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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00365209
First received: August 16, 2006
Last updated: August 28, 2013
Last verified: August 2013
  Purpose

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.


Condition Intervention Phase
Healthy, no Evidence of Disease
Tobacco Use Disorder
Other: laboratory biomarker analysis
Other: pharmacological study
Drug: curcumin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Phase IIA Trial of Curcumin Among Patients With Prevalent Subclinical Neoplastic Lesions (Aberrant Crypt Foci)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Mean change from baseline in PGE2 within ACF pre and post 30 days of curcumin administration at a specified dose [ Time Frame: Baseline to 30 days ] [ Designated as safety issue: No ]
    The changes in ACF PGE2 will be calculated as absolute change from baseline in paired specimens of log-transformed values. The logarithmic transformation of PGE2 is applied only as required for variance stabilization. To estimate treatment effect, the median and 95% percent confidence interval for the median percent change will be calculated. Significance will be assessed by the distribution-free Sign test.


Secondary Outcome Measures:
  • Mean change from baseline in 5-HETE within ACF pre and post 30 days of curcumin administration at a specified dose [ Time Frame: Baseline to 30 days ] [ Designated as safety issue: No ]
    The overall approach will be to rank percent differences and analyze these data by a non-parametric paired sample method such as the Sign test.

  • Mean change from baseline in PGE2 and 5-HETE within comparison normal mucosa pre and post 30 days of curcumin administration at a specified dose [ Time Frame: Baseline to 30 days ] [ Designated as safety issue: No ]
    These changes will be compared directly to changes in ACF tissue and significance addressed by the distribution-free Sign test.

  • Change in COX-1, COX-2, and 5-LOX protein abundance [ Time Frame: Baseline to 30 days ] [ Designated as safety issue: No ]
    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 ACF number [ Time Frame: Baseline to 30 days ] [ Designated as safety issue: No ]
    The number of ACF, pre and post therapy will be analyzed by the Wilcoxon matched-pairs signed-ranks test with a significance level of 0.05.

  • Proliferation by Ki-67 IHC in rectal mucosa [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Mean changes in labeling per crypt compartment will be assessed in aggregate and statistically evaluated by paired t-test or Wilcoxon matched-pairs signed-ranks test, as appropriate.

  • Proliferation by Ki-67 IHC in rectal mucosa [ Time Frame: 30 days ] [ Designated as safety issue: No ]
  • Curcumin concentration in rectal mucosa [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    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.

  • Glutathione peroxidase activity within the colon [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Changes pre and post therapy will be measured and the data will be analyzed with age and pack-years smoked as covariates. Multiple regressions will be applied with outcome, mean percent change in GP-x activity, and predictor variables, age and pack years smoked. Models also will be considered with age and years smoked as continuous and/or categorical variables, and with interactions between age and years smoked. The present sample may be under-powered to analyze these subgroup effects but will potentially provide useful preliminary data for future larger-sized trials.

  • Glutathione peroxidase activity within the colon [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Changes pre and post therapy will be measured and the data will be analyzed with age and pack-years smoked as covariates. Multiple regressions will be applied with outcome, mean percent change in GP-x activity, and predictor variables, age and pack years smoked. Models also will be considered with age and years smoked as continuous and/or categorical variables, and with interactions between age and years smoked. The present sample may be under-powered to analyze these subgroup effects but will potentially provide useful preliminary data for future larger-sized trials.

  • Curcumin plasma concentrations [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Curcumin plasma concentrations [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    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.


Enrollment: 48
Study Start Date: October 2006
Primary Completion Date: September 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prevention (curcumin)
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.
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Drug: curcumin
Given orally
Other Names:
  • C.I. 75300
  • C.I. Natural Yellow 3
  • CU
  • Diferuloylmethane

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.

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00365209

Locations
United States, California
Chao Family Comprehensive Cancer Center
Orange, California, United States, 92868
Sponsors and Collaborators
Investigators
Principal Investigator: Frank Meyskens Chao Family Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00365209     History of Changes
Other Study ID Numbers: NCI-2013-00449, NCI-2013-00449, UIC-2005-0617, CDR0000483003, UCIRVINE-2005-4586, UIC HS# 2005-0617, CCUM-HUM00000731, P30CA062203, 2005-0617, UCI04-2-01, N01CN35160
Study First Received: August 16, 2006
Last Updated: August 28, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Aberrant Crypt Foci
Tobacco Use Disorder
Chemically-Induced Disorders
Mental Disorders
Neoplasms
Precancerous Conditions
Substance-Related Disorders
Curcumin
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antineoplastic Agents
Antirheumatic Agents
Central Nervous System Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014