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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Multi-Center Phase III Trial Of Irinotecan In Combination With Three Different Methods Of Administration Of Fluoropyrimidine: Infusional 5-FU (FOLFIRI), Modified-Bolus 5-FU (Day 1 & 8), And Oral Capecitabine (Day 1-14); With Celecoxib Versus Placebo As First-Line Treatment For Patients With Metastatic Colorectal Cancer Study Amended April 23, 2004 To Include Bevacizumab

Conditions
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Colorectal Neoplasms

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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Modified Bolus 5-FU/LV with Irinotecan<br> | Drug: Modified Bolus 5-FU/LV with Irinotecan<br>* Day 1 & 8: Irinotecan (125 mg/m2 IV over 90 minutes), LV (20 mg/m2 IV bolus), 5-FU (500 mg/m2 IV bolus). All chemotherapy cycles repeated every 3 weeks. Celecoxib/placebo treatment will commence on the same day as chemotherapy treatment (i.e. Day 1 of treatment on study). Celecoxib/placebo will be taken at a dose of 400 mg po BID [two times a day] (800 mg/day) and will continue daily without interruption (no rest period for celecoxib/placebo treatment).<br>|
| Experimental: FOLFIRI + bevacizumab<br> | Drug: FOLFIRI + bevacizumab<br>* Day 1 Bevacizumab 5mg/kg IV 90 minutes prior to irinotecan/LV Irinotecan 180 mg/m2 IV 90 minutes Leucovorin 400 mg/m2 IV 2 hours - given with irinotecan without mixing. I m m e d i a t e l y f o l l o w e d b y : 5-FU 400 mg/m2 IV bolus 5-FU 2400 mg/m2 IV Continuous infusion over 46 hours Every 2 weeks Amendment 2 Bevacizumab 5mg/kg IV 90 minutes prior to irinotecan/LV Irinotecan 180 mg/m2 IV 90 minutes Leucovorin 400 mg/m2 IV 2 hours - given with irinotecan without mixing. I m m e d i a t e l y f o l l o w e d b y : 5-FU 400 mg/m2 IV bolus 5-FU 2400 mg/m2 IV Continuous infusion over 46 hours Celecoxib/placebo 400 mg BID [two times a day] oral Every 2 weeks<br>|
| Experimental: miFL + bevacizumab<br> | Drug: miFL + bevacizumab<br>* Day 1 Bevacizumab 7.5mg/kg IV *over 90 minutes - given prior to irinotecan, 5-FU, and leucovorin Irinotecan 125 mg/m2 IV over 90 minutes Leucovorin 20 mg/m2 IV bolus 5-FU 500 mg/m2 IV bolus Day 8 Irinotecan 125 mg/m2 IV over 90 minutes Leucovorin 20 mg/m2 IV bolus 5-FU 500 mg/m2 IV bolus Every 3 weeks Amendment 2 Day 1 Bevacizumab 7.5mg/kg IV over 90 minutes - given prior to irinotecan, 5-FU, and leucovorin Irinotecan 125 mg/m2 IV over 90 minutes Leucovorin 20 mg/m2 IV bolus 5-FU 500 mg/m2 IV bolus Celecoxib/placebo 400 mg BID [two times a day] oral Day 8 Irinotecan 125 mg/m2 IV over 90 minutes Leucovorin 20 mg/m2 IV bolus 5-FU 500 mg/m2 IV bolus Celecoxib/placebo -- 400 mg po BID [two times a day] continues daily without interruption Every 3 weeks<br>|
| Experimental: Infusional 5-FU/LV with Irinotecan<br> | Drug: Infusional 5-FU/LV with Irinotecan<br>* Day 1: Irinotecan (180 mg/m2) IV over 90 minutes, LV (racemic mixture 400 mg/m2) over 2 hours during irinotecan infusion but without mixing, immediately followed by 5-FU IV bolus (400 mg/m2) and 5-FU continuous infusion (2400 mg/m2) over 46 hours. FOLFIRI regimen is repeated every 2 weeks. Celecoxib/placebo treatment will commence on the same day at a dose of 400 mg po BID [two times a day](800 mg/day) and will continue daily without interruption (no rest period for celecoxib/placebo treatment).<br>|
| Other: Oral Capecitabine with Irinotecan<br> | Drug: Oral Capecitabine with Irinotecan<br>* Day 1: Irinotecan (250 mg/m2 IV) over 90 minutes; Day 1-14: capecitabine 1000 mg/m2 PO BID [two times a day] (28 single doses). All chemotherapy cycles repeated every 3 weeks. Celecoxib/placebo treatment will commence on the same day as chemotherapy treatment (i.e. Day 1 of treatment on study). Celecoxib/placebo will be taken at a dose of 400 mg po BID (800 mg/day) and will continue daily without interruption (no rest period for celecoxib/placebo treatment).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) at Primary Completion: FOLFIRI and mIFL | 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). | every 6 weeks until disease progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression: FOLFIRI, mIFL and CapeIRI | 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). | every 6 weeks until disease progression | 
| Overall Response: FOLFIRI, mIFL and CapeIRI | 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. ) | every 6 weeks during chemotherapy until disease progression | 
| Survival Time: FOLFIRI, mIFL and CapeIRI | 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. | assessed at least every week during treatment and at least every 3 months during follow-up | 
| 1 Year Survival: FOLFIRI, mIFL and CapeIRI | 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. | 1 year from date of randomization | 
| Time to Progression : Celecoxib and Placebo | 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). | every 6 weeks until disease progression | 
| Overall Response: Celecoxib and Placebo | 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. ) | every 6 weeks during chemotherapy until disease progression | 
| Survival Time: Celecoxib and Placebo | 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. | assessed at least every week during treatment and at least every 3 months during follow-up | 
| Time to Progression: Bevacizumab With FOLFIRI, mIFL | 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). | every 6 weeks until disease progression | 
| Overall Response: Bevacizumab With FOLFIRI, mIFL | 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. ) | every 6 weeks during chemotherapy until disease progression | 
| 1 Year Survival: Bevacizumab With FOLFIRI, mIFL | 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. | 1 year from date of randomization | 
| Survival Time at Last Follow-Up Visit: Bevacizumab With FOLFIRI, mIFL | 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. | Last Follow-Up Visit | 
| Dose Reduction Due to Treatment Emergent Adverse Events | 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. | Day 1; Day 8; and at end of every 3 treatment cycles for FOLFIRI; end of every 2 cycles for mIRI | 
| Overall Relative Dose Intensity of Irinotecan | 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.) | End of treatment cycle |