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Clinical Trial Results:
Open-label, randomized, controlled, multicenter Phase II study investigating 2 cilengitide regimens in combination with cetuximab and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/gemcitabine) compared to cetuximab and platinum-based chemotherapy alone as first-line treatment for patients with advanced Non Small Cell Lung Cancer (NSCLC).

Summary
EudraCT number	2008-004148-35
Trial protocol	IE BE DE ES FR IT CZ
Global end of trial date	29 Jul 2013

Results information
Results version number	v1(current)
This version publication date	23 May 2016
First version publication date	29 Jul 2015
Other versions

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

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Trial information

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Sponsor protocol code

EMR200037-014

ISRCTN number

US NCT number

NCT00842712

WHO universal trial number (UTN)

Sponsor organisation name

Merck KGaA

Sponsor organisation address

Frankfurter Str. 250, Darmstadt, Germany, 64293

Public contact

Communication Centre, Merck KGaA, 49 6151-72-5200, service@merckgroup.com

Scientific contact

Communication Centre, Merck KGaA, 49 6151-72-5200, service@merckgroup.com

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

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?

Analysis stage

Final

Date of interim/final analysis

29 Jul 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Jul 2013

Was the trial ended prematurely?

Main objective of the trial

To assess the efficacy of cilengitide in combination with cetuximab and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/gemcitabine) compared to cetuximab and platinum-based chemotherapy alone in terms of progression free survival (PFS) time (based on independent assessment, IRC) in the total population (regardless of endothelial growth factor receptor [EGFR] expression) and in the subgroup of subjects with high EGFR expression.

Protection of trial subjects

In this trial highest medical and ethical standards were followed, in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Feb 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 35

Country: Number of subjects enrolled

France: 61

Country: Number of subjects enrolled

Germany: 60

Country: Number of subjects enrolled

Ireland: 4

Country: Number of subjects enrolled

Italy: 23

Country: Number of subjects enrolled

Spain: 12

Country: Number of subjects enrolled

Poland: 37

Worldwide total number of subjects

232

EEA total number of subjects

232

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)

182

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

First/last subject (informed consent): Feb 2009/Jun 2012. Clinical data cut-off: 26 Jun 2013, Study completion date: July 2013.

Screening details

In safety run-in part of study, a total of 12 subjects were enrolled and treated. In randomized part of study, 220 subjects were enrolled and out of these 220 subjects, 215 were treated.

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

Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy

Arm description

Cilengitide (Cil) was administered at a dose of 2000 mg as intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] 25 mg/m^2 or Cisplatin at a dose of 75 mg/m^2 was administered as intravenous infusion on Day 1 + Gemcitabine (Gem) was administed at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Arm type

Experimental

Investigational medicinal product name

Cilengitide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cetuximab was administered at a dose of 400 milligram per square meter (mg/m^2) as intravenous infusion over 2 hours on Day 1.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1.

Investigational medicinal product name

Vinorelbine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Vinorelbine was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8.

Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy

Arm description

Cilengitide (cil) was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1, 4, 8, 11, 15, and 18 of each 3-week cycle followed by once weekly administration after end of chemotherapy + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab at a dose of 250 mg/m^2 as intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] at a dose of 25 mg/m^2 or Cisplatin [Cis] at a dose of 75 mg/m^2 as intravenous infusion on Day 1 + Gemcitabine at a dos 1250 mg/m^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Arm type

Experimental

Investigational medicinal product name

Cilengitide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cilengitide was administered at a dose of 2000 mg as intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle until progressive disease, death, unacceptable toxicity, or consent withdrawal.

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal.

Investigational medicinal product name

Chemotherapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin was administered at a dose of 80 mg/m^2 intravenous infusion on Day 1 + Vinorelbine was administered at a dose of 25 mg/m^2 or Cisplatin at a dose of 75 mg/m^2 was administered as intravenous infusion on Day 1 + Gemcitabine was administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 of each 3-week cycle along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Randomized Part: Cetuximab + Chemotherapy

Arm description

Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab at a dose of 250 mg/m^2 was administered as intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [Cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] was administered at a dose of 25 mg/m^2 or Cisplatin at a dose of 75 mg/m^2 was administered as intravenous infusion on Day 1 + Gemcitabine [Gem] at a dose of 1250 mg/m^2 was administered as intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Arm type

Active comparator

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Chemotherapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine was administered at a dose of 25 mg/m^2 or Cisplatin was administered at a dose of 75 mg/m^2 as intravenous infusion on Day 1 + Gemcitabine was administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 of each 3-week cycle along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem

Arm description

Cilengitide (Cil) was administered at a dose of 1000 milligram (mg) as intravenous infusion twice weekly over 1 hour on Days 1 and 4 along with Cetuximab at a dose of 400 milligram per square meter (mg/m^2) as intravenous infusion over 2 hours on Day 1 plus Cisplatin (Cis) 75 mg/m^2 intravenous infusion on Day 1 and Gemcitabine (Gem) at a dose of 1250 mg/m^2 was administered as intravenous infusion on Days 1 and 8 for a period of 3 weeks.

