A Prospective Evaluation of the Effect of Curcumin on Dose-limiting Toxicity and Pharmacokinetics of Irinotecan in Colorectal Cancer Patients
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 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 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,
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
Maximum tolerated dose (MTD)
During Part 1 of study dose escalation will be used to determine the MTD of curcumin based on a DLT rate of 0.25 for the combination with irinotecan.
Gary Asher, MD, MPH
University of North Carolina at Chapel Hill Lineberger Comprehensive cancer Center
United States: Food and Drug Administration
|University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center||Chapel Hill, North Carolina 27599|