Cancer, Colon Cancer, Colorectal Cancer, Fever, Locally Advanced, Metastatic Colorectal Cancer, Neutropenia, Rectal Cancer
Conditions
Keywords
adenocarcinoma of the colon or rectum, febrile neutropenia, Bevacizumab, Avastin, 5-fluorouracil, Oxaliplatin, Leucovorin (FOLFOX), 5-fluorouracil, Irinotecan, Leucovorin (FOLFIRI)
Brief summary
This is a phase 3, randomized, double-blind, placebo-controlled multi-center study evaluating the efficacy of pegfilgrastim to reduce the incidence of febrile neutropenia (FN) in patients with newly diagnosed, locally-advanced or metastatic colorectal cancer receiving first-line treatment with bevacizumab and either 5-fluorouracil, Oxaliplatin, Leucovorin (FOLFOX) or 5-fluorouracil, Irinotecan, Leucovorin (FOLFIRI). This study will also investigate the effect of adding pegfilgrastim to bevacizumab and either FOLFOX or FOLFIRI by evaluating overall survival, progression-free survival, and overall response rate in each arm at regular intervals over a maximum of 60 months follow-up.
Interventions
DRUGPegfilgrastim
Administered as a single 6 mg subcutaneous injection using a pre-filled syringe. There will be no dosage adjustments for investigational product.
DRUGPlacebo
Administered as a single subcutaneous injection using a pre-filled syringe.
BIOLOGICALBevacizumab
5 mg/kg by intravenous (IV) infusion on day 1 of each 14-day cycle.
DRUGStandard Chemotherapy
Each participant received one of the following chemotherapy regimens at the discretion of treating physician: FOLFOX: Oxaliplatin, leucovorin, and 5-fluorouracil; FOLFIRI: Irinotecan, leucovorin and 5-flurouracil.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Disease-related: * Histologically or cytologically-confirmed adenocarcinoma of the colon or rectum * Locally-advanced or metastatic disease by radiographic evaluation * Measurable disease * Has not previously received chemotherapy for locally-advanced or metastatic colorectal cancer. Patient may have received adjuvant therapy for primary colorectal cancer provided that at least 6 months have elapsed from the time the adjuvant therapy was concluded and recurrent/metastatic disease was documented. * Eastern Cooperative Oncology Group (ECOG) Performance status 0-2 Demographic: \- Age of 18 years or over Laboratory: Adequate organ and marrow function as defined below: * Absolute neutrophil count at least 1.5 x 10\^9/L * Platelet count at least 100 x 10\^9/L * Bilirubin ≤ 1.5 times upper limit of normal * Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal or Aspartate aminotransferase and alanine aminotransferase ≤ 5.0 x upper limit of normal if attributable to liver metastasis * An in-range international normalized ratio (INR) (in-range is usually defined as between 2 and 3) for patients on a stable dose of oral anticoagulant or stable dose of low molecular weight heparin * Has no active bleeding or pathological condition that carries high risk of bleeding (eg, tumor involving major vessels or known varices). If a suspicion of bleeding diathesis exists, a bleeding time should be performed * Creatinine ≤ 1.5 times upper limit of normal General: * Written informed consent obtained * Afebrile on day 1 of cycle 1 * Must be able and willing to comply with study and/or follow-up procedures
Exclusion criteria
Disease-Related: * Known brain metastases * History of another primary malignancy less than/equal to 5 years prior to randomization, with the exception of non-melanoma skin cancer, carcinoma in situ of uterine cervix, and prostatic intraepithelial neoplasia without evidence of prostate cancer * Prior major surgical procedure less than 28 days prior to day 1 of cycle 1 chemotherapy dosing; anticipated need for major surgical procedure during the 4 cycle treatment period of the study * Fine needle aspirations or core biopsies within 7 days prior to day 1 of cycle 1 chemotherapy dosing * Serious nonhealing wound, ulcer, or bone fracture, or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 1 of cycle 1 * Uncontrolled high blood pressure, history of labile hypertension, uncontrolled congestive heart failure, unstable angina within the past 3 months, myocardial infarction or history of stroke within the past 12 months, unstable symptomatic arrhythmia requiring medication, or clinically significant peripheral vascular disease * History of clinically significant bleeding within 6 months prior to randomization * History of arterial or venous thromboembolism within 6 months prior to randomization * History of other disease including uncontrolled diabetes, serious active or uncontrolled infection, metabolic dysfunction; physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of the prescribed therapy or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications Laboratory: \- Proteinuria \> 1+, or total quantitative protein \> 500 mg protein/day as determined by 24-hr urine collection Medications: * Prior radiotherapy unless treatment was limited to the target lesion and only 1 measurable lesion was treated. Progression of the irradiated lesion must be demonstrated. Patients may not have received prior radiotherapy to