Metastatic Colorectal Cancer
Conditions
Brief summary
To estimate the effect of KRAS mutation status (Wild-type versus Mutant) on objective response rate and other measures of efficacy for patients treated with panitumumab in combination with a chemotherapy regimen of irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as first-line therapy for metastatic colorectal cancer (mCRC).
Interventions
DRUGPanitumumab
Administered by intravenous infusion
DRUGFOLFIRI
FOLFIRI chemotherapy was initiated on Day 1 of each treatment cycle at the following starting doses: irinotecan 180 mg/m², leucovorin 400 mg/m², 5-fluorouracil bolus 400 mg/m², 5-fluorouracil infusion 2400 mg/m².
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosed with histologically- or cytologically-confirmed metastatic adenocarcinoma of the colon and/or rectum. * Measurable disease according to modified RECIST guidelines. * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. * Paraffin-embedded tissue or unstained tumour slides from primary or metastatic tumour available for central lab analysis. * Adequate haematologic, renal, hepatic and metabolic function.
Exclusion criteria
* Central nervous system metastases. * Prior systemic therapy for the treatment of metastatic colorectal carcinoma with the exception of adjuvant fluoropyrimidine-based chemotherapy given at least six months prior to initiating study treatment. * Prior anti-epidermal growth factor receptor (EGFr) antibody therapy (e.g. cetuximab) or treatment with small molecule EGFr tyrosine kinase inhibitors (e.g. erlotinib). * Prior radiotherapy within 14 days prior to screening, and for which all signs of early radiological toxicity have not abated. * Significant cardiovascular disease including unstable angina or myocardial infarction within six months before initiating study treatment or a history of ventricular arrhythmia. * History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest computed tomography (CT scan. * Active inflammatory bowel disease or other bowel disease causing chronic diarrhoea (defined as \> 4 loose stools per day). * History of Gilbert's syndrome or dihydropyrimidine deficiency. * Known positive test for human immunodeficiency virus infection, hepatitis C virus, chronic active hepatitis B infection. * Any investigational agent within 30 days before initiation of study treatment. * Must not have had a major surgical procedure within 28 days prior to initiation of study treatment. * Subject who is pregnant or breast-feeding. * Woman or man of childbearing potential not consenting to use adequate contraceptive precautions during the course of the study and for six months after the last study drug administration for women, and one month for men. * Other protocol specified criteria and specific details may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks | Objective response rate is defined as the percentage of participants with a best response of complete response or partial response. Disease assessments are based on investigator review of scans using modified Response Evaluation Criteria in Solid Tumors (RECIST) V1.0 criteria. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Participants with no post-baseline assessment were considered non-responders. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate | Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks | The percentage of participants whose best response was either a complete or partial response or stable disease, based on modified RECIST v1.0 criteria as assessed by the Investigator. Stable diease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD of target lesions and no progression of existing non-target lesions and no new lesions, or, the persistence of 1 or more non-target lesions not qualifying for either CR or PD if no target lesions were identified at Baseline. |
| Duration of Response | Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks. | Duration of response was calculated only for those participants who had a confirmed complete or partial response, and is defined as the time from first confirmed response to first observed progression. For participants who responded and did not progress by the analysis data cut-off date, duration of response was censored at their last evaluable disease assessment date. Duration of response was analyzed using the Kaplan-Meier method. |
| Time to Initial Objective Response | Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks. | Time to response is the time from the date of enrollment to the date of first confirmed complete or partial response. Participants with a best response of stable disease at the analysis data cut-off date were censored at their last assessment of SD and participants with all other categories of best response were censored at the maximum observed time to a first confirmed response among all responders. Time to initial objective response was analyzed using Kaplan-Meier methods. |
| Progression-free Survival | From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks. | Progression-free survival is the time from the date of enrollment to the date of first observed progression or death, whichever comes first. Participants who were alive and did not progress by the analysis data cut-off date were censored at the last evaluable disease assessment date. Progression-free survival was analyzed using Kaplan-Meier methods. |
| Objective Response by 17 Weeks | Up to Week 17 | The percentage of participants with a best response of complete response or partial response by Week 17. Disease assessments are based on investigator review of scans using modified RECIST V1.0 criteria. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Participants with no post-baseline assessment were considered non-responders. |
| Duration of Stable Disease | Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks. | Duration of stable disease was calculated only for participants with a best response of stable disease and is defined as the time from enrollment to first observed PD. For participants who did not progress by the analysis data cut-off date, duration of SD was censored at their last evaluable disease assessment date. Duration of stable disease was estimated using Kaplan-Meier methods. |
