Study Of Sunitinib With FOLFIRI In Colorectal Cancer

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00668863
• Collaborator: (none)
• Enrollment: 71
• Locations: 11
• Arm: 1
• Duration (Months): 28
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Unresectable or Metastatic Colorectal Cancer	Drug: FOLFIRI (The combination regimen of Irinotecan, l-Leucovorin and 5-Fluorouracil); Drug: Sunitinib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study Of Sunitinib In Combination With Irinotecan, L-leucovorin, And 5-Fluorouracil In Patients With Unresectable Or Metastatic Colorectal Cancer
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 1

Drug: FOLFIRI (The combination regimen of Irinotecan, l-Leucovorin and 5-Fluorouracil); 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.; Drug: Sunitinib; 37.5mg daily P.O., 4 weeks On 2weeks Off each 42 day cycle. Number of cycles: until progression or unacceptable toxicity develops.; Other Names: Sutent

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) [Up to 11 cycles (1 cycle = 6 weeks)]

   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.

Secondary Outcome Measures

1. Overall Survival (OS) [Up to 11 cycles (1 cycle = 6 weeks)]

   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.

2. Percentage of Participants Who Presented Objective Response: Objective Response Rate (ORR) [Up to 11 cycles (1 cycle = 6 weeks)]

   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.

3. Duration of Response (DR) [Up to 11 cycles (1 cycle = 6 weeks)]

   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.

4. Maximum Observed Plasma Concentration (Cmax) and Predose Concentration (Ctrough) of Sunitinib. [Cycle 1 Day 15]

   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.

5. Time to Reach Maximum Plasma Concentration (Tmax) of Sunitinib [Cycle 1 Day 15]

6. Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC 0-24) of Sunitinib [Cycle 1 Day 15]

   AUC 0-24 was determined using the Linear/Log trapezoidal method.

7. Apparent Oral Clearance (CL/F) of Sunitinib [Cycle 1 Day 15]

   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.

8. Maximum Observed Plasma Concentration (Cmax) of Irinotecan [Cycle 1 Day 15]

   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.

9. Time to Reach Maximum Plasma Concentration (Tmax) of Irinotecan [Cycle 1 Day 15]

10. 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 [Cycle 1 Day 15]

    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.

11. Terminal Phase Elimination Half-life (t1/2) of Irinotecan [Cycle 1 Day 15]

    Terminal phase half-life of irinotecan was calculated as ln 2/ kel.

12. Clearance of Irinotecan [Cycle 1 Day 15]

    CL is calculated as dose divided by AUC 0-∞

13. Volume of Distribution at Steady State (Vss) of Irinotecan [Cycle 1 Day 15]

    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.

14. Plasma Concentration at Steady State (Css) of 5-FU [Cycle 1 Day 15]

    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.

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). [Up to 11 cycles (1 cycle = 6 weeks)]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Nagoya	Aichi	Japan
2	Pfizer Investigational Site	Chiba-shi	Chiba-ken	Japan
3	Pfizer Investigational Site	Matsuyama-shi	Ehime	Japan
4	Pfizer Investigational Site	Sapporo-shi	Hokkaido	Japan
5	Pfizer Investigational Site	Sapporo	Hokkaido	Japan
6	Pfizer Investigational Site	Kochi-shi	Kochi	Japan
7	Pfizer Investigational Site	Saku	Nagano	Japan
8	Pfizer Investigational Site	Osakasayama-shi	Osaka	Japan
9	Pfizer Investigational Site	Takatsuki	Osaka	Japan
10	Pfizer Investigational Site	Shimotsuke-shi	Tochigi	Japan
11	Pfizer Investigational Site	Minoh/Osaka		Japan

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00668863
• Other Study ID Numbers: A6181151
• First Posted: Apr 29, 2008
• Last Update Posted: Oct 17, 2011
• Last Verified: Oct 1, 2011

