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The European Union Clinical Trials Register allows you to search for protocol and results information on:

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Clinical Trial Results:
A phase II, multi-center, open-label study of AUY922 administered i.v. on a once weekly schedule in patients with advanced non-small-cell lung cancer (NSCLC) who have received at least two lines of prior chemotherapy.

Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.

Summary
EudraCT number	2010-020116-11
Trial protocol	NL ES FR DE
Global end of trial date	12 Aug 2014

Results information
Results version number	v1(current)
This version publication date	27 May 2016
First version publication date	27 May 2016
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

CAUY922A2206

ISRCTN number

-

US NCT number

NCT01124864

WHO universal trial number (UTN)

-

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, trialandresults.registries@novartis.com

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

Analysis stage

Final

Date of interim/final analysis

12 Aug 2014

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

12 Aug 2014

Was the trial ended prematurely?

No

Main objective of the trial

To estimate efficacy for each study strata at 18 weeks as assessed by Response Evaluation Criteria in Solid Tumors (RECIST).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

27 Oct 2010

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 3

Country: Number of subjects enrolled

France: 25

Country: Number of subjects enrolled

Netherlands: 12

Country: Number of subjects enrolled

Norway: 5

Country: Number of subjects enrolled

Singapore: 3

Country: Number of subjects enrolled

Spain: 41

Country: Number of subjects enrolled

United States: 32

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Korea, Republic of: 29

Worldwide total number of subjects

153

EEA total number of subjects

86

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)

108

From 65 to 84 years

45

85 years and over

0

Subject disposition

Top of page

Recruitment details

Two patients who were ongoing at the data cut-off of 30-Jul-2013 are considered as 'completed' in this study.

Screening details

All patients were to receive weekly i.v. administrations of AUY922 at a dose of 70 mg/m2. However, patients were also stratified to one of the following five groups based on the molecular etiology of their baseline tumors: EGFR mutant, KRAS mutant, EML4-ALK translocations, EGFR and KRAS wild type, and modified EGFR mutant.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Kras mutant patients

Arm description

Patients with KRAS mutant tumors. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Arm type

Experimental

Investigational medicinal product name

AUY922

Investigational medicinal product code

AUY922

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational treatment consisted of AUY922. This was supplied by Novartis in individual

EGFR mutant patients

Arm description

Patients with EGFR activating mutation tumors (Note: These patients must have progressed on one prior EGFR TKI containing regimen unless they have documented T790M activating mutation). Patients received AUY922 at 70 mg/m^2 weekly infusions.

Arm type

Experimental

Investigational medicinal product name

AUY922

Investigational medicinal product code

AUY922

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational treatment consisted of AUY922. This was supplied by Novartis in individual

EGFR and Kras wild type patients

Arm description

Patients exhibiting both mutations were stratified to the KRAS mutation stratum. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Arm type

Experimental

Investigational medicinal product name

AUY922

Investigational medicinal product code

AUY922

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational treatment consisted of AUY922. This was supplied by Novartis in individual

Patients with EML4-ALK translocation

Arm description

Patients with NSCLC who have tumors with an inversion in the short arm of chromosome 2 that results in the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the ALK gene leading to the production of an EML4-ALK fusion tyrosine kinase. ALK is a transmembrane protein, which has a kinase domain and is not usually expressed in the lung. EML4 mediate ligand-independent dimerization, and therefore constitutive activity of the ALK tyrosine kinase domain. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Arm type

Experimental

Investigational medicinal product name

AUY922

Investigational medicinal product code

AUY922

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational treatment consisted of AUY922. This was supplied by Novartis in individual

Modified EGFR mutant patients

Arm description

The modified EGFR stratum was defined as patients less heavily pretreated who had received one or two lines of prior therapy, with a documented response to a EGFR tyrosine kinase inhibitor (TKI) (complete response (CR), partial response (PR) or stable disease (SD) for ≥ 6 months), unless the patient had de novo resistance to EGFR TKI. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Arm type

Experimental

Investigational medicinal product name

AUY922

Investigational medicinal product code

AUY922

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational treatment consisted of AUY922. This was supplied by Novartis in individual

Unknown

Arm description

For some patients, it was not possible to determine their genotype, and hence their stratum membership could not be determined. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Arm type

Experimental

Investigational medicinal product name

AUY922

Investigational medicinal product code

AUY922

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational treatment consisted of AUY922. This was supplied by Novartis in individual

