Colorectal Cancer
Conditions
Keywords
Panitumumab Advanced Colorectal Cancer Evaluation Study (PACCE Study), Colorectal, Colon, Rectal Cancer, Metastatic Colorectal, Cancer, EGFr, Clinical Trial, Panitumumab, ABX-EGF, Immunex, Abgenix, Amgen, Metastatic Colorectal Cancer, Oncology
Brief summary
The purpose of this study is to assess whether treatment with the study drug, panitumumab given concomitantly with every 2 (Q2) week oxaliplatin-based chemotherapy and bevacizumab improves progression-free survival (PFS) compared to treatment Q2-week with oxaliplatin-based chemotherapy and bevacizumab alone. All subjects will receive Q2-week oxaliplatin- or irinotecan-based chemotherapy and bevacizumab. Control arm subjects will not receive concomitant panitumumab therapy.
Interventions
DRUGOxaliplatin Based Chemotherapy
Oxaliplatin-based Chemotherapy Every 2 Week Regimens (Q2W Cycles) consisting of Oxaliplatin, Leucovorin (LV), 5-Fluorouracil (5-FU) - To be determined by physician. On Day 1 irinotecan and LV are given at the same time using different bags and a Y-line followed by 5-FU administration.
DRUGPanitumumab
PanitumumabPanitumumab is a high affinity (Kd = 5 x 10-11 M) fully human IgG2 monoclonal antibody that is directed against the human EGFr. Panitumumab will be administered by a 30-60 minute IV infusion at a dose of 6 mg/kg once every 2 weeks on the same day of the oxaliplatin- or irinotecan-based chemotherapy and bevacizumab.
DRUGIrinotecan Based Chemotherapy
Irinotecan-based Chemotherapy Every 2 Week Regimens (Q2W Cycles) - Irinotecan, Leucovorin (LV), 5-Fluorouracil (5-FU) - To be determined by physician. On Day 1 irinotecan and LV are given at the same time using different bags and a Y-line followed by 5-FU administration.
DRUGBevacizumab
Bevacizumab is a vascular endothelial growth factor (VEGF)-targeted antibody therapy that was administered to subjects intravenously Q2 weeks as per usual standard of care on the same day of chemotherapy and panitumumab administration .
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
* Adenocarcinoma of the colon or rectum * Metastatic colorectal cancer (mCRC) * Measurable disease per modified response evaluation criteria in solid tumors (RECIST) criteria * ECOG performance status of 0 or 1 * Available paraffin-embedded tumor tissue (from primary tumor or metastasis) or unstained slides of paraffin-embedded tissue * If history of other primary cancer, subject will be eligible only if she or he has: * Curatively resected non-melanomatous skin cancer; * Curatively treated cervical carcinoma in situ; * Other primary solid tumor curatively treated with no known active disease present and no treatment administered for the last 5 years. * Adequate hematologic data as follows: * Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10\^9 cells/L; * Platelet count greater than or equal to 100 x 10\^9/L; * Hemoglobin greater than or equal to 9.0 g/dL. - Adequate renal function: * Serum creatinine less than or equal to 1.5 x upper limit of normal (ULN); * Urinary protein dipstick of less than 2+ (if urinary dipstick 2+ or greater, then excretion of less than or equal to 1000 mg of protein per day as determined by 24-hour urine collection). * Adequate hepatic function: * Alkaline phosphatase less than or equal to 3 x ULN (if liver metastases, less than or equal to 5 x ULN); * Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase)(AST) less than or equal to 3 x ULN (if liver metastases, less than or equal to 5 x ULN); * Alanine aminotransferase (serum glutamic-pyruvic transaminase) (ALT) less than or equal to 3 x ULN (if liver metastases, less than or equal to 5 x ULN); * Bilirubin less than or equal to 2 x ULN. - Competent to comprehend, sign, and date an IRB-approved informed consent form * Before any study-specific procedure, the appropriate written informed consent must be obtained.
