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

NCT02978547 | Unknown Phase 2

• 1 other identifier: H16-02566
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Resectable Pancreatic Ductal Adenocarcinoma

Keywords

Resectable pancreatic ductal adenocarcinoma; PDAC; Metformin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• R0 resection rates in patients undergoing curative PDAC resection

  6 months

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

  6 months

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

  6 months

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

  6 months

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

  6 months

Study Arms (1)

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.

Drug: Metformin Hydrochloride 500Mg Tablet

Interventions

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.

Metformin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• British Columbia Cancer Agency: lead
• Pancreatic Cancer Canada: collaborator
• BC Cancer Foundation: collaborator

Study Sites (1)

BC Cancer Agency - Vancouver Cancer Centre

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Related Publications (51)

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MeSH Terms

Interventions

Metformin; Tablets

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Dosage Forms; Pharmaceutical Preparations

Study Officials

• Daniel J Renouf, MD

  British Columbia Cancer Agency

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Daniel J Renouf, MD

CONTACT

6048776000; drenouf@bccancer.bc.ca

Hui-li Wong, MD

CONTACT

6048776000; HuiLi.Wong@bccancer.bc.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2016
• First Posted: December 1, 2016
• Study Start: January 1, 2019
• Primary Completion: June 1, 2020
• Study Completion: January 1, 2021
• Last Updated: January 18, 2018

Record last verified: 2018-01

Locations

CA (1)