Study Of Sunitinib With FOLFIRI In Colorectal Cancer

Study Overview
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Brief Summary
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To evaluate the efficacy, safety and pharmacokinetics of sunitinib plus FOLFIRI (irinotecan, 5-FU and l-leucovorin) in the first-line treatment of Japanese mCRC patients

Official Title
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A Phase II Study Of Sunitinib In Combination With Irinotecan, L-leucovorin, And 5-Fluorouracil In Patients With Unresectable Or Metastatic Colorectal Cancer

Conditions
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Unresectable or Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: FOLFIRI (The combination regimen of Irinotecan, l-Leucovorin and 5-Fluorouracil)
* Drug: Sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with histologically- or cytologically-confirmed colorectal adenocarcinoma with unresectable or metastatic disease documented on diagnostic imaging studies. Patient must have at least one RECIST-defined measurable lesion that has not been treated with prior local therapy. Exclusion Criteria: History of another primary malignancy within 3 years prior to study entry, with the exception of non-melanoma skin cancer and in situ carcinoma of the uterine cervix. Current, recent, or planned participation in an experimental treatment drug study other than this protocol.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: FOLFIRI (The combination regimen of Irinotecan, l-Leucovorin and 5-Fluorouracil)<br>* FOLFIRI treatment with Sunitinib on Day, Irinotecan 180M/M IV , l-Leucovorin 200M/M, 5FU 400M/M bolus and 2400M/M in 46-hour continuous infusion on Day1 each 42 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.<br>Drug: Sunitinib<br>* 37.5mg daily P.O., 4 weeks On 2weeks Off each 42 day cycle. Number of cycles: until progression or unacceptable toxicity develops.<br>* Other names: Sutent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from the date of enrollment to the date of the first documentation of objective tumor progression or death due to any cause, whichever occurs first. PFS data was censored on the day following the date of the last tumor assessment documenting absence of progressive disease for patients who 1) were given anti-tumor treatment other than the study treatment prior to observing objective tumor progression; 2) were removed from the study prior to documentation of objective tumor progression; and 3) were ongoing at the time of the analysis. | Up to 11 cycles (1 cycle = 6 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from the date of enrollment to the date of death due to any cause. OS data was censored on the day following the date of the last contact at which the patient is known to be alive. | Up to 11 cycles (1 cycle = 6 weeks) | 
| Percentage of Participants Who Presented Objective Response: Objective Response Rate (ORR) | ORR is defined as the percentage of participants with best overall response of either a confirmed complete (CR) or partial response (PR) relative to the number of participants in FAS. Based on the response evaluation criteria in solid tumors (RECIST), CR is defined as the disappearance of all target lesions and PR is defined as a greater than or equal to 30% decrease in the sum of the longest dimensions of the target lesion. | Up to 11 cycles (1 cycle = 6 weeks) | 
| Duration of Response (DR) | DR is defined as the time from the first objective documentation of complete or partial response that is subsequently confirmed to the first documentation of disease progression or to death due to any cause, whichever occurs first. The definition of censorship is the same as PFS. | Up to 11 cycles (1 cycle = 6 weeks) | 
| Maximum Observed Plasma Concentration (Cmax) and Predose Concentration (Ctrough) of Sunitinib. | Plasma concentrations were assessed at predose, 2, 4, 6, 8, and 24 hours postdose and Cmax and Ctrough of sunitinib, its metabolite SU012662, and the total (sunitinib + SU0122662) were determined. | Cycle 1 Day 15 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Sunitinib |  | Cycle 1 Day 15 | 
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC 0-24) of Sunitinib | AUC 0-24 was determined using the Linear/Log trapezoidal method. | Cycle 1 Day 15 | 
| Apparent Oral Clearance (CL/F) of Sunitinib | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Cycle 1 Day 15 | 
| Maximum Observed Plasma Concentration (Cmax) of Irinotecan | Plasma samples were assessed at prior to initiation of irinotecan (and l-leucovorin) infusion, 1, 2 (predose for 5-FU bolus), 4, 8, and 24 hours after initiation of irinotecan infusion, and Cmax of irinotecan and its metabolite SN-38 were determined. | Cycle 1 Day 15 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Irinotecan |  | Cycle 1 Day 15 | 
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUC Last) and Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC ∞) of Irinotecan | AUC last of irinotecan and its metabolite SN-38 were calculated using the Linear/Log trapezoidal method. AUC∞ of irinotecan was calculated using following equation; AUC last+(C*t/kel), where Ct* is the estimated concentration at the time of the last quantifiable concentration, kel is terminal phase rate constant that is estimated as the absolute value of the slope of a linear regression during the terminal phase of the natural-logarithm (ln) transformed concentration-time profile. | Cycle 1 Day 15 | 
| Terminal Phase Elimination Half-life (t1/2) of Irinotecan | Terminal phase half-life of irinotecan was calculated as ln 2/ kel. | Cycle 1 Day 15 | 
| Clearance of Irinotecan | CL is calculated as dose divided by AUC 0-∞ | Cycle 1 Day 15 | 
| Volume of Distribution at Steady State (Vss) of Irinotecan | Vss was calculated using following equation: CL x mean residence time (MRT), where MRT = the area under the first moment curve from zero time to infinity (AUMC 0-∞)/AUC 0-∞- (infusion time/2), AUMC 0-∞ = the area under the first moment curve from zero time to time t (AUMC t)+ ((t x Ct*)/ kel) + (Ct* / kel^2), AUMC t is calculated using the linear trapezoidal method. | Cycle 1 Day 15 | 
| Plasma Concentration at Steady State (Css) of 5-FU | Concentration at 22 hour post start of 5-FU infusion were to be used as Css if 5-FU concentrations suggested steady state at 22 hours time point. | Cycle 1 Day 15 | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Grade 3 or Higher Adverse Events According to Common Terminology Criteria (CTCAE). | Any untoward medical occurrence in a patient who received study drug was considered an adverse event (AE), without regard to possibility of causal relationship. Treatment-emergent adverse events (TEAE): those which occurred or worsened after baseline. An adverse event resulting in any of the following outcomes, or deemed to be significant for any other reason, was considered to be a serious adverse event (SAE): death; initial or prolonged inpatient hospitalization; a life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Up to 11 cycles (1 cycle = 6 weeks) |