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

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00911170
• Collaborator: (none)
• Enrollment: 847
• Locations: 154
• Arms: 2
• Actual Duration (Months): 62
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cancer; Colon Cancer; Colorectal Cancer; Fever; Locally Advanced; Metastatic Colorectal Cancer; Neutropenia; Rectal Cancer	Drug: Pegfilgrastim; Drug: Placebo; Biological: Bevacizumab; Drug: Standard Chemotherapy	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 847 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Supportive Care
• Official Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Pegfilgrastim Admininstered to Subjects With Newly Diagnosed, Locally-advanced or Metastatic Colorectal Cancer Treated With Bevacizumab & Either 5-fluorouracil, Oxaliplatin, Leucovorin (FOLFOX) or 5-fluorouracil, Irinotecan, Leucovorin (FOLFIRI)
• Actual Study Start Date: Nov 3, 2009
• Actual Primary Completion Date: Sep 17, 2012
• Actual Study Completion Date: Jan 2, 2015

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 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).	Drug: Placebo; Administered as a single subcutaneous injection using a pre-filled syringe.; Biological: Bevacizumab; 5 mg/kg by intravenous (IV) infusion on day 1 of each 14-day cycle.; Other Names: Avastin® ; Drug: Standard 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.
Placebo Comparator: 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).	Drug: Pegfilgrastim; Administered as a single 6 mg subcutaneous injection using a pre-filled syringe. There will be no dosage adjustments for investigational product.; Other Names: Neulasta® ; Biological: Bevacizumab; 5 mg/kg by intravenous (IV) infusion on day 1 of each 14-day cycle.; Other Names: Avastin® ; Drug: Standard 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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).

5. 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.

6. 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.

7. 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.

8. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Muscle Shoals	Alabama	United States	35661
2	Research Site	Jonesboro	Arkansas	United States	72401
3	Research Site	Anaheim	California	United States	92801
4	Research Site	Beverly Hills	California	United States	90211
5	Research Site	Modesto	California	United States	95355
6	Research Site	San Diego	California	United States	92161
7	Research Site	Greenwich	Connecticut	United States	06830
8	Research Site	Dover	Delaware	United States	19901
9	Research Site	Gainesville	Florida	United States	32605
10	Research Site	Loxahatchee Groves	Florida	United States	33470
11	Research Site	Port Saint Lucie	Florida	United States	34952
12	Research Site	Tamarac	Florida	United States	33321
13	Research Site	Honolulu	Hawaii	United States	96813
14	Research Site	Gurnee	Illinois	United States	60031
15	Research Site	Maywood	Illinois	United States	60153
16	Research Site	Quincy	Illinois	United States	62301
17	Research Site	Rockford	Illinois	United States	61108
18	Research Site	New Albany	Indiana	United States	47150
19	Research Site	South Bend	Indiana	United States	46617
20	Research Site	Council Bluffs	Iowa	United States	51503
21	Research Site	Sioux City	Iowa	United States	51101
22	Research Site	Waterloo	Iowa	United States	50701
23	Research Site	Waterloo	Iowa	United States	50702
24	Research Site	Hutchinson	Kansas	United States	67502
25	Research Site	Hazard	Kentucky	United States	41701
26	Research Site	Lexington	Kentucky	United States	40503
27	Research Site	Paducah	Kentucky	United States	42001
28	Research Site	Shreveport	Louisiana	United States	71103
29	Research Site	Bethesda	Maryland	United States	20817
30	Research Site	Cumberland	Maryland	United States	21502
31	Research Site	Randallstown	Maryland	United States	21133
32	Research Site	Towson	Maryland	United States	21204
33	Research Site	Boston	Massachusetts	United States	02130
34	Research Site	Boston	Massachusetts	United States	02135
35	Research Site	Jefferson City	Missouri	United States	65109
36	Research Site	Kansas City	Missouri	United States	64118
37	Research Site	Saint Louis	Missouri	United States	63136
38	Research Site	Springfield	Missouri	United States	65807
39	Research Site	Billings	Montana	United States	59101
40	Research Site	Grand Island	Nebraska	United States	68803
41	Research Site	Kearney	Nebraska	United States	68845
42	Research Site	Omaha	Nebraska	United States	68131
43	Research Site	Portsmouth	New Hampshire	United States	03801
44	Research Site	Little Silver	New Jersey	United States	07739
45	Research Site	Somerville	New Jersey	United States	08876
46	Research Site	Albuquerque	New Mexico	United States	87131
47	Research Site	Lake Success	New York	United States	11042
48	Research Site	Nyack	New York	United States	10960
49	Research Site	Asheville	North Carolina	United States	28801
50	Research Site	Hickory	North Carolina	United States	28602
51	Research Site	High Point	North Carolina	United States	27262
52	Research Site	Winston-Salem	North Carolina	United States	27103
53	Research Site	Canton	Ohio	United States	44708
54	Research Site	Cincinnati	Ohio	United States	45219
55	Research Site	Massillon	Ohio	United States	44646
56	Research Site	Middletown	Ohio	United States	45042
57	Research Site	Lancaster	Pennsylvania	United States	17605
58	Research Site	Langhorne	Pennsylvania	United States	19047
59	Research Site	Reading	Pennsylvania	United States	19605
60	Research Site	Upland	Pennsylvania	United States	19013
61	Research Site	West Reading	Pennsylvania	United States	19611
62	Research Site	Willow Grove	Pennsylvania	United States	19090
63	Research Site	Hilton Head Island	South Carolina	United States	29926
64	Research Site	Myrtle Beach	South Carolina	United States	29572
65	Research Site	Nashville	Tennessee	United States	37203
66	Research Site	Bryan	Texas	United States	77802
67	Research Site	Corpus Christi	Texas	United States	78405
68	Research Site	Corpus Christi	Texas	United States	78412
69	Research Site	Abingdon	Virginia	United States	24211
70	Research Site	Lynchburg	Virginia	United States	24501
71	Research Site	Kennewick	Washington	United States	99336
72	Research Site	Spokane	Washington	United States	99220
73	Research Site	Hobart	Tasmania	Australia	7000
74	Research Site	Ballarat	Victoria	Australia	3350
75	Research Site	Coburg	Victoria	Australia	3058
76	Research Site	Footscray	Victoria	Australia	3011
77	Research Site	Frankston	Victoria	Australia	3199
78	Research Site	Aalst		Belgium	9300
79	Research Site	Roeselare		Belgium	8800
80	Research Site	Verviers		Belgium	4800
81	Research Site	Sofia		Bulgaria	1606
82	Research Site	Sofia		Bulgaria	1756
83	Research Site	Sofia		Bulgaria	1784
84	Research Site	Varna		Bulgaria	9000
85	Research Site	Brampton	Ontario	Canada	L6R 3J7
86	Research Site	London	Ontario	Canada	N6A 4L6
87	Research Site	Sault Ste. Marie	Ontario	Canada	P6A 5K7
88	Research Site	Sudbury	Ontario	Canada	P3E 5J1
89	Research Site	Toronto	Ontario	Canada	M6R 1B5
90	Research Site	Laval	Quebec	Canada	H7M 3L9
91	Research Site	Levis	Quebec	Canada	G6V 3Z1
92	Research Site	Montreal	Quebec	Canada	H2W 1S6
93	Research Site	Montreal	Quebec	Canada	H4J 1C5
94	Research Site	Horovice		Czechia	268 31
95	Research Site	Nova Ves pod Plesi		Czechia	262 04
96	Research Site	Olomouc		Czechia	775 20
97	Research Site	Znojmo		Czechia	669 02
98	Research Site	Amiens		France	80000
99	Research Site	Bordeaux Cedex		France	33076
100	Research Site	Cahors Cedex		France	46005
101	Research Site	Lille cedex 01		France	59037
102	Research Site	Rouen		France	76000
103	Research Site	Budapest		Hungary	1097
104	Research Site	Budapest		Hungary	1125
105	Research Site	Debrecen		Hungary	4012
106	Research Site	Gyor		Hungary	9023
107	Research Site	Gyula		Hungary	5700
108	Research Site	Kaposvar		Hungary	7400
109	Research Site	Kecskemet		Hungary	6000
110	Research Site	Szeged		Hungary	6720
111	Research Site	Szolnok		Hungary	5004
112	Research Site	Cork		Ireland
113	Research Site	Dublin		Ireland	24
114	Research Site	Dublin		Ireland	7
115	Research Site	Dublin		Ireland	8
116	Research Site	Dublin		Ireland	9
117	Research Site	Galway		Ireland
118	Research Site	Waterford		Ireland
119	Research Site	Benevento		Italy	82100
120	Research Site	Palermo		Italy	90100
121	Research Site	Roma (RM)		Italy	00133
122	Research Site	Rozzano (MI)		Italy	20089
123	Research Site	Taormina (ME)		Italy	98039
124	Research Site	Daugavpils		Latvia	5417
125	Research Site	Riga		Latvia	1002
126	Research Site	Riga		Latvia	1079
127	Research Site	San Luis Potosi	San Luis P	Mexico	78200
128	Research Site	Colima		Mexico	28030
129	Research Site	Toluca		Mexico	50080
130	Research Site	Gdansk		Poland	80-952
131	Research Site	Lodz		Poland	93-509
132	Research Site	Olsztyn		Poland	10-228
133	Research Site	Suwalki		Poland	16-400
134	Research Site	Warszawa		Poland	04-125
135	Research Site	Bucharest		Romania	022328
136	Research Site	Bucharest		Romania	022338
137	Research Site	Cluj Napoca		Romania	400015
138	Research Site	Sibiu		Romania	550245
139	Research Site	Chelyabinsk		Russian Federation	454087
140	Research Site	Kazan		Russian Federation	420029
141	Research Site	Moscow		Russian Federation	115478
142	Research Site	Saint Petersburg		Russian Federation	197022
143	Research Site	Samara		Russian Federation	443031
144	Research Site	Yaroslavl		Russian Federation	150054
145	Research Site	Bratislava		Slovakia	833 10
146	Research Site	Kosice		Slovakia	041 91
147	Research Site	Rimavska Sobota		Slovakia	979 01
148	Research Site	Trnava		Slovakia	917 75
149	Research Site	Dnipropetrovsk		Ukraine	49102
150	Research Site	Donetsk		Ukraine	83092
151	Research Site	Ivano-Frankivsk		Ukraine	76018
152	Research Site	Kyiv		Ukraine	03115
153	Research Site	Lviv		Ukraine	79031
154	Research Site	Uzhgorod		Ukraine	88000

