Trial Outcomes & Findings for PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Factor (VEGF) Evaluation Study (NCT NCT00911170)

Last Updated: 2017-12-29

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

847 participants

Primary outcome timeframe

Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)

Results posted on

2017-12-29

Participant Flow

The first participant was enrolled into the study on 03 November 2009 and the last participant on 03 January 2012.

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).

Participant milestones

Participant milestones
Measure	Placebo 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 placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). During the long-term follow-up period, further chemotherapy and/or biologic agents (for example, bevacizumab) were to continue at the discretion of the treating physician.	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). During the long-term follow-up period, further chemotherapy and/or biologic agents (for example, bevacizumab) were to continue at the discretion of the treating physician.
Treatment Period STARTED	424	423
Treatment Period Received Chemotherapy	423	422
Treatment Period Received Bevacizumab	423	420
Treatment Period Received Investigational Product	422	419
Treatment Period COMPLETED	397	386
Treatment Period NOT COMPLETED	27	37
Long Term Follow-Up STARTED	423	422
Long Term Follow-Up COMPLETED	0	0
Long Term Follow-Up NOT COMPLETED	423	422

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo 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 placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). During the long-term follow-up period, further chemotherapy and/or biologic agents (for example, bevacizumab) were to continue at the discretion of the treating physician.	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). During the long-term follow-up period, further chemotherapy and/or biologic agents (for example, bevacizumab) were to continue at the discretion of the treating physician.
Treatment Period Randomized in error	1	1
Treatment Period Ineligibility determined	1	3
Treatment Period Protocol deviation	1	2
Treatment Period Adverse Event	9	10
Treatment Period Withdrawal by Subject	4	4
Treatment Period Disease progression	0	2
Treatment Period Physician Decision	5	5
Treatment Period Lost to Follow-up	0	1
Treatment Period Death	6	9
Long Term Follow-Up Continuing in study	274	269
Long Term Follow-Up Withdrawal by Subject	20	21
Long Term Follow-Up Physician Decision	5	4
Long Term Follow-Up Lost to Follow-up	8	7
Long Term Follow-Up Death	116	121

Baseline Characteristics

PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Factor (VEGF) Evaluation Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=423 Participants 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).	Pegfilgrastim n=422 Participants 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).	Total n=845 Participants Total of all reporting groups
Age, Continuous	60.7 years STANDARD_DEVIATION 10.7 • n=5 Participants	60.6 years STANDARD_DEVIATION 10.4 • n=7 Participants	60.6 years STANDARD_DEVIATION 10.5 • n=5 Participants
Sex: Female, Male Female	159 Participants n=5 Participants	174 Participants n=7 Participants	333 Participants n=5 Participants
Sex: Female, Male Male	264 Participants n=5 Participants	248 Participants n=7 Participants	512 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Asian	3 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	6 participants n=5 Participants	4 participants n=7 Participants	10 participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	8 participants n=5 Participants	11 participants n=7 Participants	19 participants n=5 Participants
Race/Ethnicity, Customized Japanese	0 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized White	404 participants n=5 Participants	402 participants n=7 Participants	806 participants n=5 Participants
Chemotherapy Regimen FOLFOX	207 participants n=5 Participants	207 participants n=7 Participants	414 participants n=5 Participants
Chemotherapy Regimen FOLFIRI	216 participants n=5 Participants	215 participants n=7 Participants	431 participants n=5 Participants
Region North America	79 participants n=5 Participants	77 participants n=7 Participants	156 participants n=5 Participants
Region Rest of World	344 participants n=5 Participants	345 participants n=7 Participants	689 participants n=5 Participants
Disease Status Locally Advanced	18 participants n=5 Participants	18 participants n=7 Participants	36 participants n=5 Participants
Disease Status Metastatic	405 participants n=5 Participants	404 participants n=7 Participants	809 participants n=5 Participants
Primary Tumor Diagnosis Colon	284 participants n=5 Participants	290 participants n=7 Participants	574 participants n=5 Participants
Primary Tumor Diagnosis Rectum	139 participants n=5 Participants	132 participants n=7 Participants	271 participants n=5 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Placebo n=423 Participants 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).	Pegfilgrastim n=422 Participants 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).
Percentage of Participants With Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy	5.7 percentage of participants Interval 3.7 to 8.3	2.4 percentage of participants Interval 1.1 to 4.3

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=423 Participants 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).	Pegfilgrastim n=422 Participants 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).
Overall Survival	24.6 months Interval 21.3 to Could not be estimated due to the low number of events.	21.8 months Interval 18.5 to 25.6

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=423 Participants 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).	Pegfilgrastim n=422 Participants 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).
Progression Free Survival	10.1 months Interval 9.3 to 11.1	9.7 months Interval 9.2 to 10.8

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=423 Participants 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).	Pegfilgrastim n=422 Participants 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).
Time to Progression	11.1 months Interval 10.0 to 11.8	10.8 months Interval 9.5 to 11.3

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Placebo n=420 Participants 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).	Pegfilgrastim n=420 Participants 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).
Percentage of Participants With an Objective Response	56.7 percentage of participants Interval 51.8 to 61.5	58.1 percentage of participants Interval 53.2 to 62.9

SECONDARY outcome

Timeframe: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)

Population: Primary analysis set

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.

