Phase II A Trial of Curcumin Among Patients With Prevalent Subclinical Neoplastic Lesions (Aberrant Crypt Foci)

Study Overview
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Brief Summary
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Chemoprevention is the use of certain substances to keep cancer from forming, growing, or coming back. Curcumin is a compound found in plants that may prevent colon cancer from forming. This phase II trial is studying how well curcumin works in preventing colon cancer in smokers with aberrant crypt foci.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine mean percentage change from baseline in prostaglandin E2 (PGE2) within ACF pre and post 30 days of curcumin administration at a specified dose. SECONDARY OBJECTIVS: I. To determine mean percentage change from baseline in 5-hydroxy-eicosatetraenoic acid (5-HETE) within ACF pre and post 30 days of curcumin administration at a specified dose. II. To determine mean percentage change from baseline in PGE2 and 5-HETE within comparison normal mucosa pre and post 30 days of curcumin administration at a specified dose. III. To quantify corresponding enzyme changes in the cyclooxygenases (COX-1, COX-2,) and lipoxygenase (5-LOX) protein abundance. Semi-quantitative changes in these proteins will be measured by western blotting and correlated with changes in prostaglandins and leukotrienes respectively. IV. Document changes in total ACF number. V. Determine proliferation by Ki-67 IHC in rectal mucosa pre and post therapy and correlate with changes in ACF number and size. VI. Determine curcumin concentration in rectal mucosa after 30 days therapy and correlate with PGE2 and 5-HETE changes described above. VII. Measure glutathione peroxidase (GPx) activity within the colon pre and post therapy as an indirect marker of reduced oxidative stress within the colonic epithelium. VIII. Ensure safety of all participants during course of study investigation. IX. Determine the curcumin concentration in plasma before and after treatment. OUTLINE: This is a multicenter, nonrandomized, uncontrolled study. Patients receive 1 of 2 doses of oral curcumin once daily. Treatment continues for 30 days in the absence of unacceptable toxicity or disease progression. Blood and tissue biopsies are obtained by sigmoidoscopy or colonoscopy at baseline and at day 30 for correlative biomarker studies. The change in prostaglandin E_2 (PGE_2) is assessed by enzyme immunoassay, 5-hydroxy-eicosatetraenoic acid (5-HETE) by high-performance liquid chromatography, cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) by western blotting, Ki-67 by immunohistochemistry, and glutathione peroxidase (GPx) by spectrophotometric assay. After completion of study therapy, patients are followed at 1 week. PROJECTED ACCRUAL: A total of 48 patients will be accrued for this study.

Official Title
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Phase IIA Trial of Curcumin Among Patients With Prevalent Subclinical Neoplastic Lesions (Aberrant Crypt Foci)

Conditions
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Healthy, no Evidence of Disease, Tobacco Use Disorder

Intervention / Treatment
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* Other: laboratory biomarker analysis
* Other: pharmacological study
* Drug: curcumin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current smoker with > 3 pack-year total smoking history Subjects taking NSAIDS or ASA < 10 days month are eligible but must undergo 14 day washout and refrain from use during the study Subjects who are: Having a clinically indicated screening/surveillance colonoscopy (e.g. due to risk factors, personal history, or symptoms) OR Not having a colonoscopy but are otherwise eligible. These subjects would undergo a flexible sigmoidoscopy. ECOG performance status 0-2 (Karnofsky > 60%) No severe organ dysfunction which might increase bleeding risk: Demonstrated by: Normal hematologic status (WBC > 3,000/mm^3, hemoglobin > 10.0 gm/dl, and platelet-count >100,000/mm^3), normal hepatic function (bilirubin < 1.5 mg/dl, transaminases < 1.5x institutional norms), and normal renal function (serum creatinine < 2.0 mg/dl, documented in clinical chart 28 days prior to enrollment Healthy current smokers (1 cigarette in previous yr) with > 3-pack year of cigarette smoking and able to provide written informed consent; there are no gender restrictions The effects of curcumin on the developing human fetus at the recommended therapeutic dose are unknown; for this reason women of childbearing 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 Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: NSAID or ASA use > 10 days /month; any current glucocorticoid use or omega 3-fatty acid supplement use Evidence of the following chronic medical conditions such as: Pregnant or lactating women and/or women who are contemplating pregnancy during the duration of the protocol History of chronic inflammatory bowel disease or prior pelvic irradiation History of peptic ulcer disease (PUD) endoscopically confirmed < 5 yrs from enrollment date Newly diagnosed colorectal cancer or advanced adenoma < 1 yr from enrollment Unspecified history of bleeding or coagulation disorder reported by patient or in medical history Hereditary Colon Cancer syndromes (FAP or HNPCC) Participants may not be receiving any other investigational agents History of contact dermatitis from turmeric Uncontrolled inter-current 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 women are excluded from this study because curcumin is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with curcumin, breastfeeding should be discontinued if the mother is treated with curcumin