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Pinter T, Klippel Z, Cesas A, Croitoru A, Decaestecker J, Gibbs P, Hotko Y, Jassem J, Kurteva G, Novotny J, O'Reilly S, Salek T, Reiner M, Morrow PK, Choi MR, Whittaker S, Blanke C. A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pegfilgrastim in Patients Receiving First-Line FOLFOX/Bevacizumab or FOLFIRI/Bevacizumab for Locally Advanced or Metastatic Colorectal Cancer: Final Results of the Pegfilgrastim and Anti-VEGF Evaluation Study (PAVES). Clin Colorectal Cancer. 2017 Jun;16(2):103-114.e3. doi: 10.1016/j.clcc.2016.08.008. Epub 2016 Sep 7.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00911170
• Other Study ID Numbers: 20080259
• First Posted: Jun 1, 2009
• Last Update Posted: Dec 29, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Amgen: adenocarcinoma of the colon or rectum; febrile neutropenia; Bevacizumab; Avastin; 5-fluorouracil, Oxaliplatin, Leucovorin (FOLFOX); 5-fluorouracil, Irinotecan, Leucovorin (FOLFIRI)
• Additional relevant MeSH terms: Colorectal Neoplasms; Neutropenia; Bevacizumab

Study Results

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 Detail	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).

Arm/Group Title	Placebo	Pegfilgrastim
Arm/Group Description	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.	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.
Period Title: Treatment Period
STARTED	424	423
Received Chemotherapy	423	422
Received Bevacizumab	423	420
Received Investigational Product	422	419
COMPLETED	397	386
NOT COMPLETED	27	37
Period Title: Treatment Period
STARTED	423	422
COMPLETED	0	0
NOT COMPLETED	423	422

