PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Fac... | NCT00911170

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo	Placebo Comparator	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 Biological: Bevacizumab Drug: Standard Chemotherapy
Pegfilgrastim	Placebo Comparator	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 Biological: Bevacizumab Drug: Standard Chemotherapy

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Pegfilgrastim	Drug	Administered as a single 6 mg subcutaneous injection using a pre-filled syringe. There will be no dosage adjustments for investigational product.	Pegfilgrastim

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percentage of Participants With Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy	Grade 3/4 febrile neutropenia (FN) is defined as: • A temperature ≥ 38.0°C (≥ 100.4°F) and absolute neutrophil count (ANC) < 1.0 × 10^9/L, where ANC was measured the same day or within ± 1 calendar day of a temperature ≥ 38.0°C (≥ 100.4°F), or • An ANC < 1.0 × 10^9/L in combination with: - documented sepsis or infection, OR - neutropenia-related hospitalization where ANC was measured the same day or within ± 1 calendar day. Participants monitored their oral temperatures and maintained diaries to record their temperature twice per day: once in the morning and once in the evening, as well as whenever they suspect they had fever throughout the first 4 cycles of chemotherapy treatment.	Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)

Secondary Outcomes

Measure	Description	Time Frame
Overall Survival	Median time from randomization to date of death caclulated using the Kaplan-Meier method. Participants were censored on the date of last contact (i.e., the date the participant was last known to be alive) if they were not known to have died.	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.

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
MD	Amgen	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Muscle Shoals	Alabama	35661	United States
Research Site

PubMed Identifier	Type	Citation	Retractions
28038865	Background	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.

Label	URL
AmgenTrials clinical trials website	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00060.7± 10.7 BG00160.6± 10.4 BG00260.6± 10.5

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG000159 BG001174 BG002

Race/Ethnicity, Customized

Number

participants

Title

Denominators

Categories

American Indian or Alaska Native

Title	Measurements
	BG0000 BG0011 BG002

Chemotherapy Regimen

Number

participants

Title

Denominators

Categories

FOLFOX

Title	Measurements
	BG000207 BG001207 BG002

Region

North America (Canada and the US) and the Rest of World (Australia, Belgium, Bulgaria, Czech Republic, France, Hungary, Ireland, Italy, Latvia, Mexico, Poland, Romania, Russian Federation, Slovakia, and Ukraine)

Number

participants

Title

Denominators

Categories

North America

Title	Measurements
	BG00079 BG001

Disease Status

Number

participants

Title

Denominators

Categories

Locally Advanced

Title	Measurements
	BG00018 BG00118 BG002

Primary Tumor Diagnosis

Number

participants

Title

Denominators

Categories

Colon

Title	Measurements
	BG000284 BG001290 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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

Grade 3/4 febrile neutropenia (FN) is defined as: • A temperature ≥ 38.0°C (≥ 100.4°F) and absolute neutrophil count (ANC) < 1.0 × 10^9/L, where ANC was measured the same day or within ± 1 calendar day of a temperature ≥ 38.0°C (≥ 100.4°F), or • An ANC < 1.0 × 10^9/L in combination with: - documented sepsis or infection, OR - neutropenia-related hospitalization where ANC was measured the same day or within ± 1 calendar day. Participants monitored their oral temperatures and maintained diaries to record their temperature twice per day: once in the morning and once in the evening, as well as whenever they suspect they had fever throughout the first 4 cycles of chemotherapy treatment.

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).

Posted

Number

95% Confidence Interval

percentage of participants

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

ID	Title	Description
OG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).
OG001	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).

Units	Counts
Participants	OG000423 OG001422

Title

Denominators

Categories

Title	Measurements
	OG0005.7(3.7 to 8.3) OG0012.4(1.1 to 4.3)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	Cochran-Mantel-Haenszel	The p-value is adjusted for the randomization stratification factors (chemotherapy regimen, geographic region, disease stage).	0.014		Odds Ratio (OR)	0.41			2-Sided	95	0.19	0.86			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.

Secondary

Overall Survival

Median time from randomization to date of death caclulated using the Kaplan-Meier method. Participants were censored on the date of last contact (i.e., the date the participant was last known to be alive) if they were not known to have died.

Primary analysis set

Posted

Median

95% Confidence Interval

months

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.

ID	Title	Description
OG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).
OG001	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).

Units	Counts
Participants

Secondary

Progression Free Survival

Time from randomization to date of radiological disease progression or death from any cause, whichever event occurs first, calculated using the Kaplan-Meier method. Participants without either event by the analysis data cutoff date were censored on the date of their last evaluable disease assessment. Disease progression based on the investigator's assessment of radiographic scans using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Clinical progression without radiological assessment was not be considered a disease progression in this analysis. Progression defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Primary analysis set

Posted

Median

95% Confidence Interval

months

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.

ID	Title	Description
OG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).
OG001	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).

