Colorectal Cancer, Metastases
Conditions
Keywords
Metastatic Colorectal Cancer, Colon, Colorectal, Rectal Cancer, Cancer, Metastatic, EGFr, Clinical Trial, Panitumumab, ABX-EGF, Immunex, Abgenix, Amgen
Brief summary
The purpose of this study is to determine that panitumumab, using the proposed regimen, will safely increase progression free survival in patients with metastatic colorectal cancer who have failed available treatment options (i.e., patients who developed progressive disease or relapsed while on or after prior fluoropyrimidine, irinotecan and oxaliplatin chemotherapy).
Interventions
OTHERBest supportive care
Best supportive care as site routine excluding: antineoplastic chemotherapy, investigational agents, anti-EGFr(Epidermal growth factor receptor) targeting agents other than ABX-EGF(Panitumumab), experimental or approved anti-tumor therapies (e.g. Avastin), chemotherapy, radiotherapy (with the exception of radiotherapy for pain control limited to bone metastases).
DRUGPanitumumab
Intravenous infusion at a dose of 6 mg/kg once every 2 weeks.
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
* Pathologic diagnosis of colorectal adenocarcinoma (diagnostic tissue obtained by tissue biopsy) * Metastatic colorectal carcinoma * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 * Documented evidence of disease progression during, or following treatment, with fluoropyrimidine, irinotecan and oxaliplatin chemotherapy for metastatic colorectal cancer * Radiographic documentation of disease progression during or within 6 months following the most recent chemotherapy regimen * Unidimensionally measurable disease * Tumor expressing epidermal growth factor receptor (EGFr) by immunohistochemistry * At least 2 but not more than 3 prior chemotherapy regimens for colorectal cancer * Adequate hematologic, renal and hepatic function
Exclusion criteria
* Symptomatic brain metastases requiring treatment * History or evidence of interstitial pneumonitis or pulmonary fibrosis * Use of systemic chemotherapy or radiotherapy within 30 days prior to enrollment * Prior epidermal growth factor receptor (EGFr) targeting therapies * Prior anti-tumor therapies including prior experimental agents or approved anti-tumor small molecules and biologics of short (less than a week) serum half life within 30 days before enrollment, or prior experimental or approved proteins within 3 months before enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival Time | From randomization to the data cut-off date of 30 June 2005. The median follow-up time was 20.0 weeks in the panitumumab plus BSC group and 18.2 weeks in the BSC alone group. | Kaplan-Meier estimates of median time from randomization to either death or first observed disease progression, whichever occurred first. Participants were evaluated for tumor response according to modified Response Evaluation Criteria in Solid Tumors (RECIST) based on the response assessment from a blinded review of radiographic scans by the Independent Review Committee. Progressive disease defined as least a 20% increase in the sum of the longest diameters (SLD) of target lesions, taking as reference the nadir SLD recorded since the treatment started or the appearance of one or more new lesions, or the unequivocal progression of existing non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Tumor Response | From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group. | Defined as the number of participants with a confirmed complete or partial tumor response, confirmed by a scan no less than 4 weeks after the criteria for response were first met. Participants were evaluated for tumor response according to modified Response Evaluation Criteria in Solid Tumors (RECIST) based on the response assessment from a blinded review of radiographic scans by the Independent Review Committee. Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): disappearance of all target lesions, and persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease, or, at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD, with no progressive disease of non-target lesions. |
| Duration of Response | From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group. | Kaplan-Meier estimate of the median time from first confirmed objective tumor response to first observed progression of disease or death due to progression of disease (whichever comes first). |
| Time to Response | From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group. | Time to response was defined as the time from randomization to first partial or complete response, subsequently confirmed ≥ 4 weeks after the criteria for response were first met. |
| Overall Survival | From randomization until the data cut-off date for overall survival of 15 March 2006. The median actual follow-up time was 30 weeks for the panitumumab plus BSC group and 31 weeks for the BSC alone group. | Kaplan-Meier estimates of median time from randomization to death. |
| Time to Treatment Failure | From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group. | Kaplan-Meier estimate of the median time from randomization to the date the decision was made to end treatment for any reason. |
| Duration of Stable Disease | From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group. | Kaplan-Meier estimate of the median time from randomization to date of first observed progression of disease or death due to progression of disease (whichever comes first) for those participants with a best response of stable disease. Stable disease defined as neither sufficient shrinkage to qualify for a partial response nor sufficient increase to qualify for progressive disease taking as reference the nadir longest diameter since the treatment started, no unequivocal progression of existing non-target lesions, and no new lesions. |
| Time to Disease Progression | From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group. | Kaplan-Meier estimates of median time from randomization to disease progression or death due to disease progression (whichever occurs first) |
Participant flow
Recruitment details
Participants were enrolled from 16 January 2004 through 16 March 2005. Data are up until the data cutoff of 15 March 2007.