Number of subjects in period 1	Kras mutant patients	EGFR mutant patients	EGFR and Kras wild type patients	Patients with EML4-ALK translocation	Modified EGFR mutant patients	Unknown
Started	28	35	34	22	31	3
Completed	0	0	0	1	1	0
Not completed	28	35	34	21	30	3
Adverse event, serious fatal	6	9	6	2	1	-
Consent withdrawn by subject	2	3	4	-	2	1
Follow up phase competed as per protocol	18	22	24	18	26	2
Lost to follow-up	1	1	-	1	-	-
Protocol deviation	1	-	-	-	1	-

Baseline characteristics

Top of page

Reporting group title

Kras mutant patients

Reporting group description

Patients with KRAS mutant tumors. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

EGFR mutant patients

Reporting group description

Patients with EGFR activating mutation tumors (Note: These patients must have progressed on one prior EGFR TKI containing regimen unless they have documented T790M activating mutation). Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

EGFR and Kras wild type patients

Reporting group description

Patients exhibiting both mutations were stratified to the KRAS mutation stratum. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

Patients with EML4-ALK translocation

Reporting group description

Patients with NSCLC who have tumors with an inversion in the short arm of chromosome 2 that results in the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the ALK gene leading to the production of an EML4-ALK fusion tyrosine kinase. ALK is a transmembrane protein, which has a kinase domain and is not usually expressed in the lung. EML4 mediate ligand-independent dimerization, and therefore constitutive activity of the ALK tyrosine kinase domain. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

Modified EGFR mutant patients

Reporting group description

The modified EGFR stratum was defined as patients less heavily pretreated who had received one or two lines of prior therapy, with a documented response to a EGFR tyrosine kinase inhibitor (TKI) (complete response (CR), partial response (PR) or stable disease (SD) for ≥ 6 months), unless the patient had de novo resistance to EGFR TKI. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

Unknown

Reporting group description

For some patients, it was not possible to determine their genotype, and hence their stratum membership could not be determined. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group values	Kras mutant patients	EGFR mutant patients	EGFR and Kras wild type patients	Patients with EML4-ALK translocation	Modified EGFR mutant patients	Unknown	Total
Number of subjects	28	35	34	22	31	3	153
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	20	21	23	18	25	1	108
From 65-84 years	8	14	11	4	6	2	45
85 years and over	0	0	0	0	0	0	0
Gender, Male/Female
Units: Participants
Female	11	25	18	15	19	0	88
Male	17	10	16	7	12	3	65

End points

Top of page

Reporting group title

Kras mutant patients

Reporting group description

Patients with KRAS mutant tumors. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

EGFR mutant patients

Reporting group description

Patients with EGFR activating mutation tumors (Note: These patients must have progressed on one prior EGFR TKI containing regimen unless they have documented T790M activating mutation). Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

EGFR and Kras wild type patients

Reporting group description

Patients exhibiting both mutations were stratified to the KRAS mutation stratum. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

Patients with EML4-ALK translocation

Reporting group description

Patients with NSCLC who have tumors with an inversion in the short arm of chromosome 2 that results in the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the ALK gene leading to the production of an EML4-ALK fusion tyrosine kinase. ALK is a transmembrane protein, which has a kinase domain and is not usually expressed in the lung. EML4 mediate ligand-independent dimerization, and therefore constitutive activity of the ALK tyrosine kinase domain. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

Modified EGFR mutant patients

Reporting group description

The modified EGFR stratum was defined as patients less heavily pretreated who had received one or two lines of prior therapy, with a documented response to a EGFR tyrosine kinase inhibitor (TKI) (complete response (CR), partial response (PR) or stable disease (SD) for ≥ 6 months), unless the patient had de novo resistance to EGFR TKI. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

Unknown

Reporting group description

For some patients, it was not possible to determine their genotype, and hence their stratum membership could not be determined. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Subject analysis set title

AUY922

Subject analysis set type

Full analysis

Subject analysis set description

AUY922 Plasma Concentration

Subject analysis set title

BJP762

Subject analysis set type

Full analysis

Subject analysis set description

AUY Metabolite

Subject analysis set title

AUY922

Subject analysis set type

Intention-to-treat

Subject analysis set description

AUY922 Plasma Concentration

Subject analysis set title

BJP762

Subject analysis set type

Intention-to-treat

Subject analysis set description

AUY Metabolite

Subject analysis set title

AUY922

Subject analysis set type

Safety analysis

Subject analysis set description

AUY922 Plasma Concentration

Subject analysis set title

BJP762

Subject analysis set type

Safety analysis

Subject analysis set description

AUY Metabolite

Primary: Response assessment by study stratum - per Investigator assessment

Top of page

End point title

Response assessment by study stratum - per Investigator assessment ^[1]

End point description

The primary endpoint of the study was the investigator assessment of efficacy at 18 weeks in terms of response complete response (CR)/partial response (PR), stable disease (SD), or non clinical benefit (NCB) as assessed by response evaluation criteriain solid tumors (RECIST) version 1.0. ORR = patients with confirmed complete or partial response. Stable disease at 18 weeks = patients without response and with no assessment of progressive disease up to 18 weeks, but with an assessment of stable disease or better either within 2 weeks prior to the 18 week time point, or at the next non-missing assessment after the 18 week time point. No clinical benefit = all other patients.

