Clinical Trial Results:
Randomized Phase II-III Study Comparing Bevacizumab 7.5 mg/kg in Combination with Chemotherapy Versus Chemotherapy in Extensive-Disease Small-Cell Lung Cancer After Response to PCDE or PE Chemotherapy PCDE: cisPlatin – Cyclophosphamide – epiDoxorubicin – Etoposide PE: cisPlatin – Etoposide

Trial information Top of page
Trial identification
Sponsor protocol code	IFCT-0802
Additional study identifiers
ISRCTN number	-
US NCT number	NCT00930891
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	IFCT
Sponsor organisation address	10 rue de la Grange-Batelière, PARIS, France,
Public contact	Sponsor, IFCT, contact@ifct.fr
Scientific contact	Sponsor, IFCT, contact@ifct.fr
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	26 Jan 2015
Is this the analysis of the primary completion data?	Yes
Primary completion date	26 Jul 2013
Global end of trial reached?	Yes
Global end of trial date	26 Jul 2013
Was the trial ended prematurely?	Yes
General information about the trial
Main objective of the trial	Objective response rate (complete response + partial response) after 4 cycles.
Protection of trial subjects	Reductions of dose of the study treatment. Best supportive care treatment
Background therapy	Chemotherapy is thus the standard first-line treatment for small-cell lung cancer and is the only anticancer treatment with demonstrated beneficial effect for patients with extensive-stage disease [Chute, 1999]. Cisplatin-etoposide combination chemotherapy is active in first-line therapy and is the reference combination for many collaborative groups [Chute et al, 1999; Maksymiuk et al, 1994; Ihde et al, 1994]. Two meta-analyses of literature data showed that, as for the combination chemotherapy, chemotherapies based on either one of these two drugs prolong the lives of patients [Pujol et al, 2000; Paesmans et al, 2000]. Furthermore, a recent in vitro study suggests that they have distinct synergistic effects [Jensen et al, 1997]. However, the proportion of patients surviving beyond two years remains below 10%; the low two-year survival rate is due to chemotherapy-resistant relapse [Hansen and Kristjansen, 1991; Aisner J, 1996]. An explanation for this could be the selection of a chemotherapy-resistant phenotype of tumor cells to the induction treatment. New chemotherapy methods are currently being studied to avoid or circumvent this chemotherapy-resistant relapse.
Evidence for comparator	-
Actual start date of recruitment	22 Sep 2009
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	France: 147
Worldwide total number of subjects	147
EEA total number of subjects	147
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	111
From 65 to 84 years	36
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	Recruitment period : 22/09/2009 to 19/10/2011. Territory : France
Pre-assignment
Screening details	previously untreated extensive small-cell lung cancer
Period 1
Period 1 title	Inclusion period
Is this the baseline period?	Yes
Allocation method	Not applicable
Blinding used	Not blinded
Arms
Arm title	Chemotherapy
Arm description	All patient included received 2 cycles of chemotherapy (PE or PCDE)
Arm type	Same treatment for all patients
Investigational medicinal product name	Cisplatin
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	75 mg/m², Day 2 every 21 days for patient receiving PCDE treatment 80 mg/m², Day 2 every 21 days for patient receiving PE treatment
Investigational medicinal product name	Etoposide
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	75 mg/m² Day 1, Day 2 and Day 3, every 21 days for patient receiving PCDE treatment 120 mg/m² Day 1, Day 2 and Day 3, every 21 days for patient receiving PE treatment
Investigational medicinal product name	4'-epidoxorubicin
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	30 mg/m², Day 1 every 21 days for patient receiving PCDE treatment only
Investigational medicinal product name	Cyclophosphamide
Investigational medicinal product code
Other name
Pharmaceutical forms	Powder for solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	300 mg/m², Day 1, Day 2, Day 3 every 21 days for patient receiving PCDE treatment only
Number of subjects in period 1 Chemotherapy Started 147 Completed 138 Not completed 9      Consent withdrawn by subject 1      Adverse event, non-fatal 1      Protocol deviation 1      Lack of efficacy 6
Period 2
Period 2 title	Randomization period
Is this the baseline period?	No
Allocation method	Randomised - controlled
Blinding used	Not blinded
Arms
Are arms mutually exclusive	Yes
Arm title	Chemotherapy alone
Arm description	-
Arm type	Active comparator
Investigational medicinal product name	Cisplatin
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	75 mg/m², Day 2 every 21 days for patient receiving PCDE treatment 80 mg/m², Day 2 every 21 days for patient receiving PE treatment
Investigational medicinal product name	Etoposide
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	75 mg/m² Day 1, Day 2 and Day 3, every 21 days for patient receiving PCDE treatment 120 mg/m² Day 1, Day 2 and Day 3, every 21 days for patient receiving PE treatment
Investigational medicinal product name	4'-epidoxorubicin
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	30 mg/m², Day 1 every 21 days for patient receiving PCDE treatment only
Investigational medicinal product name	Cyclophosphamide
Investigational medicinal product code
Other name
Pharmaceutical forms	Powder for solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	300 mg/m², Day 1, Day 2, Day 3 every 21 days for patient receiving PCDE treatment only
Arm title	Chemotherapy + bevacizumab
Arm description	-
Arm type	Experimental
Investigational medicinal product name	Cisplatin
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	75 mg/m², Day 2 every 21 days for patient receiving PCDE treatment 80 mg/m², Day 2 every 21 days for patient receiving PE treatment
Investigational medicinal product name	Etoposide
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	75 mg/m² Day 1, Day 2 and Day 3, every 21 days for patient receiving PCDE treatment 120 mg/m² Day 1, Day 2 and Day 3, every 21 days for patient receiving PE treatment
Investigational medicinal product name	4'-epidoxorubicin
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	30 mg/m², Day 1 every 21 days for patient receiving PCDE only
Investigational medicinal product name	Cyclophosphamide
Investigational medicinal product code
Other name
Pharmaceutical forms	Powder for solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	300 mg/m², Day 1, Day 2, Day 3 every 21 days for patient receiving PCDE only
Investigational medicinal product name	Bevacizumab
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	7,5 mg/m² Day 1 every 21 days
Number of subjects in period 2 [1] Chemotherapy alone Chemotherapy + bevacizumab Started 37 37 Completed 31 35 Not completed 6 2      Adverse event, non-fatal 4 -      Lack of efficacy 2 1      Protocol deviation - 1
Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: 64 subjects excluded because they not fulfill the randomization criteria

