Effect of Curcumin on Dose Limiting Toxicity and Pharmacokinetics of Irinotecan in Patients With Solid Tumors

Treatment Plan

This is a single-center, two-part, open label prospective study to define the maximum
tolerated dose (MTD) of curcumin plus irinotecan and the pharmacokinetic effects of curcumin
on irinotecan metabolism in patients with advanced colorectal cancer. Each cycle of
irinotecan is defined as 28 days, with a dose of irinotecan administered on D1 and D15. The
study will have two parts: Part 1 comprises the dose escalation portion of the study and Part
2 comprises the MTD expansion and pharmacokinetic study.

Patients will be recruited from the GI oncology clinic of the North Carolina Cancer Hospital.
After obtaining informed consent, patients will be entered into Part 1 of the study until the
MTD has been defined. During study Part 1, patients will be given a 4 day run-in of curcumin
prior to irinotecan dosing. The planned dose levels of curcumin will be 1, 2, 3, and 4 grams
per day. Irinotecan will be dosed at 200 mg/m2 IV on days 1 and 15.46 Additional
antineoplastic agents will not be allowed during the trial. Two patients will be enrolled at
each dose level until a DLT occurs, beginning with the lowest dose level and increasing the
level only after 2 patients have successfully completed a full irinotecan cycle at that dose
level.

Part 2 will investigate the effect of curcumin on irinotecan and SN-38 pharmacokinetics. We
will expand the cohort of patients at the defined MTD in part 1. Patients will receive
irinotecan alone for a single dose (D1). Curcumin, at the MTD, will be started on D11 and
continued until the end of the cycle (D28). Irinotecan will be administered again on D15.

Blood samples will be collected on the days of irinotecan infusion (D1 and D15) as follows:
prior to treatment with irinotecan (baseline), immediately following the end of irinotecan
infusion, and at 0.5, 1, 1.5, 2, 4, 6, and 24 hours following the end of the irinotecan
infusion for irinotecan and SN-38 PK.

All patients will continue on curcumin + irinotecan for further cycles until disease
progression or toxicity occurs at the discretion of the treating physician (see section 5.6).
For patients in study Part 1, we will offer to escalate the curcumin dose to the highest dose
level that has been safely completed until an MTD has been estimated.

Treatment Assignment Part 1:

At the end of the screening period, eligible patients are assigned in cohorts of 2 at
escalating doses until the first Dose Limiting Toxicity(DLT) is observed. DLT determination
will be made based on one cycle in initial cohorts of 2. As much information as possible is
used in the initial cohorts of 2. After the first DLT is observed, DLT rates at each dose are
estimated using isotonic regression. For that, proportions of DLTs are computed at each dose
first, then, if there is a violation of monotonicity, data at the violating dose levels are
pooled and new proportions computed. The estimated DLT rate at the current dose is used to
determine whether the dose will be increased, decreased or remained unchanged. The dose is to
remain unchanged if the estimated DLT rate at the current dose is between [0.17, 0.33]; the
dose is decreased if the estimated DLT rate is higher than 0.33; and the dose is increased if
the estimated DLT is lower than 0.17. Dose assignment will progress with successful
completion of two participants at each dose level until DLT occurs. Dose assignment after the
first DLT will be made in collaboration with the study statistician for each patient.

For Part 1, up to 20 patients will be assigned using the algorithm above. The MTD will be
estimated when either the highest dose is reached with no DLTs or after 20 patients have
completed the algorithm above.

Part 2: After the MTD has been estimated, 10 new patients will be assigned to the "expanded
MTD cohort" to estimate PK parameters for irinotecan and SN-38 (active metabolite of
irinotecan) with and without curcumin. . The "expanded MTD cohort" might have more than 10
patients if Part 1 sample size is smaller than 20, as long as the total number of patients in
the trial does not exceed 30. The estimated MTD might be re-evaluated if the estimated DLT
rate at that dose is outside [0.17, 0.33].

Inclusion Criteria

1. Age ≥21 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 Carcinoembryonic antigen (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 anti-Epidermal Growth Factor
Receptor (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)

- aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 3 x ULN

- Total bilirubin ≤ 1.5 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, Institutional Review Board(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. Patients who are already known homozygous for the UGT1A1*28 allele
(UDP-glucuronosyltransferase 1-1*28), and patients of Asian descent homozygous or
heterozygous for the UGT1A1*6 allele will be excluded due to their altered irinotecan
metabolism

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

5. History of Gilbert's syndrome

6. Active cardiac disease including any of the following:

- Congestive heart failure ≥Class 2 according to New York Heart Association [NYHA]
(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
irinotecan.

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

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

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

9. 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 or taper
(chronic steroid therapy is acceptable provided that the dose is stable for one month
prior to D1 of treatment under this study)

10. Inability to swallow oral medications or any malabsorption condition

11. Patients with diarrhea CTCAE v4 grade ≥2

12. 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)

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

14. Patients unwilling or unable to refrain from use of moderate or strong inhibitors or
inducers of Cytochrome P450, family 3, subfamily A (CYP3A) (Appendix A)