End point type

Primary

End point timeframe

18 weeks

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: There was no statistical analysis done to compare the arms.

End point values	Kras mutant patients	EGFR mutant patients	EGFR and Kras wild type patients	Patients with EML4-ALK translocation	Modified EGFR mutant patients	Unknown
Number of subjects analysed	28	35	34	22	31	3
Units: Participants
Overall respose rate (ORR)	0	6	3	7	3	1
Stable disease for ≥18 weeks	2	3	3	2	7	0
No clinical benefit	26	26	28	13	21	2

No statistical analyses for this end point

Secondary: Overall Survival rate using Kaplan Meier estimates - per Investigator radiological review

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End point title

Overall Survival rate using Kaplan Meier estimates - per Investigator radiological review

End point description

Overall survival (OS) is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival was censored at the date of last contact.

End point type

Secondary

End point timeframe

Week 12, Week 18

End point values	Kras mutant patients	EGFR mutant patients	EGFR and Kras wild type patients	Patients with EML4-ALK translocation	Modified EGFR mutant patients	Unknown
Number of subjects analysed	28	35	34	22	31	3
Units: Percentage of participants
number (not applicable)
12 weeks	68.7	77	78.6	90.7	96.7	66.7
18 weeks	55.9	74.1	72.3	71.6	93.3	33.3

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) rate as per Investigator using Kaplan Meier estimates - per Investigator radiological review

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End point title

Progression Free Survival (PFS) rate as per Investigator using Kaplan Meier estimates - per Investigator radiological review

End point description

Progression-free survival (PFS) is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient did not have an event, progression-free survival was censored at the date of last adequate tumor assessment. A Novartis modified response evaluation criteria in solid tumors RECIST 1.1 criteria was applied to CT/MRI imaging data when assessing any responses to AUY922 treatment. All images were evaluated locally by the investigator. All complete or partial responses were confirmed by a second assessment at least 4 weeks later.

End point type

Secondary

End point timeframe

Week 12, Week 18

End point values	Kras mutant patients	EGFR mutant patients	EGFR and Kras wild type patients	Patients with EML4-ALK translocation	Modified EGFR mutant patients	Unknown
Number of subjects analysed	28	35	34	22	31	3
Units: Percentage of participants
number (not applicable)
12 weeks	31.5	44.4	31.5	45.5	56.4	33.3
18 weeks	9	27.7	24	36.4	37.8	33.3

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) of plasma concentration of AUY922 and its metabolite BJP762: AUCinf

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End point title

Pharmacokinetics (PK) of plasma concentration of AUY922 and its metabolite BJP762: AUCinf

End point description

Summary of PK parameters for all patients one hour post 70 mg/m2 AUY922 infusion for area under the curve infinity. There are discrepancies between sample numbers and study population because PK samples were not collected from all study subjects and thus were not analyzed.

End point type

Secondary

End point timeframe

1 hour after infusion

End point values	AUY922	BJP762
Number of subjects analysed	119	117
Units: h*ng/mL
arithmetic mean (standard deviation)	2101.27 ( 990.32 )	13963.07 ( 13006.537 )

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) of plasma concentration of AUY922 and its metabolite BJP762: AUClast

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End point title

Pharmacokinetics (PK) of plasma concentration of AUY922 and its metabolite BJP762: AUClast

End point description

Summary of PK parameters for all patients one hour post 70 mg/m2 AUY922 infusion for area under the curve last. There are discrepancies between sample numbers and study population because PK samples were not collected from all study subjects and thus were not analyzed.

End point type

Secondary

End point timeframe

1 hour after infusion

End point values	AUY922	BJP762
Number of subjects analysed	139	142
Units: h*ng/mL
arithmetic mean (standard deviation)	1997.04 ( 894.903 )	12496.75 ( 12035.525 )

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) of plasma concentration of AUY922 and its metabolite BJP762: Cmax

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End point title

Pharmacokinetics (PK) of plasma concentration of AUY922 and its metabolite BJP762: Cmax

End point description

Summary of PK parameters for all patients one hour post 70 mg/m2 AUY922 infusion for concentration max. There are discrepancies between sample numbers and study population because PK samples were not collected from all study subjects and thus were not analyzed.

End point type

Secondary

End point timeframe

1 hour after infusion

End point values	AUY922	BJP762
Number of subjects analysed	144	144
Units: ng/mL
arithmetic mean (standard deviation)	1130.59 ( 705.177 )	2332.86 ( 1377.35 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

KRAS mutant

Reporting group description

Patients with KRAS mutant tumors. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

EGFR mutant

Reporting group description

Patients with EGFR activating mutation tumors (Note: These patients must have progressed on one prior EGFR TKI containing regimen unless they have documented T790M activating mutation). Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

Unknown

Reporting group description

For some patients, it was not possible to determine their genotype, and hence their stratum membership could not be determined. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

EML4-ALK translocation

Reporting group description

Patients with NSCLC who have tumors with an inversion in the short arm of chromosome 2 that results in the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the ALK gene leading to the production of an EML4-ALK fusion tyrosine kinase. ALK is a transmembrane protein, which has a kinase domain and is not usually expressed in the lung. EML4 mediate ligand-independent dimerization, and therefore constitutive activity of the ALK tyrosine kinase domain. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

Modified EGFR mutant

Reporting group description

The modified EGFR stratum was defined as patients less heavily pretreated who had received one or two lines of prior therapy, with a documented response to a EGFR tyrosine kinase inhibitor (TKI) (complete response (CR), partial response (PR) or stable disease (SD) for ≥ 6 months), unless the patient had de novo resistance to EGFR TKI. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Reporting group title

KRAS and EGFR wild type

Reporting group description

Patients exhibiting both mutations were stratified to the KRAS mutation stratum. Patients received AUY922 at 70 mg/m^2 weekly infusions.

Serious adverse events	KRAS mutant	EGFR mutant	Unknown	EML4-ALK translocation	Modified EGFR mutant	KRAS and EGFR wild type
Total subjects affected by serious adverse events
subjects affected / exposed	17 / 28 (60.71%)	18 / 35 (51.43%)	2 / 3 (66.67%)	6 / 22 (27.27%)	11 / 31 (35.48%)	22 / 34 (64.71%)
number of deaths (all causes)	5	7	1	2	1	4
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases To Central Nervous System
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic Pain
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep Vein Thrombosis
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 28 (3.57%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	2 / 34 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General Physical Health Deterioration
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal Inflammation
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema Peripheral
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 28 (3.57%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	3 / 28 (10.71%)	2 / 35 (5.71%)	0 / 3 (0.00%)	3 / 22 (13.64%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 4	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	4 / 31 (12.90%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Embolism
subjects affected / exposed	1 / 28 (3.57%)	3 / 35 (8.57%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Failure
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional State
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial Fibrillation
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bundle Branch Block Right
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-Respiratory Arrest
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial Effusion
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular Tachycardia
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain Compression
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Balance Disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous System Disorder
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Cord Compression
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vocal Cord Paresis
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Night Blindness
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	1 / 3 (33.33%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 28 (3.57%)	3 / 35 (8.57%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 1	3 / 4	0 / 0	0 / 0	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal Fissure
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Proctalgia
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 28 (3.57%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone Pain
subjects affected / exposed	1 / 28 (3.57%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal Pain
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neck Pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Atypical Pneumonia
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung Infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella Infection
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Perirectal Abscess
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Tract Infection
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 28 (10.71%)	1 / 35 (2.86%)	1 / 3 (33.33%)	1 / 22 (4.55%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure To Thrive
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 28 (3.57%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fluid Intake Reduced
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	KRAS mutant	EGFR mutant	Unknown	EML4-ALK translocation	Modified EGFR mutant	KRAS and EGFR wild type
Total subjects affected by non serious adverse events
subjects affected / exposed	28 / 28 (100.00%)	35 / 35 (100.00%)	3 / 3 (100.00%)	22 / 22 (100.00%)	31 / 31 (100.00%)	33 / 34 (97.06%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer Pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	1 / 3 (33.33%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Vascular disorders
Deep Vein Thrombosis
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	2	0	0	0	0
Hot Flush
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	2 / 22 (9.09%)	1 / 31 (3.23%)	1 / 34 (2.94%)
occurrences all number	2	0	0	2	1	1
Hypertension
subjects affected / exposed	0 / 28 (0.00%)	4 / 35 (11.43%)	0 / 3 (0.00%)	3 / 22 (13.64%)	5 / 31 (16.13%)	3 / 34 (8.82%)
occurrences all number	0	14	0	4	8	4
Hypotension
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	4	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	13 / 28 (46.43%)	14 / 35 (40.00%)	1 / 3 (33.33%)	10 / 22 (45.45%)	5 / 31 (16.13%)	10 / 34 (29.41%)
occurrences all number	17	18	1	14	6	16
Catheter Site Pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	2 / 31 (6.45%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	2	0