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Inclusion period
Reporting group description	-
Reporting group values Inclusion period Total Number of subjects 147 147 Age categorical Units: Subjects     Adults (18-64 years) 111 111     From 65-84 years 36 36 Gender categorical Units: Subjects     Female 39 39     Male 108 108 Produits de chimiothérapie Units: Subjects     PCDE 20 20     PE 127 127 Performance status Units: Subjects     PS 0 - 1 118 118     PS 2 29 29

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Chemotherapy
Reporting group description	All patient included received 2 cycles of chemotherapy (PE or PCDE)
Reporting group title	Chemotherapy alone
Reporting group description	-
Reporting group title	Chemotherapy + bevacizumab
Reporting group description	-

End points Top of page

Primary: Objective reponse rate Top of page
End point title	Objective reponse rate
End point description
End point type	Primary
End point timeframe	4 cycles after andomization
End point values Chemotherapy alone Chemotherapy + bevacizumab Number of subjects analysed 37 37 Units: Number of patient     Complete response 0 0     Partial response 34 34     Stable disease 0 0     Progression 1 1     Not done 1 0     Non evaluable 1 2
Statistical analysis title	Objective reponse rate
Comparison groups	Chemotherapy alone v Chemotherapy + bevacizumab
Number of subjects included in analysis	74
Analysis specification	Pre-specified
Analysis type	superiority
P-value	= 1
Method	Fisher exact
Confidence interval

Primary: Objective reponse rate Top of page

Secondary: Objective Reponse rate Top of page
End point title	Objective Reponse rate
End point description
End point type	Secondary
End point timeframe	after 6 cycles
End point values Chemotherapy alone Chemotherapy + bevacizumab Number of subjects analysed 37 37 Units: Number of patient     Complete response 3 1     Partial Response 23 27     Stable disease 0 2     Progression disease 4 3     Evaluation not done 2 0     Non evaluable 5 4
No statistical analyses for this end point

Secondary: Objective Reponse rate Top of page

Secondary: Progression free survival Top of page
End point title	Progression free survival
End point description
End point type	Secondary
End point timeframe	Time between randomization and progression or death of any cause
End point values Chemotherapy alone Chemotherapy + bevacizumab Number of subjects analysed 37 37 Units: Months     median (confidence interval 95%) 5.5 (4.9 to 6) 5.3 (5 to 6.3)
No statistical analyses for this end point

Secondary: Progression free survival Top of page

Secondary: Overall survivall Top of page
End point title	Overall survivall
End point description
End point type	Secondary
End point timeframe	Time between randomization and death any cause.
End point values Chemotherapy alone Chemotherapy + bevacizumab Number of subjects analysed 37 37 Units: Months     median (confidence interval 95%) 13 (9.7 to 19.8) 11.1 (8.6 to 13.9)
No statistical analyses for this end point

Secondary: Overall survivall Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Between inclusion and 30 days after the last injection of study drugs
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	18
Reporting groups
Reporting group title	Chemotherapy
Reporting group description	All patient included received 2 cycles of chemotherapy (PE or PCDE)
Reporting group title	Chemotherapy alone
Reporting group description	Patients randomized in the arm chemotherapy alone
Reporting group title	Chemotherapy + bevacizumab
Reporting group description	Patients randomized in the arm chemotherapy + bevacizumab
Serious adverse events Chemotherapy Chemotherapy alone Chemotherapy + bevacizumab Total subjects affected by serious adverse events      subjects affected / exposed 49 / 147 (33.33%) 6 / 37 (16.22%) 13 / 37 (35.14%)      number of deaths (all causes) 140 37 36      number of deaths resulting from adverse events 4 0 1 Vascular disorders Pulmonary embolism      subjects affected / exposed 3 / 147 (2.04%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 3 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Thrombosis      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 3 / 37 (8.11%)      occurrences causally related to treatment / all 0 / 1 0 / 0 2 / 3      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Phlebitis superficial      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Cardiac disorders Acute pulmonary oedema      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Cardiac arrest      subjects affected / exposed 2 / 147 (1.36%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 2 0 / 0 0 / 0 Cardiac disorder      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 0 Hypertension      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Nervous system disorders Convulsion      subjects affected / exposed 0 / 147 (0.00%) 1 / 37 (2.70%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 1 0 / 0 Intracranial hemorrhage      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Loss of consciousness      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Personality change      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 1 Seizure      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Subdural haematoma      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 1 / 1 Aphasia      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Coma      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 1 / 1 Consciousness disturb      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Encephalopathy      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Intracranial hypertension      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 1 General disorders and administration site conditions Asthenia      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 2 / 37 (5.41%)      occurrences causally related to treatment / all 0 / 0 0 / 0 2 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Back pain      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Fever      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Hepatic pain      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Rectal haemorrhage      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Reduced General Condition      subjects affected / exposed 3 / 147 (2.04%) 0 / 37 (0.00%) 2 / 37 (5.41%)      occurrences causally related to treatment / all 1 / 3 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 1 Sleep disorder      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Headache      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Blood and lymphatic system disorders Febrile aplasia      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Hemoglobin decreased      subjects affected / exposed 2 / 147 (1.36%) 1 / 37 (2.70%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 2 / 2 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Neutrophil count decreased      subjects affected / exposed 3 / 147 (2.04%) 3 / 37 (8.11%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 3 / 3 3 / 3 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Platelet count decreased      subjects affected / exposed 2 / 147 (1.36%) 2 / 37 (5.41%) 2 / 37 (5.41%)      occurrences causally related to treatment / all 2 / 2 2 / 2 2 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Gastrointestinal disorders Colitis      subjects affected / exposed 0 / 147 (0.00%) 1 / 37 (2.70%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Constipation      subjects affected / exposed 2 / 147 (1.36%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 1 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Diarrhoea      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Intestinal obstruction      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Nausea      subjects affected / exposed 3 / 147 (2.04%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 3 / 3 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Vomiting      subjects affected / exposed 6 / 147 (4.08%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 6 / 6 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Dehydration      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Anorexia      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders Hemoptysis      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Pneumopathy      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Respiratory failure      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Acute respiratory failure      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 1 / 1 0 / 0 0 / 0 Progression of bronchial progression      subjects affected / exposed 3 / 147 (2.04%) 0 / 37 (0.00%) 2 / 37 (5.41%)      occurrences causally related to treatment / all 0 / 3 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 2 