Metastatic Colorectal Cancer
Conditions
Keywords
Oncology, Cancer, metastatic colorectal cancer, EGFr, Panitumumab, Clinical Trail, Amgen
Brief summary
The purpose of this study is to determine the treatment effect of panitumumab in combination with FOLFOX compared to FOLFOX alone as first line therapy for metastatic colorectal cancer
Interventions
DRUGPanitumumab
Panitumumab 6 mg/kg over on Day 1 of each 14-day cycle, just prior to the administration of chemotherapy.
DRUGFOLFOX regimen
The FOLFOX regimen consisted of oxaliplatin 85 mg/m\^2 intravenous (IV) infusion on Day 1, leucovorin, 200 mg/m\^2 (racemate) on Days 1 and 2 and 5-fluorouracil 400 mg/m\^2 IV bolus followed by 600 mg/m\^2 IV infusion over 22 hours on Days 1 and 2. Each cycle was 14 days.
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 * At least 1 uni-dimensionally measurable lesion of at least 20 mm per modified RECIST * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Paraffin-embedded tumor tissue from the primary tumor or metastasis available for central analyse
Exclusion criteria
* History or known presence of central nervous system (CNS) metastases * History of another primary cancer, except: Curatively treated in situ cervical cancer, or Curatively resected non-melanoma skin cancer, or Other primary solid tumor curatively treated with no known active disease present and no treatment administered for ≥ 5 years before randomization * Prior chemotherapy or systemic therapy for the treatment of metastatic colorectal carcinoma except: adjuvant fluoropyrimidine-based chemotherapy or prior fluoropyrimidine therapy administered solely for the purpose of radiosensitization * Prior oxaliplatin therapy * Prior anti-epidermal growth factor receptor (EGFr) antibody therapy (eg, cetuximab) or treatment with small molecule EGFr inhibitors (eg, erlotinib) * Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 1 year prior to randomization History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest computed tomography (CT) scan * Active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as \> Common terminology criteria (CTC) grade 2 \[CTCAE version 3.0\]) * Peripheral sensory neuropathy with functional impairment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | From randomization until the data cutoff date of 30 September 2008. Maximum follow-up time was 109 weeks. | Progression-free survival (PFS), assessed by central radiological assessment, was defined as the time from randomization to disease progression per modified response evaluation criteria in solid tumors (RECIST) criteria or death. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization until the data cutoff date of 28 August 2009. Maximum time on follow-up was 153 weeks. | The definition of overall survival is the time from randomization to death; participants who were alive at the analysis data cutoff were censored at their last contact date. |
| Percentage of Participants With an Objective Response | Every 8 weeks until disease progression up to the data cut-off date of 30 September 2008; Maximum follow-up time was 109 weeks. | 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 by central radiological assessment was defined as the incidence of either a confirmed complete or partial response (CR or PR) while on the first-line treatment, 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 Progression | From randomization until the data cut-off date of 30 September 2008; Maximum follow-up time was 109 weeks. | Time to progression was defined as time from randomization date to date of disease progression per the modified RECIST criteria. |
| Duration of Response | Every 8 weeks until disease progression up to the data cut-off date of 30 September 2008; Maximum follow-up time was 109 weeks. | Duration of response was calculated only for those participants with a confirmed CR or PR, as the time from the first CR or PR (subsequently confirmed within no less than 4 weeks) to first observed disease progression per modified RECIST criteria, based on a blinded central review. |
| Number of Participants With Adverse Events (AEs) | From randomization until the data cut-off date of 28 August 2009; Maximum time on follow-up was 153 weeks. | A serious adverse event (SAE) is defined as an AE that • is fatal • is life threatening • 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 23 August 2006 and last patient enrolled 01 February 2008. Participant flow data are reported as of the data cut-off date of 28 August 2009.