greater than 25% of bone marrow. Radiation must have concluded ≥ 4 weeks prior to enrollment. Prior radio-sensitizing chemoradiation will be allowed as long as it was concluded ≥ 4 weeks prior to enrollment. * Radiotherapy to non-target lesions for pain control will be allowed * Prior bevacizumab use or other agents targeting VEGF * Concurrent use of other biological agents * Use of systemic anti-infectives for active infection, during the 3 calendar days before starting study chemotherapy and bevacizumab or planned during the study treatment period General: * Current, recent (within 4 weeks of the first infusion of this study), or planned participation (during the study treatment period) in an experimental therapeutics study other than this protocol * Female participants who are pregnant or lactating or men and women of reproductive potential not willing to employ an effective method of birth control during treatment and for 20 weeks for women, and 30 weeks for men after discontinuing study treatment * History of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab, irinotecan, 5-fluorouracil (5-FU), oxaliplatin, or leucovorin, including known sensitivity to E. Coli derived products (eg, Filgrastim, HUMULIN insulin, L-asparaginase) * Known dihydropyrimidine dehydrogenase deficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy | Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle) | Grade 3/4 febrile neutropenia (FN) is defined as: • A temperature ≥ 38.0°C (≥ 100.4°F) and absolute neutrophil count (ANC) \< 1.0 × 10\^9/L, where ANC was measured the same day or within ± 1 calendar day of a temperature ≥ 38.0°C (≥ 100.4°F), or • An ANC \< 1.0 × 10\^9/L in combination with: - documented sepsis or infection, OR - neutropenia-related hospitalization where ANC was measured the same day or within ± 1 calendar day. Participants monitored their oral temperatures and maintained diaries to record their temperature twice per day: once in the morning and once in the evening, as well as whenever they suspect they had fever throughout the first 4 cycles of chemotherapy treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months. | Time from randomization to date of radiological disease progression or death from any cause, whichever event occurs first, calculated using the Kaplan-Meier method. Participants without either event by the analysis data cutoff date were censored on the date of their last evaluable disease assessment. Disease progression based on the investigator's assessment of radiographic scans using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Clinical progression without radiological assessment was not be considered a disease progression in this analysis. Progression defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. |
| Time to Progression | From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months. | Time from randomization to date of radiological disease progression calculated using the Kaplan-Meier method. Participants without progression were censored on the date of their last radiographic tumor assessment. Disease progression based on the investigator's assessment of scans using the RECIST v1.1. Clinical progression without radiological assessment was not considered a disease progression. Progression defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. |
| Percentage of Participants With an Objective Response | From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months. | The percentage of participants with a complete response (CR) or partial response (PR) defined by the RECIST v1.1 criteria at any time during the study. Response was be determined by the investigator's assessment of radiographic scans. CR: Disappearance of all non-nodal target lesions and the disappearance of all non-nodal non-target lesions, and no new lesions. All nodal lesions must have reduction of short axis to \< 10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters and no new lesions and/or unequivocal progression of existing non-target lesions, or, the disappearance of all non-nodal target lesions with persistence of one or more non-target lesion(s). |
| Overall Survival | From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months. | Median time from randomization to date of death caclulated using the Kaplan-Meier method. Participants were censored on the date of last contact (i.e., the date the participant was last known to be alive) if they were not known to have died. |
| Percentage of Participants With Grade 3/4 Neutropenia Across the First 4 Cycles of Chemotherapy | Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle) | Grade 3/4 severe neutropenia is defined as neutropenia with absolute neutrophil count (ANC) \<1.0 x 10\^9/L. |
| Percentage of Participants With Grade 4 Neutropenia Across the First 4 Cycles of Chemotherapy | Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle) | Grade 4 severe neutropenia is defined as neutropenia with absolute neutrophil count (ANC) \<0.5 x 10\^9/L. |
