OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00577031
• Collaborator: (none)
• Enrollment: 205
• Locations: 38
• Arm: 1
• Duration (Months): 42
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This single arm study will evaluate the efficacy and safety of a first-line regimen of Avastin and XELOX (oxaliplatin + Xeloda) in patients with metastatic cancer of the colon or rectum. Patients will receive 21-day cycles of treatment, comprising Avastin 7.5mg/kg iv on day 1, oxaliplatin 130mg/m2 iv on day 1, and Xeloda 1000mg/m2 po twice daily on days 1-14, for a maximum of 6 months. Patients with stable disease or complete or partial response may continue on Avastin therapy. The anticipated time on study treatment is until disease progression, and the target sample size is 100-500 individuals.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: bevacizumab [Avastin]; Drug: Oxaliplatin; Drug: Xeloda	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 205 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label, Efficacy and Safety Study of Bevacizumab (Avastin®) in Combination With XELOX (Oxaliplatin Plus Xeloda®) for the First-line Treatment of Patients With Metastatic Cancer of the Colon or Rectum - 'OBELIX'
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: bevacizumab [Avastin]; 7.5mg iv on day 1 of each 3 week cycle; Drug: Oxaliplatin; 130mg/m2 iv on day 1 of each 3 week cycle; Drug: Xeloda; 1000mg/m2 po bid on days 1-14 of each 3 week cycle

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS): Percentage of Participants With Progressive Disease or Death [Baseline and Day 1 of every cycle until disease progression or death up to 5 years]

   PFS was defined as the time period in months from the start of study treatment to the first observation of disease progression or death from any cause, whichever occurred first. Data for participants with no tumor assessments after baseline but who were still alive at the time of the clinical cutoff were censored at Day 1. Participants who underwent surgery after experiencing a sufficient shrinkage of the tumor, had any relapse, new occurrence of colorectal cancer, or who died were all considered as having had an event. Participants who underwent surgery without any such event were censored at the date of the last tumor assessment that documented neither a relapse nor a new colorectal cancer had occurred. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20 percent (%) increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

2. PFS: Time to Event [Baseline and Day 1 of every cycle until disease progression or death up to 5 years]

   PFS was defined as the time period in months from the start of study treatment to the first observation of disease progression or death from any cause, whichever occurred first. Data for participants with no tumor assessments after baseline but who were still alive at the time of the clinical cutoff were censored at Day 1. Participants who underwent surgery after experiencing a sufficient shrinkage of the tumor, had any relapse, new occurrence of colorectal cancer, or who died were all considered as having had an event. Participants who underwent surgery without any such event were censored at the date of the last tumor assessment that documented that neither a relapse nor a new colorectal cancer had occurred. Median PFS was estimated using the Kaplan-Meier method.

Secondary Outcome Measures

1. Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) Among Participants in the ITT Population Who Had at Least 1 Post-Baseline Assessment [Baseline, every 9 weeks (every 3 cycles) until end of treatment, disease progression, or withdrawal up to 5 years]

   The percentage of participants with a best overall response of CR or PR according to RECIST. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis less than [<]10 millimeters [mm]). No new lesions. PR was defined as a greater than or equal to (≥) 30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

2. Percentage of Participants With a CR or PR Among Participants in the ITT Population [Baseline, every 9 weeks (every 3 cycles) until end of treatment, disease progression, or withdrawal up to 5 years]

   CR and PR were defined using RECIST v1.0. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis <10 mm). No new lesions. PR was defined as a ≥30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

3. Time to CR or PR Overall Response - Time to Event [Baseline, every 9 weeks (every 3 cycles) until end of treatment, disease progression, or withdrawal up to 5 years]

   Time to overall response (CR or PR) was calculated as the time between the date of start of treatment until first documented response (CR or PR defined per RECIST v1.0). Participants who did not achieve CR or PR were censored at the date of progression, death, or at last adequate tumor assessment date. Median time to CR or PR overall response was estimated using the Kaplan-Meier method.

4. Percentage of Participants With a Best Overall Response of CR or PR During First Line Treatment [Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years]

   CR and PR were defined using RECIST v1.0 criteria. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis <10 mm). No new lesions. PR was defined as a ≥30% decrease under baseline of the sum of diameters of all target lesions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

5. Duration of Overall Response Among Participants Whose Best Response Was CR or PR During First Line Treatment - Time to Event [Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years]

   For participants with a best overall response of CR or PR, the duration of overall response was measured from the time that the criteria for CR or PR (whichever occurred first) was met until the first date that progressive disease was objectively documented or until the date of death due to underlying cancer, whichever occurred first. Data for participants who did not have an event or who were alive without an objectively documented progressive disease were censored at the date of last adequate tumor assessment. Median duration of overall response was estimated using the Kaplan-Meier method.

