Metformin Combined With Gemcitabine as Adjuvant Therapy for Pancreatic Cancer After Curative Resection

Study Overview
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Brief Summary
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Pancreatic cancer represents the most lethal of the common malignancies with a 5-year survival rate of less than 5%. For patients who are eligible for potentially curative resection, despite mortality and morbidity rates after surgery have improved, the recurrence rate is up to 85% within 2 years. Data from clinical trials indicate that adjuvant chemotherapy enhances 5-year survival to  25% for patients who have undergone surgery to remove their tumor; and gemcitabine is the standard regimen of chemotherapy. Metformin is the first-line treatment for type 2 diabetes mellitus. Literatures reported that metformin might inhibit tumor growth by blocking some enzymes needed for cell growth. Some retrospective studies have revealed that diabetic patients taking metformin were less likely to develop pancreatic cancer. Additionally, pancreatic cancer patients treated with metformin showed a better survival than those without metformin. In this study, the researchers intend to investigate the activity and safety of the combination of gemcitabine and metformin in treating patients with pancreatic cancer that have removed by surgery.

Official Title
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A Phase II, Randomized, Double-blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of the Combination of Gemcitabine and Metformin in Treating Patients With Pancreatic Cancer After Curative Resection

Conditions
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Stage IA Pancreatic Adenocarcinoma, Stage IB Pancreatic Adenocarcinoma, Stage IIA Pancreatic Adenocarcinoma, Stage IIB Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Metformin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed content obtained prior to treatment Age ≥ 18 years and ≤ 80 years Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Patients must have histologically confirmed pancreatic adenocarcinoma (or any mixed pathology if adenocarcinoma is predominant) after curative resection (R0). The pathological staging does not exceed the stage IIB. No tumor lesions are seen by abdominal and thoracic CT scan 4 8 weeks after surgery, and no serious adverse events are occurred during this period The expected survival after surgery ≥ 6 months White blood cell (WBC) ≥ 3 × 10^9/L; Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; Platelets (PLT) ≥ 100 × 10^9/L; Hemoglobin (Hgb) ≥ 9 g/dL Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]/ alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤ 2.5 × institutional upper limit of normal (ULN); Total bilirubin (TBIL) ≤ ULN; Creatinine (CRE) ≤ 1.5 × ULN Prothrombin time (PT) and international normalized ratio (INR) ≤ 1.5 × ULN Patients with diabetes (diagnosed after surgery) are eligible for this trial; all diabetic patients who are enrolled on this study should discuss the need to change their diabetes management regimen with their primary care physician or endocrinologist prior to enrollment Diabetic patients who are on metformin are eligible as long as they have been on metformin for less than 6 months (estimated 6 months or less duration of metformin therapy from start of metformin to enrollment on study) Exclusion Criteria: Active second primary malignancy or history of second primary malignancy within the last 3 years Patients who have received any form of anti-tumor therapy before surgery, including chemotherapy, radiotherapy, interventional chemoembolization, radiofrequency ablation, and molecular targeted therapy Use of any other investigational agents Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, internal hemorrhage, pancreatic leakage, bile leakage, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements History of allergic reactions attributed to compounds of similar chemical or biological composition to metformin or gemcitabine Current use of metformin for more than 6 months prior to enrollment on study Metabolic acidosis, acute or chronic, including ketoacidosis Pregnant or nursing women Human immunodeficiency virus (HIV)-positive patients Patients who are unwilling or unable to comply with study procedures

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: gemcitabine + placebo<br>gemcitabine at 1000 mg/m^2 on days 1, 8, and 15; placebo at 2 g on days 1-28 | Drug: Gemcitabine<br>* Patients receive gemcitabine 1000 mg/m^2 (iv, 30 minutes) on days 1, 8, and 15 for 3 weeks, followed by one week without treatment, and also receive placebo (Arm I)/ metformin (Arm II) on days 1-28. Treatment repeats every 4 weeks for up to 6 circles in the absence of disease recurrence or unacceptable toxicity.<br>* Other names: GEMZAR;Drug: placebo<br>* Placebo will be administered at a dose of 500 mg twice daily. If well tolerated, the dose will be increased to 1000 mg twice daily in the second week. Treatment repeats every 4 weeks (2 g on days 1-28) for up to 6 circles in the absence of disease recurrence or unacceptable toxicity.<br>|
| Experimental: gemcitabine + metformin<br>gemcitabine at 1000 mg/m^2 on days 1, 8, and 15; metformin at 2 g on days 1-28 | Drug: Gemcitabine<br>* Patients receive gemcitabine 1000 mg/m^2 (iv, 30 minutes) on days 1, 8, and 15 for 3 weeks, followed by one week without treatment, and also receive placebo (Arm I)/ metformin (Arm II) on days 1-28. Treatment repeats every 4 weeks for up to 6 circles in the absence of disease recurrence or unacceptable toxicity.<br>* Other names: GEMZAR;Drug: Metformin<br>* Metformin will be administered at a dose of 500 mg twice daily. If well tolerated, the dose will be increased to 1000 mg twice daily in the second week. Treatment repeats every 4 weeks (2 g on days 1-28) for up to 6 circles in the absence of disease recurrence or unacceptable toxicity.<br>* Other names: glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival at one year after curative resection | To evaluate the therapeutic efficacy of gemcitabine chemotherapy with versus without metformin hydrochloride in terms of recurrence-free survival in patients with pancreatic cancer at one year after curative resection. Computed tomography (CT) scan | From date of randomization (after curative resection) until the date of first documented recurrence or date of death from any cause, whichever came first, assessed 2 months during therapy and 3 months thereafter up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival after curative resection | To evaluate the overall survival of patients (after curative resection) treated with this regimen. Outpatient visit, phone interview | From date of randomization (after curative resection) until the date of death from any cause, assessed one month during therapy and 3 months thereafter up to 24 months | 
| Quality of life score after curative resection | To evaluate the quality of life score of patients (after curative resection) treated with this regimen. Outpatient visit, phone interview | One month during therapy and 3 months thereafter up to 24 months | 
| Number of grade 3 and 4 toxicities according to NCI CTCAE version 4.0 | To evaluate the occurrence of grade 3 and 4 toxicities according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE; version 4.0) in patients treated with this regimen. The toxicity profile includes but not limits neutropenia, thrombocytopenia, peripheral neuropathy, hypoglycemia, metabolic acidosis (acute or chronic, including ketoacidosis), which will be summarized as the percentage of patients by type and grade according to treatment group. Outpatient visit, laboratory findings | One week during therapy and 3 months thereafter up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic Cancer, Pancreatic Adenocarcinoma, Metformin, Gemcitabine, Adjuvant Therapy