| Number of Participants With Adverse Events (AEs) | Approximately 8 weeks (4 treatment cycles) | A serious adverse event (SAE) is defined as an adverse event that - is fatal; - is life threatening (places the participant at immediate risk of death); - requires inpatient hospitalization or prolongation of existing hospitalization; - results in persistent or significant disability/incapacity; - is a congenital anomaly/birth defect; - other significant medical hazard. AEs were assessed for severity according to National Cancer Institute, Common Terminology Criteria for Adverse Events, Version 3.0, based on this general guideline: Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death related to AE. |
| Percentage of Participants With Grade 4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy | Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle) | Grade 4 febrile neutropenia (FN) is defined as: * A temperature ≥ 38.0ºC (≥ 100.4ºF) and absolute neutrophil count (ANC) \< 0.5 × 10\^9/L, where ANC is measured the same day or within +/- 1 calendar day of a temperature ≥ 38.0ºC (≥ 100.4ºF), or * An ANC \<0.5 × 10\^9/L in combination with: * Documented sepsis or infection, OR * Neutropenia-related hospitalization where ANC is measured the same day or within +/- 1 calendar day. |
Countries
Australia, Belgium, Bulgaria, Canada, Czechia, France, Hungary, Ireland, Italy, Latvia, Mexico, Poland, Romania, Russia, Slovakia, Ukraine, United States
Participant flow
Recruitment details
The first participant was enrolled into the study on 03 November 2009 and the last participant on 03 January 2012.
Pre-assignment details
This study included a a study treatment period (approximately 8 weeks), and a long-term follow-up period (up to 36 months after the last participant was enrolled).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). | 423 |
| Pegfilgrastim Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2 and bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus pegfilgrastim 6 mg administered as a single subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). | 422 |
| Total | 845 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long Term Follow-Up | Continuing in study | 274 | 269 |
| Long Term Follow-Up | Death | 116 | 121 |
| Long Term Follow-Up | Lost to Follow-up | 8 | 7 |
| Long Term Follow-Up | Physician Decision | 5 | 4 |
| Long Term Follow-Up | Withdrawal by Subject | 20 | 21 |
| Treatment Period | Adverse Event | 9 | 10 |
| Treatment Period | Death | 6 | 9 |
| Treatment Period | Disease progression | 0 | 2 |
| Treatment Period | Ineligibility determined | 1 | 3 |
| Treatment Period | Lost to Follow-up | 0 | 1 |
| Treatment Period | Physician Decision | 5 | 5 |
| Treatment Period | Protocol deviation | 1 | 2 |
| Treatment Period | Randomized in error | 1 | 1 |
| Treatment Period | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | Pegfilgrastim |
|---|---|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 10.7 | 60.6 years STANDARD_DEVIATION 10.5 | 60.6 years STANDARD_DEVIATION 10.4 |
| Chemotherapy Regimen FOLFIRI | 216 participants | 431 participants | 215 participants |
| Chemotherapy Regimen FOLFOX | 207 participants | 414 participants | 207 participants |
| Disease Status Locally Advanced | 18 participants | 36 participants | 18 participants |
| Disease Status Metastatic | 405 participants | 809 participants | 404 participants |
| Primary Tumor Diagnosis Colon | 284 participants | 574 participants | 290 participants |
| Primary Tumor Diagnosis Rectum | 139 participants | 271 participants | 132 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 3 participants | 5 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 6 participants | 10 participants | 4 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 8 participants | 19 participants | 11 participants |
| Race/Ethnicity, Customized Japanese | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized White | 404 participants | 806 participants | 402 participants |
| Region North America | 79 participants | 156 participants | 77 participants |
| Region Rest of World | 344 participants | 689 participants | 345 participants |
| Sex: Female, Male Female | 159 Participants | 333 Participants | 174 Participants |
| Sex: Female, Male Male | 264 Participants | 512 Participants | 248 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 310 / 421 | 298 / 420 |
| serious Total, serious adverse events | 56 / 421 | 68 / 420 |
Outcome results
Primary
Percentage of Participants With Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy
Grade 3/4 febrile neutropenia (FN) is defined as: • A temperature ≥ 38.0°C (≥ 100.4°F) and absolute neutrophil count (ANC) \< 1.0 × 10\^9/L, where ANC was measured the same day or within ± 1 calendar day of a temperature ≥ 38.0°C (≥ 100.4°F), or • An ANC \< 1.0 × 10\^9/L in combination with: - documented sepsis or infection, OR - neutropenia-related hospitalization where ANC was measured the same day or within ± 1 calendar day. Participants monitored their oral temperatures and maintained diaries to record their temperature twice per day: once in the morning and once in the evening, as well as whenever they suspect they had fever throughout the first 4 cycles of chemotherapy treatment.
