Download PDF

Clinical Trial Results:
Open-label, multi-center, randomized, phase II study evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients presenting with metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma

Summary
EudraCT number	2007-005017-19
Trial protocol	GB FR NL IT BE ES PL DE CZ Outside EU/EEA
Global end of trial date	30 Apr 2019

Results information
Results version number	v3(current)
This version publication date	20 Dec 2019
First version publication date	07 Aug 2016
Other versions	v1 , v2
Version creation reason	Correction of full data set Correction made to Subject number by country data.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

BO20924

ISRCTN number

US NCT number

NCT00643565

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland,

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000056-PIP01-07

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

30 Apr 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Apr 2019

Was the trial ended prematurely?

Main objective of the trial

An open-label, multi-center, randomized, Phase 2 study designed to evaluate the benefit of the addition of bevacizumab to chemotherapy in participants presenting with metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Jul 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 7

Country: Number of subjects enrolled

Poland: 5

Country: Number of subjects enrolled

Spain: 11

Country: Number of subjects enrolled

United Kingdom: 35

Country: Number of subjects enrolled

Belgium: 8

Country: Number of subjects enrolled

France: 59

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Italy: 20

Country: Number of subjects enrolled

Brazil: 2

Country: Number of subjects enrolled

Israel: 3

Country: Number of subjects enrolled

Chile: 1

Country: Number of subjects enrolled

Czech Republic: 2

Worldwide total number of subjects

154

EEA total number of subjects

148

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

Participants with metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma underwent screening assessments. An eligibility screening form was completed documenting the investigator's assessment of each screened participant with regard to inclusion and exclusion criteria. A screening failure log was maintained by the investigator.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Chemotherapy

Arm description

Participants received 9 cycles of induction chemotherapy (4 cycles of IVADo-containing chemotherapy i.e. with ifosfamide [I], vincristine [V], actinomycin D [A] and doxorubicin [Do] followed by 5 cycles of IVA-containing chemotherapy [i.e. without doxorubicin]) administered every 3 weeks as per institutional practice. As per the investigator evaluation, participants had option to undergo local therapy (radiotherapy and/or surgery) during last 3 cycles of IVA (i.e. from Cycle 6 to Cycle 9). During maintenance treatment phase, participants received vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles.

Arm type

Active comparator

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received ifosfamide at 3 grams per square meter (g/m^2) on Day 1 and Day 2 of each cycle for the first 9 cycles only.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received vincristine at 1.5 milligrams per square meter (mg/m^2) (maximum single dose of 2 mg) every week for first 7 weeks and then on Day 1 of each cycle up to Cycle 9.

Investigational medicinal product name

Actinomycin D

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received actinomycin D at 1.5 mg/m^2 (maximum single dose of 2 mg) on Day 1 of each cycle for the first 9 cycles only.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received doxorubicin at 30 mg/m^2 on Day 1 and Day 2 from Cycles 1 to 4 only.

Investigational medicinal product name

Vinorelbine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received vinorelbine at 25 mg/m^2 on Days 1, 8, and 15 of each cycle for 12 cycles of maintenance therapy phase.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Participants received cyclophosphamide at 25 mg/m^2 every day for the entire duration of the cycle (i.e. 28 days).

Bevacizumab + Chemotherapy

Arm description

Participants received continuous intravenous (IV) infusion of bevacizumab (7.5 milligrams per kilogram [mg/kg] every 3 weeks) on Day 1 of 3-week cycles followed by induction chemotherapy (4cycles of IVADo-containing chemotherapy followed by 5 cycles of IVA-containing chemotherapy) as per institutional practice for a total of 9 cycles during induction treatment phase. As per the investigator decision, local therapy (radiotherapy and/or surgery) was expected to start after 4 weeks of the last bevacizumab administration in the induction phase and resumed to bevacizumab in maintenance phase at least 4 weeks after the last dose of local therapy. During maintenance treatment phase, participants received IV infusion of bevacizumab (5 mg/kg every 2 weeks) followed by vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles.

Arm type

Experimental

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

RO4876646

Other name

Avastin

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received IV infusion of bevacizumab at 7.5 mg/kg every 3 weeks in 3-week cycles for 9 cycles during induction treatment phase and at 5 mg/kg every 2 weeks in 4-weeks cycles for a total of 12 weeks.

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received ifosfamide at 3 g/m^2 on Day 1 and Day 2 of each cycle for the first 9 cycles only.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received vincristine at 1.5 mg/m^2 (maximum single dose of 2 mg) every week for first 7 weeks and then on Day 1 of each cycle up to Cycle 9.

Investigational medicinal product name

Actinomycin D

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received actinomycin D at 1.5 mg/m^2 (maximum single dose of 2 mg) on Day 1 of each cycle for the first 9 cycles only.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received doxorubicin at 30 mg/m^2 on Day 1 and Day 2 from Cycles 1 to 4 only.

Investigational medicinal product name

Vinorelbine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received vinorelbine at 25 mg/m^2 on Days 1, 8, and 15 of each cycle for 12 cycles of maintenance therapy phase.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Participants received cyclophosphamide at 25 mg/m^2 every day for the entire duration of the cycle (i.e. 28 days).

Number of subjects in period 1	Chemotherapy	Bevacizumab + Chemotherapy
Started	80	74
Completed	7	7
Not completed	73	67
Consent withdrawn by subject	4	1
Adverse event, non-fatal	5	8
Death	12	11
Refused Treat/Did Not Cooperate	-	1
Did Not Cooperate	-	1
Unknown	7	8
Progression Of Disease	18	14
Administrative/Other	22	16
Lost to follow-up	-	6
Recurrence Of Disease	2	1
Protocol deviation	3	-

Baseline characteristics

Top of page

Reporting group title

Chemotherapy

Reporting group description

Reporting group title

Bevacizumab + Chemotherapy

Reporting group description

Reporting group values	Chemotherapy	Bevacizumab + Chemotherapy	Total
Number of subjects	80	74	154
Age categorical
Units: Subjects
Infants and toddlers (28 days-23 months)	3	3	6
Children (2-11 years)	39	38	77
Adolescents (12-17 years)	38	33	71
Age continuous
Units: years
arithmetic mean (standard deviation)	10.5 ± 4.8	10.3 ± 4.9	-
Gender categorical
Units: Subjects
Female	40	29	69
Male	40	45	85

End points

Top of page

Reporting group title

Chemotherapy

Reporting group description

Reporting group title

Bevacizumab + Chemotherapy

Reporting group description

Primary: Percentage of Participants Who Experienced Event-Free Survival (EFS) Events as Per Independent Review Committee (IRC) Assessment

Top of page

End point title

Percentage of Participants Who Experienced Event-Free Survival (EFS) Events as Per Independent Review Committee (IRC) Assessment ^[1]

End point description

EFS events included tumor progression (IRC assessed), no evidence of response after 3 cycles of induction (derived from IRC assessment), second primary cancer, or death due to any cause. Data for participants who had not experienced an event by the time of clinical cut-off were censored at the date of the last disease assessment prior to the clinical cut-off date. Data for participants who did not have any post-baseline disease assessments were censored at the time of randomization. Tumor progression was defined using Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0) as at least a 20 percent (%) increase in the disease measurement, taking as reference the smallest disease measurement recorded since the start of treatment, or appearance of one or more new lesions, or evidence of clinical progression and unequivocal progression of existing non-target lesions. Intent-to-treat (ITT) population included all participants randomized to the treatment group in the study

End point type

Primary

End point timeframe

Screening up to approximately 6.75 years (assessed at screening, Cycles 4, 7 of induction phase, Cycles 1, 4, 7, 10 of maintenance, then every 3 months for 1.5 years and thereafter every 6 months for 2.5 years)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint.

End point values	Chemotherapy	Bevacizumab + Chemotherapy
Number of subjects analysed	80	74
Units: percentage of participants
number (not applicable)	52.5	68.9

No statistical analyses for this end point

Primary: EFS Duration as Per IRC Assessment

Top of page

End point title

EFS Duration as Per IRC Assessment

End point description

EFS was defined as the time between randomization and occurrence of EFS event (described in endpoint "Percentage of Participants Who Experienced EFS Events as Per IRC"). Median EFS was estimated using Kaplan-Meier estimates and 95% confidence intervals (CI) for median was computed using the method of Brookmeyer and Crowley. ITT population.

End point type

Primary

End point timeframe

End point values	Chemotherapy	Bevacizumab + Chemotherapy
Number of subjects analysed	80	74
Units: months
median (confidence interval 95%)	14.85 (10.84 to 35.88)	20.63 (15.15 to 24.87)

EFS Duration as Per IRC Assessment

Comparison groups

Bevacizumab + Chemotherapy v Chemotherapy

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7189 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

1.41

Notes
[2] - The HR was calculated based on a stratified Cox proportional hazards model, with stratification factors of age and histology/disease risk.

Secondary: Percentage of Participants with Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria

Top of page

End point title

Percentage of Participants with Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria

End point description

Objective response prior to first local therapy (surgery and/or radiotherapy) was defined as complete response (CR) or partial response (PR) determined on two consecutive occasions greater than equal to (>=) 4 weeks apart. Tumor response were assessed as per IRC using RECIST 1.0. CR was defined as disappearance of all target and non-target lesions. If immunocytology was available, no disease was to be detected by that methodology. PR was defined as at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry. ITT population.

End point type

Secondary

End point timeframe

Screening up to end approximately 6.75 years

End point values	Chemotherapy	Bevacizumab + Chemotherapy
Number of subjects analysed	80	74
Units: percentage of participants
number (confidence interval 95%)	36 (25.23 to 47.91)	54 (40.94 to 66.61)

No statistical analyses for this end point

Secondary: Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response

Top of page

End point title

Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response

End point description

EFS events was described in endpoint "Percentage of Participants Who Experienced EFS Events as Per IRC" and in endpoint "Percentage of Participants with Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria". ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Screening up to end approximately 6.75 years

End point values	Chemotherapy	Bevacizumab + Chemotherapy
Number of subjects analysed	27	34
Units: percentage of participants
number (not applicable)	40.7	76.5

No statistical analyses for this end point

Secondary: Duration of Response

Top of page

End point title

Duration of Response

End point description

Duration of Response was defined as the time between first objective response and the occurrence of an EFS event (described in endpoint "Percentage of Participants Who Experienced EFS Events as Per IRC"). Objective response is defined in Outcome Measure “Percentage of Participants With Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria”. Median duration of response was estimated using Kaplan-Meier estimates and 95% CI for median was computed using the method of Brookmeyer and Crowley. ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome measure. Here, “99.9” and “999.9”was used as median and upper limit of 95% CI, respectively, as data was not estimable because of higher number (more than 50%) of censored participants in this arm group.

End point type

Secondary

End point timeframe

Screening up to end approximately 6.75 years

End point values	Chemotherapy	Bevacizumab + Chemotherapy
Number of subjects analysed	27	34
Units: months
median (confidence interval 95%)	99.9 (10.18 to 999.9)	17.48 (12.29 to 25.23)

No statistical analyses for this end point

Secondary: Percentage of Participants Who Died

Top of page

End point title

Percentage of Participants Who Died

End point description

ITT population.

End point type

Secondary

End point timeframe

Screening up to approximately 10.75 years (assessed at screening, Cycles 4, 7 of induction phase, Cycles 1, 4, 7, 10 of maintenance, then every 3 months for 1.5 years and thereafter every 6 months for 2.5 years.

End point values	Chemotherapy	Bevacizumab + Chemotherapy
Number of subjects analysed	80	74
Units: percentage of participants
number (not applicable)	50	51.4

No statistical analyses for this end point

Secondary: Overall Survival Duration

Top of page

End point title

Overall Survival Duration

End point description

Overall survival was defined as the time between randomization and death due to any cause. Participants without an event were censored at the last time they were known to be alive. Median overall survival was estimated using Kaplan-Meier estimates and 95% CI for median was computed using the method of Brookmeyer and Crowley. ITT population. Here number of participants analyzed = participants available for the analysis of this outcome measure. Here, "999" was used as upper limit of 95% CI, which was not estimable because of higher number (more than 50%) of censored participants in this arm group.

End point type

Secondary

End point timeframe

End point values	Chemotherapy	Bevacizumab + Chemotherapy
Number of subjects analysed	80	74
Units: months
median (confidence interval 95%)	24.02 (17.97 to 999)	32.79 (25.33 to 999)

Chemotherapy, Bevacizumab + Chemotherapy

Comparison groups

Chemotherapy v Bevacizumab + Chemotherapy

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3211 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.25

Notes
[3] - The HR was calculated based on a stratified Cox proportional hazards model, with stratification factors of age and histology/disease risk.

Secondary: Area Under the Curve at Steady State (AUCss) of Bevacizumab

Top of page

End point title

Area Under the Curve at Steady State (AUCss) of Bevacizumab ^[4]

End point description

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUCss is expressed in milligrams times days per milliliter (mg*day/mL). Pharmacokinetic (PK)-evaluable population included all randomized participants for whom at least one blood sample was taken for PK assessment following bevacizumab administration. Only participants who received bevacizumab were to be analyzed for PK assessment.

End point type

Secondary

End point timeframe

Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The PK data were analyzed for bevacizumab, which was not administered to Chemotherapy arm group.

End point values	Bevacizumab + Chemotherapy
Number of subjects analysed	70
Units: mg*day/mL
arithmetic mean (standard deviation)	1010 ± 256

No statistical analyses for this end point

Secondary: Volume of Distribution of Bevacizumab

Top of page

End point title

Volume of Distribution of Bevacizumab ^[5]

End point description

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. PK-evaluable population. Only participants who received bevacizumab were to be analyzed for PK assessment.

End point type

Secondary

End point timeframe

Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The PK data were analyzed for bevacizumab, which was not administered to Chemotherapy arm group.

End point values	Bevacizumab + Chemotherapy
Number of subjects analysed	70
Units: mL
arithmetic mean (standard deviation)	2070 ± 891

No statistical analyses for this end point

Secondary: Half-Life of Bevacizumab

Top of page

End point title

Half-Life of Bevacizumab ^[6]

End point description

Half-life is the time measured for the plasma concentration to decrease by one half. PK-evaluable population. Only participants who received bevacizumab were to be analyzed for PK assessment.

End point type

Secondary

End point timeframe

Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The PK data were analyzed for bevacizumab, which was not administered to Chemotherapy arm group.

End point values	Bevacizumab + Chemotherapy
Number of subjects analysed	70
Units: days
arithmetic mean (standard deviation)	20.8 ± 8.58

No statistical analyses for this end point

Secondary: Clearance (CL) of Bevacizumab

Top of page

End point title

Clearance (CL) of Bevacizumab ^[7]

End point description

CL is a quantitative measure of the rate at which a drug substance is removed from the body. CL is expressed in milliliters per day (mL/day). PK-evaluable population. Only participants who received bevacizumab were to be analyzed for PK assessment.

End point type

Secondary

End point timeframe

Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The PK data were analyzed for bevacizumab, which was not administered to Chemotherapy arm group.

End point values	Bevacizumab + Chemotherapy
Number of subjects analysed	70
Units: mL/day
arithmetic mean (standard deviation)	167 ± 76.4

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Screening up to approximately 10.75 years

Adverse event reporting additional description

The safety-evaluable population included all randomized participants who received any dose of study treatment.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Chemotherapy

Reporting group description

Participants received 9 cycles of induction chemotherapy (4 cycles of IVADo-containing chemotherapy followed by 5 cycles of IVA-containing chemotherapy administered every 3 weeks as per institutional practice. As per the investigator evaluation, participants had option to undergo local therapy (radiotherapy and/or surgery) during last 3 cycles of IVA (i.e. from Cycle 6 to Cycle 9). During maintenance treatment phase, participants received vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Day 1 and 15 of 4-week cycles for a total of 12 cycles.

Reporting group title

Bevacizumab + Chemotherapy

Reporting group description

Participants received continuous IV infusion of bevacizumab (7.5 mg/kg every 3 weeks) on Day 1 of 3-week cycles followed by induction chemotherapy (4 cycles of IVADo-containing chemotherapy followed by 5 cycles of IVA-containing chemotherapy) as per institutional practice for a total of 9 cycles during induction treatment phase. As per the investigator decision, local therapy (radiotherapy and/or surgery) was expected to start after 4 weeks of the last bevacizumab administration in the induction phase and resumed to bevacizumab in maintenance phase at least 4 weeks after the last dose of local therapy. During maintenance treatment phase, participants received IV infusion of bevacizumab (5 mg/kg every 2 weeks) followed by vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles.

Serious adverse events	Chemotherapy	Bevacizumab + Chemotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	68 / 79 (86.08%)	66 / 71 (92.96%)
number of deaths (all causes)	40	37
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour necrosis
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	2 / 79 (2.53%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jugular vein thrombosis
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Microangiopathy
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venoocclusive disease
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Central venous catheter removal
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Face oedema
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 79 (1.27%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	7 / 79 (8.86%)	10 / 71 (14.08%)
occurrences causally related to treatment / all	14 / 14	18 / 18
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	15 / 79 (18.99%)	14 / 71 (19.72%)
occurrences causally related to treatment / all	19 / 26	3 / 14
deaths causally related to treatment / all	0 / 0	0 / 0
Performance status decreased
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis in device
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 79 (2.53%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 79 (1.27%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	1 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoventilation
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 79 (1.27%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 79 (1.27%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device malfunction
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Haemoglobin decreased
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Candida test positive
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil toxic granulation present
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	3 / 79 (3.80%)	5 / 71 (7.04%)
occurrences causally related to treatment / all	2 / 3	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Foot fracture
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pneumothorax
subjects affected / exposed	1 / 79 (1.27%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular procedure complication
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Torus fracture
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Recall phenomenon
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheostomy malfunction
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access complication
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Fanconi syndrome
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial thrombosis
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiotoxicity
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular dysfunction
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Facial nerve disorder
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	2 / 79 (2.53%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 79 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neurotoxicity
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral sensorimotor neuropathy
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	2 / 79 (2.53%)	4 / 71 (5.63%)
occurrences causally related to treatment / all	1 / 2	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxic encephalopathy
subjects affected / exposed	2 / 79 (2.53%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vocal cord paresis
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 79 (3.80%)	4 / 71 (5.63%)
occurrences causally related to treatment / all	8 / 8	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile bone marrow aplasia
subjects affected / exposed	9 / 79 (11.39%)	19 / 71 (26.76%)
occurrences causally related to treatment / all	24 / 24	49 / 49
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	47 / 79 (59.49%)	46 / 71 (64.79%)
occurrences causally related to treatment / all	134 / 135	120 / 120
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	3 / 79 (3.80%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	4 / 4	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Eyelid oedema
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 79 (2.53%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal inflammation
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 79 (1.27%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	3 / 79 (3.80%)	4 / 71 (5.63%)
occurrences causally related to treatment / all	2 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	2 / 79 (2.53%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal obstruction
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	3 / 79 (3.80%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	4 / 79 (5.06%)	3 / 71 (4.23%)
occurrences causally related to treatment / all	5 / 5	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	7 / 79 (8.86%)	8 / 71 (11.27%)
occurrences causally related to treatment / all	7 / 8	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 79 (1.27%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Erythema multiforme
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash papular
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin disorder
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin exfoliation
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 79 (2.53%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysuria
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder necrosis
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	4 / 79 (5.06%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	3 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 79 (1.27%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	1 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 79 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Candida sepsis
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	2 / 79 (2.53%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis bacterial
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 79 (1.27%)	3 / 71 (4.23%)
occurrences causally related to treatment / all	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	5 / 79 (6.33%)	3 / 71 (4.23%)
occurrences causally related to treatment / all	4 / 8	5 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonas infection
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	3 / 79 (3.80%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella
subjects affected / exposed	0 / 79 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 79 (1.27%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vulvitis
subjects affected / exposed	0 / 79 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular Device Infection
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic infection
subjects affected / exposed	3 / 79 (3.80%)	4 / 71 (5.63%)
occurrences causally related to treatment / all	4 / 4	6 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 79 (1.27%)	4 / 71 (5.63%)
occurrences causally related to treatment / all	1 / 1	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	2 / 79 (2.53%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	2 / 79 (2.53%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 79 (2.53%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	1 / 79 (1.27%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 79 (1.27%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	1 / 79 (1.27%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Chemotherapy	Bevacizumab + Chemotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	78 / 79 (98.73%)	71 / 71 (100.00%)
Vascular disorders
Hypotension
subjects affected / exposed	3 / 79 (3.80%)	4 / 71 (5.63%)
occurrences all number	3	5
General disorders and administration site conditions
Asthenia
subjects affected / exposed	10 / 79 (12.66%)	17 / 71 (23.94%)
occurrences all number	12	23
Chest pain
subjects affected / exposed	6 / 79 (7.59%)	4 / 71 (5.63%)
occurrences all number	7	4
Fatigue
subjects affected / exposed	16 / 79 (20.25%)	18 / 71 (25.35%)
occurrences all number	27	26
Mucosal inflammation
subjects affected / exposed	38 / 79 (48.10%)	42 / 71 (59.15%)
occurrences all number	54	74
Pain
subjects affected / exposed	10 / 79 (12.66%)	5 / 71 (7.04%)
occurrences all number	11	6
Pyrexia
subjects affected / exposed	33 / 79 (41.77%)	27 / 71 (38.03%)
occurrences all number	73	46
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 79 (1.27%)	4 / 71 (5.63%)
occurrences all number	1	5
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	13 / 79 (16.46%)	19 / 71 (26.76%)
occurrences all number	20	29
Epistaxis
subjects affected / exposed	8 / 79 (10.13%)	23 / 71 (32.39%)
occurrences all number	10	57
Oropharyngeal pain
subjects affected / exposed	7 / 79 (8.86%)	9 / 71 (12.68%)
occurrences all number	10	11
Rhinorrhoea
subjects affected / exposed	6 / 79 (7.59%)	4 / 71 (5.63%)
occurrences all number	6	7
Psychiatric disorders
Anxiety
subjects affected / exposed	7 / 79 (8.86%)	9 / 71 (12.68%)
occurrences all number	7	9
Insomnia
subjects affected / exposed	2 / 79 (2.53%)	5 / 71 (7.04%)
occurrences all number	2	5
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 79 (2.53%)	6 / 71 (8.45%)
occurrences all number	2	7
Gamma-glutamyltransferase increased
subjects affected / exposed	3 / 79 (3.80%)	4 / 71 (5.63%)
occurrences all number	3	5
Haemoglobin decreased
subjects affected / exposed	13 / 79 (16.46%)	7 / 71 (9.86%)
occurrences all number	27	18
Neutrophil count decreased
subjects affected / exposed	4 / 79 (5.06%)	3 / 71 (4.23%)
occurrences all number	7	15
Platelet count decreased
subjects affected / exposed	5 / 79 (6.33%)	4 / 71 (5.63%)
occurrences all number	13	13
Weight decreased
subjects affected / exposed	27 / 79 (34.18%)	22 / 71 (30.99%)
occurrences all number	31	26
White blood cell count decreased
subjects affected / exposed	2 / 79 (2.53%)	4 / 71 (5.63%)
occurrences all number	3	6
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	1 / 79 (1.27%)	7 / 71 (9.86%)
occurrences all number	1	8
Radiation skin injury
subjects affected / exposed	12 / 79 (15.19%)	8 / 71 (11.27%)
occurrences all number	12	9
Radiation Injury
subjects affected / exposed	1 / 79 (1.27%)	4 / 71 (5.63%)
occurrences all number	1	4
Cardiac disorders
Left ventricular dysfunction
subjects affected / exposed	4 / 79 (5.06%)	5 / 71 (7.04%)
occurrences all number	4	5
Tachycardia
subjects affected / exposed	4 / 79 (5.06%)	1 / 71 (1.41%)
occurrences all number	4	1
Nervous system disorders
Dizziness
subjects affected / exposed	6 / 79 (7.59%)	7 / 71 (9.86%)
occurrences all number	7	8
Headache
subjects affected / exposed	16 / 79 (20.25%)	32 / 71 (45.07%)
occurrences all number	23	49
Neuralgia
subjects affected / exposed	5 / 79 (6.33%)	2 / 71 (2.82%)
occurrences all number	6	2
Neuropathy peripheral
subjects affected / exposed	2 / 79 (2.53%)	9 / 71 (12.68%)
occurrences all number	2	10
Paraesthesia
subjects affected / exposed	3 / 79 (3.80%)	6 / 71 (8.45%)
occurrences all number	3	6
Peripheral sensory neuropathy
subjects affected / exposed	2 / 79 (2.53%)	5 / 71 (7.04%)
occurrences all number	3	6
Polyneuropathy
subjects affected / exposed	1 / 79 (1.27%)	4 / 71 (5.63%)
occurrences all number	1	4
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	50 / 79 (63.29%)	55 / 71 (77.46%)
occurrences all number	141	128
Febrile neutropenia
subjects affected / exposed	14 / 79 (17.72%)	12 / 71 (16.90%)
occurrences all number	23	16
Leukopenia
subjects affected / exposed	11 / 79 (13.92%)	13 / 71 (18.31%)
occurrences all number	30	36
Neutropenia
subjects affected / exposed	53 / 79 (67.09%)	56 / 71 (78.87%)
occurrences all number	244	264
Thrombocytopenia
subjects affected / exposed	37 / 79 (46.84%)	31 / 71 (43.66%)
occurrences all number	116	101
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	4 / 79 (5.06%)	5 / 71 (7.04%)
occurrences all number	4	6
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	27 / 79 (34.18%)	31 / 71 (43.66%)
occurrences all number	43	58
Abdominal pain upper
subjects affected / exposed	8 / 79 (10.13%)	8 / 71 (11.27%)
occurrences all number	10	12
Anal fissure
subjects affected / exposed	5 / 79 (6.33%)	13 / 71 (18.31%)
occurrences all number	7	15
Anal inflammation
subjects affected / exposed	4 / 79 (5.06%)	6 / 71 (8.45%)
occurrences all number	7	7
Constipation
subjects affected / exposed	40 / 79 (50.63%)	48 / 71 (67.61%)
occurrences all number	61	95
Diarrhoea
subjects affected / exposed	27 / 79 (34.18%)	30 / 71 (42.25%)
occurrences all number	54	56
Dyspepsia
subjects affected / exposed	5 / 79 (6.33%)	4 / 71 (5.63%)
occurrences all number	5	4
Mouth ulceration
subjects affected / exposed	4 / 79 (5.06%)	3 / 71 (4.23%)
occurrences all number	4	3
Nausea
subjects affected / exposed	42 / 79 (53.16%)	44 / 71 (61.97%)
occurrences all number	146	145
Oral pain
subjects affected / exposed	4 / 79 (5.06%)	2 / 71 (2.82%)
occurrences all number	6	2
Stomatitis
subjects affected / exposed	23 / 79 (29.11%)	15 / 71 (21.13%)
occurrences all number	29	21
Vomiting
subjects affected / exposed	61 / 79 (77.22%)	64 / 71 (90.14%)
occurrences all number	186	202
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	1 / 79 (1.27%)	4 / 71 (5.63%)
occurrences all number	1	4
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	22 / 79 (27.85%)	17 / 71 (23.94%)
occurrences all number	23	18
Dry skin
subjects affected / exposed	2 / 79 (2.53%)	5 / 71 (7.04%)
occurrences all number	2	6
Erythema
subjects affected / exposed	6 / 79 (7.59%)	12 / 71 (16.90%)
occurrences all number	7	13
Pruritus
subjects affected / exposed	6 / 79 (7.59%)	10 / 71 (14.08%)
occurrences all number	7	14
Rash
subjects affected / exposed	10 / 79 (12.66%)	5 / 71 (7.04%)
occurrences all number	13	6
Renal and urinary disorders
Dysuria
subjects affected / exposed	3 / 79 (3.80%)	7 / 71 (9.86%)
occurrences all number	3	10
Haematuria
subjects affected / exposed	2 / 79 (2.53%)	8 / 71 (11.27%)
occurrences all number	3	9
Proteinuria
subjects affected / exposed	4 / 79 (5.06%)	4 / 71 (5.63%)
occurrences all number	6	8
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	8 / 79 (10.13%)	10 / 71 (14.08%)
occurrences all number	10	15
Back pain
subjects affected / exposed	6 / 79 (7.59%)	15 / 71 (21.13%)
occurrences all number	8	23
Bone pain
subjects affected / exposed	2 / 79 (2.53%)	4 / 71 (5.63%)
occurrences all number	2	6
Myalgia
subjects affected / exposed	4 / 79 (5.06%)	6 / 71 (8.45%)
occurrences all number	4	9
Pain in extremity
subjects affected / exposed	16 / 79 (20.25%)	20 / 71 (28.17%)
occurrences all number	22	30
Pain in jaw
subjects affected / exposed	12 / 79 (15.19%)	5 / 71 (7.04%)
occurrences all number	14	5
Infections and infestations
Candida infection
subjects affected / exposed	5 / 79 (6.33%)	0 / 71 (0.00%)
occurrences all number	5	0
Conjunctivitis
subjects affected / exposed	5 / 79 (6.33%)	7 / 71 (9.86%)
occurrences all number	5	7
Ear infection
subjects affected / exposed	3 / 79 (3.80%)	6 / 71 (8.45%)
occurrences all number	4	7
Herpes zoster
subjects affected / exposed	4 / 79 (5.06%)	3 / 71 (4.23%)
occurrences all number	4	3
Infection
subjects affected / exposed	3 / 79 (3.80%)	5 / 71 (7.04%)
occurrences all number	5	5
Nasopharyngitis
subjects affected / exposed	5 / 79 (6.33%)	10 / 71 (14.08%)
occurrences all number	8	15
Oral candidiasis
subjects affected / exposed	7 / 79 (8.86%)	5 / 71 (7.04%)
occurrences all number	11	7
Paronychia
subjects affected / exposed	0 / 79 (0.00%)	5 / 71 (7.04%)
occurrences all number	0	5
Pharyngitis
subjects affected / exposed	0 / 79 (0.00%)	4 / 71 (5.63%)
occurrences all number	0	5
Rhinitis
subjects affected / exposed	6 / 79 (7.59%)	12 / 71 (16.90%)
occurrences all number	7	20
Upper respiratory tract infection
subjects affected / exposed	7 / 79 (8.86%)	9 / 71 (12.68%)
occurrences all number	13	13
Urinary tract infection
subjects affected / exposed	2 / 79 (2.53%)	8 / 71 (11.27%)
occurrences all number	2	8
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	18 / 79 (22.78%)	21 / 71 (29.58%)
occurrences all number	21	27
Hypokalaemia
subjects affected / exposed	18 / 79 (22.78%)	8 / 71 (11.27%)
occurrences all number	20	9
Hypomagnesaemia
subjects affected / exposed	5 / 79 (6.33%)	2 / 71 (2.82%)
occurrences all number	5	2
Hyponatraemia
subjects affected / exposed	2 / 79 (2.53%)	4 / 71 (5.63%)
occurrences all number	2	4
Hypophosphataemia
subjects affected / exposed	4 / 79 (5.06%)	5 / 71 (7.04%)
occurrences all number	5	7

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

05 Mar 2008

Amended inclusion criteria as related to assessment of cardiac function and related sections as to cardiac toxicity, documenting the stress-velocity index information on smaller age ranges (less than [<] 1 year, versus 1 to 2 years, 2 to 3 years, >3 years). In healthy children less than 3 years of age, the minimal shortening fraction documented was between 35% and 45%, compared to between 28% and 38% for children aged 3 years and older. Adequate cardiac function at screen was redefined as shortening fraction (SF) >=28% for participants of at least 3 years of age, and SF >=35% for participants below 3 years of age. The diagnosis of congestive heart failure was redefined to include a decrease of SF below 28% for participants of at least 3 years of age and below 35% for participants below 3 years of age, or if the SF decreased by an absolute of >=10 percentile points from the previous test. Dose modification guidelines for doxorubicin and bevacizumab in cases of treatment-emergent cardiotoxicity events were rewritten to included the redefinitions above.

22 Jan 2009

This amendment was done to describe study design and endpoints, radiological tumor assessment. Statistical analysis plan was amended to add the futility analysis which was performed on 80 participants who completed 6 cycles. Due to new requirements for safety follow-up after randomization that extended study duration by 4 years, and with the requirement that the events of the primary endpoint were to be assessed by magnetic resonance imaging and evaluated by a central independent image reviewing committee, the schedule of assessments and study procedures section were completely revised to provide clear guidance for treating physicians and to allow for a meaningful review of trial efficacy data. Amended the study population criteria.

30 May 2011

Updated with increased investigational site from 50 to 60. Updated with possibility of omission of the first two doses of bevacizumab (induction therapy Cycles 1 and 2) for participants who presented with a surgical wound, bone fracture, or bleeding related to tumor oozing not satisfactorily healed at randomization or transient clotting diathesis or transient obstructive renal failure that had not resolved at randomization. Updated randomization timeframe from 4 weeks to 3 weeks for participants who underwent a major surgical procedure or open biopsy, or had suffered from a significant traumatic injury or bone fracture prior to study entry.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Clinical trials

Clinical Trial Results:
Open-label, multi-center, randomized, phase II study evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients presenting with metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Who Experienced Event-Free Survival (EFS) Events as Per Independent Review Committee (IRC) Assessment

Primary: Percentage of Participants Who Experienced Event-Free Survival (EFS) Events as Per Independent Review Committee (IRC) Assessment

Primary: EFS Duration as Per IRC Assessment

Primary: EFS Duration as Per IRC Assessment

Secondary: Percentage of Participants with Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria

Secondary: Percentage of Participants with Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria

Secondary: Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response

Secondary: Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response

Secondary: Duration of Response

Secondary: Duration of Response

Secondary: Percentage of Participants Who Died

Secondary: Percentage of Participants Who Died

Secondary: Overall Survival Duration

Secondary: Overall Survival Duration

Secondary: Area Under the Curve at Steady State (AUCss) of Bevacizumab

Secondary: Area Under the Curve at Steady State (AUCss) of Bevacizumab

Secondary: Volume of Distribution of Bevacizumab

Secondary: Volume of Distribution of Bevacizumab

Secondary: Half-Life of Bevacizumab

Secondary: Half-Life of Bevacizumab

Secondary: Clearance (CL) of Bevacizumab

Secondary: Clearance (CL) of Bevacizumab

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: Open-label, multi-center, randomized, phase II study evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients presenting with metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Who Experienced Event-Free Survival (EFS) Events as Per Independent Review Committee (IRC) Assessment

Primary: Percentage of Participants Who Experienced Event-Free Survival (EFS) Events as Per Independent Review Committee (IRC) Assessment

Primary: EFS Duration as Per IRC Assessment

Primary: EFS Duration as Per IRC Assessment

Secondary: Percentage of Participants with Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria

Secondary: Percentage of Participants with Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria

Secondary: Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response

Secondary: Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response

Secondary: Duration of Response

Secondary: Duration of Response

Secondary: Percentage of Participants Who Died

Secondary: Percentage of Participants Who Died

Secondary: Overall Survival Duration

Secondary: Overall Survival Duration

Secondary: Area Under the Curve at Steady State (AUCss) of Bevacizumab

Secondary: Area Under the Curve at Steady State (AUCss) of Bevacizumab

Secondary: Volume of Distribution of Bevacizumab

Secondary: Volume of Distribution of Bevacizumab

Secondary: Half-Life of Bevacizumab

Secondary: Half-Life of Bevacizumab

Secondary: Clearance (CL) of Bevacizumab

Secondary: Clearance (CL) of Bevacizumab

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Open-label, multi-center, randomized, phase II study evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients presenting with metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma