Metastatic Colorectal Cancer
Conditions
Keywords
Oncology, Cancer, Metastatic Colorectal Cancer, EGFr, Panitumumab, Clinical Trial, Amgen
Brief summary
The purpose of this study is to evaluate the treatment effect of panitumumab plus FOLFIRI compared to FOLFIRI alone as second line therapy for metastatic colorectal cancer.
Interventions
DRUGPanitumumab
Panitumumab was administered by IV infusion on Day 1 of each 14-day cycle, just before administration of FOLFIRI chemotherapy.
DRUGFOLFIRI
FOLFIRI chemotherapy was initiated on Day 1 of each treatment cycle at the following starting doses: irinotecan 180 mg/m\^2, leucovorin 400 mg/m\^2 racemate (or 200 mg/m\^2 I-leucovorin), 5-FU bolus 400 mg/m\^2, 5-FU infusion 2400 mg/m\^2.
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
* Man or woman at least 18 years old * Diagnosis of metastatic colorectal cancer (mCRC) * One and only one chemotherapy regimen for mCRC consisting of first-line 5-FU -based chemotherapy * Radiologically documented disease progression per modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria during treatment or within 6 months of last dose of first-line chemotherapy * At least 1 uni-dimensionally measurable lesion of at least 20 mm per modified RECIST * Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2 * Paraffin-embedded tumor tissue from the primary tumor or metastasis available for central analyses * Adequate hematologic, renal, and hepatic functions * Negative pregnancy test within 72 hours of enrollment * Other protocol-specified criteria may apply
Exclusion criteria
* History of or known presence of central nervous system (CNS) metastases * History of another primary cancer within 5 years of randomization * Prior irinotecan therapy * Prior anti-epidermal growth factor receptor (EGFr) antibody therapy or treatment with small molecule EGFr inhibitors * Any investigational agent or therapy within 30 days before randomization * Known allergy or hypersensitivity to irinotecan, 5-FU or leucovorin * History of interstitial lung disease or evidence of interstitial lung disease on baseline chest computed tomography (CT) scan * Active inflammatory bowel disease or other bowel disease causing chronic diarrhea * Known positive tests for human immunodefiency virus (HIV), hepatitis C viris (HCV), acute or chronic active hepatitis B virus (HBV) * Major surgery within 28 days of randomization or minor surgical procedure within 14 days of randomization * Pregnant or breast-feeding * Man or woman of child-bearing potential not consenting to use adequate contraceptive methods or abstinence during the course of the study and for 6 months after last study drug administration (women) or 1 month after last study drug administration (men) * Other protocol-specified criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From randomization until the data cut-off date of 8 April 2008. Maximum follow-up time was 17 months. | Progression-free survival was defined as the time from randomization to first disease progression per modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria or death, based on independent central radiological assessment. Participants who were alive but did not meet criteria for progression by the data cutoff date were censored at their last evaluable disease assessment date. Progressive disease is defined as a ≥ 20% increase in the size of target lesions or unequivocal progression of existing non-target lesions or any new lesions. |
| Overall Survival | From randomization until the data cut-off date of 30 April 2009. Maximum follow-up time was 33 months | Overall survival was defined as the time from randomization to the date of death. Participants who had not died by the analysis data cutoff date had their time of death censored at their last contact date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Objective Response | Every 8 weeks until disease progression up to the data cut-off date of 30 April 2009. Maximum time on follow-up was 33 months. | Participants were evaluated for tumor response per the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria every 8 weeks until disease progression. Objective response was defined as the incidence of either a confirmed complete or partial response (CR or PR) while on study, as determined by blinded independent central review and confirmed no less than 4-weeks after the criteria for response are first met. CR: Disappearance of all target and non-target lesions and no new lesions. PR: At least a 30% decrease in the sum of the longest diameter of target lesions and no progression of non-target or no new lesions, or, disappearance of all target lesions and the persistence of ≥ 1 non-target lesion not qualifying for either CR or progressive disease. Participants without a post-baseline assessment were considered non-responders. |
| Time to Disease Progression | From randomization until the data cut-off date of 30 April 2009. Maximum follow-up time was 33 months | Time to progression was defined as the time from the randomization date to the date of first observed disease progression per the modified RECIST criteria. Participants not meeting these criteria by the analysis data cutoff date were censored at their last evaluable disease assessment date. Progressive disease is defined as a ≥ 20% increase in the size of target lesions or unequivocal progression of existing non-target lesions or any new lesions. |
| Duration of Response | From randomization until the data cut-off date of 30 April 2009. Maximum follow-up time was 33 months | Calculated only for those participants with an objective response as the time from the first objective response (subsequently confirmed within no less than 4 weeks) to first observed disease progression per modified-RECIST criteria. Participants not meeting these criteria by the analysis data cutoff date were censored at their last evaluable disease assessment date. Progressive disease is defined as a ≥ 20% increase in the size of target lesions or unequivocal progression of existing non-target lesions or any new lesions. |
| Number of Participants With Adverse Events (AEs) | From randomization until the data cut-off date of 30 April 2009. Maximum follow-up time was 33 months. | A serious adverse event (SAE) is defined by regulatory authorities as one that • is fatal • is life threatening (places the subject at immediate risk of death) • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • other significant medical hazard. The relationship of the adverse event to the study treatment was assessed by the Investigator by means of the question: Is there a reasonable possibility that the event may have been caused by the study treatment? |
Participant flow
Recruitment details
First patient enrolled 30 June 2006; Last patient enrolled 13 March 2008.
Participants by arm
| Arm | Count |
|---|---|
| Panitumumab Plus FOLFIRI Participants were randomized to 6 mg/kg panitumumab intravenous infusion plus a standard chemotherapy regimen (FOLFIRI) consisting of 5-FU, leucovorin and irinotecan. Treatment was administered in cycles every two weeks. | 591 |
| FOLFIRI Alone Participants were randomized to receive a standard chemotherapy regimen (FOLFIRI) consisting of 5-FU, leucovorin and irinotecan. Treatment was administered in cycles every two weeks. | 595 |
| Total | 1,186 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 3 |
| Overall Study | Lost to Follow-up | 17 | 17 |
| Overall Study | Missing reason | 3 | 1 |
| Overall Study | Ongoing | 20 | 13 |
| Overall Study | Other | 46 | 40 |
| Overall Study | Physician Decision | 2 | 4 |
| Overall Study | Protocol-specified criteria | 12 | 8 |
| Overall Study | Withdrawal by Subject | 16 | 19 |
Baseline characteristics
| Characteristic | FOLFIRI Alone | Panitumumab Plus FOLFIRI | Total |
|---|---|---|---|
| Age, Continuous | 60.9 years STANDARD_DEVIATION 10.6 | 60.2 years STANDARD_DEVIATION 10.5 | 60.6 years STANDARD_DEVIATION 10.5 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 or 1 | 565 participants | 564 participants | 1129 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 2 | 30 participants | 27 participants | 57 participants |
| KRAS Status Mutant KRAS | 248 participants | 238 participants | 486 participants |
| KRAS Status Unevaluable KRAS | 53 participants | 50 participants | 103 participants |
| KRAS Status Wild-type KRAS | 294 participants | 303 participants | 597 participants |
| Prior Bevacizumab Exposure for mCRC No | 483 participants | 480 participants | 963 participants |
| Prior Bevacizumab Exposure for mCRC Yes | 112 participants | 111 participants | 223 participants |
| Prior Oxaliplatin Exposure for mCRC No | 182 participants | 179 participants | 361 participants |
| Prior Oxaliplatin Exposure for mCRC Yes | 413 participants | 412 participants | 825 participants |
| Race/Ethnicity, Customized Aborigine | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Asian | 3 participants | 2 participants | 5 participants |
| Race/Ethnicity, Customized Black or African American | 5 participants | 4 participants | 9 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 participants | 2 participants | 5 participants |
| Race/Ethnicity, Customized Japanese | 11 participants | 9 participants | 20 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Other | 2 participants | 3 participants | 5 participants |
| Race/Ethnicity, Customized White or Caucasian | 569 participants | 568 participants | 1137 participants |
| Sex: Female, Male Female | 219 Participants | 245 Participants | 464 Participants |
| Sex: Female, Male Male | 376 Participants | 346 Participants | 722 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 575 / 587 | 546 / 594 |
| serious Total, serious adverse events | 232 / 587 | 175 / 594 |
Outcome results
Primary
Overall Survival
Overall survival was defined as the time from randomization to the date of death. Participants who had not died by the analysis data cutoff date had their time of death censored at their last contact date.
Time frame: From randomization until the data cut-off date of 30 April 2009. Maximum follow-up time was 33 months
Population: KRAS Efficacy Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Overall Survival | 14.5 months |
| Wild-type KRAS - FOLFIRI Alone | Overall Survival | 12.5 months |
| Mutant KRAS - Panitumumab Plus FOLFIRI | Overall Survival | 11.8 months |
| Mutant KRAS - FOLFIRI Alone | Overall Survival | 11.1 months |
Comparison: An overall 5% significance level was used to compare treatments with respect to both overall survival (OS) and PFS. A 4% and 1% level (2-sided) was used to independently test OS and PFS, respectively.p-value: 0.1154Stratified log-rank test
Comparison: The treatment effect on OS in the Mutant KRAS Efficacy Analysis Set was compared at the 4% level conditional on first demonstrating a significant OS treatment effect in the Wild-type KRAS Efficacy Analysis Set.p-value: 0.5503Stratified log-rank test
Primary
Progression-free Survival (PFS)
Progression-free survival was defined as the time from randomization to first disease progression per modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria or death, based on independent central radiological assessment. Participants who were alive but did not meet criteria for progression by the data cutoff date were censored at their last evaluable disease assessment date. Progressive disease is defined as a ≥ 20% increase in the size of target lesions or unequivocal progression of existing non-target lesions or any new lesions.
Time frame: From randomization until the data cut-off date of 8 April 2008. Maximum follow-up time was 17 months.
Population: KRAS Efficacy Analysis Set (participants for whom KRAS status was assessed)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Progression-free Survival (PFS) | 5.9 months |
| Wild-type KRAS - FOLFIRI Alone | Progression-free Survival (PFS) | 3.9 months |
| Mutant KRAS - Panitumumab Plus FOLFIRI | Progression-free Survival (PFS) | 5.0 months |
| Mutant KRAS - FOLFIRI Alone | Progression-free Survival (PFS) | 4.9 months |
Comparison: An overall 5% significance level was used to compare treatments with respect to both overall survival (OS) and PFS. A 4% and 1% level (2-sided) was used to independently test OS and PFS, respectively.p-value: 0.0036Stratified log-rank test
Comparison: PFS in the Mutant Efficacy Analysis Set was compared at a 1% level conditional upon first demonstrating a significant difference in PFS in the Wild-type KRAS Efficacy Analysis Set.p-value: 0.1448Stratified log-rank test
Secondary
Duration of Response
Calculated only for those participants with an objective response as the time from the first objective response (subsequently confirmed within no less than 4 weeks) to first observed disease progression per modified-RECIST criteria. Participants not meeting these criteria by the analysis data cutoff date were censored at their last evaluable disease assessment date. Progressive disease is defined as a ≥ 20% increase in the size of target lesions or unequivocal progression of existing non-target lesions or any new lesions.
Time frame: From randomization until the data cut-off date of 30 April 2009. Maximum follow-up time was 33 months
Population: KRAS Central Tumor Response Analysis Set: Responders
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Duration of Response | 7.6 months |
| Wild-type KRAS - FOLFIRI Alone | Duration of Response | 6.6 months |
| Mutant KRAS - Panitumumab Plus FOLFIRI | Duration of Response | 6.0 months |
| Mutant KRAS - FOLFIRI Alone | Duration of Response | 7.4 months |
Secondary
Number of Participants With Adverse Events (AEs)
A serious adverse event (SAE) is defined by regulatory authorities as one that • is fatal • is life threatening (places the subject at immediate risk of death) • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • other significant medical hazard. The relationship of the adverse event to the study treatment was assessed by the Investigator by means of the question: Is there a reasonable possibility that the event may have been caused by the study treatment?