Participants by arm
| Arm | Count |
|---|---|
| FOLFOX + Panitumumab Participants were randomized to panitumumab, 6 mg/kg on Day 1 and FOLFOX chemotherapy regimen on Days 1 and 2 of each 14-day cycle until disease progression or unacceptable toxicity. | 593 |
| FOLFOX Alone Participants were randomized to FOLFOX chemotherapy regimen on Days 1 and 2 of each 14-day cycle until disease progression or until unacceptable toxicity. | 590 |
| Total | 1,183 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Ineligibility determined | 4 | 2 |
| Overall Study | Lost to Follow-up | 10 | 3 |
| Overall Study | Ongoing | 20 | 13 |
| Overall Study | Other | 41 | 47 |
| Overall Study | Physician Decision | 3 | 3 |
| Overall Study | Protocol-specified criteria | 6 | 6 |
| Overall Study | Withdrawal by Subject | 13 | 18 |
Baseline characteristics
| Characteristic | FOLFOX + Panitumumab | FOLFOX Alone | Total |
|---|---|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 10.1 | 60.3 years STANDARD_DEVIATION 11 | 60.9 years STANDARD_DEVIATION 10.6 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 | 332 participants | 320 participants | 652 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1 | 230 participants | 238 participants | 468 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 2 | 31 participants | 29 participants | 60 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 3 | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 4 | 0 participants | 1 participants | 1 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Mising/Unknown | 0 participants | 2 participants | 2 participants |
| Geographic Region Rest of world | 261 participants | 261 participants | 522 participants |
| Geographic Region Western Europe, Canada and Australia | 332 participants | 329 participants | 661 participants |
| KRAS Status Mutant KRAS | 221 participants | 219 participants | 440 participants |
| KRAS Status Unevaluable KRAS | 47 participants | 40 participants | 87 participants |
| KRAS Status Wild-type KRAS | 325 participants | 331 participants | 656 participants |
| Primary tumor type Colon cancer | 394 participants | 398 participants | 792 participants |
| Primary tumor type Rectal cancer | 199 participants | 192 participants | 391 participants |
| Race/Ethnicity, Customized Asian | 8 participants | 4 participants | 12 participants |
| Race/Ethnicity, Customized Black or African American | 8 participants | 15 participants | 23 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 42 participants | 26 participants | 68 participants |
| Race/Ethnicity, Customized Other | 5 participants | 5 participants | 10 participants |
| Race/Ethnicity, Customized White or Caucasian | 530 participants | 540 participants | 1070 participants |
| Sex: Female, Male Female | 207 Participants | 232 Participants | 439 Participants |
| Sex: Female, Male Male | 386 Participants | 358 Participants | 744 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 577 / 585 | 571 / 584 |
| serious Total, serious adverse events | 262 / 585 | 198 / 584 |
Outcome results
Primary
Progression-free Survival
Progression-free survival (PFS), assessed by central radiological assessment, was defined as the time from randomization to disease progression per modified response evaluation criteria in solid tumors (RECIST) criteria or death. 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 cutoff date of 30 September 2008. Maximum follow-up time was 109 weeks.
Population: KRAS Efficacy Analysis Set (participants for whom KRAS status was assessed)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS - FOLFOX + Panitumumab | Progression-free Survival | 9.6 months |
| Wild-type KRAS - FOLFOX | Progression-free Survival | 8.0 months |
| Mutant KRAS - FOLFOX + Panitumumab | Progression-free Survival | 7.3 months |
| Mutant KRAS - FOLFOX | Progression-free Survival | 8.8 months |
Comparison: PFS in the Wild-type KRAS Efficacy Analysis Set was compared at a significance level of 5%.p-value: 0.0234Stratified log-rank test
Comparison: PFS in the Mutant KRAS Efficacy Analysis Set was compared at a significance level of 5% conditional on first demonstrating a significant treatment effect in PFS in the Wild-type KRAS Efficacy Analysis Set.p-value: 0.0227Stratified log-rank test
Secondary
Duration of Response
Duration of response was calculated only for those participants with a confirmed CR or PR, as the time from the first CR or PR (subsequently confirmed within no less than 4 weeks) to first observed disease progression per modified RECIST criteria, based on a blinded central review.
Time frame: Every 8 weeks until disease progression up to the data cut-off date of 30 September 2008; Maximum follow-up time was 109 weeks.
Population: KRAS Evaluable Central Tumor Response Analysis Set: Responders
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS - FOLFOX + Panitumumab | Duration of Response | 11.1 months |
| Wild-type KRAS - FOLFOX | Duration of Response | 8.8 months |
| Mutant KRAS - FOLFOX + Panitumumab | Duration of Response | 7.4 months |
| Mutant KRAS - FOLFOX | Duration of Response | 8.0 months |
Secondary
Number of Participants With Adverse Events (AEs)
A serious adverse event (SAE) is defined as an AE that • is fatal • is life threatening • 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 28 August 2009; Maximum time on follow-up was 153 weeks.