Arm type

Experimental

Investigational medicinal product name

Cilengitide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cetuximab was administered at a dose of 400 milligram per square meter (mg/m^2) as intravenous infusion over 2 hours on Day 1.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin (Cis) was administered at a dose of 75 mg/m^2 as intravenous infusion on Day 1.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine (Gem) was administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin

Arm description

Cilengitide was administered at a dose of 1000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin [Cis] was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine (Vin) was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

Arm type

Experimental

Investigational medicinal product name

Cilengitide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin was administered ata dose of 75 mg/m^2 as intravenous infusion on Day 1.

Investigational medicinal product name

Vinorelbine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Vinorelbine was administered at a dose of 25 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks.

Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem

Arm description

Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) was administered at a dose of 75 mg/m^2 as intravenous infusion on Day 1 + Gemcitabine (Gem) was administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

Arm type

Experimental

Investigational medicinal product name

Cilengitide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin was administered at dose of 75 mg/m^2 as intravenous infusion on Day 1.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Gem was administered at a dose of 1250 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks.

Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin

Arm description

Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine (Vin) was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

Arm type

Experimental

Investigational medicinal product name

Cilengitide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cetuximab was administered at a dose of 400 mg/m^2 intravenous infusion over 2 hours on Day 1.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1.

Investigational medicinal product name

Vinorelbine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Vinorelbine was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

Number of subjects in period 1	Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cetuximab + Chemotherapy	Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem	Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin	Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem	Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin
Started	85	51	84	3	3	3	3
Completed	85	50	78	3	1	3	2
Not completed	0	1	6	0	2	0	1
Randomized but not treated	-	1	4	-	-	-	-
Adverse event, non-fatal	-	-	-	-	1	-	-
Progressive disease	-	-	-	-	1	-	1
Ongoing at cut-off date	-	-	2	-	-	-	-

Baseline characteristics

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Reporting group title

Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy

Reporting group description

Reporting group title

Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy

Reporting group description

Reporting group title

Randomized Part: Cetuximab + Chemotherapy

Reporting group description

Reporting group title

Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem

Reporting group description

Reporting group title

Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin

Reporting group description

Reporting group title

Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem

Reporting group description

Reporting group title

Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin

Reporting group description

Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine (Vin) was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

Reporting group values	Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cetuximab + Chemotherapy	Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem	Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin	Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem	Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin	Total
Number of subjects	85	51	84	3	3	3	3	232
Age categorical
Units: Subjects
Less than 65 years	68	37	66	3	2	3	3	182
Greater than or equal to 65 years	17	14	18	0	1	0	0	50
Gender categorical
Units: Subjects
Female	34	19	27	1	0	2	2	85
Male	51	32	57	2	3	1	1	147

End points

Top of page

Reporting group title

Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy

Reporting group description

Reporting group title

Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy

Reporting group description

Reporting group title

Randomized Part: Cetuximab + Chemotherapy

Reporting group description

Reporting group title

Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem

Reporting group description

Reporting group title

Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin

Reporting group description

Reporting group title

Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem

Reporting group description

Reporting group title

Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin

Reporting group description

Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine (Vin) was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

Primary: Safety run-in Part: Number of subjects with dose limiting toxicities (DLTs)

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End point title

Safety run-in Part: Number of subjects with dose limiting toxicities (DLTs) ^[1] ^[2]

End point description

The DLT population included all subjects who completed first 3 weeks of treatment (first chemotherapy cycle) or who discontinued treatment due to any DLT during the first 3 weeks of treatment in the safetyrun-in part.

End point type

Primary

End point timeframe

Up to Week 3

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: The statistical analyses was not planned for this outcome measure.
[2] - 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 statistics was reported only for the groups in the safety run-in part of the study as per planned analysis

End point values	Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem	Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin	Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem	Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin
Number of subjects analysed	3	3	3	3
Units: Subjects
Independent Read	0	0	0	0

No statistical analyses for this end point

Primary: Randomized part: Progression free survival (PFS) time - Independent read

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End point title

Randomized part: Progression free survival (PFS) time - Independent read ^[3]

End point description

The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. Independent Read is the assessment of all imaging centrally by an Independent Review Committee (IRC). Intent-to-treat (ITT) population included all participants who were randomized to trial treatment.

End point type

Primary

End point timeframe

Time from randomization until disease progression, death or last tumor assessment, reported between day of first subject randomized, that is, Feb 2009 until cut-off date, (26 Jun 2013).

