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

Phase 2

Completed

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

Interventions: Drug: Gemcitabine
Drug: placebo
Drug: Metformin

Registration Number: NCT02005419

Lead Sponsor: Xian-Jun Yu

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 300

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

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
gemcitabine + placebo	Gemcitabine	gemcitabine at 1000 mg/m\^2 on days 1, 8, and 15; placebo at 2 g on days 1-28
gemcitabine + placebo	placebo	gemcitabine at 1000 mg/m\^2 on days 1, 8, and 15; placebo at 2 g on days 1-28
gemcitabine + metformin	Gemcitabine	gemcitabine at 1000 mg/m\^2 on days 1, 8, and 15; metformin at 2 g on days 1-28
gemcitabine + metformin	Metformin	gemcitabine at 1000 mg/m\^2 on days 1, 8, and 15; metformin at 2 g on days 1-28

Primary Outcome Measures

Name	Time	Method
Recurrence-free survival at one year after curative resection	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	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

Secondary Outcome Measures

Name	Time	Method
Overall survival after curative resection	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	To evaluate the overall survival of patients (after curative resection) treated with this regimen. Outpatient visit, phone interview
Quality of life score after curative resection	One month during therapy and 3 months thereafter up to 24 months	To evaluate the quality of life score of patients (after curative resection) treated with this regimen. Outpatient visit, phone interview
Number of grade 3 and 4 toxicities according to NCI CTCAE version 4.0	One week during therapy and 3 months thereafter up to 24 months	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

Trial Locations

Locations (1): Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Pancreatic Cancer Institute, Fudan University
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Shanghai, China

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

Recruitment & Eligibility

Study & Design

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