6. Percentage of Participants With a Stable Response During First Line Treatment [Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years]

   Stable response defined as participants with a best overall response of CR, PR, or stable disease (SD), defined using RECIST v1.0 criteria. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis <10 mm). No new lesions. PR was defined as a ≥30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. SD defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.

7. Duration of Stable Response [Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years]

   For participants with a best overall response of CR, PR, or SD during first line treatment, the duration of stable response was measured from the time that the criteria for CR, PR, or SD (whichever occurred first) was met until the first date that progressive disease was objectively documented or until the date of death due to underlying cancer, whichever occurred first. Data for participants who did not have an event or who were alive without an objectively documented progressive disease were censored at the date of last adequate tumor assessment. Median duration of stable response was estimated using the Kaplan-Meier method.

8. Percentage of Participants With Treatment Failure [Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years]

   Treatment-failure was defined as discontinuation of treatment for any reason, including the following qualifying events: death due to any cause, adverse event, insufficient therapeutic response (progression of disease), failure to return (lost to follow-up), refusing treatment (participant non-compliance), being unwilling to cooperate and withdrawing consent (participant withdrew consent).

9. Time to Treatment Failure [Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years]

   Time to treatment-failure was defined as the time from the first day of treatment to discontinuation of treatment for any reason, including: death due to any cause, adverse event, insufficient therapeutic response (progression of disease), failure to return (lost to follow-up), refusing treatment (participant non-compliance), being unwilling to cooperate and withdrawing consent (participant withdrew consent). For participants who did not experience a qualifying event, their data were censored at the earlier of either the date of last tumour assessment or the date of the last intake of study medication. Median time to treatment-failure was estimated using the Kaplan-Meier method.

10. Overall Survival: Percentage of Participants That Died Due to Any Cause [Baseline, Day 1 of every cycle to end-of-treatment, every 3 months during longer-term follow-up, or to death due to any cause up to 5 years]

    Overall survival was defined as the time from the date of the first day of treatment until the date of death from any cause. If a participant was not known to have died, survival was censored at the last date the participant was known to be alive.

11. Overall Survival: Time to Event [Baseline, Day 1 of every cycle to end-of-treatment, every 3 months during longer-term follow-up, or to death due to any cause up to 5 years]

    Overall survival was defined as the time from the date of the first day of treatment until the date of death from any cause. If a participant was not known to have died, survival was censored at the last date the participant was known to be alive. Median overall survival was estimated using the Kaplan-Meier method.

12. Percentage of Participants Undergoing Surgical Intervention With Residual Disease Status Post-surgery [At surgery, at least 6 to 8 weeks after last dose of bevacizumab up to 5 years]

    The percentage of participants who underwent surgery during the study period with an evaluation of their disease status after surgery. The surgery during the study period was described by reason: curative, palliative, biopsy, other, or unknown. Residual disease status after surgery was described as: no residual disease due to radical surgery, presence of residual disease, unknown or not applicable.

13. Percentage of Participants With Best Overall Response of CR or PR by Kirsten Rat Sarcoma Viral Oncogene Homolog (K-Ras)/V-Raf Murine Sarcoma Viral Oncogene Homolog B (B-Raf) Mutation Status [Baseline, every 9 weeks (every 3 cycles) until end of treatment, disease progression, or withdrawal up to 5 years]

    The percentage of participants with a best overall response of CR or PR according to RECIST. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis <10 mm). No new lesions. PR was defined as ≥30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. The K-Ras and/or the B-Raf gene mutation status of participants was evaluated by the central laboratory using tumor samples. Wild-type participants did not have a mutation in either gene.

14. European Quality of Life 5 Dimension (EQ-5D) Raw-Index Score [Baseline, every 9 weeks (every 3 cycles), at end-of-treatment up to 5 years]

    Quality of life (QoL) assessments were used to derive pre-specified QoL scores according to the QoL manual "EQ-5D-3 Level (3L)" user guide for instrument version 4.0. The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The visual analog scale (VAS) component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The overall health score absolute changes were calculated for each participant as follows: (score at the end of treatment minus score at baseline). EQ-5D health states were converted into EQ-5D-3L raw index value by applying the scoring algorithm based on the European EQ-net VAS set. The raw index was chosen instead of rescaled index, since the questionnaire was used in order to obtain a quality of life assessment. The raw index scores ranged from 0 (worst health state) to 100 (best health state).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• adult patients, >=18 years of age;

• locally advanced or metastatic colorectal cancer;

• no previous treatment with chemotherapy for metastatic disease;

• at least one measurable lesion.