Outcome measures

Outcome measures
Measure	Placebo n=423 Participants 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).	Pegfilgrastim n=422 Participants 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).
Percentage of Participants With Grade 4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy	3.5 percentage of participants Interval 2.0 to 5.8	2.4 percentage of participants Interval 1.1 to 4.3

SECONDARY outcome

Timeframe: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)

Population: Primary analysis set

Grade 3/4 severe neutropenia is defined as neutropenia with absolute neutrophil count (ANC) \<1.0 x 10\^9/L.

Outcome measures

Outcome measures
Measure	Placebo n=423 Participants 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).	Pegfilgrastim n=422 Participants 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).
Percentage of Participants With Grade 3/4 Neutropenia Across the First 4 Cycles of Chemotherapy	17.0 percentage of participants Interval 13.6 to 20.9	3.6 percentage of participants Interval 2.0 to 5.8

SECONDARY outcome

Timeframe: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)

Population: Primary analysis set

Grade 4 severe neutropenia is defined as neutropenia with absolute neutrophil count (ANC) \<0.5 x 10\^9/L.

Outcome measures

Outcome measures
Measure	Placebo n=423 Participants 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).	Pegfilgrastim n=422 Participants 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).
Percentage of Participants With Grade 4 Neutropenia Across the First 4 Cycles of Chemotherapy	8.3 percentage of participants Interval 5.8 to 11.3	2.4 percentage of participants Interval 1.1 to 4.3

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=421 Participants 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).	Pegfilgrastim n=420 Participants 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).
Number of Participants With Adverse Events (AEs) Any adverse event	355 participants	344 participants
Number of Participants With Adverse Events (AEs) Worst Grade of > 2	254 participants	240 participants
Number of Participants With Adverse Events (AEs) Worst Grade of > 3	119 participants	115 participants
Number of Participants With Adverse Events (AEs) Worst Grade of > 4	45 participants	31 participants
Number of Participants With Adverse Events (AEs) Serious adverse events	55 participants	68 participants
Number of Participants With Adverse Events (AEs) Severe adverse events	103 participants	106 participants
Number of Participants With Adverse Events (AEs) Life-threatening adverse events	43 participants	27 participants
Number of Participants With Adverse Events (AEs) Fatal adverse events	11 participants	10 participants
Number of Participants With Adverse Events (AEs) Leading to discontinuation of IP	1 participants	3 participants
Number of Participants With Adverse Events (AEs) Leading to discontinuation from study treatment	9 participants	8 participants

Adverse Events

Placebo

Serious events: 56 serious events

Other events: 310 other events

Deaths: 0 deaths

Pegfilgrastim

Serious events: 68 serious events

Other events: 298 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results aftercompletion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=421 participants at risk 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).	Pegfilgrastim n=420 participants at risk 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).
Blood and lymphatic system disorders Anaemia	5.5% 23/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	8.1% 34/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Blood and lymphatic system disorders Neutropenia	28.7% 121/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	11.0% 46/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Gastrointestinal disorders Abdominal pain	5.0% 21/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	6.0% 25/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Gastrointestinal disorders Constipation	11.2% 47/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	10.5% 44/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Gastrointestinal disorders Diarrhoea	24.5% 103/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	25.5% 107/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Gastrointestinal disorders Nausea	21.6% 91/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	27.4% 115/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Gastrointestinal disorders Stomatitis	5.7% 24/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	2.1% 9/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Gastrointestinal disorders Vomiting	10.7% 45/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	11.2% 47/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
General disorders Asthenia	8.1% 34/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	7.4% 31/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
General disorders Fatigue	15.2% 64/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	16.7% 70/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
General disorders Pyrexia	7.4% 31/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	13.3% 56/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Investigations Weight decreased	4.5% 19/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	6.2% 26/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Metabolism and nutrition disorders Decreased appetite	7.4% 31/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	9.5% 40/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Metabolism and nutrition disorders Hypokalaemia	3.6% 15/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	7.6% 32/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Musculoskeletal and connective tissue disorders Back pain	3.3% 14/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	5.5% 23/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Nervous system disorders Neuropathy peripheral	5.9% 25/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	6.9% 29/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.5% 23/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	7.1% 30/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Skin and subcutaneous tissue disorders Alopecia	4.0% 17/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	6.0% 25/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
Vascular disorders Hypertension	6.7% 28/421 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.	7.9% 33/420 • Approximately 8 weeks (4 treatment cycles) All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.