Clinical trial NCT02978547: The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma
Official title: The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Resectable Pancreatic Ductal Adenocarcinoma
Keywords: Resectable pancreatic ductal adenocarcinoma
PDAC
Metformin
Lead sponsor: British Columbia Cancer Agency
Sponsor class: OTHER
Collaborators: name: Pancreatic Cancer Canada
name: BC Cancer Foundation
First posted: 2016-12-01
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: The effect of neoadjuvant metformin treatment on tumour cell proliferation in PDAC tumours
timeFrame: 6 months
Secondary outcomes:
measure: R0 resection rates in patients undergoing curative PDAC resection
timeFrame: 6 months
measure: The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting GGT (mmol/L)
timeFrame: 6 months
measure: The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting glucose (mmol/L)
timeFrame: 6 months
measure: The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting insulin (mU/L)
timeFrame: 6 months
measure: The effect of metformin on glucose and insulin metabolism as assessed by serum marker, HOMA index
timeFrame: 6 months
measure: The effect of metformin on glucose and insulin metabolism as assessed by clinical marker, weight (kg)
timeFrame: 6 months
measure: The effect of metformin on metabolomic profile of pre- and post-metformin samples
timeFrame: 6 months
measure: Transcriptome sequencing (RNAseq) of pre- and post-treatment tumour samples.
timeFrame: 6 months
measure: Plasma ctDNA, measured as percentage of mutant to total DNA fragments in plasma
timeFrame: 6 months
measure: Correlation between imaging and pathologic parameters
timeFrame: 6 months
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: BC Cancer Agency - Vancouver Cancer Centre
state: British Columbia
Study officials:
affiliation: British Columbia Cancer Agency
name: Daniel J Renouf, MD
role: PRINCIPAL_INVESTIGATOR
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