Gemcitabine Hydrochloride, Paclitaxel Albumin-Stabilized Nanoparticle Formulation, Metformin Hydrochloride, and a Standardized Dietary Supplement in Treating Patients With Pancreatic Cancer That Cannot be Removed by Surgery

Study Overview
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Brief Summary
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This pilot phase I trial studies the side effects of gemcitabine hydrochloride, nab-paclitaxel, metformin hydrochloride, and a standardized dietary supplement in treating patients with pancreatic cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Metformin hydrochloride, used for diabetes, may also help kill cancer cells. Dietary supplements (curcumin, vitamin D, vitamin K2, vitamin K1, B-6, high selenium broccoli sprouts, epigallocatechin gallate, L-carnitine, garlic extract, genistein, zinc amino chelate, mixed toxopherols, ascorbic acid, D-limonene) can block different targets in the cancer cell simultaneously and may slow down cancer growth. Giving gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, and metformin hydrochloride with a dietary supplement may work better in treating patients with pancreatic cancer that cannot be removed by surgery.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the compliance, toxicity and feasibility of administering gemcitabine hydrochloride (gemcitabine), nab-paclitaxel (abraxane), metformin hydrochloride (metformin), and the dietary supplement (DS). SECONDARY OBJECTIVES: I. To assess the response rate associated with this combination therapy in pancreatic cancer patients. II. To assess the progression-free survival and overall survival of all patients who start protocol therapy, and describe the outcomes based on measures of compliance during the lead-in week, and compliance with supplement during chemotherapy. III. To collect and analyze peripheral blood and pre-treatment biopsy samples for an exploratory analysis of biological correlatives. IV. To assess quality of life utilizing the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. OUTLINE: Patients receive gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) on days 1, 8, and 15. Patients also receive metformin hydrochloride orally (PO) twice daily (BID) starting day -6 and dietary supplement PO BID starting day -3. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months.

Official Title
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A Pilot Study of Gemcitabine, Abraxane, Metformin and a Standardized Dietary Supplement (DS) in Patients With Unresectable Pancreatic Cancer

Conditions
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Pancreatic Adenocarcinoma, Unresectable Pancreatic Carcinoma, Stage III Pancreatic Cancer AJCC v6 and v7, Stage IV Pancreatic Cancer AJCC v6 and v7

Intervention / Treatment
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* Drug: Gemcitabine Hydrochloride
* Drug: Paclitaxel Albumin-Stabilized Nanoparticle Formulation
* Drug: Metformin Hydrochloride
* Dietary Supplement: Therapeutic Dietary Intervention
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a histologic diagnosis of pancreatic adenocarcinoma Patient must have unresectable disease Patients must not have received prior chemotherapy except for the following circumstances; gemcitabine and capecitabine chemotherapy given in the adjuvant setting is allowed if the recurrence is greater than 6 months from the completion of chemotherapy; radiation sensitizing doses of 5-fluororuracil or capecitabine are allowed as part of adjuvant treatment and recurrence must be documented greater than 6 months from the completion of adjuvant therapy Computed tomography (CT) or magnetic resonance imaging (MRI) scan must be obtained within 4 weeks prior to study entry Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Absolute neutrophil count > 1,500/mcl Platelet count > 100,000/mcl Creatinine < 1.4 mg/dl and/or a measured creatinine clearance > 60 cc/min Bilirubin < 1.4 mg/dl Alanine aminotransferase (ALT), aspartate aminotransferase (AST) no greater than 3.0 times the upper limit of normal Patients currently being treated for severe infections or who are recovering from major surgery or other intercurrent illnesses are ineligible until recovery is deemed complete by the investigator Patients must not be pregnant or nursing; women and men of reproductive potential must have agreed to use an effective contraceptive method All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines Patients must be able to swallow pills and must not have malabsorption problems or ongoing nausea and vomiting that would affect oral treatment No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years Patients currently taking metformin will be eligible Patients allergic to eggs are not eligible Patients taking additional dietary/herbal supplements (excluding Senekot) outside of this protocol and refusing to stop are not eligible Patients requiring warfarin are not eligible

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 (gemcitabine, Abraxane, metformin, DS)<br>Patients receive gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation IV on days 1, 8, and 15. Patients also receive metformin hydrochloride PO BID starting day -6 and dietary supplement PO BID starting day -3. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: dFdCyd;Drug: Paclitaxel Albumin-Stabilized Nanoparticle Formulation<br>* Given IV<br>* Other names: Abraxane;Drug: Metformin Hydrochloride<br>* Given PO<br>* Other names: Metformin HCl;Dietary Supplement: Therapeutic Dietary Intervention<br>* Given PO<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of the combination of gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, metformin hydrochloride, and a dietary supplement | Feasibility is defined at 1 or fewer patients experiencing a dose limiting toxicity within the first 6 patients. | Up to 24 months | 
| Compliance of the combination of gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, metformin hydrochloride, and a dietary supplement (percent of patients who are fully compliant) | The percent of patients who are fully compliant in the first week will be estimated with a 95% confidence interval. The compliance will be measured similarly for each course prior to study treatment discontinuation. The impact of less than full compliance (both during the lead-in period and during chemotherapy) on the biomarkers and outcome, and qualitatively study patient reasons and specific supplement patterns related to non-compliance will be explored. | Up to 24 months | 
| Toxicity of the combination of gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, metformin hydrochloride, and a dietary supplement (National Cancer Institute Common Terminology for Adverse Events criteria version 4) | Summarized using the National Cancer Institute Common Terminology for Adverse Events criteria version 4. Tables will summarize the highest grade per patient that is possibly related to treatment, and the number of patients requiring dose modifications will also be presented. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Evaluated using the Kaplan-Meier methods. | Up to 24 months | 
| Overall survival | Evaluated using the Kaplan-Meier methods. | Up to 24 months | 
| Time to treatment failure | Evaluated using the Kaplan-Meier methods. | Up to 24 months |