Exclusion criteria
* Prior chemotherapy or biologic (i.e., antibody or vaccine) treatment for mCRC disease - Last dose of adjuvant or radiosensitizing chemotherapy less than 6 months before randomization - Radiotherapy within 14 days before randomization * Elective and/or planned major surgical procedure to be performed during the course of this trial (surgery that arises as needed or necessary during the course of the study, not agreed a priori, will not make the subject ineligible) * Major surgery within 28 days before randomization * Central nervous system metastases * History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest X-ray or CT-scan * Clinically significant ascites * Preexisting bleeding diathesis or coagulopathy or the need for full-dose anticoagulation * Any of the following within 1 year before randomization: * Myocardial infarction; * Unstable angina; * Symptomatic congestive heart failure; * Serious uncontrolled cardiac arrhythmia; * Cerebrovascular accident or transient ischemic attack; * Gastrointestinal ulcer or hemorrhage; * Hemoptysis; * Pulmonary embolism; * Deep vein thrombosis, or other significant thromboembolic event. * Regular use of non-steroidal anti-inflammatory agents * Female subject of childbearing potential, not abstinent, and not willing to use contraceptives during the course of the study and for 6 months following the last dose of first-line treatment * Female subject who is breast-feeding or who has positive serum pregnancy test 72 hours prior to randomization * Male subject, not abstinent, and not willing to use adequate contraception upon enrollment into this study and for 6 months following the last dose of first-line treatment * Subject known to be human immunodeficiency virus (HIV) positive * Subject allergic to panitumumab or any components of panitumumab formulation * History of any 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 the conduct of the study or interpretation of study results * Subject unwilling or unable to comply with study requirements * Any kind of disorder that compromises the ability of the subject to give written informed consent and/or comply with the study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (Oxaliplatin) | Overall study | Kaplan-Meier estimate of the median time from randomization to death from any cause or first observed disease progression |
| Objective Tumor Response Through Week 12 (Irinotecan) | Overall Study | Objective tumor response (complete or partial) rate through week 12 based on central review in the Irinotecan stratum |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (Oxaliplatin) | Overall Study | Kaplan-Meier estimate of the median time from randomization to disease progression or death due to disease progression within the oxaliplatin stratum |
| Time to Treatment Failure (Oxaliplatin) | Overall study | Kaplan-Meier estimate of the median time from randomization to the date the decision was made to discontinue treatment for a reason other than a complete response to treatment within the oxaliplatin stratum. |
| Overall Survival (Irinotecan) | Overall study | Incidence of mortality from any cause in groups treated with Irinotecan. Incidence is provided in lieu of the median time to death since the median or its measure of dispersion was not estimable for at least one treatment arm. |
| Overall Survival (Oxaliplatin) | Overall study | Kaplan-Meier estimate of the median time from randomization to death from any cause in groups treated with Oxaliplatin |
| Objective Tumor Response Rate (Irinotecan) | Overall Study | Best overall response of complete or partial response within irinotecan stratum |
| Time to Progression (Irinotecan) | Overall Study | Kaplan-Meier estimate of the median time from randomization to disease progression or death due to disease progression within the irinotecan stratum |
| Time to Treatment Failure (Irinotecan) | Overall Study | Kaplan-Meier estimate of the median time from randomization to the date the decision was made to discontinue treatment for a reason other than a complete response to treatment within the irinotecan stratum |
| Progression-free Survival (Irinotecan) | Overall Study | Kaplan-Meier estimate of the median time from randomization to death from any cause or first observed disease progression |
| Objective Tumor Response Rate (Oxaliplatin) | Overall study | Best overall response of complete or partial response within oxaliplatin stratum |
Participant flow
Recruitment details
Participants were enrolled from 10 March 2005 through 19 October 2006.