Time frame: From randomization until the data cut-off date of 30 April 2009. Maximum follow-up time was 33 months.
Population: Safety analysis set: all participants who received at least 1 dose of panitumumab or chemotherapy. One participant was randomized to Panitumumab Plus FOLFIRI, but received FOLFIRI Alone and is included in the FOLFIRI Alone group for safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Number of Participants With Adverse Events (AEs) | Any adverse event | 584 participants |
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Number of Participants With Adverse Events (AEs) | Serious adverse event | 232 participants |
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Number of Participants With Adverse Events (AEs) | Leading to discontinuation of any study drug | 123 participants |
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event (TRAE) | 577 participants |
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Number of Participants With Adverse Events (AEs) | Serious treatment-related adverse event | 124 participants |
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of any study drug | 97 participants |
| Wild-type KRAS - FOLFIRI Alone | Number of Participants With Adverse Events (AEs) | Serious treatment-related adverse event | 90 participants |
| Wild-type KRAS - FOLFIRI Alone | Number of Participants With Adverse Events (AEs) | Any adverse event | 573 participants |
| Wild-type KRAS - FOLFIRI Alone | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event (TRAE) | 542 participants |
| Wild-type KRAS - FOLFIRI Alone | Number of Participants With Adverse Events (AEs) | Serious adverse event | 175 participants |
| Wild-type KRAS - FOLFIRI Alone | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of any study drug | 34 participants |
| Wild-type KRAS - FOLFIRI Alone | Number of Participants With Adverse Events (AEs) | Leading to discontinuation of any study drug | 64 participants |
Secondary
Percentage of Participants With an Objective Response
Participants were evaluated for tumor response per the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria every 8 weeks until disease progression. Objective response was defined as the incidence of either a confirmed complete or partial response (CR or PR) while on study, as determined by blinded independent central review and confirmed no less than 4-weeks after the criteria for response are first met. CR: Disappearance of all target and non-target lesions and no new lesions. PR: At least a 30% decrease in the sum of the longest diameter of target lesions and no progression of non-target or no new lesions, or, disappearance of all target lesions and the persistence of ≥ 1 non-target lesion not qualifying for either CR or progressive disease. Participants without a post-baseline assessment were considered non-responders.
Time frame: Every 8 weeks until disease progression up to the data cut-off date of 30 April 2009. Maximum time on follow-up was 33 months.
Population: KRAS Central Tumor Response Analysis Set: subset of participants with at least one uni-dimensionally measurable lesion per the modified RECIST criteria per blinded central radiology review for whom KRAS was assessed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Percentage of Participants With an Objective Response | 35.35 percentage of participants |
| Wild-type KRAS - FOLFIRI Alone | Percentage of Participants With an Objective Response | 9.82 percentage of participants |
| Mutant KRAS - Panitumumab Plus FOLFIRI | Percentage of Participants With an Objective Response | 13.36 percentage of participants |
| Mutant KRAS - FOLFIRI Alone | Percentage of Participants With an Objective Response | 13.92 percentage of participants |
p-value: <0.000195% CI: [3.21, 8.6]Stratified exact test
p-value: 195% CI: [0.56, 1.76]Stratified exact test
Secondary
Time to Disease Progression
Time to progression was defined as the time from the randomization date to the date of first observed disease progression per the modified RECIST criteria. Participants not meeting these criteria by the analysis data cutoff date were censored at their last evaluable disease assessment date. Progressive disease is defined as a ≥ 20% increase in the size of target lesions or unequivocal progression of existing non-target lesions or any new lesions.
Time frame: From randomization until the data cut-off date of 30 April 2009. Maximum follow-up time was 33 months
Population: KRAS Efficacy Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS - Panitumumab Plus FOLFIRI | Time to Disease Progression | 7.3 months |
| Wild-type KRAS - FOLFIRI Alone | Time to Disease Progression | 5.3 months |
| Mutant KRAS - Panitumumab Plus FOLFIRI | Time to Disease Progression | 5.5 months |
| Mutant KRAS - FOLFIRI Alone | Time to Disease Progression | 5.5 months |