Population: Safety analysis set; One participant was randomized to 'Panitumumab Plus FOLFOX', but received 'FOLFOX Alone' so is counted in that group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Wild-type KRAS - FOLFOX + Panitumumab | Number of Participants With Adverse Events (AEs) | Any adverse event | 583 participants |
| Wild-type KRAS - FOLFOX + Panitumumab | Number of Participants With Adverse Events (AEs) | Serious adverse event | 262 participants |
| Wild-type KRAS - FOLFOX + Panitumumab | Number of Participants With Adverse Events (AEs) | Leading to discontinuation of any study drug | 136 participants |
| Wild-type KRAS - FOLFOX + Panitumumab | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event (TRAE) | 581 participants |
| Wild-type KRAS - FOLFOX + Panitumumab | Number of Participants With Adverse Events (AEs) | Serious treatment-related adverse event | 162 participants |
| Wild-type KRAS - FOLFOX + Panitumumab | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of any study drug | 117 participants |
| Wild-type KRAS - FOLFOX | Number of Participants With Adverse Events (AEs) | Serious treatment-related adverse event | 89 participants |
| Wild-type KRAS - FOLFOX | Number of Participants With Adverse Events (AEs) | Any adverse event | 579 participants |
| Wild-type KRAS - FOLFOX | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event (TRAE) | 565 participants |
| Wild-type KRAS - FOLFOX | Number of Participants With Adverse Events (AEs) | Serious adverse event | 198 participants |
| Wild-type KRAS - FOLFOX | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of any study drug | 63 participants |
| Wild-type KRAS - FOLFOX | Number of Participants With Adverse Events (AEs) | Leading to discontinuation of any study drug | 84 participants |
Secondary
Overall Survival
The definition of overall survival is the time from randomization to death; participants who were alive at the analysis data cutoff were censored at their last contact date.
Time frame: From randomization until the data cutoff date of 28 August 2009. Maximum time on follow-up was 153 weeks.
Population: KRAS Efficacy Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS - FOLFOX + Panitumumab | Overall Survival | 23.9 months |
| Wild-type KRAS - FOLFOX | Overall Survival | 19.7 months |
| Mutant KRAS - FOLFOX + Panitumumab | Overall Survival | 15.5 months |
| Mutant KRAS - FOLFOX | Overall Survival | 19.3 months |
Comparison: Overall survival comparisons in the wild-type KRAS Efficacy Analysis Set was performed at a significance level of 4.99% conditional on a statistically significant difference for PFS in the Wild-type KRAS Efficacy Analysis Set.p-value: 0.0723Stratified log-rank test
Comparison: Overall survival comparisons in the mutant KRAS Efficacy Analysis Set was performed at an significance level of 4.99% conditional on a statistically significant difference for PFS in the Mutant KRAS Efficacy Analysis Set.p-value: 0.0678Stratified log-rank test
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 by central radiological assessment was defined as the incidence of either a confirmed complete or partial response (CR or PR) while on the first-line treatment, 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 September 2008; Maximum follow-up time was 109 weeks.
Population: KRAS Evaluable 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Wild-type KRAS - FOLFOX + Panitumumab | Percentage of Participants With an Objective Response | 55.21 percentage of participants |
| Wild-type KRAS - FOLFOX | Percentage of Participants With an Objective Response | 47.68 percentage of participants |
| Mutant KRAS - FOLFOX + Panitumumab | Percentage of Participants With an Objective Response | 39.53 percentage of participants |
| Mutant KRAS - FOLFOX | Percentage of Participants With an Objective Response | 40.28 percentage of participants |
p-value: 0.068495% CI: [0.98, 1.87]Stratified exact test
p-value: 0.982295% CI: [0.65, 1.47]Stratified exact test
Secondary
Time to Progression
Time to progression was defined as time from randomization date to date of disease progression per the modified RECIST criteria.
Time frame: From randomization until the data cut-off date of 30 September 2008; Maximum follow-up time was 109 weeks.
Population: KRAS Efficacy Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS - FOLFOX + Panitumumab | Time to Progression | 10.8 months |
| Wild-type KRAS - FOLFOX | Time to Progression | 9.2 months |
| Mutant KRAS - FOLFOX + Panitumumab | Time to Progression | 7.5 months |
| Mutant KRAS - FOLFOX | Time to Progression | 9.0 months |