Notes
[3] - 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 statistics was reported only for the groups in the randomized part of the study as per planned analysis

End point values	Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cetuximab + Chemotherapy
Number of subjects analysed	85	51	84
Units: Months
median (confidence interval 95%)	6.2 (5.6 to 7.4)	5.6 (4 to 7.5)	5 (4.2 to 5.6)

Statistical Analysis 1

Comparison groups

Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy v Randomized Part: Cetuximab + Chemotherapy

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0845

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.718

Confidence interval

level

95%

sides

2-sided

lower limit

0.492

upper limit

1.048

Secondary: Randomized Part: Progression Free Survival (PFS) Time - Investigator Read

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End point title

Randomized Part: Progression Free Survival (PFS) Time - Investigator Read ^[4]

End point description

The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. Investigator read is the assessment of all imaging by the treating physician at the local trial site. ITT population included all participants who were randomized to trial treatment.

End point type

Secondary

End point timeframe

Time from randomization until disease progression, death or last tumor assessment, reported between day of first subject randomized, that is, Feb 2009 until cut-off date, (26 Jun 2013).

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 statistics was reported only for the groups in the randomized part of the study as per planned analysis

End point values	Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cetuximab + Chemotherapy
Number of subjects analysed	85	51	84
Units: Months
median (confidence interval 95%)	5.6 (5.4 to 6.7)	5.6 (4.2 to 7)	5.3 (4.2 to 5.7)

Statistical Analysis 1

Comparison groups

Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy v Randomized Part: Cetuximab + Chemotherapy

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5912

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.909

Confidence interval

level

95%

sides

2-sided

lower limit

0.642

upper limit

1.286

Secondary: Randomized Part: Overall Survival (OS) Time

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End point title

Randomized Part: Overall Survival (OS) Time ^[5]

End point description

The OS time is defined as the time (in months) from randomization to death or last day known to be alive. Subjects without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier. ITT population included all participants who were randomized to trial treatment.

End point type

Secondary

End point timeframe

Time from randomization until death or last day known to be alive, reported between day of first subject randomized, that is, Feb 2009 until cut-off date,(26 Jun 2013).

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 statistics was reported only for the groups in the randomized part of the study as per planned analysis

End point values	Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cetuximab + Chemotherapy
Number of subjects analysed	85	51	84
Units: months
median (confidence interval 95%)	13.6 (9.5 to 18.6)	13.6 (8.7 to 16.7)	9.7 (7.9 to 13.4)

Statistical Analysis 1

Comparison groups

Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy v Randomized Part: Cetuximab + Chemotherapy

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2648

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.813

Confidence interval

level

95%

sides

2-sided

lower limit

0.564

upper limit

1.171

Secondary: Randomized Part: Best Overall Response (BOR) Rate

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End point title

Randomized Part: Best Overall Response (BOR) Rate ^[6]

End point description

The BOR rate is defined as the percentage of subjects having achieved confirmed complete response (CR) or partial response (PR) as the best overall response, based on radiological assessments (based on response evaluation criteria in solid tumors [RECIST]) as assessed by Independent Review Committee (IRC): CR = disappearance of all target lesions; PR = at least 30% decrease in the sum of the longest diameter of target lesions. ITT population included all participants who were randomized to trial treatment.

End point type

Secondary

End point timeframe

Time from randomization until treatment failure or last tumor assessment, reported between day of first subject randomized, that was, Feb 2009 until cut-off date,(26 Jun 2013)

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 statistics was reported only for the groups in the randomized part of the study as per planned analysis

End point values	Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cetuximab + Chemotherapy
Number of subjects analysed	85	51	84
Units: percentage
number (confidence interval 95%)	37.6 (27.4 to 48.8)	27.5 (15.9 to 41.7)	29.8 (20.3 to 40.7)

No statistical analyses for this end point

Secondary: Randomized Part: Time to Treatment Failure

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End point title

Randomized Part: Time to Treatment Failure ^[7]

End point description

Time to treatment failure was defined as the time from first administration of trial treatment until the date of the first occurrence of one of the events defining treatment failure: Progressive Disease (PD) assessed by the investigator, discontinuation of treatment due to PD, discontinuation of treatment due to an adverse event (AE), start of any new anticancer therapy, or withdrawal of consent or death within 60 days of the last tumor assessment or first administration of trial treatment. Time to treatment failure was assessed according to modified World Health Organization (WHO) criteria by Independent Review Committee (IRC). ITT population included all participants who were randomized to trial treatment.

End point type

Secondary

End point timeframe

Time from randomization until treatment failure or last tumor assessment, reported between day of first subject randomized, that is, Feb 2009 until cut-off date,(26 Jun 2013).