Participants by arm
| Arm | Count |
|---|---|
| Panitumumab Plus BSC Panitumumab plus best supportive care (BSC). Panitumumab was administered by intravenous infusion at a dose of 6 mg/kg once every 2 weeks until participants developed progressive disease or were unable to tolerate study drug. | 231 |
| BSC Alone Best supportive care defined as the best care available as judged appropriate by the investigator and according to institutional guidelines, including antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any symptomatic therapy as clinically indicated. For the purpose of this study, best supportive care does not include anti-neoplastic chemotherapy. | 232 |
| Total | 463 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Disease Progression | 28 | 14 |
| Overall Study | Lost to Follow-up | 10 | 0 |
| Overall Study | Non-compliance | 1 | 0 |
| Overall Study | Ongoing | 1 | 0 |
| Overall Study | Other | 27 | 6 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | BSC Alone | Total | Panitumumab Plus BSC |
|---|---|---|---|
| Age, Continuous | 61.4 years STANDARD_DEVIATION 10.8 | 61.3 years STANDARD_DEVIATION 10.5 | 61.2 years STANDARD_DEVIATION 10.3 |
| Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 | 202 participants | 402 participants | 200 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 2 | 30 participants | 61 participants | 31 participants |
| Race/Ethnicity, Customized Aborigine | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Japanese | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White or Caucasian | 228 participants | 457 participants | 229 participants |
| Region of Enrollment Central and Eastern Europe | 19 participants | 39 participants | 20 participants |
| Region of Enrollment Rest of World | 33 participants | 66 participants | 33 participants |
| Region of Enrollment Western Europe | 180 participants | 358 participants | 178 participants |
| Sex: Female, Male Female | 84 Participants | 169 Participants | 85 Participants |
| Sex: Female, Male Male | 148 Participants | 294 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 224 / 229 | 171 / 234 |
| serious Total, serious adverse events | 101 / 229 | 62 / 234 |
Outcome results
Primary
Progression-free Survival Time
Kaplan-Meier estimates of median time from randomization to either death or first observed disease progression, whichever occurred first. Participants were evaluated for tumor response according to modified Response Evaluation Criteria in Solid Tumors (RECIST) based on the response assessment from a blinded review of radiographic scans by the Independent Review Committee. Progressive disease defined as least a 20% increase in the sum of the longest diameters (SLD) of target lesions, taking as reference the nadir SLD recorded since the treatment started or the appearance of one or more new lesions, or the unequivocal progression of existing non-target lesions.
Time frame: From randomization to the data cut-off date of 30 June 2005. The median follow-up time was 20.0 weeks in the panitumumab plus BSC group and 18.2 weeks in the BSC alone group.
Population: Intention-to-treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab Plus BSC | Progression-free Survival Time | 8.0 weeks |
| BSC Alone | Progression-free Survival Time | 7.3 weeks |
Comparison: Null hypothesis was no difference between treatment groupsp-value: <0.0001Log Rank
Secondary
Duration of Response
Kaplan-Meier estimate of the median time from first confirmed objective tumor response to first observed progression of disease or death due to progression of disease (whichever comes first).
Time frame: From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group.
Population: Intention-to-treat participants who had a confirmed objective tumor response. No objective tumor responses were observed in the BSC alone treatment arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab Plus BSC | Duration of Response | 18.4 weeks |
Secondary
Duration of Stable Disease
Kaplan-Meier estimate of the median time from randomization to date of first observed progression of disease or death due to progression of disease (whichever comes first) for those participants with a best response of stable disease. Stable disease defined as neither sufficient shrinkage to qualify for a partial response nor sufficient increase to qualify for progressive disease taking as reference the nadir longest diameter since the treatment started, no unequivocal progression of existing non-target lesions, and no new lesions.
Time frame: From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group.
Population: Participants who had a best overall response of stable disease
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab Plus BSC | Duration of Stable Disease | 24.0 weeks |
| BSC Alone | Duration of Stable Disease | 17.6 weeks |
Secondary
Objective Tumor Response
Defined as the number of participants with a confirmed complete or partial tumor response, confirmed by a scan no less than 4 weeks after the criteria for response were first met. Participants were evaluated for tumor response according to modified Response Evaluation Criteria in Solid Tumors (RECIST) based on the response assessment from a blinded review of radiographic scans by the Independent Review Committee. Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): disappearance of all target lesions, and persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease, or, at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD, with no progressive disease of non-target lesions.