Time frame: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)
Population: The primary analysis set which included all participants with a signed informed consent, and who were randomized and received at least 1 dose of protocol-specified study treatment (chemotherapy, bevacizumab, or investigational product).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy | 5.7 percentage of participants |
| Pegfilgrastim | Percentage of Participants With Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy | 2.4 percentage of participants |
Comparison: The primary hypothesis was that the percentage of participants treated with study chemotherapy and bevacizumab who experience grade 3/4 febrile neutropenia (FN) would be lower in participants randomized to the pegfilgrastim arm compared to placebo arm. The study was designed to have at least 90% power at the 2-sided 0.05 significance level to detect a 6% difference in incidence of grade 3/4 FN from 9% to 3%, which is approximately a 66.7% relative reduction.p-value: 0.01495% CI: [0.19, 0.86]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Adverse Events (AEs)
A serious adverse event (SAE) is defined as an adverse event that - is fatal; - is life threatening (places the participant at immediate risk of death); - requires inpatient hospitalization or prolongation of existing hospitalization; - results in persistent or significant disability/incapacity; - is a congenital anomaly/birth defect; - other significant medical hazard. AEs were assessed for severity according to National Cancer Institute, Common Terminology Criteria for Adverse Events, Version 3.0, based on this general guideline: Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death related to AE.
Time frame: Approximately 8 weeks (4 treatment cycles)
Population: Safety analysis set, defined as all participants in the Primary Analysis Set who received at least one dose of investigational product (IP; placebo or pegfilgrastim). One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs) | Any adverse event | 355 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Worst Grade of > 2 | 254 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Worst Grade of > 3 | 119 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Worst Grade of > 4 | 45 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Serious adverse events | 55 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Severe adverse events | 103 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Life-threatening adverse events | 43 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 11 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Leading to discontinuation of IP | 1 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Leading to discontinuation from study treatment | 9 participants |
| Pegfilgrastim | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 10 participants |
| Pegfilgrastim | Number of Participants With Adverse Events (AEs) | Any adverse event | 344 participants |
| Pegfilgrastim | Number of Participants With Adverse Events (AEs) | Severe adverse events | 106 participants |
| Pegfilgrastim | Number of Participants With Adverse Events (AEs) | Worst Grade of > 2 | 240 participants |
| Pegfilgrastim | Number of Participants With Adverse Events (AEs) | Leading to discontinuation from study treatment | 8 participants |
| Pegfilgrastim | Number of Participants With Adverse Events (AEs) | Worst Grade of > 3 | 115 participants |
| Pegfilgrastim | Number of Participants With Adverse Events (AEs) | Life-threatening adverse events | 27 participants |
| Pegfilgrastim | Number of Participants With Adverse Events (AEs) | Worst Grade of > 4 | 31 participants |
| Pegfilgrastim | Number of Participants With Adverse Events (AEs) | Leading to discontinuation of IP | 3 participants |
| Pegfilgrastim | Number of Participants With Adverse Events (AEs) | Serious adverse events | 68 participants |
Secondary
Overall Survival
Median time from randomization to date of death caclulated using the Kaplan-Meier method. Participants were censored on the date of last contact (i.e., the date the participant was last known to be alive) if they were not known to have died.
Time frame: From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months.