Exclusion Criteria:

• radiotherapy to any site within 4 weeks before study;

• untreated brain metastases or primary brain tumors;

• clinically significant cardiovascular disease;

• chronic daily treatment with high dose aspirin (>325 mg/day);

• other co-existing malignancies or malignancies diagnosed within last 5 years.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Bologna		Italy	40138
2		Brescia		Italy	25122
3		Cagliari		Italy	09100
4		Cagliari		Italy	09121
5		Caserta		Italy	81100
6		Catanzaro		Italy	88100
7		Cefalu		Italy	90015
8		Fano		Italy	61032
9		Firenze		Italy	50139
10		Frattaminore		Italy	80026
11		Grosseto		Italy	58100
12		Ivrea		Italy	10015
13		Latisana		Italy	33053
14		Lecce		Italy	73100
15		Legnago		Italy	37045
16		Legnano		Italy	20025
17		Macerata		Italy	62100
18		Napoli		Italy	80131
19		Negrar		Italy	37024
20		Orbassano		Italy	10043
21		Padova		Italy	35128
22		Palermo		Italy	90127
23		Palermo		Italy	90146
24		Pavia		Italy	27100
25		Reggio Calabria		Italy	89100
26		Reggio Emilia		Italy	42100
27		Rionero in Vulture		Italy	85028
28		Roma		Italy	00152
29		Roma		Italy	00184
30		Roma		Italy	00186
31		Roma		Italy	00189
32		Salerno		Italy	84131
33		San Giovanni Rotondo		Italy	71013
34		Sondrio		Italy	23100
35		Taormina		Italy	98030
36		Torino		Italy	10125
37		Torino		Italy	10153
38		Verbania		Italy	28921

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00577031
• Other Study ID Numbers: ML21380
• First Posted: Dec 19, 2007
• Last Update Posted: Aug 18, 2015
• Last Verified: Jul 1, 2015

• Additional relevant MeSH terms: Neoplasm Metastasis; Colonic Neoplasms; Bevacizumab; Oxaliplatin

Study Results

Participant Flow

Arm/Group Title	Bevacizumab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 milligrams per kilogram (mg/kg) intravenously (IV) and oxaliplatin 130 mg per square meter (mg/m^2) IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression, participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Period Title: Overall Study
STARTED	205
COMPLETED	0
NOT COMPLETED	205

Baseline Characteristics

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Overall Participants	197
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.25 (9.94)
Sex: Female, Male (Count of Participants)
Female	86 43.7%
Male	111 56.3%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS): Percentage of Participants With Progressive Disease or Death
Description	PFS was defined as the time period in months from the start of study treatment to the first observation of disease progression or death from any cause, whichever occurred first. Data for participants with no tumor assessments after baseline but who were still alive at the time of the clinical cutoff were censored at Day 1. Participants who underwent surgery after experiencing a sufficient shrinkage of the tumor, had any relapse, new occurrence of colorectal cancer, or who died were all considered as having had an event. Participants who underwent surgery without any such event were censored at the date of the last tumor assessment that documented neither a relapse nor a new colorectal cancer had occurred. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20 percent (%) increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Baseline and Day 1 of every cycle until disease progression or death up to 5 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: all enrolled participants who received at least 1 dose of all study medications and had at least 1 measurable lesion according to the Response Evaluation Criteria In Solid Tumours (RECIST) criteria.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV) and oxaliplatin 130 mg mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	197
Number [percentage of participants]	50.25 25.5%

2. Secondary Outcome

Title	Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) Among Participants in the ITT Population Who Had at Least 1 Post-Baseline Assessment
Description	The percentage of participants with a best overall response of CR or PR according to RECIST. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis less than [<]10 millimeters [mm]). No new lesions. PR was defined as a greater than or equal to (≥) 30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.
Time Frame	Baseline, every 9 weeks (every 3 cycles) until end of treatment, disease progression, or withdrawal up to 5 years

Outcome Measure Data

Analysis Population Description

Subset of participants in the ITT population who had at least 1 post-baseline tumor assessment.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	165
Number [percentage of participants]	58.79 29.8%

3. Secondary Outcome

Title	Percentage of Participants With a CR or PR Among Participants in the ITT Population
Description	CR and PR were defined using RECIST v1.0. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis <10 mm). No new lesions. PR was defined as a ≥30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.
Time Frame	Baseline, every 9 weeks (every 3 cycles) until end of treatment, disease progression, or withdrawal up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	197
Number [percentage of participants]	49.24 25%

4. Primary Outcome

Title	PFS: Time to Event
Description	PFS was defined as the time period in months from the start of study treatment to the first observation of disease progression or death from any cause, whichever occurred first. Data for participants with no tumor assessments after baseline but who were still alive at the time of the clinical cutoff were censored at Day 1. Participants who underwent surgery after experiencing a sufficient shrinkage of the tumor, had any relapse, new occurrence of colorectal cancer, or who died were all considered as having had an event. Participants who underwent surgery without any such event were censored at the date of the last tumor assessment that documented that neither a relapse nor a new colorectal cancer had occurred. Median PFS was estimated using the Kaplan-Meier method.
Time Frame	Baseline and Day 1 of every cycle until disease progression or death up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV) and oxaliplatin 130 mg mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	197
Median (95% Confidence Interval) [months]	9.70