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 statistics was reported only for the groups in the randomized part of the study as per planned analysis

End point values	Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cetuximab + Chemotherapy
Number of subjects analysed	85	51	84
Units: months
median (confidence interval 95%)	4.4 (3.5 to 5.6)	2.8 (1.4 to 4.2)	4.2 (2.8 to 5.3)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Time from first dose up to 28 days after last dose of study treatment, reported between day of first subject randomized, that was, Feb 2009 until cut-off date (26 Jun 2013)

Adverse event reporting additional description

The analysis was performed on safety population, defined as all subjects who received any dose of the trial treatment (cilengitide, cetuximab, or chemotherapy), whereby subjects were analyzed according to the actual treatment they received.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Cil (Once Weekly) + Cetuximab + Chemotherapy

Reporting group description

Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 or Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Reporting group title

Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy

Reporting group description

Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1, 4, 8, 11, 15, and 18 of each 3-week cycle followed by once weekly administration after end of chemotherapy + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 or Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Reporting group title

Cetuximab + Chemotherapy

Reporting group description

Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 or Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Serious adverse events	Cil (Once Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy	Cetuximab + Chemotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	42 / 85 (49.41%)	29 / 50 (58.00%)	45 / 80 (56.25%)
number of deaths (all causes)	56	39	58
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MALIGNANT PLEURAL EFFUSION
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
METASTASES TO MENINGES
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
TUMOUR EMBOLISM
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
Vascular disorders
AORTIC THROMBOSIS
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARTERIAL DISORDER
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARTERIAL THROMBOSIS LIMB
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
AXILLARY VEIN THROMBOSIS
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEEP VEIN THROMBOSIS
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOVOLAEMIC SHOCK
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (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
JUGULAR VEIN THROMBOSIS
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIPHERAL EMBOLISM
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
SHOCK
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
SUBCLAVIAN VEIN THROMBOSIS
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUPERIOR VENA CAVA SYNDROME
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THROMBOSIS
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VENA CAVA THROMBOSIS
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHEST PAIN
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DISEASE PROGRESSION
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
FATIGUE
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	4 / 85 (4.71%)	1 / 50 (2.00%)	3 / 80 (3.75%)
occurrences causally related to treatment / all	1 / 4	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
IMPAIRED HEALING
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MALAISE
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MEDICAL DEVICE COMPLICATION
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
PYREXIA
subjects affected / exposed	1 / 85 (1.18%)	1 / 50 (2.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
ANAPHYLACTIC REACTION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DRUG HYPERSENSITIVITY
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
ACUTE RESPIRATORY DISTRESS SYNDROME
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
DYSPNOEA
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSPNOEA EXERTIONAL
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPISTAXIS
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMOPTYSIS
subjects affected / exposed	1 / 85 (1.18%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	1 / 85 (1.18%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMOTHORAX
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	4 / 85 (4.71%)	5 / 50 (10.00%)	8 / 80 (10.00%)
occurrences causally related to treatment / all	3 / 4	1 / 5	1 / 8
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 1
PULMONARY THROMBOSIS
subjects affected / exposed	1 / 85 (1.18%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY DISTRESS
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed	0 / 85 (0.00%)	2 / 50 (4.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
ANXIETY
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CONFUSIONAL STATE
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
HAEMOGLOBIN DECREASED
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PLATELET COUNT DECREASED
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
Injury, poisoning and procedural complications
FAILURE TO ANASTOMOSE
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HIP FRACTURE
subjects affected / exposed	2 / 85 (2.35%)	0 / 50 (0.00%)	0 / 80 (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
INCISIONAL HERNIA
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LIMB INJURY
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPINAL COMPRESSION FRACTURE
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
SPLENIC RUPTURE
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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 disorders
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARRHYTHMIA SUPRAVENTRICULAR
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
ATRIAL FIBRILLATION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERICARDIAL EFFUSION
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STRESS CARDIOMYOPATHY
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
CENTRAL NERVOUS SYSTEM LESION
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	0 / 85 (0.00%)	2 / 50 (4.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COMA
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
CONVULSION
subjects affected / exposed	2 / 85 (2.35%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SOMNOLENCE
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
STATUS EPILEPTICUS
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
SYNCOPE
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	1 / 85 (1.18%)	1 / 50 (2.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE BONE MARROW APLASIA
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	3 / 85 (3.53%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	3 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	4 / 85 (4.71%)	1 / 50 (2.00%)	3 / 80 (3.75%)
occurrences causally related to treatment / all	3 / 4	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
THROMBOCYTOPENIA
subjects affected / exposed	1 / 85 (1.18%)	1 / 50 (2.00%)	4 / 80 (5.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
HYPOACUSIS
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
PERIORBITAL OEDEMA
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	1 / 85 (1.18%)	1 / 50 (2.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	1 / 85 (1.18%)	1 / 50 (2.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIVERTICULAR PERFORATION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DUODENAL ULCER HAEMORRHAGE
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
LARGE INTESTINE PERFORATION
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
NAUSEA
subjects affected / exposed	1 / 85 (1.18%)	2 / 50 (4.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	1 / 1	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PROCTITIS
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed	2 / 85 (2.35%)	1 / 50 (2.00%)	4 / 80 (5.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
CHOLECYSTITIS
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
RENAL FAILURE
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (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
RENAL FAILURE ACUTE
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
BACK PAIN
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
BRONCHITIS
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHOPNEUMONIA
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHOPULMONARY ASPERGILLOSIS
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CYSTITIS
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEVICE RELATED INFECTION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL INFECTION
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG INFECTION
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
NAIL BED INFECTION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	1 / 85 (1.18%)	1 / 50 (2.00%)	4 / 80 (5.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	2 / 2
PNEUMONIA BACTERIAL
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
PROTEUS INFECTION
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
SEPSIS
subjects affected / exposed	0 / 85 (0.00%)	2 / 50 (4.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	1 / 85 (1.18%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL SKIN INFECTION
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
URINARY TRACT INFECTION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
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
DECREASED APPETITE
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (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
DEHYDRATION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERCALCAEMIA
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOKALAEMIA
subjects affected / exposed	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 80 (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
HYPOMAGNESAEMIA
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 80 (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