Hepatobiliary disorders Hepatic cytolysis      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 1 / 1 0 / 0 0 / 0 Renal and urinary disorders Acute Renal failure      subjects affected / exposed 3 / 147 (2.04%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 3 / 3 0 / 0 0 / 0      deaths causally related to treatment / all 1 / 1 0 / 0 0 / 0 Renal failure      subjects affected / exposed 1 / 147 (0.68%) 1 / 37 (2.70%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 1 / 1 1 / 1 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Infections and infestations Abcess      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Febrile neutropenia      subjects affected / exposed 4 / 147 (2.72%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 4 / 4 0 / 0 0 / 0      deaths causally related to treatment / all 1 / 1 0 / 0 0 / 0 Lung abscess      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Sepsis      subjects affected / exposed 5 / 147 (3.40%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 4 / 5 0 / 0 0 / 1      deaths causally related to treatment / all 1 / 1 0 / 0 0 / 0 Bronchitis      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Metabolism and nutrition disorders Hyponatremia      subjects affected / exposed 2 / 147 (1.36%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Chemotherapy Chemotherapy alone Chemotherapy + bevacizumab Total subjects affected by non serious adverse events      subjects affected / exposed 146 / 147 (99.32%) 37 / 37 (100.00%) 35 / 37 (94.59%) Vascular disorders Venous thromboembolism disorder      subjects affected / exposed 5 / 147 (3.40%) 6 / 37 (16.22%) 5 / 37 (13.51%)      occurrences all number 7 13 14 General disorders and administration site conditions Generals disorders      subjects affected / exposed 75 / 147 (51.02%) 30 / 37 (81.08%) 29 / 37 (78.38%)      occurrences all number 228 131 172 Haemorrhage      subjects affected / exposed 3 / 147 (2.04%) 2 / 37 (5.41%) 7 / 37 (18.92%)      occurrences all number 5 3 17 Pain      subjects affected / exposed 49 / 147 (33.33%) 14 / 37 (37.84%) 24 / 37 (64.86%)      occurrences all number 173 58 69 Respiratory, thoracic and mediastinal disorders Respiratory disorder      subjects affected / exposed 63 / 147 (42.86%) 14 / 37 (37.84%) 16 / 37 (43.24%)      occurrences all number 351 77 75 Cardiac disorders Cardiac Disorders      subjects affected / exposed 6 / 147 (4.08%) 3 / 37 (8.11%) 1 / 37 (2.70%)      occurrences all number 20 21 62 Hypertension      subjects affected / exposed 6 / 147 (4.08%) 2 / 37 (5.41%) 7 / 37 (18.92%)      occurrences all number 10 13 60 Nervous system disorders Neurological disorder      subjects affected / exposed 19 / 147 (12.93%) 9 / 37 (24.32%) 13 / 37 (35.14%)      occurrences all number 90 26 51 Peripheral neurological disorder      subjects affected / exposed 6 / 147 (4.08%) 12 / 37 (32.43%) 12 / 37 (32.43%)      occurrences all number 11 19 23 Blood and lymphatic system disorders Anemia      subjects affected / exposed 94 / 147 (63.95%) 32 / 37 (86.49%) 34 / 37 (91.89%)      occurrences all number 165 170 181 Neutrophil count decreased      subjects affected / exposed 78 / 147 (53.06%) 17 / 37 (45.95%) 22 / 37 (59.46%)      occurrences all number 141 74 99 Thrombocytopenia      subjects affected / exposed 69 / 147 (46.94%) 25 / 37 (67.57%) 28 / 37 (75.68%)      occurrences all number 114 103 130 Ear and labyrinth disorders Auditory disorder      subjects affected / exposed 5 / 147 (3.40%) 3 / 37 (8.11%) 5 / 37 (13.51%)      occurrences all number 13 13 20 Eye disorders Occular disorder      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 1 / 37 (2.70%)      occurrences all number 0 0 1 Gastrointestinal disorders Gastrointestinal disorders      subjects affected / exposed 88 / 147 (59.86%) 23 / 37 (62.16%) 29 / 37 (78.38%)      occurrences all number 305 152 180 Skin and subcutaneous tissue disorders Skin disorder      subjects affected / exposed 43 / 147 (29.25%) 15 / 37 (40.54%) 12 / 37 (32.43%)      occurrences all number 94 81 61 Renal and urinary disorders Proteinuria      subjects affected / exposed 0 / 147 (0.00%) 0 / 37 (0.00%) 3 / 37 (8.11%)      occurrences all number 0 0 4 Renal disorders      subjects affected / exposed 12 / 147 (8.16%) 8 / 37 (21.62%) 9 / 37 (24.32%)      occurrences all number 18 18 24 Cystitis and urinary retention      subjects affected / exposed 1 / 147 (0.68%) 0 / 37 (0.00%) 6 / 37 (16.22%)      occurrences all number 1 0 6 Musculoskeletal and connective tissue disorders Cramps      subjects affected / exposed 5 / 147 (3.40%) 0 / 37 (0.00%) 0 / 37 (0.00%)      occurrences all number 8 0 0 Infections and infestations Infection      subjects affected / exposed 14 / 147 (9.52%) 4 / 37 (10.81%) 11 / 37 (29.73%)      occurrences all number 41 13 44 Metabolism and nutrition disorders Metabolic disorder      subjects affected / exposed 27 / 147 (18.37%) 12 / 37 (32.43%) 13 / 37 (35.14%)      occurrences all number 148 100 125

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Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
19 May 2009	- New investigators - Modification of exclusion criteria: patient with cerebral metastasis are eligible if the metastasis are asymptomatic
26 Oct 2009	- Modification of the sponsor adress - 4 new investigators - The exclusion criteria regarding the tumor invading large vessels or invading the proximal tracheobronchial tree is transfered in randomisation criteria
19 Oct 2011	- New investigators - Principal investigators modification for 3 sites - Insurance modification - IDMC only for the phase III part of the trial
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
Occurence of adverse events not precisely recorded in the CRF.
Online references
http://www.ncbi.nlm.nih.gov/pubmed/25688059

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