Trial Of Irinotecan In Combination With Three Methods Of Administration Of Fluoropyrimidine.

Phase 3

Completed

Conditions: Colorectal Neoplasms

Interventions: Drug: Oral Capecitabine with Irinotecan
Drug: Modified Bolus 5-FU/LV with Irinotecan
Drug: FOLFIRI + bevacizumab
Drug: miFL + bevacizumab
Drug: Infusional 5-FU/LV with Irinotecan

Registration Number: NCT00101686

Lead Sponsor: Pfizer

Brief Summary: This study compares in the first study period combination of Irinotecan with three different methods of administration by Fluoropyrimidine. (ie. infusion, bolus and oral). In the second period of study it compares FOLFIRI \[a chemotherapy regime that combines bolus irinotecan and leucovorin \[LV\] with infusional 5-fluorouracil (5-FU)\] + bevacizumab and mlFL + bevacizumab. Measures of efficacy and safety will be reported.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 547

Inclusion Criteria

Diagnosis of colorectal cancer (either newly diagnosed or recurrent disease) with evidence of metastatic disease. (Stage IV distant disease)
Present or past histological documentation of adenocarcinoma of the colon or rectum. The site of the primary lesion must be or have been confirmed endoscopically, radiologically, or surgically to be or have been in the large bowel. Patients with a history of colorectal cancer treated by surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless:
An interval of greater than five years has elapsed between the primary surgery and the development of metastatic disease.
The primary cancer was a Duke's A or B1.
Physicians should consider biopsy of lesions to establish the diagnosis of metastatic colorectal cancer in each case if there is substantial clinical ambiguity regarding the nature of source of apparent metastases.

Exclusion Criteria

Patients who received any prior systemic anticancer therapy for metastatic colorectal cancer (e.g., chemotherapy, antibody therapy, immunotherapy, gene therapy, vaccine therapy, cytokine therapy, or other experimental agents).
Patients cannot have concurrent malignancies at study entry.
Exceptions: Patients with prior non-colorectal malignancies will be eligible if they have been disease-free for ³ 3 years or are deemed at low risk for recurrence by their treating physician (e.g., early stage prostate cancer, melanoma or bladder cancer). Patients with squamous or basal cell carcinoma of the skin or in situ cervical cancer that have been effectively treated are eligible, even if these were diagnosed within 3 years before randomization.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Oral Capecitabine with Irinotecan	Oral Capecitabine with Irinotecan	-
Modified Bolus 5-FU/LV with Irinotecan	Modified Bolus 5-FU/LV with Irinotecan	-
FOLFIRI + bevacizumab	FOLFIRI + bevacizumab	-
miFL + bevacizumab	miFL + bevacizumab	-
Infusional 5-FU/LV with Irinotecan	Infusional 5-FU/LV with Irinotecan	-

Primary Outcome Measures

Name	Time	Method
Time to Progression (TTP) at Primary Completion: FOLFIRI and mIFL	every 6 weeks until disease progression	Time to disease progression is defined as the number of months from date of randomization to the date of first documentation of disease progression (PD).

Secondary Outcome Measures

Name	Time	Method
Time to Progression: FOLFIRI, mIFL and CapeIRI	every 6 weeks until disease progression	Time to disease progression is defined as the number of months from date of randomization to the date of first documentation of disease progression (PD).
Overall Response: FOLFIRI, mIFL and CapeIRI	every 6 weeks during chemotherapy until disease progression	A subject will be considered achieving an overall response if the subject has a sustained Complete Response (CR) or Partial Response (PR) for at least 4 weeks, confirmed by tumor assessments. (CR: Disappearance of all target lesions. PR: greater than or equal to 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the Pre-treatment sum LD. )
Survival Time: FOLFIRI, mIFL and CapeIRI	assessed at least every week during treatment and at least every 3 months during follow-up	Survival time defined as time from date of randomization to date of death. In the absence of confirmation of death, survival time was censored to last date the subject known to be alive.
1 Year Survival: FOLFIRI, mIFL and CapeIRI	1 year from date of randomization	Number of patients alive or dead at 1 year. In the absence of confirmation of death, survival time was censored to last date the subject known to be alive.
Time to Progression : Celecoxib and Placebo	every 6 weeks until disease progression	Time to disease progression is defined as the number of months from date of randomization to the date of first documentation of disease progression (PD).
Overall Response: Celecoxib and Placebo	every 6 weeks during chemotherapy until disease progression	A subject will be considered achieving an overall response if the subject has a sustained CR or PR for at least 4 weeks, confirmed by tumor assessments. (Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): ≥ 30% decrease in the sum of the LD of target lesions, taking as reference the Pre-treatment sum LD. )
Survival Time: Celecoxib and Placebo	assessed at least every week during treatment and at least every 3 months during follow-up	Survival time defined as time from date of randomization to date of death. In the absence of confirmation of death, survival time was censored to last date the subject known to be alive.
Time to Progression: Bevacizumab With FOLFIRI, mIFL	every 6 weeks until disease progression	Time to disease progression is defined as the number of months from date of randomization to the date of first documentation of disease progression (PD).
Overall Response: Bevacizumab With FOLFIRI, mIFL	every 6 weeks during chemotherapy until disease progression	A subject will be considered achieving an overall response if the subject has a sustained CR or PR for at least 4 weeks, confirmed by tumor assessments. (Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): ≥ 30% decrease in the sum of the LD of target lesions, taking as reference the Pre-treatment sum LD. )
1 Year Survival: Bevacizumab With FOLFIRI, mIFL	1 year from date of randomization	Number of patients alive or dead at 1 year. In the absence of confirmation of death, survival time was censored to last date the subject known to be alive.
Survival Time at Last Follow-Up Visit: Bevacizumab With FOLFIRI, mIFL	Last Follow-Up Visit	Survival time defined as time from date of randomization to date of death. In the absence of confirmation of death, survival time was censored to last date the subject known to be alive. Zero subjects analyzed indicates median could not be analyzed based on number of subjects who died.
Dose Reduction Due to Treatment Emergent Adverse Events	Day 1; Day 8; and at end of every 3 treatment cycles for FOLFIRI; end of every 2 cycles for mIRI	Number of subjects that had at least one Treatment-Emergent Adverse Event (TEAE) that led to a dose reduction. TEAE includes all reported Adverse Events that occurred within 30 days of last study medication.
Overall Relative Dose Intensity of Irinotecan	End of treatment cycle	Relative dose intensity for a cycle was calculated as the percentage of the actual dose intensity of the cycle divided by the planned dose intensity of the cycle. Overall relative dose intensity was calculated as the average relative dose intensities over all cycles. (Dose intensity for each cycle was calculated as the actual dose level of the study medication received in that cycle divided by the number of weeks in the cycle.)