• Additional relevant MeSH terms: Colorectal Neoplasms; Leucovorin; Fluorouracil; Irinotecan; Sunitinib; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Period Title: Overall Study
STARTED	71
COMPLETED	0
NOT COMPLETED	71

Baseline Characteristics

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Overall Participants	71
Age, Customized (participants) [Number]
<=44 years	6 8.5%
45 to 64 years	44 62%
>=65 years	21 29.6%
Sex: Female, Male (Count of Participants)
Female	29 40.8%
Male	42 59.2%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS)
Description	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.
Time Frame	Up to 11 cycles (1 cycle = 6 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set was defined as all enrolled subjects who met the following criteria :1) Those who were diagnosed as having adenocarcinoma of the colon or rectum with documented locally advanced or metastatic disease and 2) those who received at least one dose of the study medication.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	71
Median (95% Confidence Interval) [weeks]	28.9

2. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	Up to 11 cycles (1 cycle = 6 weeks)

Outcome Measure Data

Analysis Population Description

Median OS was not calculable due to the large number of censored events (63 out of 71 were censored).

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	0

3. Secondary Outcome

Title	Percentage of Participants Who Presented Objective Response: Objective Response Rate (ORR)
Description	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.
Time Frame	Up to 11 cycles (1 cycle = 6 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set was defined as all enrolled subjects who met the following criteria :1) Those who were diagnosed as having adenocarcinoma of the colon or rectum with documented locally advanced or metastatic disease and 2) those who received at least one dose of the study medication.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	71
Median (95% Confidence Interval) [percentage of participants]	36.6 51.5%

4. Secondary Outcome

Title	Duration of Response (DR)
Description	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.
Time Frame	Up to 11 cycles (1 cycle = 6 weeks)

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants with a confirmed objective tumor response (CR or PR) among Full Analysis Set.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	26
Median (95% Confidence Interval) [weeks]	28.3

5. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) and Predose Concentration (Ctrough) of Sunitinib.
Description	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.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Sunitinib Cmax	54.3 (6.54)
Sunitinib Ctrough	41.8 (16.4)
SU012662 Cmax	15.8 (3.96)
SU012662 Ctrough	11.3 (1.41)
Total (sunitinib + SU0122662) Cmax	70.0 (4.67)
Total (sunitinib + SU0122662) Ctrough	53.1 (15.4)

6. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax) of Sunitinib
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Sunitinib Tmax	6
SU012662 Tmax	4
Total (sunitinib + SU0122662) Tmax	6

7. Secondary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC 0-24) of Sunitinib
Description	AUC 0-24 was determined using the Linear/Log trapezoidal method.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Sunitinib AUC 0-24	1161 (200)
SU012662 AUC 0-24	346 (108)
Total (sunitinib + SU0122662) AUC 0-24	1507 (114)

8. Secondary Outcome

Title	Apparent Oral Clearance (CL/F) of Sunitinib
Description	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.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Mean (Standard Deviation) [L/hour]	32.9 (6.25)

9. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Irinotecan
Description	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.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Irinotecan Cmax	1963 (492)
SN-38 Cmax	25.1 (7.29)

10. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax) of Irinotecan
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Irinotecan tmax	2
SN-38 tmax	4

11. Secondary Outcome

Title	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
Description	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.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Irinotecan AUC last	13100 (1323)
Irinotecan AUC ∞	13800 (1400)
SN-38 AUC last	274 (117)

12. Secondary Outcome

Title	Terminal Phase Elimination Half-life (t1/2) of Irinotecan
Description	Terminal phase half-life of irinotecan was calculated as ln 2/ kel.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Mean (Standard Deviation) [hours]	5.36 (0.221)

13. Secondary Outcome

Title	Clearance of Irinotecan
Description	CL is calculated as dose divided by AUC 0-∞
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Mean (Standard Deviation) [L/hour]	23.0 (1.53)