Participants by arm
| Arm | Count |
|---|---|
| Oxaliplatin and Bevacizumab Without Panitumumab Oxaliplatin-based chemotherapy and Bevacizumab Q2W alone | 410 |
| Irinotecan and Bevacizumab Plus Panitumumab Irinotecan-based chemotherapy and Bevacizumab Q2W plus panitumumab 6 mg/kg Q2W | 115 |
| Irinotecan and Bevacizumab Without Panitumumab Irinotecan-based chemotherapy and Bevacizumab Q2W alone | 115 |
| Oxaliplatin and Bevacizumab Plus Panitumumab Oxaliplatin-based chemotherapy and Bevacizumab Q2W plus panitumumab 6 mg/kg Q2W | 413 |
| Total | 1,053 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 20 | 18 | 1 |
| Overall Study | Other | 6 | 12 | 9 | 2 |
| Overall Study | Physician Decision | 4 | 15 | 18 | 13 |
| Overall Study | Withdrawal by Subject | 22 | 53 | 76 | 15 |
Baseline characteristics
| Characteristic | Irinotecan and Bevacizumab Plus Panitumumab | Oxaliplatin and Bevacizumab Without Panitumumab | Total | Oxaliplatin and Bevacizumab Plus Panitumumab | Irinotecan and Bevacizumab Without Panitumumab |
|---|---|---|---|---|---|
| Age, Continuous | 59.4 Year STANDARD_DEVIATION 11.7 | 61.0 Year STANDARD_DEVIATION 11.9 | 60.4 Year STANDARD_DEVIATION 11.8 | 60.8 Year STANDARD_DEVIATION 11.7 | 57.8 Year STANDARD_DEVIATION 12 |
| ECOG Score 0 | 68 Participant | 239 Participant | 634 Participant | 253 Participant | 74 Participant |
| ECOG Score 1 | 47 Participant | 171 Participant | 419 Participant | 160 Participant | 41 Participant |
| Number of Metastatic Organs 1 | 46 Participant | 199 Participant | 502 Participant | 204 Participant | 53 Participant |
| Number of Metastatic Organs >1 | 69 Participant | 211 Participant | 550 Participant | 208 Participant | 62 Participant |
| Number of Metastatic Organs None | 0 Participant | 0 Participant | 1 Participant | 1 Participant | 0 Participant |
| Primary Site of Disease Colon | 92 Participant | 326 Participant | 835 Participant | 322 Participant | 95 Participant |
| Primary Site of Disease Rectal | 23 Participant | 84 Participant | 218 Participant | 91 Participant | 20 Participant |
| Prior adjuvant chemotherapy No | 77 Participant | 333 Participant | 822 Participant | 333 Participant | 79 Participant |
| Prior adjuvant chemotherapy Yes | 38 Participant | 77 Participant | 231 Participant | 80 Participant | 36 Participant |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participant | 1 Participant | 3 Participant | 0 Participant | 0 Participant |
| Race/Ethnicity, Customized Asian | 2 Participant | 10 Participant | 22 Participant | 10 Participant | 0 Participant |
| Race/Ethnicity, Customized Black or African American | 18 Participant | 41 Participant | 110 Participant | 35 Participant | 16 Participant |
| Race/Ethnicity, Customized Hispanic or Latino | 6 Participant | 25 Participant | 70 Participant | 25 Participant | 14 Participant |
| Race/Ethnicity, Customized Japanese | 0 Participant | 2 Participant | 2 Participant | 0 Participant | 0 Participant |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participant | 1 Participant | 1 Participant | 0 Participant | 0 Participant |
| Race/Ethnicity, Customized Other | 1 Participant | 0 Participant | 1 Participant | 0 Participant | 0 Participant |
| Race/Ethnicity, Customized White or Caucasian | 86 Participant | 330 Participant | 844 Participant | 343 Participant | 85 Participant |
| Sex: Female, Male Female | 59 Participants | 172 Participants | 455 Participants | 180 Participants | 44 Participants |
| Sex: Female, Male Male | 56 Participants | 238 Participants | 598 Participants | 233 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 516 / 518 | 505 / 510 |
| serious Total, serious adverse events | 306 / 518 | 188 / 510 |
Outcome results
Primary
Objective Tumor Response Through Week 12 (Irinotecan)
Objective tumor response (complete or partial) rate through week 12 based on central review in the Irinotecan stratum
Time frame: Overall Study
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Objective Tumor Response Through Week 12 (Irinotecan) | 29 Participant |
| Oxaliplatin and Bevacizumab Without Panitumumab | Objective Tumor Response Through Week 12 (Irinotecan) | 27 Participant |
p-value: 0.73895% CI: [0.6, 2.05]Regression, Logistic
Primary
Progression-Free Survival (Oxaliplatin)
Kaplan-Meier estimate of the median time from randomization to death from any cause or first observed disease progression
Time frame: Overall study
Population: Intention-to-Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Progression-Free Survival (Oxaliplatin) | 10.0 Month |
| Oxaliplatin and Bevacizumab Without Panitumumab | Progression-Free Survival (Oxaliplatin) | 11.4 Month |
p-value: 0.01195% CI: [1.06, 1.52]Regression, Cox
Secondary
Objective Tumor Response Rate (Irinotecan)
Best overall response of complete or partial response within irinotecan stratum
Time frame: Overall Study
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Objective Tumor Response Rate (Irinotecan) | 49 Participant |
| Oxaliplatin and Bevacizumab Without Panitumumab | Objective Tumor Response Rate (Irinotecan) | 46 Participant |
Secondary
Objective Tumor Response Rate (Oxaliplatin)
Best overall response of complete or partial response within oxaliplatin stratum
Time frame: Overall study
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Objective Tumor Response Rate (Oxaliplatin) | 190 Participant |
| Oxaliplatin and Bevacizumab Without Panitumumab | Objective Tumor Response Rate (Oxaliplatin) | 196 Participant |
Secondary
Overall Survival (Irinotecan)
Incidence of mortality from any cause in groups treated with Irinotecan. Incidence is provided in lieu of the median time to death since the median or its measure of dispersion was not estimable for at least one treatment arm.
