Metformin Plus Modified FOLFOX 6 in Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well metformin hydrochloride, leucovorin calcium, fluorouracil, and oxaliplatin work in treating patients with metastatic pancreatic cancer. Metformin hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving metformin hydrochloride together with combination chemotherapy may kill more tumor cells

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if metformin (metformin hydrochloride) when added to FOLFOX ( leucovorin calcium, fluorouracil, oxaliplatin) improves overall survival in patients with metastatic pancreatic cancer. SECONDARY OBJECTIVES: I. To assess response rate (RR). II. To assess progression free survival (PFS). III. To assess toxicity in patients with metastatic pancreatic cancer receiving FOLFOX and metformin. IV. To identify tumor/serum correlative markers. OUTLINE: Patients receive metformin hydrochloride orally (PO) twice daily (BID) on days 1-7 for an introductory period before the addition of FOLFOX. After the introductory period, patients will continue metformin twice daily and FOLFOX therapy comprising leucovorin calcium intravenously (IV) over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for periodically.

Official Title
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A Phase II Study of Metformin Plus Modified FOLFOX 6 in Patients With Metastatic Pancreatic Cancer

Conditions
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Acinar Cell Adenocarcinoma of the Pancreas, Duct Cell Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer

Intervention / Treatment
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* Drug: metformin hydrochloride
* Drug: oxaliplatin
* Drug: leucovorin calcium
* Drug: fluorouracil
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed metastatic pancreatic adenocarcinoma (or any mixed pathology if adenocarcinoma is predominant) Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan Patient must have not received systemic chemotherapy for metastatic disease; prior chemotherapy, radiation therapy, concurrent chemoradiation are allowed if used for treatment of non-metastatic disease; prior palliative radiation for symptom management is allowed; any chemotherapy must have been completed 4 weeks prior to enrollment; any radiotherapy must have been completed 2 weeks prior to enrollment Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Absolute neutrophil count ≥ 1,500/L Platelets ≥ 100,000/L Hemoglobin ≥ 9 g/dL Total bilirubin ≤ 2 mg/dL Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤ 2.5 x institutional upper limit of normal Creatinine ≤ 1.5 Women of childbearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately Subjects must have the ability to understand and the willingness to sign a written informed consent document Patients with diabetes 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: Chemotherapy within 4 weeks prior to entering the study, radiotherapy within 2 weeks prior to entering the study or failure to recover from adverse events due to agents administered more than 4 weeks earlier Prior treatment toxicities must be resolved to ≤ grade 1 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Current use of metformin for more than 6 months prior to enrollment on study Use of any other investigational agents Patients with untreated brain metastases should be excluded from this clinical trial History of allergic reactions attributed to compounds of similar chemical or biological composition to metformin or oxaliplatin or fluorouracil (5-FU) Active second primary malignancy or history of second primary malignancy within the last 3 years, with the exception of basal cell skin cancers or carcinoma in situ that have been adequately treated Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant or nursing women Human immunodeficiency virus (HIV)-positive patients Chronic or planned acute alcohol use of three or more drinks per day Metabolic acidosis, acute or chronic, including ketoacidosis

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (metformin hydrochloride, FOLFOX)<br>Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | Drug: metformin hydrochloride<br>* Given PO<br>* Other names: Glucophage;Drug: oxaliplatin<br>* Given IV<br>* Other names: L-OHP;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival (OS) | Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution. | Time from first day of treatment to death from any cause, assessed up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR) Objective Tumor Response Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to Response Evaluation Criteria in Solid Tumors (RECIST) | CBR is the number of participants of the total analysis population who experience confirmed complete (CR) or partial response (PR) per RECIST CR = all detectable tumor has disappeared PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum Stable Disease (SD) = small changes that do not meet previously given criteria. Progressive disease (PD) = a >=20% increase in target lesions The true response rate of the combination therapy for this patient population will be estimated based on the number of response using a binomial distribution and its confidence intervals will be estimated using Wilson's method. | 1 year | 
| Clinical Benefit Rate (CBR) Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to RECIST | CBR is the number of participants of the total analysis population who experience a CR, PR, or SD per RECIST CR = all detectable tumor has disappeared PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum SD = small changes that do not meet previously given criteria. PD = a >=20% increase in target lesions | 1 year | 
| Progression Free Survival According to RECIST 1.1 Criteria | Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution. | Time from first day of treatment received to the earlier documented disease progression or death from any cause, assessed up to 1 year | 
| Number of Grade 3 and 4 Toxicities According to NCI CTCAE Version 4.0 | The toxicity profile of the combination will be tabulated. | Up to 1 year |