Baseline Characteristics

Arm/Group Title	Placebo	Pegfilgrastim	Total
Arm/Group Description	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).	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 of all reporting groups
Overall Participants	423	422	845
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.7 (10.7)	60.6 (10.4)	60.6 (10.5)
Sex: Female, Male (Count of Participants)
Female	159 37.6%	174 41.2%	333 39.4%
Male	264 62.4%	248 58.8%	512 60.6%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	0 0%	1 0.2%	1 0.1%
Asian	3 0.7%	2 0.5%	5 0.6%
Black or African American	6 1.4%	4 0.9%	10 1.2%
Hispanic or Latino	8 1.9%	11 2.6%	19 2.2%
Japanese	0 0%	2 0.5%	2 0.2%
Native Hawaiian or Other Pacific Islander	2 0.5%	0 0%	2 0.2%
White	404 95.5%	402 95.3%	806 95.4%
Chemotherapy Regimen (participants) [Number]
FOLFOX	207 48.9%	207 49.1%	414 49%
FOLFIRI	216 51.1%	215 50.9%	431 51%
Region (participants) [Number]
North America	79 18.7%	77 18.2%	156 18.5%
Rest of World	344 81.3%	345 81.8%	689 81.5%
Disease Status (participants) [Number]
Locally Advanced	18 4.3%	18 4.3%	36 4.3%
Metastatic	405 95.7%	404 95.7%	809 95.7%
Primary Tumor Diagnosis (participants) [Number]
Colon	284 67.1%	290 68.7%	574 67.9%
Rectum	139 32.9%	132 31.3%	271 32.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Pegfilgrastim
Arm/Group Description	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).	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).
Measure Participants	423	422
Number (95% Confidence Interval) [percentage of participants]	5.7 1.3%	2.4 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pegfilgrastim
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The p-value is adjusted for the randomization stratification factors (chemotherapy regimen, geographic region, disease stage).
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; 0.19 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio adjusted for the randomization stratification factors. An OR < 1.0 indicates a lower event rate for the pegfilgrastim arm relative to the placebo arm.

2. Secondary Outcome

Title	Overall Survival
Description	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.

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Placebo	Pegfilgrastim
Arm/Group Description	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).	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).
Measure Participants	423	422
Median (95% Confidence Interval) [months]	24.6	21.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pegfilgrastim
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.704
	Comments
	Method	Log Rank
	Comments	P-values based on the log-rank test statistic from the Kaplan-Meier survival analysis stratified by the 3 randomization factors.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional Hazard model stratified by chemotherapy regimen, region and disease status. A HR< 1.0 indicates a lower average event rate and a longer survival time for the pegfilgrastim arm relative to the placebo arm.

3. Secondary Outcome

Title	Progression Free Survival
Description	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.

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Placebo	Pegfilgrastim
Arm/Group Description	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).	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).
Measure Participants	423	422
Median (95% Confidence Interval) [months]	10.1	9.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pegfilgrastim
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.552
	Comments
	Method	Log Rank
	Comments	P-values are based on the log-rank test statistic from the Kaplan-Meier survival analysis stratified by the 3 randomization factors.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional Hazard model stratified by chemotherapy regimen, region and disease status. A HR< 1.0 indicates a lower average event rate and a longer survival time for the pegfilgrastim arm relative to the placebo arm.

4. Secondary Outcome

Title	Time to Progression
Description	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.

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Placebo	Pegfilgrastim
Arm/Group Description	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).	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).
Measure Participants	423	422
Median (95% Confidence Interval) [months]	11.1	10.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pegfilgrastim
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.502
	Comments
	Method	Log Rank
	Comments	P-values are based on the log-rank test statistic from the Kaplan-Meier survival analysis stratified by the 3 randomization factors.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional Hazard model stratified by chemotherapy regimen, region and disease status. A HR< 1.0 indicates a lower average event rate and a longer survival time for the pegfilgrastim arm relative to the placebo arm.

5. Secondary Outcome

Title	Percentage of Participants With an Objective Response
Description	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.

Outcome Measure Data

Analysis Population Description

Primary analysis set participants with measurable disease at Baseline.

Arm/Group Title	Placebo	Pegfilgrastim
Arm/Group Description	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).	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).
Measure Participants	420	420
Number (95% Confidence Interval) [percentage of participants]	56.7 13.4%	58.1 13.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pegfilgrastim
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.683
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The p-value is from the Cochran Mantel Haenszel (CMH) test adjusting for the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (OR) adjusted for the randomization stratification factors. An OR > 1.0 indicates a higher event rate for the pegfilgrastim arm relative to the placebo arm.

6. Secondary Outcome

Title	Percentage of Participants With Grade 4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy
Description	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)

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Placebo	Pegfilgrastim
Arm/Group Description	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).	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).
Measure Participants	423	422
Number (95% Confidence Interval) [percentage of participants]	3.5 0.8%	2.4 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pegfilgrastim
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.312
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The p-value is from the Cochran Mantel Haenszel (CMH) test adjusting for the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.66
	Confidence Interval	() 95%; 0.29 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (OR) adjusted for the randomization stratification factors. An OR < 1.0 indicates a lower event rate for the pegfilgrastim arm relative to the placebo arm.