5. Secondary Outcome

Title	Time to CR or PR Overall Response - Time to Event
Description	Time to overall response (CR or PR) was calculated as the time between the date of start of treatment until first documented response (CR or PR defined per RECIST v1.0). Participants who did not achieve CR or PR were censored at the date of progression, death, or at last adequate tumor assessment date. Median time to CR or PR overall response was estimated using the Kaplan-Meier method.
Time Frame	Baseline, every 9 weeks (every 3 cycles) until end of treatment, disease progression, or withdrawal up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	197
Median (95% Confidence Interval) [months]	3.93

6. Secondary Outcome

Title	Percentage of Participants With a Best Overall Response of CR or PR During First Line Treatment
Description	CR and PR were defined using RECIST v1.0 criteria. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis <10 mm). No new lesions. PR was defined as a ≥30% decrease under baseline of the sum of diameters of all target lesions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.
Time Frame	Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population, only those participants who achieved a best overall response of CR or PR during first line treatment were included in the analysis.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles):If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	97
Number [percentage of participants]	54.64 27.7%

7. Secondary Outcome

Title	Duration of Overall Response Among Participants Whose Best Response Was CR or PR During First Line Treatment - Time to Event
Description	For participants with a best overall response of CR or PR, the duration of overall response was measured from the time that the criteria for CR or PR (whichever occurred first) was met until the first date that progressive disease was objectively documented or until the date of death due to underlying cancer, whichever occurred first. Data for participants who did not have an event or who were alive without an objectively documented progressive disease were censored at the date of last adequate tumor assessment. Median duration of overall response was estimated using the Kaplan-Meier method.
Time Frame	Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population, only those participants who achieved a best overall response of CR or PR during first line treatment were included in the analysis.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles):If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	97
Median (95% Confidence Interval) [months]	8.52

8. Secondary Outcome

Title	Percentage of Participants With a Stable Response During First Line Treatment
Description	Stable response defined as participants with a best overall response of CR, PR, or stable disease (SD), defined using RECIST v1.0 criteria. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis <10 mm). No new lesions. PR was defined as a ≥30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. SD defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.
Time Frame	Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population, only participants who achieved a best overall response of CR, PR, or SD during first line treatment were included in the analysis.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	152
Number [percentage of participants]	52.63 26.7%

9. Secondary Outcome

Title	Duration of Stable Response
Description	For participants with a best overall response of CR, PR, or SD during first line treatment, the duration of stable response was measured from the time that the criteria for CR, PR, or SD (whichever occurred first) was met until the first date that progressive disease was objectively documented or until the date of death due to underlying cancer, whichever occurred first. Data for participants who did not have an event or who were alive without an objectively documented progressive disease were censored at the date of last adequate tumor assessment. Median duration of stable response was estimated using the Kaplan-Meier method.
Time Frame	Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population, only participants who achieved a best overall response of CR, PR, or SD during first line treatment were included in the analysis.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	152
Median (95% Confidence Interval) [months]	10.39

10. Secondary Outcome

Title	Percentage of Participants With Treatment Failure
Description	Treatment-failure was defined as discontinuation of treatment for any reason, including the following qualifying events: death due to any cause, adverse event, insufficient therapeutic response (progression of disease), failure to return (lost to follow-up), refusing treatment (participant non-compliance), being unwilling to cooperate and withdrawing consent (participant withdrew consent).
Time Frame	Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	197
Number [percentage of participants]	82.74 42%

11. Secondary Outcome

Title	Time to Treatment Failure
Description	Time to treatment-failure was defined as the time from the first day of treatment to discontinuation of treatment for any reason, including: death due to any cause, adverse event, insufficient therapeutic response (progression of disease), failure to return (lost to follow-up), refusing treatment (participant non-compliance), being unwilling to cooperate and withdrawing consent (participant withdrew consent). For participants who did not experience a qualifying event, their data were censored at the earlier of either the date of last tumour assessment or the date of the last intake of study medication. Median time to treatment-failure was estimated using the Kaplan-Meier method.
Time Frame	Baseline, every 3 weeks (every cycle) to disease progression or death up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	197
Median (95% Confidence Interval) [months]	6.69