Secondary

Time to Progression

Time from randomization to date of radiological disease progression calculated using the Kaplan-Meier method. Participants without progression were censored on the date of their last radiographic tumor assessment. Disease progression based on the investigator's assessment of scans using the RECIST v1.1. Clinical progression without radiological assessment was not considered a disease progression. Progression defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Primary analysis set

Posted

Median

95% Confidence Interval

months

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.

ID	Title	Description
OG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).
OG001	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).

Secondary

Percentage of Participants With an Objective Response

The percentage of participants with a complete response (CR) or partial response (PR) defined by the RECIST v1.1 criteria at any time during the study. Response was be determined by the investigator's assessment of radiographic scans. CR: Disappearance of all non-nodal target lesions and the disappearance of all non-nodal non-target lesions, and no new lesions. All nodal lesions must have reduction of short axis to < 10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters and no new lesions and/or unequivocal progression of existing non-target lesions, or, the disappearance of all non-nodal target lesions with persistence of one or more non-target lesion(s).

Primary analysis set participants with measurable disease at Baseline.

Posted

Number

95% Confidence Interval

percentage of participants

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.

ID	Title	Description
OG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).
OG001	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).

Secondary

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

Grade 4 febrile neutropenia (FN) is defined as:

A temperature ≥ 38.0ºC (≥ 100.4ºF) and absolute neutrophil count (ANC) < 0.5 × 10^9/L, where ANC is measured the same day or within +/- 1 calendar day of a temperature ≥ 38.0ºC (≥ 100.4ºF), or
An ANC <0.5 × 10^9/L in combination with:
- Documented sepsis or infection, OR
- Neutropenia-related hospitalization where ANC is measured the same day or within +/- 1 calendar day.

Primary analysis set

Posted

Number

95% Confidence Interval

percentage of participants

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

ID	Title	Description
OG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).
OG001	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).

Secondary

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

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

Primary analysis set

Posted

Number

95% Confidence Interval

percentage of participants

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

ID	Title	Description
OG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).
OG001	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).

Units	Counts
Participants

Secondary

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

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

Primary analysis set

Posted

Number

95% Confidence Interval

percentage of participants

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

ID	Title	Description
OG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).
OG001	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).

Units	Counts
Participants

Secondary

Number of Participants With Adverse Events (AEs)

A serious adverse event (SAE) is defined as an adverse event that - is fatal; - is life threatening (places the participant at immediate risk of death); - requires inpatient hospitalization or prolongation of existing hospitalization; - results in persistent or significant disability/incapacity; - is a congenital anomaly/birth defect; - other significant medical hazard. AEs were assessed for severity according to National Cancer Institute, Common Terminology Criteria for Adverse Events, Version 3.0, based on this general guideline: Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death related to AE.

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.

Posted

Number

participants

Approximately 8 weeks (4 treatment cycles)

ID	Title	Description
OG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).
OG001	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).

