Colorectal Cancer
Conditions
Keywords
Immunex, Panitumumab, ABX-EGF, Abgenix
Brief summary
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
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)
Interventions
DRUGIrinotecan
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.
BIOLOGICALPanitumumab
Intravenous (IV) infusions of panitumumab 2.5 mg/kg once a week delivered in 6-week cycles.
DRUG5-Fluorouracil
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.
DRUGLeucovorin
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.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 3 or Grade 4 Diarrhea (Part 2) | Until disease progression (median 47 weeks) | 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). |
| Number of Participants With Grade 3 or Grade 4 Diarrhea (Part 1) | Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival Time (Part 2) | From enrollment until disease progression or death. Maximum follow-up time was 16 months. | 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. |
| Survival Time (Part 2) | From enrollment until death. Maximum follow-up time was 16 months. | 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. |
| Number of Participants Who Died (Part 2) | From enrollment until last contact. Maximum follow-up was 16 months. | The number of participants in Part 2 who died during the study. |
| Number of Participants With Objective Tumor Response (Part 1) | Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first | 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. |
| Number of Participants With an Objective Tumor Response (Part 2) | Until disease progression (median 47 weeks) | 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. |
| Time to Disease Progression (Part 1) | From enrollment until disease progression or death. Maximum follow-up time was 25 months. | 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. |
| Survival Time (Part 1) | From enrollment until death. Maximum follow-up time was 25 months. | 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. |
| Time to Treatment Failure (Part 1) | Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first | 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. |
| Time to Initial Objective Tumor Response (Part 1) | Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first | Median time to first observed objective tumor response (complete or partial) among responders in Part 1 of the study. |
| Progression-free Survival Time (Part 1) | From enrollment until disease progression or death. Maximum follow-up time was 25 months. | 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. |
| Time to Disease Progression (Part 2) | From enrollment until death or diease progression. Maximum follow-up time was 16 months. | 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. |
Participant flow
Recruitment details
Participants were enrolled from 19 Jul 2002 through 20 April 2004
Participants by arm
| Arm | Count |
|---|---|
| Panitumumab With IFL Panitumumab in combination with irinotecan, 5-fluorouracil and leucovorin (IFL chemotherapy regimen) | 19 |
| Panitumumab With FOLFIRI Panitumumab in combination with irinotecan/5-FU/leucovorin chemotherapy (the FOLFIRI regimen) | 24 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part 1 | Death | 0 | 2 |
| Part 1 | Other | 0 | 1 |
| Part 1 | Physician Decision | 0 | 1 |
| Part 1 | Withdrawal by Subject | 0 | 1 |
| Part 2 | Adverse Event | 1 | 0 |
| Part 2 | Death | 1 | 0 |
| Part 2 | Disease progression | 3 | 0 |
| Part 2 | Other | 1 | 0 |
| Part 2 | Physician Decision | 1 | 0 |
| Part 2 | Protocol-specified criteria | 1 | 0 |
Baseline characteristics
| Characteristic | Panitumumab With FOLFIRI | Total | Panitumumab With IFL |
|---|---|---|---|
| Age Continuous | 60.7 Years STANDARD_DEVIATION 15 | 58.9 Years STANDARD_DEVIATION 13.8 | 56.6 Years STANDARD_DEVIATION 12.1 |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 7 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White or Caucasian | 18 Participants | 31 Participants | 13 Participants |
| Sex: Female, Male Female | 10 Participants | 13 Participants | 3 Participants |
| Sex: Female, Male Male | 14 Participants | 30 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 19 | 24 / 24 |
| serious Total, serious adverse events | 12 / 19 | 11 / 24 |
Outcome results
Primary
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).
Time frame: Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first
Population: Subjects Treated Analysis Set, composed of all consented participants who received at least 1 dose of panitumumab and at least 1 dose of chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab With FOLFIRI | Number of Participants With Grade 3 or Grade 4 Diarrhea (Part 1) | 11 Participants |
95% CI: [34, 80]
Primary
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).