7. Secondary Outcome

Title	Percentage of Participants With Grade 3/4 Neutropenia Across the First 4 Cycles of Chemotherapy
Description	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)

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Placebo	Pegfilgrastim
Arm/Group Description	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).	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).
Measure Participants	423	422
Number (95% Confidence Interval) [percentage of participants]	17.0 4%	3.6 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pegfilgrastim
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The p-value is from the Cochran Mantel Haenszel (CMH) test adjusting for the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.18
	Confidence Interval	() 95%; 0.10 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (OR) adjusted for the randomization stratification factors. An OR < 1.0 indicates a lower event rate for the pegfilgrastim arm relative to the placebo arm.

8. Secondary Outcome

Title	Percentage of Participants With Grade 4 Neutropenia Across the First 4 Cycles of Chemotherapy
Description	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)

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Placebo	Pegfilgrastim
Arm/Group Description	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).	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).
Measure Participants	423	422
Number (95% Confidence Interval) [percentage of participants]	8.3 2%	2.4 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pegfilgrastim
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The p-value is from the Cochran Mantel Haenszel (CMH) test adjusting for the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.27
	Confidence Interval	(2-Sided) 95%; 0.13 to 0.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (OR) adjusted for the randomization stratification factors. An OR < 1.0 indicates a lower event rate for the pegfilgrastim arm relative to the placebo arm.

9. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Pegfilgrastim
Arm/Group Description	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).	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).
Measure Participants	421	420
Any adverse event	355 83.9%	344 81.5%
Worst Grade of > 2	254 60%	240 56.9%
Worst Grade of > 3	119 28.1%	115 27.3%
Worst Grade of > 4	45 10.6%	31 7.3%
Serious adverse events	55 13%	68 16.1%
Severe adverse events	103 24.3%	106 25.1%
Life-threatening adverse events	43 10.2%	27 6.4%
Fatal adverse events	11 2.6%	10 2.4%
Leading to discontinuation of IP	1 0.2%	3 0.7%
Leading to discontinuation from study treatment	9 2.1%	8 1.9%