Time frame: Overall study
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Overall Survival (Irinotecan) | 26 Participant |
| Oxaliplatin and Bevacizumab Without Panitumumab | Overall Survival (Irinotecan) | 18 Participant |
p-value: 0.25795% CI: [0.77, 2.62]Regression, Cox
Secondary
Overall Survival (Oxaliplatin)
Kaplan-Meier estimate of the median time from randomization to death from any cause in groups treated with Oxaliplatin
Time frame: Overall study
Population: Intention-to-Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Overall Survival (Oxaliplatin) | 19.4 Month |
| Oxaliplatin and Bevacizumab Without Panitumumab | Overall Survival (Oxaliplatin) | 24.5 Month |
p-value: 0.00595% CI: [1.11, 1.83]Regression, Cox
Secondary
Progression-free Survival (Irinotecan)
Kaplan-Meier estimate of the median time from randomization to death from any cause or first observed disease progression
Time frame: Overall Study
Population: Intention-to-Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Progression-free Survival (Irinotecan) | 10.1 Month |
| Oxaliplatin and Bevacizumab Without Panitumumab | Progression-free Survival (Irinotecan) | 11.7 Month |
Secondary
Time to Progression (Irinotecan)
Kaplan-Meier estimate of the median time from randomization to disease progression or death due to disease progression within the irinotecan stratum
Time frame: Overall Study
Population: Intention-to-Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Time to Progression (Irinotecan) | 11.1 Month |
| Oxaliplatin and Bevacizumab Without Panitumumab | Time to Progression (Irinotecan) | 11.9 Month |
Secondary
Time to Progression (Oxaliplatin)
Kaplan-Meier estimate of the median time from randomization to disease progression or death due to disease progression within the oxaliplatin stratum
Time frame: Overall Study
Population: Intention-to-Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Time to Progression (Oxaliplatin) | 10.8 Month |
| Oxaliplatin and Bevacizumab Without Panitumumab | Time to Progression (Oxaliplatin) | 11.4 Month |
Secondary
Time to Treatment Failure (Irinotecan)
Kaplan-Meier estimate of the median time from randomization to the date the decision was made to discontinue treatment for a reason other than a complete response to treatment within the irinotecan stratum
Time frame: Overall Study
Population: Intention-to-Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Time to Treatment Failure (Irinotecan) | 6.6 Month |
| Oxaliplatin and Bevacizumab Without Panitumumab | Time to Treatment Failure (Irinotecan) | 6.0 Month |
Secondary
Time to Treatment Failure (Oxaliplatin)
Kaplan-Meier estimate of the median time from randomization to the date the decision was made to discontinue treatment for a reason other than a complete response to treatment within the oxaliplatin stratum.
