Adenocarcinoma focused on measuring Resectable pancreatic ductal adenocarcinoma, PDAC, Metformin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

BC Cancer Agency - Vancouver Cancer Centre

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Metformin

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

R0 resection rates in patients undergoing curative PDAC resection

Proportion of patients with R0 resections.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT02978547

First Posted

November 2, 2016

Last Updated

January 16, 2018

Sponsor

British Columbia Cancer Agency

Collaborators

Pancreatic Cancer Canada, BC Cancer Foundation

1. Study Identification

Unique Protocol Identification Number

NCT02978547

Brief Title

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

Acronym

Metformin 001

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2018

Overall Recruitment Status

Unknown status

Study Start Date

January 2019 (Anticipated)

Primary Completion Date

June 2020 (Anticipated)

Study Completion Date

January 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

British Columbia Cancer Agency

Collaborators

Pancreatic Cancer Canada, BC Cancer Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Resectable Pancreatic Ductal Adenocarcinoma

Keywords

Resectable pancreatic ductal adenocarcinoma, PDAC, Metformin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Metformin

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Metformin Hydrochloride 500Mg Tablet

Intervention Description

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 Measure Information:

Title

The effect of neoadjuvant metformin treatment on tumour cell proliferation in PDAC tumours

Description

Assessment of Ki-67 fraction as assessed by IHC of pre- and post-metformin tumour samples.

Time Frame

6 months

Secondary Outcome Measure Information:

Title

R0 resection rates in patients undergoing curative PDAC resection

Description

Proportion of patients with R0 resections.

Time Frame

6 months

Title

The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting GGT (mmol/L)

Description

The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.

Time Frame

6 months

Title

The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting glucose (mmol/L)

Description

The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.

Time Frame

6 months

Title

The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting insulin (mU/L)

Description

The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.

Time Frame

6 months

Title

The effect of metformin on glucose and insulin metabolism as assessed by serum marker, HOMA index

Description

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.

Time Frame

6 months

Title

The effect of metformin on glucose and insulin metabolism as assessed by clinical marker, weight (kg)

Description

The clinical marker will be reported with pre- and post-metformin values compared.

Time Frame

6 months

Title

The effect of metformin on metabolomic profile of pre- and post-metformin samples

Description

Serum and urine metabolomic profile. Comparison of metabolite levels in pre-and post-metformin samples.

Time Frame

6 months

Title

Transcriptome sequencing (RNAseq) of pre- and post-treatment tumour samples.

Description

Time Frame

6 months

Title

Plasma ctDNA, measured as percentage of mutant to total DNA fragments in plasma

Description

Time Frame

6 months

Title

Correlation between imaging and pathologic parameters

Description

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Daniel J Renouf, MD

Phone

6048776000

Ext

2445

drenouf@bccancer.bc.ca

First Name & Middle Initial & Last Name or Official Title & Degree

Hui-li Wong, MD

Phone

6048776000

Ext

2445

HuiLi.Wong@bccancer.bc.ca

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Daniel J Renouf, MD

Organizational Affiliation

British Columbia Cancer Agency

Official's Role

Principal Investigator

Facility Information:

Facility Name

BC Cancer Agency - Vancouver Cancer Centre

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V5Z 4E6

Country

Canada

12. IPD Sharing Statement

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

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