Time frame: From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group.
Population: Intention-to-treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab Plus BSC | Objective Tumor Response | 22 participants |
| BSC Alone | Objective Tumor Response | 0 participants |
Secondary
Overall Survival
Kaplan-Meier estimates of median time from randomization to death.
Time frame: From randomization until the data cut-off date for overall survival of 15 March 2006. The median actual follow-up time was 30 weeks for the panitumumab plus BSC group and 31 weeks for the BSC alone group.
Population: Intention-to-treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab Plus BSC | Overall Survival | 6.4 months |
| BSC Alone | Overall Survival | 6.3 months |
Comparison: Null hypothesis was no difference between treatment groupsp-value: 0.806Log Rank
Secondary
Time to Disease Progression
Kaplan-Meier estimates of median time from randomization to disease progression or death due to disease progression (whichever occurs first)
Time frame: From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group.
Population: Intention-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab Plus BSC | Time to Disease Progression | 8.0 weeks |
| BSC Alone | Time to Disease Progression | 7.3 weeks |
Secondary
Time to Response
Time to response was defined as the time from randomization to first partial or complete response, subsequently confirmed ≥ 4 weeks after the criteria for response were first met.
Time frame: From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group.
Population: Intention-to-treat (ITT) participants who had a confirmed objective tumor response. No objective tumor responses were observed in the BSC alone treatment arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab Plus BSC | Time to Response | 7.9 weeks |
Secondary
Time to Treatment Failure
Kaplan-Meier estimate of the median time from randomization to the date the decision was made to end treatment for any reason.
Time frame: From randomization until the data cutoff of 15 March 2007. The median follow-up time was 29.6 weeks in the panitumumab plus BSC group and 31.8 weeks in the BSC alone group.
Population: Intention-to-treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab Plus BSC | Time to Treatment Failure | 9.0 weeks |
| BSC Alone | Time to Treatment Failure | 7.1 weeks |
Post Hoc
Progression-free Survival Time (Mutant KRAS)
Kaplan-Meier estimates of median time from randomization to either death or first observed disease progression among participants with mutant Kirsten Rat Sarcoma Virus Oncogene (KRAS) status. Participants were evaluated for tumor response according to modified Response Evaluation Criteria in Solid Tumors (RECIST) based on the response assessment from a blinded review of radiographic scans by the Independent Review Committee. Progressive disease defined as least a 20% increase in the sum of the longest diameters (SLD) of target lesions, taking as reference the nadir SLD recorded since the treatment started or the appearance of one or more new lesions, or the unequivocal progression of existing non-target lesions.
Time frame: From randomization until the data cutoff of 15 March 2007. The median follow-up time in patients with mutant KRAS was 24.4 weeks in the panitumumab plus BSC group and 23.9 weeks in the BSC alone group.
Population: Mutant KRAS Efficacy Analysis Set, a subset of the Intention-to-Treat set with mutant Kirsten Rat Sarcoma Virus Oncogene (KRAS) status.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab Plus BSC | Progression-free Survival Time (Mutant KRAS) | 7.4 weeks |
| BSC Alone | Progression-free Survival Time (Mutant KRAS) | 7.3 weeks |
Post Hoc
Progression-free Survival Time (Wild-type KRAS)
Kaplan-Meier estimates of median time from randomization to either death or first observed disease progression among participants with wild-type Kirsten Rat Sarcoma Virus Oncogene (KRAS) status. Participants were evaluated for tumor response according to modified Response Evaluation Criteria in Solid Tumors (RECIST) based on the response assessment from a blinded review of radiographic scans by the Independent Review Committee. Progressive disease defined as least a 20% increase in the sum of the longest diameters (SLD) of target lesions, taking as reference the nadir SLD recorded since the treatment started or the appearance of one or more new lesions, or the unequivocal progression of existing non-target lesions.
Time frame: From randomization until the data cutoff of 15 March 2007. The median follow-up time in patients with wild-type KRAS was 36.8 weeks in the panitumumab plus BSC group and 35.7 weeks in the BSC alone group.
Population: Wild-type KRAS Efficacy Analysis Set, a subset of the Intention-to-Treat set with wild-type Kirsten Rat Sarcoma Virus Oncogene (KRAS) status.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab Plus BSC | Progression-free Survival Time (Wild-type KRAS) | 12.3 weeks |
| BSC Alone | Progression-free Survival Time (Wild-type KRAS) | 7.3 weeks |