Time frame: Overall study
Population: Intention-to-Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Time to Treatment Failure (Oxaliplatin) | 5.7 Month |
| Oxaliplatin and Bevacizumab Without Panitumumab | Time to Treatment Failure (Oxaliplatin) | 5.9 Month |
Post Hoc
Objective Tumor Response Rate (Mutant KRAS)
Best overall response of complete or partial response in participants treated with irinotecan and having a mutant Kirsten Rat Sarcoma Virus Oncogene (KRAS)
Time frame: Overall Study
Population: Subset of the KRAS Efficacy Analysis Set, composed of participants from the intention-to-treat set who received at least 1 dose of first-line treatment and for whom KRAS mutation status was assessed as mutant, who were treated with irinotecan
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Objective Tumor Response Rate (Mutant KRAS) | 14 Participant |
| Oxaliplatin and Bevacizumab Without Panitumumab | Objective Tumor Response Rate (Mutant KRAS) | 15 Participant |
95% CI: [0.28, 1.67]
Post Hoc
Objective Tumor Response Rate (Wild-type KRAS)
Best overall response of complete or partial response in participants treated with irinotecan and having a wild-type Kirsten Rat Sarcoma Virus Oncogene (KRAS)
Time frame: Overall Study
Population: Subset of the KRAS Efficacy Analysis Set, composed of participants from the intention-to-treat set who received at least 1 dose of first-line treatment and for whom KRAS mutation status was assessed as wild-type, who were treated with irinotecan
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Objective Tumor Response Rate (Wild-type KRAS) | 31 Participant |
| Oxaliplatin and Bevacizumab Without Panitumumab | Objective Tumor Response Rate (Wild-type KRAS) | 28 Participant |
95% CI: [0.61, 2.66]
Post Hoc
Overall Survival (Mutant KRAS)
Kaplan-Meier estimate of the median time from randomization to death from any cause in groups treated with Oxaliplatin and having a mutant Kirsten Rat Sarcoma Virus Oncogene (KRAS). Since the measure of dispersion could not be estimated for at least one treatment arm, participant incidence is provided in lieu of the median.
Time frame: Overall Study
Population: Subset of the KRAS Efficacy Analysis Set, composed of participants from the intention-to-treat set who received at least 1 dose of first-line treatment and for whom KRAS mutation status was assessed as mutant, who were treated with oxaliplatin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Overall Survival (Mutant KRAS) | 47 Participant |
| Oxaliplatin and Bevacizumab Without Panitumumab | Overall Survival (Mutant KRAS) | 45 Participant |
95% CI: [0.67, 1.54]
Post Hoc
Overall Survival (Wild-type KRAS)
Kaplan-Meier estimate of the median time from randomization to death from any cause in groups treated with Oxaliplatin and having a wild-type Kirsten Rat Sarcoma Virus Oncogene (KRAS). Since the measure of dispersion could not be estimated for at least one treatment arm, participant incidence is provided in lieu of the median
Time frame: Overall Study
Population: Subset of the KRAS Efficacy Analysis Set, composed of participants from the intention-to-treat set who received at least 1 dose of first-line treatment and for whom KRAS mutation status was assessed as wild-type, who were treated with oxaliplatin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Overall Survival (Wild-type KRAS) | 71 Participant |
| Oxaliplatin and Bevacizumab Without Panitumumab | Overall Survival (Wild-type KRAS) | 46 Participant |
95% CI: [1.3, 2.75]
Post Hoc
Progression-free Survival (Mutant KRAS)
Kaplan-Meier estimate of the median time from randomization to death from any cause or first observed disease progression in groups treated with oxaliplatin and having a mutant Kirsten Rat Sarcoma Virus Oncogene (KRAS)
Time frame: Overall Study
Population: Subset of the KRAS Efficacy Analysis Set, composed of participants from the intention-to-treat set who received at least 1 dose of first-line treatment and for whom KRAS mutation status was assessed as mutant, who were treated with oxaliplatin
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Progression-free Survival (Mutant KRAS) | 10.4 Month |
| Oxaliplatin and Bevacizumab Without Panitumumab | Progression-free Survival (Mutant KRAS) | 11.0 Month |
95% CI: [0.91, 1.71]
Post Hoc
Progression-free Survival (Wild-type KRAS)
Kaplan-Meier estimate of the median time from randomization to death from any cause or first observed disease progression in groups treated with oxaliplatin and having a wild-type Kirsten Rat Sarcoma Virus Oncogene (KRAS)
Time frame: Overall Study
Population: Subset of the KRAS Efficacy Analysis Set, composed of participants from the intention-to-treat set who received at least 1 dose of first-line treatment and for whom KRAS mutation status was assessed as wild-type, who were treated with oxaliplatin
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin and Bevacizumab Plus Panitumumab | Progression-free Survival (Wild-type KRAS) | 9.8 Month |
| Oxaliplatin and Bevacizumab Without Panitumumab | Progression-free Survival (Wild-type KRAS) | 11.5 Month |
95% CI: [1.04, 1.77]