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

Non-serious adverse events	Cil (Once Weekly) + Cetuximab + Chemotherapy	Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy	Cetuximab + Chemotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	84 / 85 (98.82%)	48 / 50 (96.00%)	78 / 80 (97.50%)
Vascular disorders
DEEP VEIN THROMBOSIS
subjects affected / exposed	5 / 85 (5.88%)	1 / 50 (2.00%)	0 / 80 (0.00%)
occurrences all number	5	1	0
HYPERTENSION
subjects affected / exposed	9 / 85 (10.59%)	6 / 50 (12.00%)	5 / 80 (6.25%)
occurrences all number	9	6	5
HYPOTENSION
subjects affected / exposed	1 / 85 (1.18%)	4 / 50 (8.00%)	4 / 80 (5.00%)
occurrences all number	1	4	4
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	20 / 85 (23.53%)	15 / 50 (30.00%)	23 / 80 (28.75%)
occurrences all number	20	15	23
CHEST PAIN
subjects affected / exposed	5 / 85 (5.88%)	5 / 50 (10.00%)	2 / 80 (2.50%)
occurrences all number	5	5	2
CHILLS
subjects affected / exposed	2 / 85 (2.35%)	3 / 50 (6.00%)	2 / 80 (2.50%)
occurrences all number	2	3	2
FATIGUE
subjects affected / exposed	29 / 85 (34.12%)	13 / 50 (26.00%)	19 / 80 (23.75%)
occurrences all number	29	13	19
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	2 / 85 (2.35%)	0 / 50 (0.00%)	4 / 80 (5.00%)
occurrences all number	2	0	4
NON-CARDIAC CHEST PAIN
subjects affected / exposed	5 / 85 (5.88%)	2 / 50 (4.00%)	2 / 80 (2.50%)
occurrences all number	5	2	2
OEDEMA PERIPHERAL
subjects affected / exposed	5 / 85 (5.88%)	5 / 50 (10.00%)	5 / 80 (6.25%)
occurrences all number	5	5	5
PYREXIA
subjects affected / exposed	8 / 85 (9.41%)	14 / 50 (28.00%)	15 / 80 (18.75%)
occurrences all number	8	14	15
XEROSIS
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	4 / 80 (5.00%)
occurrences all number	0	1	4
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	13 / 85 (15.29%)	11 / 50 (22.00%)	12 / 80 (15.00%)
occurrences all number	13	11	12
DYSPHONIA
subjects affected / exposed	2 / 85 (2.35%)	2 / 50 (4.00%)	5 / 80 (6.25%)
occurrences all number	2	2	5
DYSPNOEA
subjects affected / exposed	11 / 85 (12.94%)	6 / 50 (12.00%)	5 / 80 (6.25%)
occurrences all number	11	6	5
DYSPNOEA EXERTIONAL
subjects affected / exposed	9 / 85 (10.59%)	10 / 50 (20.00%)	7 / 80 (8.75%)
occurrences all number	9	10	7
EPISTAXIS
subjects affected / exposed	10 / 85 (11.76%)	10 / 50 (20.00%)	13 / 80 (16.25%)
occurrences all number	10	10	13
HAEMOPTYSIS
subjects affected / exposed	3 / 85 (3.53%)	4 / 50 (8.00%)	7 / 80 (8.75%)
occurrences all number	3	4	7
PRODUCTIVE COUGH
subjects affected / exposed	0 / 85 (0.00%)	1 / 50 (2.00%)	5 / 80 (6.25%)
occurrences all number	0	1	5
Psychiatric disorders
ANXIETY
subjects affected / exposed	4 / 85 (4.71%)	4 / 50 (8.00%)	9 / 80 (11.25%)
occurrences all number	4	4	9
DEPRESSION
subjects affected / exposed	3 / 85 (3.53%)	2 / 50 (4.00%)	4 / 80 (5.00%)
occurrences all number	3	2	4
INSOMNIA
subjects affected / exposed	4 / 85 (4.71%)	3 / 50 (6.00%)	9 / 80 (11.25%)
occurrences all number	4	3	9
HAEMATURIA
subjects affected / exposed	0 / 85 (0.00%)	3 / 50 (6.00%)	1 / 80 (1.25%)
occurrences all number	0	3	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	6 / 85 (7.06%)	1 / 50 (2.00%)	1 / 80 (1.25%)
occurrences all number	6	1	1
BLOOD CREATININE INCREASED
subjects affected / exposed	3 / 85 (3.53%)	5 / 50 (10.00%)	5 / 80 (6.25%)
occurrences all number	3	5	5
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	5 / 85 (5.88%)	0 / 50 (0.00%)	4 / 80 (5.00%)
occurrences all number	5	0	4