12. Secondary Outcome

Title	Overall Survival: Percentage of Participants That Died Due to Any Cause
Description	Overall survival was defined as the time from the date of the first day of treatment until the date of death from any cause. If a participant was not known to have died, survival was censored at the last date the participant was known to be alive.
Time Frame	Baseline, Day 1 of every cycle to end-of-treatment, every 3 months during longer-term follow-up, or to death due to any cause up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	197
Number [percentage of participants]	50.76 25.8%

13. Secondary Outcome

Title	Overall Survival: Time to Event
Description	Overall survival was defined as the time from the date of the first day of treatment until the date of death from any cause. If a participant was not known to have died, survival was censored at the last date the participant was known to be alive. Median overall survival was estimated using the Kaplan-Meier method.
Time Frame	Baseline, Day 1 of every cycle to end-of-treatment, every 3 months during longer-term follow-up, or to death due to any cause up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	197
Median (95% Confidence Interval) [months]	23.15

14. Secondary Outcome

Title	Percentage of Participants Undergoing Surgical Intervention With Residual Disease Status Post-surgery
Description	The percentage of participants who underwent surgery during the study period with an evaluation of their disease status after surgery. The surgery during the study period was described by reason: curative, palliative, biopsy, other, or unknown. Residual disease status after surgery was described as: no residual disease due to radical surgery, presence of residual disease, unknown or not applicable.
Time Frame	At surgery, at least 6 to 8 weeks after last dose of bevacizumab up to 5 years

Outcome Measure Data

Analysis Population Description

The 52 participant subpopulation of the ITT population who underwent surgery during the time period of the study.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	52
Curative, no residual disease	55.77 28.3%
Curative, residual disease	13.46 6.8%
Curative, unknown	3.85 2%
Curative, not applicable	7.69 3.9%
Palliative, no residual disease	3.85 2%
Palliative, residual disease	7.69 3.9%
Palliative, unknown	3.85 2%
Palliative, not applicable	1.92 1%
Biopsy, residual disease	1.92 1%
Biopsy, not applicable	1.92 1%
Unknown, unknown	1.92 1%
Unknown, not applicable	3.85 2%
Other, residual disease	1.92 1%
Other, not applicable	3.85 2%

15. Secondary Outcome

Title	Percentage of Participants With Best Overall Response of CR or PR by Kirsten Rat Sarcoma Viral Oncogene Homolog (K-Ras)/V-Raf Murine Sarcoma Viral Oncogene Homolog B (B-Raf) Mutation Status
Description	The percentage of participants with a best overall response of CR or PR according to RECIST. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis <10 mm). No new lesions. PR was defined as ≥30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. The K-Ras and/or the B-Raf gene mutation status of participants was evaluated by the central laboratory using tumor samples. Wild-type participants did not have a mutation in either gene.
Time Frame	Baseline, every 9 weeks (every 3 cycles) until end of treatment, disease progression, or withdrawal up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population; only participants with a known K-Ras and/or B-Raf gene mutation status and at least 1 post-baseline tumor assessment. Number (n) equals (=) number of participants with either wild-type or K-Ras/B-Raf gene mutation.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	33
Wild-type (n=18)	88.89 45.1%
Gene mutation (n=15)	66.67 33.8%

16. Secondary Outcome

Title	European Quality of Life 5 Dimension (EQ-5D) Raw-Index Score
Description	Quality of life (QoL) assessments were used to derive pre-specified QoL scores according to the QoL manual "EQ-5D-3 Level (3L)" user guide for instrument version 4.0. The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The visual analog scale (VAS) component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The overall health score absolute changes were calculated for each participant as follows: (score at the end of treatment minus score at baseline). EQ-5D health states were converted into EQ-5D-3L raw index value by applying the scoring algorithm based on the European EQ-net VAS set. The raw index was chosen instead of rescaled index, since the questionnaire was used in order to obtain a quality of life assessment. The raw index scores ranged from 0 (worst health state) to 100 (best health state).
Time Frame	Baseline, every 9 weeks (every 3 cycles), at end-of-treatment up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population, only participants who had EQ-5D-3L scores for both baseline and last visit were included in the analysis.

Arm/Group Title	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV and oxaliplatin 130 mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
Measure Participants	114
Baseline	80.24 (14.32)
Last visit	74.94 (19.08)
Absolute change from baseline	-5.30 (19.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevucizamab+Oxaliplatin+Capecitabine/Bevacizumab
	Comments	Change from baseline to last visit
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0076
	Comments
	Method	Signed-rank test
	Comments

