Evaluating Panitumumab (ABX-EGF) in Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine if panitumumab, in combination with irinotecan, leucovorin, and 5-fluorouracil (5-FU) is safe and efficacious in patients with metastatic colorectal cancer.

Detailed Description
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Indication Metastatic Colorectal Cancer Primary Objective To assess the safety of ABX-EGF in combination with the FOLFIRI regimen in subjects with metastatic colorectal cancer. (The primary objective in the original protocol was to assess progression free survival after treatment with ABX-EGF in combination with the Saltz regimen in subjects with metastatic colorectal cancer). Secondary Objective(s) To assess the clinical efficacy of ABX-EGF in combination with the FOLFIRI regimen in subjects with metastatic colorectal cancer. (Secondary objectives in the original protocol were to assess safety and additional measures of the clinical efficacy of ABX-EGF in combination with the Saltz regimen in subjects with metastatic colorectal cancer). To assess the pharmacokinetics (PK) of ABX-EGF in combination with the FOLFIRI regimen in subjects with metastatic colorectal cancer. (Secondary objectives in the original protocol were to assess the PK of ABX-EGF in combination with the Saltz regimen, and the PK of irinotecan (IR) and its active metabolite SN-38 when IR is given in combination with ABX-EGF, leucovorin (LV), and 5-fluorouracil (5-FU) in subjects with metastatic colorectal cancer)

Official Title
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A Clinical Trial of the Safety and Efficacy of ABX-EGF in Combination With Irinotecan, Leucovorin, and 5-Fluorouracil in Subjects With Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Irinotecan
* Biological: Panitumumab
* Drug: 5-Fluorouracil
* Drug: Leucovorin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to comprehend and sign an Institutional Review Board (IRB)-approved informed consent form Pathologic diagnosis of colorectal cancer - Metastatic colorectal adenocarcinoma If history of adjuvant chemotherapy for colorectal cancer, must have been free of disease for greater than or equal to 1 year after completion of adjuvant chemotherapy Unidimensionally measurable disease Paraffin-embedded tumor tissue available for immunohistochemistry studies of epidermal growth factor receptor (EGFr) expression (archived tissue is acceptable) Tumor over-expressing EGFr by immunohistochemistry (staining must be the sum of 1+, 2+ and 3+ in greater than or equal to 10% of evaluated tumor cells; staining and evaluation to be conducted at a central laboratory) Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 Adequate hematologic, renal, and hepatic function Exclusion Criteria: Female (of childbearing potential, post-menopausal for less than 6 months, not surgically sterilized, or not abstinent) not consenting to use adequate contraceptive precautions during the course of the study and for 6 months after the last ABX-EGF infusion Female who is breast-feeding or pregnant Any kind of disorder that compromises the ability of the patient to give written informed consent and/or comply with the study procedures History of any chronic medical or psychiatric condition or laboratory abnormality that, in the opinion of the investigator, may increase the risks associated with study participation or study drug administration or may interfere with compliance or the interpretation of study results Untreated brain metastases Therapy for colorectal cancer other than surgery and 5-FU-based adjuvant therapy Prior treatment for metastatic colorectal cancer Prior irinotecan Prior or concurrent radiation therapy for colorectal cancer, including prior adjuvant radiation therapy to the pelvis Known allergy to irinotecan, 5-fluorouracil, or leucovorin Known Gilbert's disease Known dihydropyrimidine dehydrogenase (DPD) deficiency Prior EGFr-targeting agents Use of investigational therapy used with adjuvant intent within 30 days before the first ABX-EGF infusion If prior history of cancer other than colorectal carcinoma, basal cell carcinoma, or cervical carcinoma in situ, no treatment or active disease within 5 years Active inflammatory bowel disease or other bowel disease (other than colorectal carcinoma) causing chronic diarrhea (defined as greater than 4 stools per day) Partial or complete bowel obstruction, known chronic malabsorption, total colectomy, or other major abdominal surgery that might result in substantial alteration in transit to absorption of oral medication Ascites or pleural effusion requiring therapeutic paracentesis or thoracentesis; subject with small, stable, asymptomatic pleural effusions or ascites may be enrolled; subject who has been rendered asymptomatic by successful sclerosis of an effusion may be enrolled. Active interstitial pneumonia or interstitial fibrosis Left ventricular ejection fraction (LVEF) less than 45%, as measured by multiple-gated acquisition (MUGA) scan - Myocardial infarction within 1 year before the first ABX-EGF infusion Any of the following within 6 months before the first study drug dose: Unstable angina; Symptomatic congestive heart failure; Serious uncontrolled cardiac arrhythmia; Cerebrovascular accident or transient ischemic attack; Pulmonary embolism; Deep vein thrombosis; Other significant thromboembolic event. Subject known to be human immunodeficiency virus (HIV) positive History of any chronic medical or psychiatric condition or laboratory abnormality that, in the opinion of the Investigator, may increase the risks associated with study participation or study drug administration or may interfere with patient compliance or the interpretation of study results Unwilling or unable to comply with study requirements Known allergy to the ingredients of the study drug or to Staphylococcus protein A