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2g (curcumin)<br>Patients receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. | Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Drug: curcumin<br>* Given orally<br>* Other names: Diferuloylmethane;|
| Experimental: 4g (curcumin)<br>Patients receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. | Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Drug: curcumin<br>* Given orally<br>* Other names: Diferuloylmethane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF) | Baseline prostaglandin E2 (PGE2) values found in rectal aberrant crypt foci (ACF) tissue | Baseline | 
| Post-treatment in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF) | Post-treatment prostaglandin E2 (PGE2) values found in rectal aberrant crypt foci (ACF) tissue | At 30 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Within Aberrant Crypt Foci (ACF) | Baseline 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in rectal aberrant crypt foci (ACF) tissue | Baseline | 
| Post-treatment in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Within Aberrant Crypt Foci (ACF) | Post-treatment 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in rectal aberrant crypt foci (ACF) tissue | At 30 Day | 
| Baseline in Prostaglandin E2 (PGE2) Level in Normal Mucosa | Baseline prostaglandin E2 (PGE2) values found in normal mucosa rectal tissue | Baseline | 
| Post-treatment in Prostaglandin E2 (PGE2) Level in Normal Mucosa | Post-treatment prostaglandin E2 (PGE2) values found in normal mucosa rectal tissue | At 30 day | 
| Baseline in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Level in Normal Mucosa | Baseline 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in normal mucosa rectal tissue | Baseline | 
| Post-treatment in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Level in Normal Mucosa | Post-treatment 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in normal mucosa rectal tissue | At 30 day | 
| Change in Cyclooxygenases (COX-1, COX-2), and Lipoxygenase (5-LOX) Protein Abundance | The protein levels for each enzyme will be expressed as an absolute change from baseline and graphed against % change of its enzyme product in the same individual. The degree of correlation between these parameters will be assessed by either Pearson's correlation coefficient or Spearman's rank order correlation coefficient. | Baseline to 30 days | 
| Changes in Total Aberrant Crypt Foci (ACF) Number | Changes in total aberrant crypt foci (ACF) number = Number of ACF at pre-treatment - Number of ACF at post-treatment | Baseline to 30 days | 
| Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third |  | Baseline | 
| Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third |  | At 30 day | 
| Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third |  | Baseline | 
| Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third |  | At 30 day | 
| Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third |  | Baseline | 
| Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third |  | At 30 day | 
| Baseline Curcumin Concentration in Rectal Mucosa | If detectable in the rectal mucosa, it is predicted that curcumin concentrations and potentially curcumin conjugate concentrations will be associated with reduction in PGE2 and 5-HETE measured from colorectal mucosal biopsies. Pearson correlation coefficients between changes in baseline levels in these 2 parameters and curcumin concentration in rectal mucosa will be calculated. Endpoints may be log transformed as appropriate prior to analysis. | Baseline | 
| Post-treatment Curcumin Concentration in Rectal Mucosa | If detectable in the rectal mucosa, it is predicted that curcumin concentrations and potentially curcumin conjugate concentrations will be associated with reduction in PGE2 and 5-HETE measured from colorectal mucosal biopsies. Pearson correlation coefficients between changes in baseline levels in these 2 parameters and curcumin concentration in rectal mucosa will be calculated. Endpoints may be log transformed as appropriate prior to analysis. | At 30 day | 
| Baseline Curcumin Plasma Concentrations | Baseline curcumin conjugate concentrations will be measured directly from the subject's plasma and then the change in concentrations after the last dose of study drug will be measured. Concentrations will be measured and statistically evaluated by paired t-test or Wilcoxon matched-pairs signed-ranks test, as appropriate. | Baseline | 
| Post-treatment Curcumin Plasma Concentrations | Baseline curcumin conjugate concentrations will be measured directly from the subject's plasma and then the change in concentrations after the last dose of study drug will be measured. Concentrations will be measured and statistically evaluated by paired t-test or Wilcoxon matched-pairs signed-ranks test, as appropriate. | At 30 day | 
| Baseline Curcumin Conjugates Concentration in Rectal Mucosa | If detectable in the rectal mucosa, it is predicted that curcumin concentrations and potentially curcumin conjugate concentrations will be associated with reduction in PGE2 and 5-HETE measured from colorectal mucosal biopsies. Pearson correlation coefficients between changes in baseline levels in these 2 parameters and curcumin concentration in rectal mucosa will be calculated. Endpoints may be log transformed as appropriate prior to analysis. | Baseline | 
| Post-treatment Curcumin Conjugates Concentration in Rectal Mucosa | If detectable in the rectal mucosa, it is predicted that curcumin concentrations and potentially curcumin conjugate concentrations will be associated with reduction in PGE2 and 5-HETE measured from colorectal mucosal biopsies. Pearson correlation coefficients between changes in baseline levels in these 2 parameters and curcumin concentration in rectal mucosa will be calculated. Endpoints may be log transformed as appropriate prior to analysis. | At 30 day | 
| Baseline Curcumin Conjugates Plasma Concentrations | Baseline curcumin conjugate concentrations will be measured directly from the subject's plasma and then the change in concentrations after the last dose of study drug will be measured. Concentrations will be measured and statistically evaluated by paired t-test or Wilcoxon matched-pairs signed-ranks test, as appropriate. | Baseline | 
| Post-treatment Curcumin Conjugates Plasma Concentrations | Post-treatment curcumin conjugate concentrations will be measured directly from the subject's plasma and then the change in concentrations after the last dose of study drug will be measured. Concentrations will be measured and statistically evaluated by paired t-test or Wilcoxon matched-pairs signed-ranks test, as appropriate. | At 30 day | 
| Number of Participants at Each Adverse Event Grade Level |  | Baseline to 30 days |