Chest Pain
subjects affected / exposed	1 / 28 (3.57%)	2 / 35 (5.71%)	1 / 3 (33.33%)	4 / 22 (18.18%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	3	1	8	0	0
Pain
subjects affected / exposed	1 / 28 (3.57%)	2 / 35 (5.71%)	1 / 3 (33.33%)	0 / 22 (0.00%)	1 / 31 (3.23%)	6 / 34 (17.65%)
occurrences all number	1	2	1	0	1	8
Fatigue
subjects affected / exposed	7 / 28 (25.00%)	9 / 35 (25.71%)	0 / 3 (0.00%)	3 / 22 (13.64%)	15 / 31 (48.39%)	13 / 34 (38.24%)
occurrences all number	7	14	0	3	17	17
Gait Disturbance
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	2 / 22 (9.09%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	2	0	2	0	2
Non-Cardiac Chest Pain
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	2 / 22 (9.09%)	1 / 31 (3.23%)	2 / 34 (5.88%)
occurrences all number	1	0	0	2	1	2
Oedema Peripheral
subjects affected / exposed	2 / 28 (7.14%)	2 / 35 (5.71%)	0 / 3 (0.00%)	3 / 22 (13.64%)	3 / 31 (9.68%)	1 / 34 (2.94%)
occurrences all number	3	2	0	3	3	1
Pyrexia
subjects affected / exposed	5 / 28 (17.86%)	3 / 35 (8.57%)	2 / 3 (66.67%)	6 / 22 (27.27%)	4 / 31 (12.90%)	4 / 34 (11.76%)
occurrences all number	5	3	2	7	5	5
Reproductive system and breast disorders
Pelvic Pain
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	2	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	2 / 31 (6.45%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	2	1
Cough
subjects affected / exposed	5 / 28 (17.86%)	8 / 35 (22.86%)	1 / 3 (33.33%)	7 / 22 (31.82%)	8 / 31 (25.81%)	9 / 34 (26.47%)
occurrences all number	7	12	1	11	9	16
Dyspnoea
subjects affected / exposed	5 / 28 (17.86%)	11 / 35 (31.43%)	1 / 3 (33.33%)	2 / 22 (9.09%)	2 / 31 (6.45%)	9 / 34 (26.47%)
occurrences all number	5	11	1	3	3	9
Dysphonia
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	1 / 22 (4.55%)	1 / 31 (3.23%)	2 / 34 (5.88%)
occurrences all number	0	1	0	1	1	2
Dyspnoea Exertional
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	2	0	0	0	2
Haemoptysis
subjects affected / exposed	4 / 28 (14.29%)	3 / 35 (8.57%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	4 / 34 (11.76%)
occurrences all number	5	3	0	1	0	4
Epistaxis
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	1 / 3 (33.33%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	1	0	0	1
Oropharyngeal Pain
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	3 / 31 (9.68%)	1 / 34 (2.94%)
occurrences all number	0	1	0	0	3	2
Pleural Effusion
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	2 / 22 (9.09%)	2 / 31 (6.45%)	3 / 34 (8.82%)
occurrences all number	0	2	0	2	2	3
Wheezing
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	2	0	1	0	0
Rhinorrhoea
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	2	0	0	0	2
Productive Cough
subjects affected / exposed	1 / 28 (3.57%)	4 / 35 (11.43%)	0 / 3 (0.00%)	2 / 22 (9.09%)	1 / 31 (3.23%)	7 / 34 (20.59%)
occurrences all number	1	5	0	5	2	7
Psychiatric disorders
Anxiety
subjects affected / exposed	2 / 28 (7.14%)	2 / 35 (5.71%)	0 / 3 (0.00%)	2 / 22 (9.09%)	2 / 31 (6.45%)	3 / 34 (8.82%)
occurrences all number	2	2	0	2	2	3
Depressed Mood
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	2 / 22 (9.09%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	1	0	3	0	2
Hallucination
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	2 / 22 (9.09%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	2	0	0
Insomnia
subjects affected / exposed	0 / 28 (0.00%)	3 / 35 (8.57%)	0 / 3 (0.00%)	5 / 22 (22.73%)	4 / 31 (12.90%)	6 / 34 (17.65%)
occurrences all number	0	3	0	6	4	6
Nervousness
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	2 / 22 (9.09%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	2	0	1
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 28 (3.57%)	2 / 35 (5.71%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	1	2	0	1	0	1
Blood Alkaline Phosphatase Increased
subjects affected / exposed	0 / 28 (0.00%)	4 / 35 (11.43%)	0 / 3 (0.00%)	1 / 22 (4.55%)	3 / 31 (9.68%)	1 / 34 (2.94%)
occurrences all number	0	5	0	1	3	1
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	2 / 22 (9.09%)	2 / 31 (6.45%)	1 / 34 (2.94%)
occurrences all number	0	1	0	2	3	1
Blood Creatinine Increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	1 / 3 (33.33%)	1 / 22 (4.55%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences all number	0	0	1	1	1	0
C-Reactive Protein Increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	1 / 3 (33.33%)	0 / 22 (0.00%)	2 / 31 (6.45%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	2	0
Gamma-Glutamyltransferase Increased
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	3 / 31 (9.68%)	1 / 34 (2.94%)
occurrences all number	0	2	0	0	3	1
Heart Rate Increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	1 / 3 (33.33%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Hypophonesis
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	2 / 22 (9.09%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	2	0	1
Transaminases Increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	2 / 31 (6.45%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	2	0
Weight Decreased
subjects affected / exposed	4 / 28 (14.29%)	1 / 35 (2.86%)	0 / 3 (0.00%)	1 / 22 (4.55%)	4 / 31 (12.90%)	3 / 34 (8.82%)
occurrences all number	4	1	0	1	4	3
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	1 / 22 (4.55%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	2	0	2	0	1
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	1 / 3 (33.33%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Balance Disorder
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	1 / 22 (4.55%)	3 / 31 (9.68%)	0 / 34 (0.00%)
occurrences all number	2	0	0	1	3	0
Dizziness
subjects affected / exposed	1 / 28 (3.57%)	2 / 35 (5.71%)	1 / 3 (33.33%)	1 / 22 (4.55%)	3 / 31 (9.68%)	1 / 34 (2.94%)
occurrences all number	1	2	1	1	3	1
Dysgeusia
subjects affected / exposed	2 / 28 (7.14%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	1 / 34 (2.94%)
occurrences all number	2	1	0	0	1	1
Headache
subjects affected / exposed	8 / 28 (28.57%)	8 / 35 (22.86%)	2 / 3 (66.67%)	14 / 22 (63.64%)	13 / 31 (41.94%)	8 / 34 (23.53%)
occurrences all number	10	25	3	41	15	13
Hypoaesthesia
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	2 / 22 (9.09%)	2 / 31 (6.45%)	2 / 34 (5.88%)
occurrences all number	0	0	0	4	2	2
Neuralgia
subjects affected / exposed	0 / 28 (0.00%)	3 / 35 (8.57%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	3	0	0	0	1
Memory Impairment
subjects affected / exposed	2 / 28 (7.14%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	2	0	0	0	0	1
Neuropathy Peripheral
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	2 / 34 (5.88%)
occurrences all number	0	0	0	0	1	2
Somnolence
subjects affected / exposed	1 / 28 (3.57%)	1 / 35 (2.86%)	0 / 3 (0.00%)	2 / 22 (9.09%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	1	1	0	2	0	2
Peripheral Sensory Neuropathy
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	0	0	0	0	2
Paraesthesia
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	3 / 22 (13.64%)	3 / 31 (9.68%)	2 / 34 (5.88%)
occurrences all number	0	0	0	3	5	2
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	0	0	0	0	2
Anaemia
subjects affected / exposed	1 / 28 (3.57%)	3 / 35 (8.57%)	0 / 3 (0.00%)	3 / 22 (13.64%)	4 / 31 (12.90%)	5 / 34 (14.71%)
occurrences all number	1	3	0	3	4	6
Lymphopenia
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	2 / 31 (6.45%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	2	0
Ear and labyrinth disorders
Ear Pain
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	1	0	0	0	3
Vertigo
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	0 / 3 (0.00%)	2 / 22 (9.09%)	1 / 31 (3.23%)	2 / 34 (5.88%)
occurrences all number	0	1	0	2	1	2
Eye disorders
Accommodation Disorder
subjects affected / exposed	1 / 28 (3.57%)	2 / 35 (5.71%)	0 / 3 (0.00%)	2 / 22 (9.09%)	5 / 31 (16.13%)	2 / 34 (5.88%)
occurrences all number	3	2	0	2	5	2
Blepharitis
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	2 / 31 (6.45%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	2	0
Cataract Subcapsular
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	1	0	0	0	0	2
Lacrimation Increased
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences all number	0	2	0	0	1	0
Eye Pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	2 / 31 (6.45%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	2	1
Dry Eye
subjects affected / exposed	2 / 28 (7.14%)	0 / 35 (0.00%)	0 / 3 (0.00%)	2 / 22 (9.09%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	2	0	0	2	0	2
Colour Blindness Acquired
subjects affected / exposed	0 / 28 (0.00%)	3 / 35 (8.57%)	1 / 3 (33.33%)	5 / 22 (22.73%)	4 / 31 (12.90%)	2 / 34 (5.88%)
occurrences all number	0	3	1	6	4	2
Night Blindness
subjects affected / exposed	3 / 28 (10.71%)	10 / 35 (28.57%)	1 / 3 (33.33%)	5 / 22 (22.73%)	10 / 31 (32.26%)	6 / 34 (17.65%)
occurrences all number	3	12	1	9	13	7
Loss Of Visual Contrast Sensitivity
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	0	0	0	0	2
Ocular Toxicity
subjects affected / exposed	4 / 28 (14.29%)	4 / 35 (11.43%)	1 / 3 (33.33%)	3 / 22 (13.64%)	3 / 31 (9.68%)	1 / 34 (2.94%)
occurrences all number	4	7	1	3	5	1
Photophobia
subjects affected / exposed	3 / 28 (10.71%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	2 / 31 (6.45%)	5 / 34 (14.71%)
occurrences all number	3	2	0	0	2	5
Retinal Disorder
subjects affected / exposed	1 / 28 (3.57%)	3 / 35 (8.57%)	0 / 3 (0.00%)	5 / 22 (22.73%)	7 / 31 (22.58%)	1 / 34 (2.94%)
occurrences all number	1	4	0	5	7	1
Photopsia
subjects affected / exposed	3 / 28 (10.71%)	5 / 35 (14.29%)	0 / 3 (0.00%)	10 / 22 (45.45%)	6 / 31 (19.35%)	10 / 34 (29.41%)