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: Part 1: Panitumumab + IFL<br>Panitumumab (2.5 mg/kg once weekly for up to 48 weeks or until disease progression, intolerable adverse event or other reason for discontinuation) in combination with irinotecan, 5-fluorouracil (5-FU)and leucovorin (IFL chemotherapy regimen) | Drug: Irinotecan<br>* Part 1: 125 mg/m^2 IV infusion once a week on weeks 1 through 4 of each 6-week treatment cycle. Part 2: 180 mg/m^2 IV infusion every other week until disease progression or unable to tolerate.<br>Biological: Panitumumab<br>* Intravenous (IV) infusions of panitumumab 2.5 mg/kg once a week delivered in 6-week cycles.<br>* Other names: ABX-EGF;Drug: 5-Fluorouracil<br>* Part 1: IV bolus 500 mg/m^2 on weeks 1 through 4 of each 6-week cycle. Part 2: IV bolus 400 mg/m^2 and infusional 2400-3000 mg/m^2 over 46 hours once every other week until disease progression or unable to tolerate.<br>Drug: Leucovorin<br>* Part 1: IV bolus 20 mg/m^2 on weeks 1 through 4 of each 6-week cycle. Part 2: 400 mg/m^2 every other week until disease progression or unable to tolerate.<br>|
| Experimental: Part 2: Panitumumab + FOLFIRI<br>Panitumumab (2.5 mg/kg once weekly until disease progression, intolerable adverse event or other reason for discontinuation) in combination with irinotecan/5-FU/leucovorin chemotherapy (the FOLFIRI regimen) | Drug: Irinotecan<br>* Part 1: 125 mg/m^2 IV infusion once a week on weeks 1 through 4 of each 6-week treatment cycle. Part 2: 180 mg/m^2 IV infusion every other week until disease progression or unable to tolerate.<br>Biological: Panitumumab<br>* Intravenous (IV) infusions of panitumumab 2.5 mg/kg once a week delivered in 6-week cycles.<br>* Other names: ABX-EGF;Drug: 5-Fluorouracil<br>* Part 1: IV bolus 500 mg/m^2 on weeks 1 through 4 of each 6-week cycle. Part 2: IV bolus 400 mg/m^2 and infusional 2400-3000 mg/m^2 over 46 hours once every other week until disease progression or unable to tolerate.<br>Drug: Leucovorin<br>* Part 1: IV bolus 20 mg/m^2 on weeks 1 through 4 of each 6-week cycle. Part 2: 400 mg/m^2 every other week until disease progression or unable to tolerate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 3 or Grade 4 Diarrhea (Part 2) | The number of participants with grade 3 or grade 4 diarrhea in Part 2 of the study. Grading of diarrhea followed the grading scale in Version 2.0 of the National Cancer Institute Common Toxicity Criteria (NCI CTC). | Until disease progression (median 47 weeks) | 
| Number of Participants With Grade 3 or Grade 4 Diarrhea (Part 1) | The number of participants with grade 3 or grade 4 diarrhea in Part 1 of the study. Grading of diarrhea followed the grading scale in Version 2.0 of the National Cancer Institute Common Toxicity Criteria (NCI CTC). | Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Objective Tumor Response (Part 2) | Objective tumor response (complete or partial) in Part 2 of the study, based on Response Evaluation Criteria in Solid Tumors (RECIST), where complete response = disappearance of all target lesions, partial response = ≥30% reduction in lesion size, progressive disease = ≥20% increase in tumor size; otherwise stable disease. | Until disease progression (median 47 weeks) | 
| Time to Disease Progression (Part 2) | Kaplan-Meier estimate of median time from the first dose of study drug to first observed disease progression or death if the death was due to disease progression (whichever comes first) in Part 2 of the study. Participants who had not progressed or died for reasons other than disease progression were censored at their last disease assessment date. | From enrollment until death or diease progression. Maximum follow-up time was 16 months. | 
| Progression-free Survival Time (Part 2) | Kaplan-Meier estimate of median time from enrollment to death or disease progression in Part 2 of the study. Participants who had not progressed and had not died were censored at their last disease assessment date. | From enrollment until disease progression or death. Maximum follow-up time was 16 months. | 
| Survival Time (Part 2) | Kaplan-Meier estimate of the median time from enrollment to death from any cause. Participants who did not die on study were censored at their last contact date. | From enrollment until death. Maximum follow-up time was 16 months. | 
| Number of Participants Who Died (Part 2) | The number of participants in Part 2 who died during the study. | From enrollment until last contact. Maximum follow-up was 16 months. | 
| Number of Participants With Objective Tumor Response (Part 1) | Objective tumor response (complete or partial) in Part 1 of the study, based on Response Evaluation Criteria in Solid Tumors (RECIST), where complete response = disappearance of all target lesions, partial response = ≥30% reduction in lesion size, progressive disease = ≥20% increase in tumor size; otherwise stable disease. | Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first | 
| Progression-free Survival Time (Part 1) | Kaplan-Meier estimate of median time from enrollment to death or disease progression in Part 1 of the study. Participants who had not progressed and had not died were censored at their last disease assessment date. | From enrollment until disease progression or death. Maximum follow-up time was 25 months. | 
| Time to Disease Progression (Part 1) | Kaplan-Meier estimate of the median time from the first dose of study drug to disease progression or death if due to disease progression (whichever comes first) in Part 1 of the study. Participants who had not progressed or died for reasons other than disease progression were censored at their last disease assessment date. | From enrollment until disease progression or death. Maximum follow-up time was 25 months. | 
| Survival Time (Part 1) | Kaplan-Meier estimate of the median time from enrollment to death from any cause. Participants who did not die on study were censored at their last contact date. | From enrollment until death. Maximum follow-up time was 25 months. | 
| Time to Treatment Failure (Part 1) | Kaplan-Meier estimate of the median time from the date of first dose of panitumumab or chemotherapy to the date the decision was made to end treatment for any reason in Part 1 of the study. | Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first | 
| Time to Initial Objective Tumor Response (Part 1) | Median time to first observed objective tumor response (complete or partial) among responders in Part 1 of the study. | Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunex, Panitumumab, ABX-EGF, Abgenix