Adverse Events

Time Frame	Approximately 8 weeks (4 treatment cycles)
Adverse Event Reporting Description	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.
Arm/Group Title	Placebo		Pegfilgrastim
Arm/Group Description	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).		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).
All Cause Mortality
	Placebo		Pegfilgrastim
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Pegfilgrastim
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/421 (13.3%)		68/420 (16.2%)
Blood and lymphatic system disorders
Agranulocytosis	1/421 (0.2%)		0/420 (0%)
Anaemia	1/421 (0.2%)		1/420 (0.2%)
Coagulopathy	1/421 (0.2%)		0/420 (0%)
Febrile neutropenia	1/421 (0.2%)		2/420 (0.5%)
Granulocytopenia	0/421 (0%)		1/420 (0.2%)
Leukocytosis	0/421 (0%)		1/420 (0.2%)
Leukopenia	1/421 (0.2%)		1/420 (0.2%)
Neutropenia	4/421 (1%)		3/420 (0.7%)
Thrombocytopenia	0/421 (0%)		1/420 (0.2%)
Cardiac disorders
Atrial fibrillation	0/421 (0%)		1/420 (0.2%)
Cardiac arrest	1/421 (0.2%)		2/420 (0.5%)
Cardio-respiratory arrest	0/421 (0%)		1/420 (0.2%)
Coronary artery disease	1/421 (0.2%)		0/420 (0%)
Gastrointestinal disorders
Abdominal pain	3/421 (0.7%)		5/420 (1.2%)
Ascites	0/421 (0%)		1/420 (0.2%)
Colitis	0/421 (0%)		3/420 (0.7%)
Colonic obstruction	0/421 (0%)		1/420 (0.2%)
Colonic stenosis	1/421 (0.2%)		0/420 (0%)
Constipation	1/421 (0.2%)		2/420 (0.5%)
Diarrhoea	5/421 (1.2%)		10/420 (2.4%)
Duodenal ulcer	1/421 (0.2%)		0/420 (0%)
Enteritis	0/421 (0%)		1/420 (0.2%)
Gastrointestinal haemorrhage	1/421 (0.2%)		0/420 (0%)
Gastrointestinal inflammation	1/421 (0.2%)		0/420 (0%)
Gastrointestinal perforation	0/421 (0%)		1/420 (0.2%)
Haemorrhoidal haemorrhage	0/421 (0%)		1/420 (0.2%)
Ileus	0/421 (0%)		4/420 (1%)
Ileus paralytic	0/421 (0%)		1/420 (0.2%)
Intestinal fistula	1/421 (0.2%)		0/420 (0%)
Intestinal obstruction	2/421 (0.5%)		3/420 (0.7%)
Intestinal perforation	1/421 (0.2%)		0/420 (0%)
Large intestine perforation	2/421 (0.5%)		2/420 (0.5%)
Nausea	1/421 (0.2%)		3/420 (0.7%)
Neutropenic colitis	0/421 (0%)		1/420 (0.2%)
Oral pain	1/421 (0.2%)		0/420 (0%)
Rectal haemorrhage	3/421 (0.7%)		2/420 (0.5%)
Rectal perforation	0/421 (0%)		1/420 (0.2%)
Small intestinal obstruction	1/421 (0.2%)		1/420 (0.2%)
Subileus	1/421 (0.2%)		1/420 (0.2%)
Vomiting	3/421 (0.7%)		4/420 (1%)
General disorders
Asthenia	1/421 (0.2%)		1/420 (0.2%)
Chest pain	1/421 (0.2%)		1/420 (0.2%)
Fatigue	2/421 (0.5%)		0/420 (0%)
General physical health deterioration	2/421 (0.5%)		0/420 (0%)
Hernia	0/421 (0%)		1/420 (0.2%)
Local swelling	0/421 (0%)		1/420 (0.2%)
Medical device complication	1/421 (0.2%)		0/420 (0%)
Mucosal inflammation	1/421 (0.2%)		0/420 (0%)
Oedema peripheral	0/421 (0%)		1/420 (0.2%)
Pyrexia	4/421 (1%)		5/420 (1.2%)
Sudden death	1/421 (0.2%)		1/420 (0.2%)
Hepatobiliary disorders
Cholecystitis	0/421 (0%)		2/420 (0.5%)
Cholecystitis acute	0/421 (0%)		1/420 (0.2%)
Hepatorenal failure	1/421 (0.2%)		1/420 (0.2%)
Hyperbilirubinaemia	1/421 (0.2%)		0/420 (0%)
Immune system disorders
Anaphylactic shock	0/421 (0%)		1/420 (0.2%)
Infections and infestations
Abscess rupture	0/421 (0%)		1/420 (0.2%)
Bacterial sepsis	1/421 (0.2%)		0/420 (0%)
Bronchopneumonia	0/421 (0%)		1/420 (0.2%)
Candidiasis	0/421 (0%)		1/420 (0.2%)
Clostridial infection	1/421 (0.2%)		0/420 (0%)
Cystitis	2/421 (0.5%)		0/420 (0%)
Device related infection	1/421 (0.2%)		1/420 (0.2%)
Device related sepsis	0/421 (0%)		1/420 (0.2%)
Helicobacter gastritis	1/421 (0.2%)		0/420 (0%)
Herpes zoster	1/421 (0.2%)		0/420 (0%)
Infection	2/421 (0.5%)		1/420 (0.2%)
Kidney infection	1/421 (0.2%)		0/420 (0%)
Neutropenic sepsis	1/421 (0.2%)		0/420 (0%)