HAEMOGLOBIN DECREASED
subjects affected / exposed	8 / 85 (9.41%)	7 / 50 (14.00%)	8 / 80 (10.00%)
occurrences all number	8	7	8
PLATELET COUNT DECREASED
subjects affected / exposed	5 / 85 (5.88%)	1 / 50 (2.00%)	3 / 80 (3.75%)
occurrences all number	5	1	3
WEIGHT DECREASED
subjects affected / exposed	9 / 85 (10.59%)	3 / 50 (6.00%)	15 / 80 (18.75%)
occurrences all number	9	3	15
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	6 / 85 (7.06%)	1 / 50 (2.00%)	3 / 80 (3.75%)
occurrences all number	6	1	3
Cardiac disorders
TACHYCARDIA
subjects affected / exposed	1 / 85 (1.18%)	3 / 50 (6.00%)	1 / 80 (1.25%)
occurrences all number	1	3	1
Nervous system disorders
DIZZINESS
subjects affected / exposed	8 / 85 (9.41%)	4 / 50 (8.00%)	2 / 80 (2.50%)
occurrences all number	8	4	2
DYSGEUSIA
subjects affected / exposed	7 / 85 (8.24%)	4 / 50 (8.00%)	5 / 80 (6.25%)
occurrences all number	7	4	5
HEADACHE
subjects affected / exposed	9 / 85 (10.59%)	6 / 50 (12.00%)	6 / 80 (7.50%)
occurrences all number	9	6	6
NEUROPATHY PERIPHERAL
subjects affected / exposed	1 / 85 (1.18%)	3 / 50 (6.00%)	1 / 80 (1.25%)
occurrences all number	1	3	1
PARAESTHESIA
subjects affected / exposed	3 / 85 (3.53%)	1 / 50 (2.00%)	8 / 80 (10.00%)
occurrences all number	3	1	8
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	33 / 85 (38.82%)	22 / 50 (44.00%)	24 / 80 (30.00%)
occurrences all number	33	22	24
LEUKOPENIA
subjects affected / exposed	20 / 85 (23.53%)	7 / 50 (14.00%)	10 / 80 (12.50%)
occurrences all number	20	7	10
LYMPHOPENIA
subjects affected / exposed	4 / 85 (4.71%)	3 / 50 (6.00%)	4 / 80 (5.00%)
occurrences all number	4	3	4
NEUTROPENIA
subjects affected / exposed	43 / 85 (50.59%)	22 / 50 (44.00%)	35 / 80 (43.75%)
occurrences all number	46	22	35
THROMBOCYTOPENIA
subjects affected / exposed	29 / 85 (34.12%)	17 / 50 (34.00%)	24 / 80 (30.00%)
occurrences all number	29	17	24
THROMBOCYTOSIS
subjects affected / exposed	3 / 85 (3.53%)	4 / 50 (8.00%)	1 / 80 (1.25%)
occurrences all number	3	4	1
Ear and labyrinth disorders
TINNITUS
subjects affected / exposed	1 / 85 (1.18%)	3 / 50 (6.00%)	6 / 80 (7.50%)
occurrences all number	1	3	6
Eye disorders
CONJUNCTIVITIS
subjects affected / exposed	10 / 85 (11.76%)	7 / 50 (14.00%)	5 / 80 (6.25%)
occurrences all number	10	7	5
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	7 / 85 (8.24%)	2 / 50 (4.00%)	6 / 80 (7.50%)
occurrences all number	7	2	6
ABDOMINAL PAIN UPPER
subjects affected / exposed	7 / 85 (8.24%)	5 / 50 (10.00%)	6 / 80 (7.50%)
occurrences all number	7	5	6
CONSTIPATION
subjects affected / exposed	17 / 85 (20.00%)	14 / 50 (28.00%)	19 / 80 (23.75%)
occurrences all number	17	14	19
DIARRHOEA
subjects affected / exposed	22 / 85 (25.88%)	14 / 50 (28.00%)	22 / 80 (27.50%)
occurrences all number	22	14	19
DYSPEPSIA
subjects affected / exposed	4 / 85 (4.71%)	5 / 50 (10.00%)	2 / 80 (2.50%)
occurrences all number	4	5	2
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	0 / 85 (0.00%)	3 / 50 (6.00%)	1 / 80 (1.25%)
occurrences all number	0	3	1
HAEMORRHOIDS
subjects affected / exposed	2 / 85 (2.35%)	4 / 50 (8.00%)	1 / 80 (1.25%)
occurrences all number	2	4	1
NAUSEA
subjects affected / exposed	50 / 85 (58.82%)	27 / 50 (54.00%)	42 / 80 (52.50%)
occurrences all number	50	27	42
STOMATITIS
subjects affected / exposed	15 / 85 (17.65%)	10 / 50 (20.00%)	11 / 80 (13.75%)
occurrences all number	15	10	11
VOMITING
subjects affected / exposed	18 / 85 (21.18%)	14 / 50 (28.00%)	23 / 80 (28.75%)
