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

Primary Purpose

Stage IA Pancreatic Adenocarcinoma, Stage IB Pancreatic Adenocarcinoma, Stage IIA Pancreatic Adenocarcinoma

Status

Completed

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

Gemcitabine

Metformin

placebo

About this trial

This is an interventional treatment trial for Stage IA Pancreatic Adenocarcinoma focused on measuring Pancreatic Cancer, Pancreatic Adenocarcinoma, Metformin, Gemcitabine, Adjuvant Therapy

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Pancreatic Cancer Institute, Fudan University

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

gemcitabine + placebo

gemcitabine + metformin

Arm Description

gemcitabine at 1000 mg/m^2 on days 1, 8, and 15; placebo at 2 g on days 1-28

gemcitabine at 1000 mg/m^2 on days 1, 8, and 15; metformin at 2 g on days 1-28

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Overall survival after curative resection

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

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

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

Full Information

NCT ID

NCT02005419

First Posted

November 24, 2013

Last Updated

February 1, 2019

Sponsor

Xian-Jun Yu

1. Study Identification

Unique Protocol Identification Number

NCT02005419

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2019

Overall Recruitment Status

Completed

Study Start Date

December 2013 (Actual)

Primary Completion Date

February 2017 (Actual)

Study Completion Date

December 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Xian-Jun Yu

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

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

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

Keywords

Pancreatic Cancer, Pancreatic Adenocarcinoma, Metformin, Gemcitabine, Adjuvant Therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

300 (Actual)

8. Arms, Groups, and Interventions

Arm Title

gemcitabine + placebo

Arm Type

Placebo Comparator

Arm Description

gemcitabine at 1000 mg/m^2 on days 1, 8, and 15; placebo at 2 g on days 1-28

Arm Title

gemcitabine + metformin

Arm Type

Experimental

Arm Description

gemcitabine at 1000 mg/m^2 on days 1, 8, and 15; metformin at 2 g on days 1-28

Intervention Type

Drug

Intervention Name(s)

Gemcitabine

Other Intervention Name(s)

GEMZAR

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Metformin

Other Intervention Name(s)

glucophage

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

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.

Primary Outcome Measure Information:

Title

Recurrence-free survival at one year after curative resection

Description

Time Frame

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 Measure Information:

Title

Overall survival after curative resection

Description

To evaluate the overall survival of patients (after curative resection) treated with this regimen. Outpatient visit, phone interview

Time Frame

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

Title

Quality of life score after curative resection

Description

To evaluate the quality of life score of patients (after curative resection) treated with this regimen. Outpatient visit, phone interview

Time Frame

One month during therapy and 3 months thereafter up to 24 months

Title

Number of grade 3 and 4 toxicities according to NCI CTCAE version 4.0

Description

Time Frame

One week during therapy and 3 months thereafter up to 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Xianjun Yu, M.D., Ph.D.

Organizational Affiliation

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center; Shanghai Pancreatic Cancer Institute; Pancreatic Cancer Institute, Fudan University. Shanghai, China.

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Pancreatic Cancer Institute, Fudan University

City

Shanghai

ZIP/Postal Code

200032

Country

China

12. IPD Sharing Statement

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

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