Adverse Events

Time Frame	Adverse events (AE) were collected from the date of first administration of study treatment until 28 days after the last dose of study treatment up to 5 years
Arm/Group Title	Bevacizumab+Oxaliplatin+Capecitabine/Bevacizumab
Arm/Group Description	Cycles 1-8 (3-week cycles): Participants received bevacizumab 7.5 mg/kg IV) and oxaliplatin 130 mg mg/m^2 IV on Day 1 and capecitabine 1000 mg/m^2 tablets, orally, every 12 hours starting the evening of Day 1 for 14 days continuously; cycle was repeated until disease progression or for a maximum of 8 cycles. Cycle 9 and beyond (3-week cycles): If the first 8 cycles were tolerated with no disease progression, participants received bevacizumab 7.5 mg/kg IV on Day 1; the cycle was repeated until disease progression.
All Cause Mortality
	Bevacizumab+Oxaliplatin+Capecitabine/Bevacizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bevacizumab+Oxaliplatin+Capecitabine/Bevacizumab
	Affected / at Risk (%)	# Events
Total	56/197 (28.4%)
Blood and lymphatic system disorders
Anaemia	1/197 (0.5%)
Cardiac disorders
Cardiac arrest	1/197 (0.5%)
Cardio-respiratory arrest	1/197 (0.5%)
Cardiovascular disorder	1/197 (0.5%)
Coronary artery disease	1/197 (0.5%)
Myocardial infarction	1/197 (0.5%)
Gastrointestinal disorders
Diarrhoea	4/197 (2%)
Intestinal obstruction	2/197 (1%)
Intestinal perforation	2/197 (1%)
Subileus	4/197 (2%)
Abdominal pain	1/197 (0.5%)
Abdominal strangulated hernia	1/197 (0.5%)
Anal fistula	1/197 (0.5%)
Constipation	1/197 (0.5%)
Gastrointestinal disorder	1/197 (0.5%)
Gastrointestinal inflammation	1/197 (0.5%)
Gastrointestinal obstruction	1/197 (0.5%)
Ileus paralytic	1/197 (0.5%)
Nausea	1/197 (0.5%)
Peritonitis	1/197 (0.5%)
Vomiting	1/197 (0.5%)
General disorders
Asthenia	2/197 (1%)
Chest pain	1/197 (0.5%)
Death	1/197 (0.5%)
Fatigue	1/197 (0.5%)
Ill-defined disorder	1/197 (0.5%)
Pyrexia	1/197 (0.5%)
Hepatobiliary disorders
Hepatic failure	1/197 (0.5%)
Immune system disorders
Hypersensitivity	3/197 (1.5%)
Anaphylactic shock	1/197 (0.5%)
Drug hypersensitivity	1/197 (0.5%)
Infections and infestations
Pneumonia	3/197 (1.5%)
Abscess	1/197 (0.5%)
Bronchitis	1/197 (0.5%)
Psoas abscess	1/197 (0.5%)
Renal abscess	1/197 (0.5%)
Sepsis	1/197 (0.5%)
Tuberculosis	1/197 (0.5%)
Injury, poisoning and procedural complications
Rib fracture	1/197 (0.5%)
Metabolism and nutrition disorders
Cachexia	2/197 (1%)
Hyperglycaemia	1/197 (0.5%)
Musculoskeletal and connective tissue disorders
Pain in extremity	1/197 (0.5%)
Nervous system disorders
Hemiparesis	1/197 (0.5%)
Neuropathy peripheral	1/197 (0.5%)
Neurotoxicity	1/197 (0.5%)
Syncope	1/197 (0.5%)
Transient ischaemic attack	1/197 (0.5%)
Renal and urinary disorders
Hydronephrosis	1/197 (0.5%)
Renal failure	1/197 (0.5%)
Renal failure acute	1/197 (0.5%)
Renal vein thrombosis	1/197 (0.5%)
Reproductive system and breast disorders
Genital haemorrhage	1/197 (0.5%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	7/197 (3.6%)
Dyspnoea	1/197 (0.5%)
Laryngeal obstruction	1/197 (0.5%)
Surgical and medical procedures
Vertebroplasty	1/197 (0.5%)
Vascular disorders
Deep vein thrombosis	2/197 (1%)
Hypertensive crisis	3/197 (1.5%)
Hypertension	1/197 (0.5%)
Other (Not Including Serious) Adverse Events
	Bevacizumab+Oxaliplatin+Capecitabine/Bevacizumab