Oral candidiasis	1/421 (0.2%)		0/420 (0%)
Oral fungal infection	1/421 (0.2%)		0/420 (0%)
Pelvic infection	1/421 (0.2%)		0/420 (0%)
Perirectal abscess	0/421 (0%)		1/420 (0.2%)
Peritonitis	0/421 (0%)		2/420 (0.5%)
Pneumonia	0/421 (0%)		1/420 (0.2%)
Postoperative abscess	0/421 (0%)		1/420 (0.2%)
Sepsis	1/421 (0.2%)		4/420 (1%)
Soft tissue infection	0/421 (0%)		1/420 (0.2%)
Urinary tract infection	2/421 (0.5%)		1/420 (0.2%)
Injury, poisoning and procedural complications
Hip fracture	1/421 (0.2%)		0/420 (0%)
Infusion related reaction	1/421 (0.2%)		0/420 (0%)
Rib fracture	0/421 (0%)		1/420 (0.2%)
Investigations
Electrocardiogram abnormal	1/421 (0.2%)		0/420 (0%)
Neutrophil count decreased	1/421 (0.2%)		0/420 (0%)
White blood cell count decreased	1/421 (0.2%)		0/420 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/421 (0.5%)		2/420 (0.5%)
Dehydration	3/421 (0.7%)		5/420 (1.2%)
Hypokalaemia	1/421 (0.2%)		4/420 (1%)
Metabolic acidosis	0/421 (0%)		1/420 (0.2%)
Tumour lysis syndrome	0/421 (0%)		1/420 (0.2%)
Musculoskeletal and connective tissue disorders
Bone pain	0/421 (0%)		1/420 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour necrosis	0/421 (0%)		1/420 (0.2%)
Nervous system disorders
Cerebral infarction	1/421 (0.2%)		0/420 (0%)
Cerebrovascular accident	1/421 (0.2%)		0/420 (0%)
Lethargy	1/421 (0.2%)		0/420 (0%)
Syncope	0/421 (0%)		1/420 (0.2%)
Psychiatric disorders
Anxiety	2/421 (0.5%)		1/420 (0.2%)
Delirium	0/421 (0%)		1/420 (0.2%)
Mental status changes	0/421 (0%)		1/420 (0.2%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/421 (0.2%)		0/420 (0%)
Epistaxis	1/421 (0.2%)		0/420 (0%)
Hiccups	0/421 (0%)		1/420 (0.2%)
Lung disorder	0/421 (0%)		1/420 (0.2%)
Pneumothorax	1/421 (0.2%)		0/420 (0%)
Pulmonary embolism	3/421 (0.7%)		2/420 (0.5%)
Rales	0/421 (0%)		1/420 (0.2%)
Respiratory failure	1/421 (0.2%)		0/420 (0%)
Vascular disorders
Deep vein thrombosis	3/421 (0.7%)		2/420 (0.5%)
Embolism venous	0/421 (0%)		1/420 (0.2%)
Hypertension	1/421 (0.2%)		1/420 (0.2%)
Hypertensive crisis	1/421 (0.2%)		0/420 (0%)
Hypotension	1/421 (0.2%)		0/420 (0%)
Orthostatic hypotension	1/421 (0.2%)		0/420 (0%)
Phlebitis deep	1/421 (0.2%)		0/420 (0%)
Subclavian vein thrombosis	1/421 (0.2%)		0/420 (0%)
Thrombophlebitis	1/421 (0.2%)		0/420 (0%)
Thrombosis	1/421 (0.2%)		0/420 (0%)
Vena cava thrombosis	1/421 (0.2%)		0/420 (0%)
Venous thrombosis	0/421 (0%)		3/420 (0.7%)
Other (Not Including Serious) Adverse Events
	Placebo		Pegfilgrastim
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	310/421 (73.6%)		298/420 (71%)
Blood and lymphatic system disorders
Anaemia	23/421 (5.5%)		34/420 (8.1%)
Neutropenia	121/421 (28.7%)		46/420 (11%)
Gastrointestinal disorders
Abdominal pain	21/421 (5%)		25/420 (6%)
Constipation	47/421 (11.2%)		44/420 (10.5%)
Diarrhoea	103/421 (24.5%)		107/420 (25.5%)
Nausea	91/421 (21.6%)		115/420 (27.4%)
Stomatitis	24/421 (5.7%)		9/420 (2.1%)
Vomiting	45/421 (10.7%)		47/420 (11.2%)
General disorders
Asthenia	34/421 (8.1%)		31/420 (7.4%)
Fatigue	64/421 (15.2%)		70/420 (16.7%)
Pyrexia	31/421 (7.4%)		56/420 (13.3%)
Investigations
Weight decreased	19/421 (4.5%)		26/420 (6.2%)
Metabolism and nutrition disorders
Decreased appetite	31/421 (7.4%)		40/420 (9.5%)
Hypokalaemia	15/421 (3.6%)		32/420 (7.6%)
Musculoskeletal and connective tissue disorders
Back pain	14/421 (3.3%)		23/420 (5.5%)
Nervous system disorders
Neuropathy peripheral	25/421 (5.9%)		29/420 (6.9%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	23/421 (5.5%)		30/420 (7.1%)
Skin and subcutaneous tissue disorders
Alopecia	17/421 (4%)		25/420 (6%)
Vascular disorders
Hypertension	28/421 (6.7%)		33/420 (7.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.