Clinical trial NCT00365209: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Healthy, no Evidence of Disease
Tobacco Use Disorder
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-08-17
Enrollment: 44
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Baseline in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF)
timeFrame: Baseline
measure: Post-treatment in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF)
timeFrame: At 30 day
Secondary outcomes:
measure: Baseline in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Within Aberrant Crypt Foci (ACF)
timeFrame: Baseline
measure: Post-treatment in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Within Aberrant Crypt Foci (ACF)
timeFrame: At 30 Day
measure: Baseline in Prostaglandin E2 (PGE2) Level in Normal Mucosa
timeFrame: Baseline
measure: Post-treatment in Prostaglandin E2 (PGE2) Level in Normal Mucosa
timeFrame: At 30 day
measure: Baseline in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Level in Normal Mucosa
timeFrame: Baseline
measure: Post-treatment in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Level in Normal Mucosa
timeFrame: At 30 day
measure: Change in Cyclooxygenases (COX-1, COX-2), and Lipoxygenase (5-LOX) Protein Abundance
timeFrame: Baseline to 30 days
measure: Changes in Total Aberrant Crypt Foci (ACF) Number
timeFrame: Baseline to 30 days
measure: Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third
timeFrame: Baseline
measure: Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third
timeFrame: At 30 day
measure: Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third
timeFrame: Baseline
measure: Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third
timeFrame: At 30 day
measure: Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third
timeFrame: Baseline
measure: Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third
timeFrame: At 30 day
measure: Baseline Curcumin Concentration in Rectal Mucosa
timeFrame: Baseline
measure: Post-treatment Curcumin Concentration in Rectal Mucosa
timeFrame: At 30 day
measure: Baseline Curcumin Plasma Concentrations
timeFrame: Baseline
measure: Post-treatment Curcumin Plasma Concentrations
timeFrame: At 30 day
measure: Baseline Curcumin Conjugates Concentration in Rectal Mucosa
timeFrame: Baseline
measure: Post-treatment Curcumin Conjugates Concentration in Rectal Mucosa
timeFrame: At 30 day
measure: Baseline Curcumin Conjugates Plasma Concentrations
timeFrame: Baseline
measure: Post-treatment Curcumin Conjugates Plasma Concentrations
timeFrame: At 30 day
measure: Number of Participants at Each Adverse Event Grade Level
timeFrame: Baseline to 30 days
Other outcomes:
Locations:
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center
state: California
Study officials:
affiliation: Chao Family Comprehensive Cancer Center
name: Frank Meyskens
role: PRINCIPAL_INVESTIGATOR
References: