Effect of Curcumin on Dose Limiting Toxicity and Pharmacokinetics of Irinotecan in Patients With Solid Tumors
Condition: Advanced Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      Curcumin is an extract of the tumeric root that has been shown to have anti-tumor properties
      in laboratory studies. Curcumin, and its parent spice, turmeric (curcuma longa), are the 4th
      most commonly purchased dietary supplement in the U.S. Many cancer patients take curcumin
      during their treatment for cancer because of the purported health benefits.

      This research study is designed to learn more about the safety, pharmacokinetics and
      effectiveness of irinotecan when given in combination with curcumin in patients with
      metastatic colorectal cancer. The study of how the body absorbs, processes and eliminates
      drugs is called pharmacokinetics (PK). One of the main purposes of this study is to better
      understand the interaction between curcumin and irinotecan by measuring levels of irinotecan
      in the blood (ie. measure irinotecan PK) when a patient also takes curcumin. Information
      collected from this study could result in improved dosing guidelines and lead to more
      effective treatment of your cancer with less toxicity.
    

Detailed description: 
      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].
    

Intervention name(s): curcumin; Irinotecan
Intervention type(s): Dietary Supplement; Drug
Other intervention name(s): tumeric; Curcuma longa; Meriva; Camptosar
Intervention MeSH terms: Curcumin; Irinotecan
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: mCRC (metastatic colorectal cancer); CRC (colorectal cancer); Advanced colorectal cancer; Metastatic colorectal cancer; Colon cancer