	Affected / at Risk (%)	# Events
Total	179/197 (90.9%)
Blood and lymphatic system disorders
Anaemia	11/197 (5.6%)
Leukopenia	13/197 (6.6%)
Neutropenia	32/197 (16.2%)
Thrombocytopenia	26/197 (13.2%)
Cardiac disorders
Atrial fibrillation	1/197 (0.5%)
Cardiac ventricular disorder	1/197 (0.5%)
Palpitations	2/197 (1%)
Tachycardia	2/197 (1%)
Congenital, familial and genetic disorders
Dihydropyrimidine dehydrogenase deficiency	1/197 (0.5%)
Ear and labyrinth disorders
Deafness	1/197 (0.5%)
Ear pain	1/197 (0.5%)
Hypoacusis	1/197 (0.5%)
Tinnitus	1/197 (0.5%)
Vertigo	8/197 (4.1%)
Eye disorders
Conjunctivitis	3/197 (1.5%)
Diplopia	1/197 (0.5%)
Eye irritation	1/197 (0.5%)
Eye pain	1/197 (0.5%)
Lacrimation increased	1/197 (0.5%)
Scleral haemorrhage	1/197 (0.5%)
Gastrointestinal disorders
Abdominal pain	29/197 (14.7%)
Abdominal pain upper	12/197 (6.1%)
Constipation	27/197 (13.7%)
Diarrhoea	73/197 (37.1%)
Nausea	84/197 (42.6%)
Stomatitis	10/197 (5.1%)
Vomiting	48/197 (24.4%)
Abdominal distension	2/197 (1%)
Abdominal hernia	1/197 (0.5%)
Anal haemorrhage	1/197 (0.5%)
Anal inflammation	1/197 (0.5%)
Anorectal discomfort	2/197 (1%)
Dental discomfort	1/197 (0.5%)
Dry mouth	1/197 (0.5%)
Dyspepsia	4/197 (2%)
Dysphagia	1/197 (0.5%)
Enteritis	1/197 (0.5%)
Enterocolitis haemorrhage	1/197 (0.5%)
Flatulence	2/197 (1%)
Gastritis	1/197 (0.5%)
Gastrointestinal pain	1/197 (0.5%)
Gastrointestinal toxicity	1/197 (0.5%)
Gingival bleeding	3/197 (1.5%)
Gingivitis	1/197 (0.5%)
Haematochezia	1/197 (0.5%)
Haemorrhoidal haemorrhage	1/197 (0.5%)
Haemorrhoids	4/197 (2%)
Inguinal hernia	1/197 (0.5%)
Mouth haemorrhage	1/197 (0.5%)
Proctalgia	3/197 (1.5%)
Rectal haemorrhage	7/197 (3.6%)
Rectal tenesmus	1/197 (0.5%)
Subileus	1/197 (0.5%)
Tooth disorder	1/197 (0.5%)
General disorders
Asthenia	60/197 (30.5%)
Fatigue	29/197 (14.7%)
Mucosal inflammation	21/197 (10.7%)
Pyrexia	40/197 (20.3%)
Chest pain	5/197 (2.5%)
Discomfort	1/197 (0.5%)
Facial pain	1/197 (0.5%)
Hyperpyrexia	2/197 (1%)
Infusion site extravasation	1/197 (0.5%)
Infusion site pain	2/197 (1%)
Injection site haematoma	1/197 (0.5%)
Oedema	1/197 (0.5%)
Oedema peripheral	7/197 (3.6%)
Pain	2/197 (1%)
Performance status decreased	1/197 (0.5%)
Hepatobiliary disorders
Hepatomegaly	2/197 (1%)
Hepatotoxicity	1/197 (0.5%)
Hyperbilirubinaemia	6/197 (3%)
Hypertransaminasaemia	2/197 (1%)
Immune system disorders
Drug hypersensitivity	4/197 (2%)
Hypersensitivity	4/197 (2%)
Infections and infestations
Bronchitis	2/197 (1%)
Cystitis	2/197 (1%)
Ear infection	1/197 (0.5%)
Folliculitis	1/197 (0.5%)
Fungal infection	2/197 (1%)
Herpes virus infection	1/197 (0.5%)
Infection	1/197 (0.5%)
Influenza	4/197 (2%)
Labyrinthitis	1/197 (0.5%)
Pharyngitis	1/197 (0.5%)
Pneumonia	1/197 (0.5%)
Psoas abscess	1/197 (0.5%)
Rhinitis	5/197 (2.5%)
Tooth abscess	2/197 (1%)
Urinary tract infection	5/197 (2.5%)
Injury, poisoning and procedural complications
Fall	1/197 (0.5%)
Foot fracture	1/197 (0.5%)
Gastrointestinal stoma complications	1/197 (0.5%)
Wrist fracture	1/197 (0.5%)
Investigations
Alanine aminotransferase increased	5/197 (2.5%)
Aspartate aminotransferase increased	7/197 (3.6%)
Blood alkaline phosphatase increased	3/197 (1.5%)
Blood bilirubin increased	2/197 (1%)
Blood creatinine increased	1/197 (0.5%)
Blood iron decreased	1/197 (0.5%)
Blood lactate dehydrogenase increased	4/197 (2%)
Blood uric acid increased	1/197 (0.5%)
Haemoglobin decreased	4/197 (2%)
Weight decreased	8/197 (4.1%)
Weight increased	1/197 (0.5%)
Metabolism and nutrition disorders
Anorexia	18/197 (9.1%)
Cachexia	1/197 (0.5%)
Decreased appetite	1/197 (0.5%)
Dehydration	1/197 (0.5%)
Gout	1/197 (0.5%)
Hypercalcaemia	1/197 (0.5%)
Hypercholesterolaemia	1/197 (0.5%)
Hyperglycaemia	3/197 (1.5%)
Hyperkalaemia	1/197 (0.5%)
Hypertriglyceridaemia	1/197 (0.5%)
Hypocalcaemia	2/197 (1%)
Hypokalaemia	8/197 (4.1%)
Hypophosphataemia	1/197 (0.5%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	10/197 (5.1%)
Pain in extremity	16/197 (8.1%)
Arthralgia	6/197 (3%)
Back pain	6/197 (3%)
Bone pain	7/197 (3.6%)
Groin pain	2/197 (1%)
Musculoskeletal discomfort	2/197 (1%)
Musculoskeletal stiffness	1/197 (0.5%)
Myalgia	4/197 (2%)
Neck pain	3/197 (1.5%)
Torticollis	1/197 (0.5%)
Nervous system disorders
Headache	10/197 (5.1%)
Neuropathy peripheral	38/197 (19.3%)
Neurotoxicity	11/197 (5.6%)
Paraesthesia	59/197 (29.9%)
Dizziness	2/197 (1%)
Dysaesthesia	2/197 (1%)
Dysgeusia	9/197 (4.6%)
Migraine	2/197 (1%)
Neuralgia	1/197 (0.5%)
Peripheral sensory neuropathy	5/197 (2.5%)
Presyncope	1/197 (0.5%)
Sciatica	1/197 (0.5%)
Syncope	4/197 (2%)
Syncope vasovagal	1/197 (0.5%)
Tremor	1/197 (0.5%)
Psychiatric disorders
Anxiety	6/197 (3%)
Depression	3/197 (1.5%)
Insomnia	6/197 (3%)
Mood altered	2/197 (1%)
Renal and urinary disorders
Proteinuria	17/197 (8.6%)
Dysuria	4/197 (2%)
Haematuria	4/197 (2%)
Nocturia	1/197 (0.5%)
Pollakiuria	1/197 (0.5%)
Strangury	2/197 (1%)
Reproductive system and breast disorders
Balanitis	1/197 (0.5%)
Genital haemorrhage	1/197 (0.5%)
Orchitis noninfective	1/197 (0.5%)
Testicular disorder	1/197 (0.5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	12/197 (6.1%)
Epistaxis	14/197 (7.1%)
Bronchospasm	2/197 (1%)
Bronchostenosis	1/197 (0.5%)
Cough	7/197 (3.6%)
Dysaesthesia pharynx	4/197 (2%)
Dysphonia	3/197 (1.5%)
Hiccups	1/197 (0.5%)
Laryngeal disorder	3/197 (1.5%)
Laryngospasm	1/197 (0.5%)
Larynx irritation	2/197 (1%)
Oropharyngeal pain	1/197 (0.5%)
Oropharyngeal spasm	1/197 (0.5%)
Pharyngeal inflammation	1/197 (0.5%)
Pleural effusion	1/197 (0.5%)
Pulmonary embolism	1/197 (0.5%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome	18/197 (9.1%)
Alopecia	1/197 (0.5%)
Dermatitis	1/197 (0.5%)
Dermatitis exfoliative	2/197 (1%)
Dry skin	1/197 (0.5%)
Erythema	3/197 (1.5%)
Hyperhidrosis	1/197 (0.5%)
Nail disorder	1/197 (0.5%)
Petechiae	1/197 (0.5%)
Pruritus	4/197 (2%)
Rash	5/197 (2.5%)
Skin disorder	1/197 (0.5%)
Skin exfoliation	2/197 (1%)
Skin lesion	2/197 (1%)
Urticaria	3/197 (1.5%)
Surgical and medical procedures
Cyst drainage	1/197 (0.5%)
Vascular disorders
Hypertension	45/197 (22.8%)
Aortic thrombosis	1/197 (0.5%)
Axillary vein thrombosis	1/197 (0.5%)
Blood pressure fluctuation	1/197 (0.5%)
Deep vein thrombosis	5/197 (2.5%)
Hot flush	1/197 (0.5%)
Hypertensive crisis	1/197 (0.5%)
Hypotension	5/197 (2.5%)
Lymphoedema	1/197 (0.5%)
Orthostatic hypotension	1/197 (0.5%)
Phlebitis	4/197 (2%)
Thrombophlebitis	1/197 (0.5%)
Thrombophlebitis superficial	1/197 (0.5%)
Thrombosis	2/197 (1%)
Vena cava thrombosis	1/197 (0.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request the Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.