Time frame: Until disease progression (median 47 weeks)
Population: Subjects Treated Analysis Set, composed of participants who received at least one dose of panitumumab or one dose of chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab With FOLFIRI | Number of Participants With Grade 3 or Grade 4 Diarrhea (Part 2) | 6 Participants |
95% CI: [9.8, 46.7]
Secondary
Number of Participants Who Died (Part 2)
The number of participants in Part 2 who died during the study.
Time frame: From enrollment until last contact. Maximum follow-up was 16 months.
Population: Subjects Treated Analysis Set, composed of participants who received at least one dose of panitumumab or one dose of chemotherapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab With FOLFIRI | Number of Participants Who Died (Part 2) | 6 participants |
Secondary
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.
Time frame: Until disease progression (median 47 weeks)
Population: Subjects Treated Analysis Set, composed of participants who received at least one dose of panitumumab or one dose of chemotherapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab With FOLFIRI | Number of Participants With an Objective Tumor Response (Part 2) | 8 Participants |
95% CI: [15.6, 55.3]
Secondary
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.
Time frame: Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first
Population: Subjects Treated Analysis Set, composed of all consented participants who received at least 1 dose of panitumumab and at least 1 dose of chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab With FOLFIRI | Number of Participants With Objective Tumor Response (Part 1) | 9 Participants |
95% CI: [24.4, 71.1]
Secondary
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.
Time frame: From enrollment until disease progression or death. Maximum follow-up time was 25 months.
Population: Subjects Treated Analysis Set, composed of all consented participants who received at least 1 dose of panitumumab and at least 1 dose of chemotherapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab With FOLFIRI | Progression-free Survival Time (Part 1) | 24.3 weeks |
Secondary
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.
Time frame: From enrollment until disease progression or death. Maximum follow-up time was 16 months.
Population: Subjects Treated Analysis Set, composed of participants who received at least one dose of panitumumab or one dose of chemotherapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab With FOLFIRI | Progression-free Survival Time (Part 2) | 41.1 weeks |
Secondary
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.
Time frame: From enrollment until death. Maximum follow-up time was 25 months.
Population: Subjects Treated Analysis Set, composed of all consented participants who received at least 1 dose of panitumumab and at least 1 dose of chemotherapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab With FOLFIRI | Survival Time (Part 1) | 73.1 weeks |
Secondary
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.
Time frame: From enrollment until death. Maximum follow-up time was 16 months.
Population: Subjects Treated Analysis Set, composed of all consented participants who received at least 1 dose of panitumumab and at least 1 dose of chemotherapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab With FOLFIRI | Survival Time (Part 2) | 73.1 weeks |
Secondary
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.
Time frame: From enrollment until disease progression or death. Maximum follow-up time was 25 months.
Population: Subjects Treated Analysis Set, composed of all consented participants who received at least 1 dose of panitumumab and at least 1 dose of chemotherapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab With FOLFIRI | Time to Disease Progression (Part 1) | 35.0 weeks |
Secondary
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.
Time frame: From enrollment until death or diease progression. Maximum follow-up time was 16 months.
Population: Subjects Treated Analysis Set, composed of participants who received at least one dose of panitumumab or one dose of chemotherapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab With FOLFIRI | Time to Disease Progression (Part 2) | 47.3 weeks |
Secondary
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.
Time frame: Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first
Population: Subset of Subjects Treated Analysis Set, composed of all consented participants who received at least 1 dose of panitumumab and at least 1 dose of chemotherapy, who had an objective tumor response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab With FOLFIRI | Time to Initial Objective Tumor Response (Part 1) | 5.9 weeks |
Secondary
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.
Time frame: Until disease progression (median 35 weeks) or 48 weeks, whichever occurred first
Population: Subjects Treated Analysis Set, composed of all consented participants who received at least 1 dose of panitumumab and at least 1 dose of chemotherapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab With FOLFIRI | Time to Treatment Failure (Part 1) | 24.3 Weeks |