occurrences all number	18	14	23
Skin and subcutaneous tissue disorders
ACNE
subjects affected / exposed	19 / 85 (22.35%)	11 / 50 (22.00%)	17 / 80 (21.25%)
occurrences all number	19	11	17
ALOPECIA
subjects affected / exposed	13 / 85 (15.29%)	7 / 50 (14.00%)	9 / 80 (11.25%)
occurrences all number	13	7	9
DERMATITIS ACNEIFORM
subjects affected / exposed	17 / 85 (20.00%)	7 / 50 (14.00%)	16 / 80 (20.00%)
occurrences all number	17	7	16
DRY SKIN
subjects affected / exposed	13 / 85 (15.29%)	5 / 50 (10.00%)	9 / 80 (11.25%)
occurrences all number	13	5	9
ERYTHEMA
subjects affected / exposed	1 / 85 (1.18%)	5 / 50 (10.00%)	4 / 80 (5.00%)
occurrences all number	1	5	4
NAIL TOXICITY
subjects affected / exposed	4 / 85 (4.71%)	3 / 50 (6.00%)	1 / 80 (1.25%)
occurrences all number	4	3	1
PRURITUS
subjects affected / exposed	7 / 85 (8.24%)	6 / 50 (12.00%)	3 / 80 (3.75%)
occurrences all number	7	6	3
RASH
subjects affected / exposed	35 / 85 (41.18%)	17 / 50 (34.00%)	29 / 80 (36.25%)
occurrences all number	35	17	29
SKIN FISSURES
subjects affected / exposed	6 / 85 (7.06%)	2 / 50 (4.00%)	6 / 80 (7.50%)
occurrences all number	6	2	6
SKIN TOXICITY
subjects affected / exposed	10 / 85 (11.76%)	8 / 50 (16.00%)	7 / 80 (8.75%)
occurrences all number	10	8	7
Renal and urinary disorders
DYSURIA
subjects affected / exposed	4 / 85 (4.71%)	4 / 50 (8.00%)	1 / 80 (1.25%)
occurrences all number	4	4	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	2 / 85 (2.35%)	1 / 50 (2.00%)	5 / 80 (6.25%)
occurrences all number	2	1	5
BACK PAIN
subjects affected / exposed	13 / 85 (15.29%)	8 / 50 (16.00%)	8 / 80 (10.00%)
occurrences all number	13	8	8
MUSCLE SPASMS
subjects affected / exposed	2 / 85 (2.35%)	4 / 50 (8.00%)	2 / 80 (2.50%)
occurrences all number	2	4	2
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	2 / 85 (2.35%)	1 / 50 (2.00%)	4 / 80 (5.00%)
occurrences all number	2	1	4
MUSCULOSKELETAL PAIN
subjects affected / exposed	4 / 85 (4.71%)	3 / 50 (6.00%)	4 / 80 (5.00%)
occurrences all number	4	3	4
PAIN IN EXTREMITY
subjects affected / exposed	10 / 85 (11.76%)	3 / 50 (6.00%)	6 / 80 (7.50%)
occurrences all number	10	3	6
Infections and infestations
BRONCHITIS
subjects affected / exposed	3 / 85 (3.53%)	3 / 50 (6.00%)	5 / 80 (6.25%)
occurrences all number	3	3	5
FOLLICULITIS
subjects affected / exposed	2 / 85 (2.35%)	5 / 50 (10.00%)	5 / 80 (6.25%)
occurrences all number	2	5	5
NASOPHARYNGITIS
subjects affected / exposed	5 / 85 (5.88%)	5 / 50 (10.00%)	7 / 80 (8.75%)
occurrences all number	5	5	7
PARONYCHIA
subjects affected / exposed	14 / 85 (16.47%)	1 / 50 (2.00%)	8 / 80 (10.00%)
occurrences all number	14	1	8
URINARY TRACT INFECTION
subjects affected / exposed	0 / 85 (0.00%)	0 / 50 (0.00%)	4 / 80 (5.00%)
occurrences all number	0	0	14
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	30 / 85 (35.29%)	13 / 50 (26.00%)	21 / 80 (26.25%)
occurrences all number	30	13	21
HYPERKALAEMIA
subjects affected / exposed	2 / 85 (2.35%)	3 / 50 (6.00%)	3 / 80 (3.75%)
occurrences all number	2	3	3
HYPOCALCAEMIA
subjects affected / exposed	6 / 85 (7.06%)	3 / 50 (6.00%)	6 / 80 (7.50%)
occurrences all number	6	3	6
HYPOKALAEMIA
subjects affected / exposed	11 / 85 (12.94%)	5 / 50 (10.00%)	7 / 80 (8.75%)
occurrences all number	11	5	7
HYPOMAGNESAEMIA
subjects affected / exposed	18 / 85 (21.18%)	10 / 50 (20.00%)	7 / 80 (8.75%)
occurrences all number	18	10	7
HYPONATRAEMIA
subjects affected / exposed	6 / 85 (7.06%)	1 / 50 (2.00%)	2 / 80 (2.50%)
occurrences all number	6	1	2