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Agranulocytosis	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0011 affected420 at risk
Coagulopathy	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0012 affected420 at risk
Granulocytopenia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Leukocytosis	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0011 affected420 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0004 affected421 at risk EG0013 affected420 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Atrial fibrillation	Cardiac disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Cardiac arrest	Cardiac disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0012 affected420 at risk
Cardio-respiratory arrest	Cardiac disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Coronary artery disease	Cardiac disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0003 affected421 at risk EG0015 affected420 at risk
Ascites	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Colitis	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0013 affected420 at risk
Colonic obstruction	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Colonic stenosis	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Constipation	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0012 affected420 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0005 affected421 at risk EG00110 affected420 at risk
Duodenal ulcer	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Enteritis	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Gastrointestinal inflammation	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Gastrointestinal perforation	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Haemorrhoidal haemorrhage	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Ileus	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0014 affected420 at risk
Ileus paralytic	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Intestinal fistula	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0002 affected421 at risk EG0013 affected420 at risk
Intestinal perforation	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Large intestine perforation	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0002 affected421 at risk EG0012 affected420 at risk
Nausea	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0013 affected420 at risk
Neutropenic colitis	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Oral pain	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Rectal haemorrhage	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0003 affected421 at risk EG0012 affected420 at risk
Rectal perforation	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Small intestinal obstruction	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0011 affected420 at risk
Subileus	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0011 affected420 at risk
Vomiting	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0003 affected421 at risk EG0014 affected420 at risk
Asthenia	General disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0011 affected420 at risk
Chest pain	General disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0011 affected420 at risk
Fatigue	General disorders	MedDRA 15.0	Systematic Assessment	EG0002 affected421 at risk EG0010 affected420 at risk
General physical health deterioration	General disorders	MedDRA 15.0	Systematic Assessment	EG0002 affected421 at risk EG0010 affected420 at risk
Hernia	General disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Local swelling	General disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Medical device complication	General disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Mucosal inflammation	General disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Oedema peripheral	General disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Pyrexia	General disorders	MedDRA 15.0	Systematic Assessment	EG0004 affected421 at risk EG0015 affected420 at risk
Sudden death	General disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0011 affected420 at risk
Cholecystitis	Hepatobiliary disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0012 affected420 at risk
Cholecystitis acute	Hepatobiliary disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Hepatorenal failure	Hepatobiliary disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0011 affected420 at risk
Hyperbilirubinaemia	Hepatobiliary disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Anaphylactic shock	Immune system disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Abscess rupture	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Bacterial sepsis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Bronchopneumonia	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Candidiasis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Clostridial infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Cystitis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0002 affected421 at risk EG0010 affected420 at risk
Device related infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0011 affected420 at risk
Device related sepsis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Helicobacter gastritis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Herpes zoster	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0002 affected421 at risk EG0011 affected420 at risk
Kidney infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Neutropenic sepsis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Oral candidiasis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Oral fungal infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Pelvic infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Perirectal abscess	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Peritonitis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0012 affected420 at risk
Pneumonia	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Postoperative abscess	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Sepsis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0014 affected420 at risk
Soft tissue infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Urinary tract infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0002 affected421 at risk EG0011 affected420 at risk
Hip fracture	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Infusion related reaction	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Rib fracture	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Electrocardiogram abnormal	Investigations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Neutrophil count decreased	Investigations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
White blood cell count decreased	Investigations	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA 15.0	Systematic Assessment	EG0002 affected421 at risk EG0012 affected420 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA 15.0	Systematic Assessment	EG0003 affected421 at risk EG0015 affected420 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0014 affected420 at risk
Metabolic acidosis	Metabolism and nutrition disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Tumour lysis syndrome	Metabolism and nutrition disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Tumour necrosis	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Cerebral infarction	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Lethargy	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Syncope	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Anxiety	Psychiatric disorders	MedDRA 15.0	Systematic Assessment	EG0002 affected421 at risk EG0011 affected420 at risk
Delirium	Psychiatric disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Mental status changes	Psychiatric disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Hiccups	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Lung disorder	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0003 affected421 at risk EG0012 affected420 at risk
Rales	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Deep vein thrombosis	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0003 affected421 at risk EG0012 affected420 at risk
Embolism venous	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0011 affected420 at risk
Hypertension	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0011 affected420 at risk
Hypertensive crisis	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Hypotension	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Orthostatic hypotension	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Phlebitis deep	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Subclavian vein thrombosis	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Thrombophlebitis	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Thrombosis	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Vena cava thrombosis	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected421 at risk EG0010 affected420 at risk
Venous thrombosis	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected421 at risk EG0013 affected420 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG00023 affected421 at risk EG00134 affected420 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG000121 affected421 at risk EG00146 affected420 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG00021 affected421 at risk EG00125 affected420 at risk
Constipation	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG00047 affected421 at risk EG00144 affected420 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG000103 affected421 at risk EG001107 affected420 at risk
Nausea	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG00091 affected421 at risk EG001115 affected420 at risk
Stomatitis	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG00024 affected421 at risk EG0019 affected420 at risk
Vomiting	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG00045 affected421 at risk EG00147 affected420 at risk
Asthenia	General disorders	MedDRA 15.0	Systematic Assessment	EG00034 affected421 at risk EG00131 affected420 at risk
Fatigue	General disorders	MedDRA 15.0	Systematic Assessment	EG00064 affected421 at risk EG00170 affected420 at risk
Pyrexia	General disorders	MedDRA 15.0	Systematic Assessment	EG00031 affected421 at risk EG00156 affected420 at risk
Weight decreased	Investigations	MedDRA 15.0	Systematic Assessment	EG00019 affected421 at risk EG00126 affected420 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA 15.0	Systematic Assessment	EG00031 affected421 at risk EG00140 affected420 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 15.0	Systematic Assessment	EG00015 affected421 at risk EG00132 affected420 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Systematic Assessment	EG00014 affected421 at risk EG00123 affected420 at risk
Neuropathy peripheral	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG00025 affected421 at risk EG00129 affected420 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG00023 affected421 at risk EG00130 affected420 at risk
Alopecia	Skin and subcutaneous tissue disorders	MedDRA 15.0	Systematic Assessment	EG00017 affected421 at risk EG00125 affected420 at risk
Hypertension	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG00028 affected421 at risk EG00133 affected420 at risk

ID	Term
D009369	Neoplasms
D003110	Colonic Neoplasms
D015179	Colorectal Neoplasms
D005334	Fever
D009503	Neutropenia
D012004	Rectal Neoplasms
D064147	Febrile Neutropenia

ID	Term
D007414	Intestinal Neoplasms
D005770	Gastrointestinal Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D004066	Digestive System Diseases
D005767	Gastrointestinal Diseases
D003108	Colonic Diseases
D007410	Intestinal Diseases
D012002	Rectal Diseases
D001832	Body Temperature Changes
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms
D000380	Agranulocytosis
D007970	Leukopenia
D000095542	Cytopenia
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D007960	Leukocyte Disorders

ID	Term
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins

ID	Title	Description
BG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).
BG001	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).
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).			56	421	310	421
EG001	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).			68	420	298	420