14. Secondary Outcome

Title	Volume of Distribution at Steady State (Vss) of Irinotecan
Description	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.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Mean (Standard Deviation) [L]	160 (16.8)

15. Secondary Outcome

Title	Plasma Concentration at Steady State (Css) of 5-FU
Description	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.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Analysis set was consisted of participants who provided an evaluable sample. Planned number of participants for pharmacokinetic analysis was 6.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	3
Mean (Standard Deviation) [ng/mL]	650 (70.5)

16. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Grade 3 or Higher Adverse Events According to Common Terminology Criteria (CTCAE).
Description	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.
Time Frame	Up to 11 cycles (1 cycle = 6 weeks)

Outcome Measure Data

Analysis Population Description

Safety analysis set was defined as the same population as the Full Analysis Set.

Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
Measure Participants	71
Treatment emergent adverse events	71 100%
Serious adverse events	32 45.1%
CTCAE grade 3 or 4 adverse events	70 98.6%
CTCAE grade 5 adverse events	1 1.4%

Adverse Events

Time Frame	Up to 11 cycles (1 cycle = 6 weeks)
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
Arm/Group Description	Sunitinib was orally administered at 37.5 mg once daily for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks (Schedule 4/2). Sunitinib was given in combination with FOLFIRI, which was administered in the standard fashion every 2 weeks: Irinotecan (180 mg/m^2) and l-leucovorin (200 mg/m^2) was infused intravenously on Day 1, immediately followed by 5 FU bolus (400 mg/m^2) and 46-hour (2400 mg/m^2) infusion. FOLFIRI was given on Days 1, 15, and 29 in each 6-week cycle of sunitinib administration.
All Cause Mortality
	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
	Affected / at Risk (%)	# Events
Total	32/71 (45.1%)
Blood and lymphatic system disorders
Febrile neutropenia	6/71 (8.5%)
Leukopenia	2/71 (2.8%)
Lymphadenitis	1/71 (1.4%)
Neutropenia	1/71 (1.4%)
Thrombocytopenia	2/71 (2.8%)
Cardiac disorders
Myocardial infarction	1/71 (1.4%)
Gastrointestinal disorders
Diarrhoea	1/71 (1.4%)
Gastric dilatation	1/71 (1.4%)
Gastrointestinal perforation	1/71 (1.4%)
Haemorrhoids	1/71 (1.4%)
Ileus	1/71 (1.4%)
Intestinal obstruction	2/71 (2.8%)
Nausea	4/71 (5.6%)
Pneumatosis intestinalis	1/71 (1.4%)
Vomiting	5/71 (7%)
General disorders
Fatigue	2/71 (2.8%)
Pyrexia	1/71 (1.4%)
Infections and infestations
Abdominal abscess	1/71 (1.4%)
Infection	1/71 (1.4%)
Influenza	1/71 (1.4%)
Localised infection	1/71 (1.4%)
Pneumonia	1/71 (1.4%)
Septic shock	1/71 (1.4%)
Injury, poisoning and procedural complications
Wound complication	1/71 (1.4%)
Wound dehiscence	1/71 (1.4%)
Investigations
Neutrophil count decreased	3/71 (4.2%)
White blood cell count decreased	1/71 (1.4%)
Metabolism and nutrition disorders
Decreased appetite	6/71 (8.5%)
