A Prospective Evaluation of the Effect of Curcumin on Dose-limiting Toxicity and Pharmacokinetics of Irinotecan in Colorectal Cancer Patients

Inclusion Criteria

Inclusion Criteria

1. Age ≥18 years of age (no upper age limit)

2. Histological or cytological documentation of metastatic adenocarcinoma of the colon
or rectum. Biopsy of primary tumor alone is adequate if the patient has clear
evidence of metastatic disease and/or elevated CEA and the treating physician does
not feel biopsy of metastatic disease is clinically warranted.

3. Prior therapy with oxaliplatin and a fluoropyrimidine is required. One prior line of
therapy with irinotecan is allowed. Prior therapy with an EGFR agent is also allowed

4. Life expectancy of at least 3 months in opinion of treating investigator

5. Eastern Cooperative Oncology Group performance status ≤1 (Appendix B)

6. Adequate bone marrow, renal, and hepatic function, as evidenced by the following
within 7 days of treatment initiation with curcumin:

- absolute neutrophil count (ANC) ≥1,500/mm3

- platelets ≥100,000/mm3

- hemoglobin ≥9.0 g/dL

- serum creatinine ≤1.5 x upper limit of normal (ULN)

- AST and ALT ≤ 3 x ULN

- Total bilirubin ≤ 1.5 x ULN

- Alkaline phosphatase ≤2.5 x ULN

7. Women of childbearing potential and male subjects must agree to use adequate
contraception for the duration of study participation. Adequate contraception is
defined as any medically recommended method (or combination of methods) as per
standard of care.

8. Medical oncologist agrees that four day window on curcumin alone is appropriate/safe
prior to start of irinotecan for trial candidate.

9. The subject is capable of understanding and complying with parameters as outlined in
the protocol

10. Signed, IRB-approved written informed consent

Exclusion Criteria:

1. Any prior allergies to curcumin or turmeric.

2. Prior intolerance of irinotecan or necessity for dose reduction greater than 20%

3. Prior treatment with single agent irinotecan is prohibited within six weeks of
enrollment. All prior toxicity from previous irinotecan administration must be
resolved prior to enrollment.

4. Patients who are already known homozygous for the UGT1A1*28 allele, and patients of
Asian descent homozygous or heterozygous for the UGT1A1*6 allele will be excluded due
to their altered irinotecan metabolism

5. Pregnant or breastfeeding patients. Women of childbearing potential must have a
documented negative pregnancy test a maximum of 7 days before start of treatment.

6. History of Gilbert's syndrome

7. Active cardiac disease including any of the following:

- Congestive heart failure (New York Heart Association [NYHA]) ≥Class 2 (see
Appendix C)

- Unstable angina (angina symptoms at rest), new-onset angina (begun within the
last 3 months). Myocardial infarction less than 6 months before start of Day 1
of irintocan.

- Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin
are permitted)

8. Ongoing infection > Grade 2 according to NCI Common Terminology Criteria for Adverse
Events version 4.0 (CTCAE v. 4.0)

9. Known history of human immunodeficiency virus (HIV) infection

10. Symptomatic metastatic brain or meningeal tumors unless the patient is >3 months from
definitive therapy, has a negative imaging study within 4 weeks of irinotecan
initiation, and is clinically stable with respect to the tumor at the time of study
entry. Also, the patient must not be undergoing acute steroid therapy ortaper
(chronic steroid therapy is acceptable provided that the dose is stable for one month
prior to D1 of treatment under this study)

11. Inability to swallow oral medications or any malabsorption condition

12. Patients with diarrhea CTCAE v4 grade ≥2

13. Unresolved toxicity higher than CTCAE v. 4.0 Grade 1 attributed to any prior
therapy/procedure excluding alopecia and oxaliplatin-induced neurotoxicity (which
must be ≤ Grade 2)

14. Substance abuse, medical, psychological, or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results

15. Patients unwilling or unable to refrain from use of moderate or strong inhibitors or
inducers of CYP3A (Appendix A)