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

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.

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