Curcumin in Preventing Gastric Cancer in Patients With Chronic Atrophic Gastritis or Gastric Intestinal Metaplasia

Study Overview
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Brief Summary
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This randomized phase IIb trial studies how well curcumin works in preventing gastric cancer in patients with chronic atrophic gastritis and/or gastric intestinal metaplasia. Curcumin is an antioxidant compound found in plants that may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the change in gastric mucosal interleukin 1beta (IL-1beta) cytokine level, quantified by Luminex assay technology, after a 6-month intervention in participants randomly assigned to the curcumin (Meriva [curcuminoids]) versus placebo arms. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of Meriva versus placebo. II. To compare changes in Histology Gastric Score (HGS) from baseline to 6 months for Meriva versus placebo. III. To compare changes in additional gastric mucosal cytokine/chemokine levels (interleukin 8 [IL-8], tumor necrosis factor-alpha [TNFalpha], and inducible protein 10 [IP-10]; quantified by Luminex assay). IV. To compare changes in gastric mucosal deoxyribonucleic acid (DNA) damage as assessed by immunohistochemistry (IHC), of the biomarkers 8-hydroxy-2'-deoxyguanosine (8-OHdG) and phosphorylated subtype of histone H2A (H2AX). V. To explore associations between proinflammatory cytokine genotype status (IL-1beta, IL-8, and TNFalpha single nucleotide polymorphisms [SNPs]; characterized at baseline) and the above outcomes. OUTLINE: Patients are randomized into 1 of 2 arms. ARM 1: Patients receive curcumin orally (PO) twice daily (BID) for 180 days in the absence of unacceptable toxicity. ARM 2: Patients receive placebo PO BID for 180 days in the absence of unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and 7 months.

Official Title
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Randomized, Double-Blind, Placebo-Controlled Trial of Meriva® (Curcuminoids) as a Candidate Chemoprevention Agent for Gastric Carcinogenesis

Conditions
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Chronic Atrophic Gastritis

Intervention / Treatment
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* Drug: Curcumin
* Other: Laboratory Biomarker Analysis
* Other: Placebo Administration
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRE-REGISTRATION INCLUSION CRITERIA Ability to understand and the willingness to sign a written informed consent document Willingness to undergo screening tests and procedures Willingness to provide blood and tissue samples for safety/toxicity monitoring and biomarker analyses Willingness to avoid the use of curcumin or any over-the-counter or prescription medications containing curcumin or curcuminoids REGISTRATION/RANDOMIZATION INCLUSION CRITERIA Histologically-confirmed chronic multifocal atrophic gastritis (MAG) and/or gastric intestinal metaplasia (GIM) Helicobacter pylori negative, defined as negative stool antigen testing and negative histological examination Eastern Cooperative Oncology Group (ECOG) performance status =< 1 Aspartate transaminase (AST), alanine transferase (ALT) within institutional limits of normal or judged to be not clinically significant by the investigator Alkaline phosphatase within institutional limits of normal or judged to be not clinically significant by the investigator Platelets within institutional limits of normal or judged to be not clinically significant by the investigator Hemoglobin within institutional limits of normal or judged to be not clinically significant by the investigator White blood cells (WBC) within institutional limits of normal or judged to be not clinically significant by the investigator Blood urea nitrogen (BUN) within institutional limits of normal or judged to be not clinically significant by the investigator Total bilirubin within institutional limits of normal or judged to be not clinically significant by the investigator Creatinine within institutional limits of normal or judged to be not clinically significant by the investigator Not pregnant or breast feeding; Note: The effects of Meriva on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, individuals of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Exclusion Criteria: PRE-REGISTRATION EXCLUSION CRITERIA History of other malignancy =< 2 years prior to the registration/randomization evaluation, with the exception of basal cell or squamous cell skin cancer History of colorectal cancer; exception: individuals with stage I or II colorectal cancer who have not received any chemotherapy Known diagnosis of human immunodeficiency virus (HIV); Note: An HIV screening test does not have to be performed to evaluate this criterion History of gastric surgery Receiving any other investigational agents Use of any anticoagulation medications, such as warfarin or Coumadin 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 breast feeding; Note: Pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Meriva, breastfeeding should be discontinued if the mother is treated with Meriva REGISTRATION/RANDOMIZATION EXCLUSION CRITERIA Receiving any other investigational, anticoagulation, and/or chemotherapy agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to Meriva

Ages Eligible for Study
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Minimum Age: 21 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (curcumin)<br>Patients receive curcumin PO BID for 180 days in the absence of unacceptable toxicity. | Drug: Curcumin<br>* Given PO<br>* Other names: Turmeric Yellow;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO BID for 180 days in the absence of unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<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 |
| --- | --- | --- |
| Absolute change in IL-1beta cytokine levels in the gastric mucosa | Will be measured by Luminex assay. If the data are not normally distributed, the Wilcoxon Rank-Sum test will be used. The 95% confidence intervals will also be provided. | Baseline up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 4. The maximum grade for each type of adverse event will be recorded for each participant and frequency tables will be reviewed to determine the overall patterns. The number and severity of adverse events (overall and by intervention group) will be tabulated and summarized. | From time of first dose of curcumin up to 7 months | 
| Change in histology gastric score | Will compare changes in histology gastric score for curcumin versus placebo. | Baseline up to 6 months | 
| Additional gastric mucosal cytokine/chemokine levels (IL-8, TNFalpha, and IP-10) | Will be quantified with Luminex assay. Changes in the concentrations (or categories) will be explored within and between the intervention arms. Fisher's exact tests, Wilcoxon rank sum tests, and two-sample t-tests will be used to assess differences between groups. McNemar's tests, Wilcoxon signed rank tests, and paired sample t-tests will be used to assess differences within each arm. Graphical methods (i.e. boxplots, scatter plots, etc.) will also be used to describe the data. | Baseline up to 6 months | 
| Gastric mucosal deoxyribonucleic acid (DNA) damage | Will be assessed by immunohistochemistry. Fisher's exact tests, Wilcoxon rank sum tests, and two-sample t-tests will be used to assess differences between groups. McNemar's tests, Wilcoxon signed rank tests, and paired sample t-tests will be used to assess differences within each arm. Graphical methods (i.e. boxplots, scatter plots, etc.) will also be used to describe the data. | Baseline up to 6 months |