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

Primary Purpose

Healthy, no Evidence of Disease, Tobacco Use Disorder

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
laboratory biomarker analysis
pharmacological study
curcumin
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Healthy, no Evidence of Disease

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Chao Family Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

2g (curcumin)

4g (curcumin)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Baseline in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF)
Baseline prostaglandin E2 (PGE2) values found in rectal aberrant crypt foci (ACF) tissue
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

Secondary Outcome Measures

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
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
Baseline in Prostaglandin E2 (PGE2) Level in Normal Mucosa
Baseline prostaglandin E2 (PGE2) values found in normal mucosa rectal tissue
Post-treatment in Prostaglandin E2 (PGE2) Level in Normal Mucosa
Post-treatment prostaglandin E2 (PGE2) values found in normal mucosa rectal tissue
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
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
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.
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
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third
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.
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.
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.
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.
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.
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.
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.
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.
Number of Participants at Each Adverse Event Grade Level

Full Information

First Posted
August 16, 2006
Last Updated
July 30, 2015
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00365209
Brief Title
Phase II A Trial of Curcumin Among Patients With Prevalent Subclinical Neoplastic Lesions (Aberrant Crypt Foci)
Official Title
Phase IIA Trial of Curcumin Among Patients With Prevalent Subclinical Neoplastic Lesions (Aberrant Crypt Foci)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2014
Overall Recruitment Status
Completed
Study Start Date
October 2006 (undefined)
Primary Completion Date
September 2008 (Actual)
Study Completion Date
January 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Healthy, no Evidence of Disease, Tobacco Use Disorder

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
44 (Actual)

8. Arms, Groups, and Interventions

Arm Title
2g (curcumin)
Arm Type
Experimental
Arm Description
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.
Arm Title
4g (curcumin)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
curcumin
Other Intervention Name(s)
C.I. 75300, C.I. Natural Yellow 3, CU, Diferuloylmethane
Intervention Description
Given orally
Primary Outcome Measure Information:
Title
Baseline in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF)
Description
Baseline prostaglandin E2 (PGE2) values found in rectal aberrant crypt foci (ACF) tissue
Time Frame
Baseline
Title
Post-treatment in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF)
Description
Post-treatment prostaglandin E2 (PGE2) values found in rectal aberrant crypt foci (ACF) tissue
Time Frame
At 30 day
Secondary Outcome Measure Information:
Title
Baseline in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Within Aberrant Crypt Foci (ACF)
Description
Baseline 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in rectal aberrant crypt foci (ACF) tissue
Time Frame
Baseline
Title
Post-treatment in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Within Aberrant Crypt Foci (ACF)
Description
Post-treatment 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in rectal aberrant crypt foci (ACF) tissue
Time Frame
At 30 Day
Title
Baseline in Prostaglandin E2 (PGE2) Level in Normal Mucosa
Description
Baseline prostaglandin E2 (PGE2) values found in normal mucosa rectal tissue
Time Frame
Baseline
Title
Post-treatment in Prostaglandin E2 (PGE2) Level in Normal Mucosa
Description
Post-treatment prostaglandin E2 (PGE2) values found in normal mucosa rectal tissue
Time Frame
At 30 day
Title
Baseline in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Level in Normal Mucosa
Description
Baseline 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in normal mucosa rectal tissue
Time Frame
Baseline
Title
Post-treatment in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Level in Normal Mucosa
Description
Post-treatment 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in normal mucosa rectal tissue
Time Frame
At 30 day
Title
Change in Cyclooxygenases (COX-1, COX-2), and Lipoxygenase (5-LOX) Protein Abundance
Description
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.
Time Frame
Baseline to 30 days
Title
Changes in Total Aberrant Crypt Foci (ACF) Number
Description
Changes in total aberrant crypt foci (ACF) number = Number of ACF at pre-treatment - Number of ACF at post-treatment
Time Frame
Baseline to 30 days
Title
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third
Time Frame
Baseline
Title
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third
Time Frame
At 30 day
Title
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third
Time Frame
Baseline
Title
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third
Time Frame
At 30 day
Title
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third
Time Frame
Baseline
Title
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third
Time Frame
At 30 day
Title
Baseline Curcumin Concentration in Rectal Mucosa
Description
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.
Time Frame
Baseline
Title
Post-treatment Curcumin Concentration in Rectal Mucosa
Description
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.
Time Frame
At 30 day
Title
Baseline Curcumin Plasma Concentrations
Description
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.
Time Frame
Baseline
Title
Post-treatment Curcumin Plasma Concentrations
Description
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.
Time Frame
At 30 day
Title
Baseline Curcumin Conjugates Concentration in Rectal Mucosa
Description
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.
Time Frame
Baseline
Title
Post-treatment Curcumin Conjugates Concentration in Rectal Mucosa
Description
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.
Time Frame
At 30 day
Title
Baseline Curcumin Conjugates Plasma Concentrations
Description
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.
Time Frame
Baseline
Title
Post-treatment Curcumin Conjugates Plasma Concentrations
Description
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.
Time Frame
At 30 day
Title
Number of Participants at Each Adverse Event Grade Level
Time Frame
Baseline to 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Frank Meyskens
Organizational Affiliation
Chao Family Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Chao Family Comprehensive Cancer Center
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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