Dehydration	1/71 (1.4%)
Nervous system disorders
Cerebral infarction	1/71 (1.4%)
Renal and urinary disorders
Hydronephrosis	1/71 (1.4%)
Vascular disorders
Hypertension	1/71 (1.4%)
Thrombosis	1/71 (1.4%)
Other (Not Including Serious) Adverse Events
	Sunitinib 37.5 mg (Schedule 4/2) + FOLFIRI
	Affected / at Risk (%)	# Events
Total	71/71 (100%)
Blood and lymphatic system disorders
Anaemia	4/71 (5.6%)
Febrile neutropenia	11/71 (15.5%)
Leukopenia	4/71 (5.6%)
Neutropenia	4/71 (5.6%)
Thrombocytopenia	4/71 (5.6%)
Endocrine disorders
Hypothyroidism	4/71 (5.6%)
Eye disorders
Eyelid oedema	5/71 (7%)
Gastrointestinal disorders
Abdominal distension	6/71 (8.5%)
Abdominal pain	13/71 (18.3%)
Abdominal pain upper	10/71 (14.1%)
Cheilitis	8/71 (11.3%)
Constipation	29/71 (40.8%)
Diarrhoea	55/71 (77.5%)
Dyspepsia	6/71 (8.5%)
Gingivitis	13/71 (18.3%)
Haemorrhoids	5/71 (7%)
Nausea	54/71 (76.1%)
Stomatitis	36/71 (50.7%)
Vomiting	39/71 (54.9%)
General disorders
Face oedema	8/71 (11.3%)
Fatigue	47/71 (66.2%)
Malaise	8/71 (11.3%)
Mucosal inflammation	9/71 (12.7%)
Oedema	6/71 (8.5%)
Oedema peripheral	6/71 (8.5%)
Pyrexia	27/71 (38%)
Infections and infestations
Infection	5/71 (7%)
Nasopharyngitis	12/71 (16.9%)
Investigations
Alanine aminotransferase increased	18/71 (25.4%)
Aspartate aminotransferase increased	16/71 (22.5%)
Blood albumin decreased	22/71 (31%)
Blood alkaline phosphatase increased	13/71 (18.3%)
Blood bilirubin increased	7/71 (9.9%)
Blood cholesterol increased	5/71 (7%)
Blood creatinine increased	6/71 (8.5%)
Blood glucose increased	9/71 (12.7%)
Blood lactate dehydrogenase increased	5/71 (7%)
Blood phosphorus decreased	15/71 (21.1%)
Blood potassium decreased	5/71 (7%)
Blood thyroid stimulating hormone increased	4/71 (5.6%)
Blood triglycerides increased	4/71 (5.6%)
C-reactive protein increased	5/71 (7%)
Gamma-glutamyltransferase increased	11/71 (15.5%)
Haemoglobin decreased	28/71 (39.4%)
Lymphocyte count decreased	24/71 (33.8%)
Neutrophil count decreased	65/71 (91.5%)
Platelet count decreased	56/71 (78.9%)
Protein total decreased	6/71 (8.5%)
Protein urine present	7/71 (9.9%)
Red blood cell count decreased	4/71 (5.6%)
Weight decreased	7/71 (9.9%)
White blood cell count decreased	64/71 (90.1%)
Metabolism and nutrition disorders
Decreased appetite	50/71 (70.4%)
Dehydration	5/71 (7%)
Diabetes mellitus	4/71 (5.6%)
Musculoskeletal and connective tissue disorders
Back pain	11/71 (15.5%)
Musculoskeletal pain	5/71 (7%)
Nervous system disorders
Dizziness	12/71 (16.9%)
Dysgeusia	35/71 (49.3%)
Headache	12/71 (16.9%)
Neuropathy peripheral	4/71 (5.6%)
Psychiatric disorders
Insomnia	11/71 (15.5%)
Renal and urinary disorders
Proteinuria	5/71 (7%)
Respiratory, thoracic and mediastinal disorders
Cough	7/71 (9.9%)
Epistaxis	10/71 (14.1%)
Hiccups	10/71 (14.1%)
Skin and subcutaneous tissue disorders
Alopecia	44/71 (62%)
Palmar-plantar erythrodysaesthesia syndrome	33/71 (46.5%)
Pruritus	5/71 (7%)
Rash	12/71 (16.9%)
Skin discolouration	22/71 (31%)
Vascular disorders
Flushing	4/71 (5.6%)
Hypertension	24/71 (33.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.