More information

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Were there any global substantial amendments to the protocol? Yes

30 Dec 2008

To be compliant with the suggestions of health authorities: Additional exclusion criteria due to contra-indications and precautions included in the approved summary of product characteristics of vinorelbine, gemcitabine, and cisplatin were included, the safety monitoring of hematological and biochemistry parameters during the safety run-in part of the protocol were intensified to rule out the synergistic toxicities. The sequence of administration of the platinum-based chemotherapy (cisplatin, vinorelbine, and gemcitabine) was corrected to comply with the summary of product characteristics information.

25 Nov 2009

As per this amendment, the final dose of cilengitide for the randomized part of the study will be increased to 2000 mg/m^2 after the safety run-in part has been completed. The dose of gemcitabine will be increased from 1000 mg/m^2 on day 1 and 8 to the standard label dose of 1250 mg/m^2 gemcitabine on day 1 and 8, additional cardiac safety monitoring would be implemented, changes in the exclusion criteria with respect to partial thromboplastin time, addition of exclusion criteria pertaining to concurrent chronic immunosuppressive or hormone anti-cancer therapy, decreasing timepoints for the collection of circulating endothelial cells or circulating tumor cells, to update safety information of cetuximab and cilengitide.

20 Dec 2010

The purpose of this amendment was to adjust the sample size and number of study centers, to stop randomizing subjects to Group B on cilengitide 2000 mg twice weekly in combination with cetuximab and platinum-based chemotherapy, a pre-screening visit was added for the assessment of EGFR expression by immunohistochemistry and selective recruitment of subjects with high epidermal growth factor receptor.

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

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Safety run-in Part: Number of subjects with dose limiting toxicities (DLTs)

Primary: Safety run-in Part: Number of subjects with dose limiting toxicities (DLTs)

Primary: Randomized part: Progression free survival (PFS) time - Independent read

Primary: Randomized part: Progression free survival (PFS) time - Independent read

Secondary: Randomized Part: Progression Free Survival (PFS) Time - Investigator Read

Secondary: Randomized Part: Progression Free Survival (PFS) Time - Investigator Read

Secondary: Randomized Part: Overall Survival (OS) Time

Secondary: Randomized Part: Overall Survival (OS) Time

Secondary: Randomized Part: Best Overall Response (BOR) Rate

Secondary: Randomized Part: Best Overall Response (BOR) Rate

Secondary: Randomized Part: Time to Treatment Failure

Secondary: Randomized Part: Time to Treatment Failure

Adverse events

Adverse events

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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
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Slovenia
Spain
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United Kingdom
Outside EU/EEA