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

Pfizer547 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

547

Conditions

Colorectal Neoplasms

Interventions

Modified Bolus 5-FU/LV with IrinotecanDRUG

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).

FOLFIRI + bevacizumabDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (175)

Outcomes

Primary Outcomes

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).

Time frame: every 6 weeks until disease progression

Secondary Outcomes

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).

Time frame: 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. )

Time frame: 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.

Time frame: 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.

Time frame: 1 year from date of randomization

Time to Progression : Celecoxib and Placebo

Data from ClinicalTrials.gov

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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

Infusional 5-FU/LV with IrinotecanDRUG

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).

Oral Capecitabine with IrinotecanDRUG

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).

Pfizer Investigational Site

Birmgingham, Alabama, United States

Pfizer Investigational Site

Birmingham, Alabama, United States

Pfizer Investigational Site

Birmngham, Alabama, United States

Pfizer Investigational Site

Mobile, Alabama, United States

Pfizer Investigational Site

Flagstaff, Arizona, United States

Pfizer Investigational Site

Sedona, Arizona, United States

Pfizer Investigational Site

Tucson, Arizona, United States

Pfizer Investigational Site

Hot Spring, Arkansas, United States

Pfizer Investigational Site

Springdale, Arkansas, United States

Pfizer Investigational Site

Arroyo Grande, California, United States

...and 165 more locations

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).

Time frame: 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. )

Time frame: 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.

Time frame: 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).

Time frame: every 6 weeks until disease progression

Overall Response: Bevacizumab With FOLFIRI, mIFL

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.)

Time frame: End of treatment cycle