| Time to Treatment Failure | From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks. | Time to treatment failure is defined as the time from enrollment to the date the decision was made to end the treatment phase for any reason. For participants who remained in the treatment phase at the analysis data cut-off date, time to treatment failure was censored at the date of their last on-study assessment. Time to treatment failure was analyzed using Kaplan-Meier methods. |
| Time to Disease Relapse Following Surgical Intervention | From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks. | Calculated only for those participants who underwent surgical intervention, and defined as the time from the date of first post-intervention radiographic disease assessment to the date of first observed PD. Participants with no post-intervention disease assessment had their time to relapse set to zero and censored in the analysis. Participants that had evidence of progression / recurrence at their first post-intervention disease assessment had a time to relapse of zero. For participants who had not progressed by the analysis data cut-off date, time to relapse was censored at the date of their last evaluable disease assessment. Time to relapse was analyzed using Kaplan-Meier metjhods. |
| Resection Rate | From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks. | The percentage of participants who underwent a surgical procedure that resulted in partial reduction or complete eradication of all metastatic disease. |
| Time to Disease Progression | From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks. | Time to progression is the time from the enrollment date to the date of first observed progression. For participants who had not progressed by the analysis data cutoff date, time to progressive disease was censored at their last evaluable disease assessment date. Time to disease progression was analyzed using Kaplan-Meier methods. |
Participant flow
Recruitment details
A total of 169 patients were screened, of whom 154 were enrolled into this study at 36 study centers in Austria, Belgium, France, Germany, and Sweden from 9 May 2007 through 18 June 2008. Results are reported through the primary analysis data cut-off date of 18 June 2009 (12 months after the last patient was enrolled).
Pre-assignment details
Participants received a FOLFIRI regimen in combination with panitumumab once every 14 days until diagnosed with radiographic disease progression, at which time the participant was withdrawn from the treatment phase. Participants were to complete a safety follow-up visit 8 weeks after the treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| Panitumumab Plus FOLFIRI Participants received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression. | 154 |
| Total | 154 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Death | 16 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Ongoing at Data Cut-off | 12 |
| Overall Study | Other - Not Specified | 3 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Protocol-specified Criteria | 2 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Panitumumab Plus FOLFIRI |
|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 10.6 |
| Kirsten Rat Sarcoma-2 Virus (KRAS) Mutation Status Mutant KRAS | 59 participants |
| Kirsten Rat Sarcoma-2 Virus (KRAS) Mutation Status Unevaluable KRAS | 9 participants |
| Kirsten Rat Sarcoma-2 Virus (KRAS) Mutation Status Wild-type KRAS | 86 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 participants |
| Race/Ethnicity, Customized Japanese | 1 participants |
| Race/Ethnicity, Customized White or Caucasian | 150 participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 154 / 154 |
| serious Total, serious adverse events | 84 / 154 |
Outcome results
Primary
Objective Response Rate
Objective response rate is defined as the percentage of participants with a best response of complete response or partial response. Disease assessments are based on investigator review of scans using modified Response Evaluation Criteria in Solid Tumors (RECIST) V1.0 criteria. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Participants with no post-baseline assessment were considered non-responders. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions.
Time frame: Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks
Population: KRAS Tumor Response Analysis Set (all participants who provided informed consent, enrolled, received at least 1 dose of panitumumab, had evaluable KRAS status data, and with at least 1 unidimensionally measurable lesion per modified RECIST by the local investigator)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Wild-type KRAS | Objective Response Rate | 56.47 percentage of participants |
| Mutant KRAS | Objective Response Rate | 37.93 percentage of participants |
95% CI: [1.02, 4.45]
Secondary
Disease Control Rate
The percentage of participants whose best response was either a complete or partial response or stable disease, based on modified RECIST v1.0 criteria as assessed by the Investigator. Stable diease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD of target lesions and no progression of existing non-target lesions and no new lesions, or, the persistence of 1 or more non-target lesions not qualifying for either CR or PD if no target lesions were identified at Baseline.
Time frame: Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks
Population: KRAS Tumor Response Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Wild-type KRAS | Disease Control Rate | 90.59 percentage of participants |
| Mutant KRAS | Disease Control Rate | 89.66 percentage of participants |
95% CI: [0.3, 3.89]
Secondary
Duration of Response
Duration of response was calculated only for those participants who had a confirmed complete or partial response, and is defined as the time from first confirmed response to first observed progression. For participants who responded and did not progress by the analysis data cut-off date, duration of response was censored at their last evaluable disease assessment date. Duration of response was analyzed using the Kaplan-Meier method.
Time frame: Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks.