Population: Primary analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Overall Survival | 24.6 months |
| Pegfilgrastim | Overall Survival | 21.8 months |
p-value: 0.70495% CI: [0.81, 1.36]Log Rank
Secondary
Percentage of Participants With an Objective Response
The percentage of participants with a complete response (CR) or partial response (PR) defined by the RECIST v1.1 criteria at any time during the study. Response was be determined by the investigator's assessment of radiographic scans. CR: Disappearance of all non-nodal target lesions and the disappearance of all non-nodal non-target lesions, and no new lesions. All nodal lesions must have reduction of short axis to \< 10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters and no new lesions and/or unequivocal progression of existing non-target lesions, or, the disappearance of all non-nodal target lesions with persistence of one or more non-target lesion(s).
Time frame: From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months.
Population: Primary analysis set participants with measurable disease at Baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With an Objective Response | 56.7 percentage of participants |
| Pegfilgrastim | Percentage of Participants With an Objective Response | 58.1 percentage of participants |
p-value: 0.68395% CI: [0.81, 1.39]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Grade 3/4 Neutropenia Across the First 4 Cycles of Chemotherapy
Grade 3/4 severe neutropenia is defined as neutropenia with absolute neutrophil count (ANC) \<1.0 x 10\^9/L.
Time frame: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)
Population: Primary analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Grade 3/4 Neutropenia Across the First 4 Cycles of Chemotherapy | 17.0 percentage of participants |
| Pegfilgrastim | Percentage of Participants With Grade 3/4 Neutropenia Across the First 4 Cycles of Chemotherapy | 3.6 percentage of participants |
p-value: <0.00195% CI: [0.1, 0.32]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Grade 4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy
Grade 4 febrile neutropenia (FN) is defined as: * A temperature ≥ 38.0ºC (≥ 100.4ºF) and absolute neutrophil count (ANC) \< 0.5 × 10\^9/L, where ANC is measured the same day or within +/- 1 calendar day of a temperature ≥ 38.0ºC (≥ 100.4ºF), or * An ANC \<0.5 × 10\^9/L in combination with: * Documented sepsis or infection, OR * Neutropenia-related hospitalization where ANC is measured the same day or within +/- 1 calendar day.
Time frame: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)
Population: Primary analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Grade 4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy | 3.5 percentage of participants |
| Pegfilgrastim | Percentage of Participants With Grade 4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy | 2.4 percentage of participants |
p-value: 0.31295% CI: [0.29, 1.49]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Grade 4 Neutropenia Across the First 4 Cycles of Chemotherapy
Grade 4 severe neutropenia is defined as neutropenia with absolute neutrophil count (ANC) \<0.5 x 10\^9/L.
Time frame: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)
Population: Primary analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Grade 4 Neutropenia Across the First 4 Cycles of Chemotherapy | 8.3 percentage of participants |
| Pegfilgrastim | Percentage of Participants With Grade 4 Neutropenia Across the First 4 Cycles of Chemotherapy | 2.4 percentage of participants |
p-value: <0.00195% CI: [0.13, 0.56]Cochran-Mantel-Haenszel
Secondary
Progression Free Survival
Time from randomization to date of radiological disease progression or death from any cause, whichever event occurs first, calculated using the Kaplan-Meier method. Participants without either event by the analysis data cutoff date were censored on the date of their last evaluable disease assessment. Disease progression based on the investigator's assessment of radiographic scans using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Clinical progression without radiological assessment was not be considered a disease progression in this analysis. Progression defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months.
Population: Primary analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Progression Free Survival | 10.1 months |
| Pegfilgrastim | Progression Free Survival | 9.7 months |
p-value: 0.55295% CI: [0.88, 1.26]Log Rank
Secondary
Time to Progression
Time from randomization to date of radiological disease progression calculated using the Kaplan-Meier method. Participants without progression were censored on the date of their last radiographic tumor assessment. Disease progression based on the investigator's assessment of scans using the RECIST v1.1. Clinical progression without radiological assessment was not considered a disease progression. Progression defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months.
Population: Primary analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Progression | 11.1 months |
| Pegfilgrastim | Time to Progression | 10.8 months |
p-value: 0.50295% CI: [0.88, 1.29]Log Rank