Population: KRAS Tumor Response Analysis Set with an objective response (CR or PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS | Duration of Response | 13.0 months |
| Mutant KRAS | Duration of Response | 7.4 months |
95% CI: [0.13, 0.614]
Secondary
Duration of Stable Disease
Duration of stable disease was calculated only for participants with a best response of stable disease and is defined as the time from enrollment to first observed PD. For participants who did not progress by the analysis data cut-off date, duration of SD was censored at their last evaluable disease assessment date. Duration of stable disease was estimated using Kaplan-Meier methods.
Time frame: Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks.
Population: KRAS Tumor Response Analysis Set with a best response of SD
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS | Duration of Stable Disease | 5.9 months |
| Mutant KRAS | Duration of Stable Disease | 6.1 months |
95% CI: [0.4, 1.43]
Secondary
Objective Response by 17 Weeks
The percentage of participants with a best response of complete response or partial response by Week 17. Disease assessments are based on investigator review of scans using modified RECIST V1.0 criteria. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Participants with no post-baseline assessment were considered non-responders.
Time frame: Up to Week 17
Population: KRAS Tumor Response Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Wild-type KRAS | Objective Response by 17 Weeks | 49.41 percentage of participants |
| Mutant KRAS | Objective Response by 17 Weeks | 34.48 percentage of participants |
95% CI: [0.88, 3.93]
Secondary
Progression-free Survival
Progression-free survival is the time from the date of enrollment to the date of first observed progression or death, whichever comes first. Participants who were alive and did not progress by the analysis data cut-off date were censored at the last evaluable disease assessment date. Progression-free survival was analyzed using Kaplan-Meier methods.
Time frame: From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.
Population: Primary Analysis Set (all participants who provided informed consent, enrolled, received at least 1 dose of panitumumab, and had evaluable KRAS status data)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS | Progression-free Survival | 8.9 months |
| Mutant KRAS | Progression-free Survival | 7.2 months |
95% CI: [0.306, 0.703]
Secondary
Resection Rate
The percentage of participants who underwent a surgical procedure that resulted in partial reduction or complete eradication of all metastatic disease.
Time frame: From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.
Population: Primary Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Wild-type KRAS | Resection Rate | 15.12 percentage of participants |
| Mutant KRAS | Resection Rate | 6.78 percentage of participants |
95% CI: [-4.01, 19.08]
Secondary
Time to Disease Progression
Time to progression is the time from the enrollment date to the date of first observed progression. For participants who had not progressed by the analysis data cutoff date, time to progressive disease was censored at their last evaluable disease assessment date. Time to disease progression was analyzed using Kaplan-Meier methods.
Time frame: From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.
Population: Primary Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS | Time to Disease Progression | 11.2 months |
| Mutant KRAS | Time to Disease Progression | 7.3 months |
95% CI: [0.252, 0.618]
Secondary
Time to Disease Relapse Following Surgical Intervention
Calculated only for those participants who underwent surgical intervention, and defined as the time from the date of first post-intervention radiographic disease assessment to the date of first observed PD. Participants with no post-intervention disease assessment had their time to relapse set to zero and censored in the analysis. Participants that had evidence of progression / recurrence at their first post-intervention disease assessment had a time to relapse of zero. For participants who had not progressed by the analysis data cut-off date, time to relapse was censored at the date of their last evaluable disease assessment. Time to relapse was analyzed using Kaplan-Meier metjhods.
Time frame: From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.
Population: Primary Analysis Set participants who underwent surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS | Time to Disease Relapse Following Surgical Intervention | NA months |
| Mutant KRAS | Time to Disease Relapse Following Surgical Intervention | NA months |
Secondary
Time to Initial Objective Response
Time to response is the time from the date of enrollment to the date of first confirmed complete or partial response. Participants with a best response of stable disease at the analysis data cut-off date were censored at their last assessment of SD and participants with all other categories of best response were censored at the maximum observed time to a first confirmed response among all responders. Time to initial objective response was analyzed using Kaplan-Meier methods.
Time frame: Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks.
Population: KRAS Tumor Response Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS | Time to Initial Objective Response | 3.8 months |
| Mutant KRAS | Time to Initial Objective Response | NA months |
95% CI: [0.99, 2.721]
Secondary
Time to Treatment Failure
Time to treatment failure is defined as the time from enrollment to the date the decision was made to end the treatment phase for any reason. For participants who remained in the treatment phase at the analysis data cut-off date, time to treatment failure was censored at the date of their last on-study assessment. Time to treatment failure was analyzed using Kaplan-Meier methods.
Time frame: From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.
Population: Primary Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Wild-type KRAS | Time to Treatment Failure | 6.9 months |
| Mutant KRAS | Time to Treatment Failure | 5.8 months |
95% CI: [0.503, 1.002]