occurrences all number	3	5	0	11	6	11
Vision Blurred
subjects affected / exposed	5 / 28 (17.86%)	6 / 35 (17.14%)	0 / 3 (0.00%)	6 / 22 (27.27%)	6 / 31 (19.35%)	7 / 34 (20.59%)
occurrences all number	5	7	0	6	6	9
Visual Acuity Reduced
subjects affected / exposed	1 / 28 (3.57%)	6 / 35 (17.14%)	0 / 3 (0.00%)	7 / 22 (31.82%)	5 / 31 (16.13%)	7 / 34 (20.59%)
occurrences all number	1	8	0	7	6	10
Vitreous Floaters
subjects affected / exposed	1 / 28 (3.57%)	3 / 35 (8.57%)	1 / 3 (33.33%)	1 / 22 (4.55%)	2 / 31 (6.45%)	1 / 34 (2.94%)
occurrences all number	1	3	1	1	2	1
Visual Impairment
subjects affected / exposed	6 / 28 (21.43%)	8 / 35 (22.86%)	0 / 3 (0.00%)	6 / 22 (27.27%)	7 / 31 (22.58%)	3 / 34 (8.82%)
occurrences all number	6	11	0	6	8	4
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	1 / 3 (33.33%)	2 / 22 (9.09%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	0	1	2	0	2
Abdominal Pain
subjects affected / exposed	5 / 28 (17.86%)	5 / 35 (14.29%)	0 / 3 (0.00%)	6 / 22 (27.27%)	2 / 31 (6.45%)	4 / 34 (11.76%)
occurrences all number	5	6	0	10	2	4
Abdominal Pain Upper
subjects affected / exposed	1 / 28 (3.57%)	3 / 35 (8.57%)	0 / 3 (0.00%)	0 / 22 (0.00%)	2 / 31 (6.45%)	2 / 34 (5.88%)
occurrences all number	1	3	0	0	3	2
Dry Mouth
subjects affected / exposed	5 / 28 (17.86%)	4 / 35 (11.43%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	6 / 34 (17.65%)
occurrences all number	5	4	0	0	1	6
Diarrhoea
subjects affected / exposed	25 / 28 (89.29%)	23 / 35 (65.71%)	3 / 3 (100.00%)	17 / 22 (77.27%)	24 / 31 (77.42%)	25 / 34 (73.53%)
occurrences all number	46	39	4	79	105	72
Constipation
subjects affected / exposed	6 / 28 (21.43%)	6 / 35 (17.14%)	0 / 3 (0.00%)	5 / 22 (22.73%)	5 / 31 (16.13%)	5 / 34 (14.71%)
occurrences all number	6	7	0	6	5	6
Dyspepsia
subjects affected / exposed	0 / 28 (0.00%)	1 / 35 (2.86%)	1 / 3 (33.33%)	4 / 22 (18.18%)	3 / 31 (9.68%)	1 / 34 (2.94%)
occurrences all number	0	1	1	11	5	1
Flatulence
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	2	0	0	0	1
Nausea
subjects affected / exposed	16 / 28 (57.14%)	19 / 35 (54.29%)	1 / 3 (33.33%)	11 / 22 (50.00%)	12 / 31 (38.71%)	13 / 34 (38.24%)
occurrences all number	27	38	1	21	22	18
Oral Pain
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	2	0	0	0	0
Rectal Haemorrhage
subjects affected / exposed	2 / 28 (7.14%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	2	0	0	0	0	1
Stomatitis
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	2 / 34 (5.88%)
occurrences all number	1	0	0	0	1	2
Vomiting
subjects affected / exposed	13 / 28 (46.43%)	13 / 35 (37.14%)	2 / 3 (66.67%)	9 / 22 (40.91%)	4 / 31 (12.90%)	4 / 34 (11.76%)
occurrences all number	18	21	2	18	26	11
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	2 / 28 (7.14%)	1 / 35 (2.86%)	0 / 3 (0.00%)	1 / 22 (4.55%)	4 / 31 (12.90%)	1 / 34 (2.94%)
occurrences all number	2	1	0	1	5	1
Pain Of Skin
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	0	0	0	0	10
Dry Skin
subjects affected / exposed	1 / 28 (3.57%)	3 / 35 (8.57%)	0 / 3 (0.00%)	0 / 22 (0.00%)	4 / 31 (12.90%)	1 / 34 (2.94%)
occurrences all number	1	3	0	0	5	1
Dermatitis Acneiform
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	1 / 22 (4.55%)	2 / 31 (6.45%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	7	0
Rash
subjects affected / exposed	2 / 28 (7.14%)	2 / 35 (5.71%)	0 / 3 (0.00%)	1 / 22 (4.55%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences all number	2	2	0	1	1	0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	8 / 28 (28.57%)	5 / 35 (14.29%)	0 / 3 (0.00%)	3 / 22 (13.64%)	7 / 31 (22.58%)	8 / 34 (23.53%)
occurrences all number	8	7	0	4	7	8
Arthralgia
subjects affected / exposed	1 / 28 (3.57%)	4 / 35 (11.43%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	2 / 34 (5.88%)
occurrences all number	2	6	0	0	1	2
Musculoskeletal Chest Pain
subjects affected / exposed	1 / 28 (3.57%)	2 / 35 (5.71%)	0 / 3 (0.00%)	1 / 22 (4.55%)	2 / 31 (6.45%)	2 / 34 (5.88%)
occurrences all number	1	2	0	1	3	2
Muscle Spasms
subjects affected / exposed	2 / 28 (7.14%)	1 / 35 (2.86%)	0 / 3 (0.00%)	3 / 22 (13.64%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	3	1	0	4	0	3
Flank Pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	4 / 31 (12.90%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	6	0
Musculoskeletal Pain
subjects affected / exposed	3 / 28 (10.71%)	2 / 35 (5.71%)	1 / 3 (33.33%)	1 / 22 (4.55%)	2 / 31 (6.45%)	5 / 34 (14.71%)
occurrences all number	3	2	2	1	2	7
Bone Pain
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	1 / 22 (4.55%)	3 / 31 (9.68%)	1 / 34 (2.94%)
occurrences all number	0	2	0	1	7	1
Myalgia
subjects affected / exposed	0 / 28 (0.00%)	4 / 35 (11.43%)	1 / 3 (33.33%)	5 / 22 (22.73%)	6 / 31 (19.35%)	4 / 34 (11.76%)
occurrences all number	0	6	1	13	13	7
Neck Pain
subjects affected / exposed	2 / 28 (7.14%)	0 / 35 (0.00%)	1 / 3 (33.33%)	1 / 22 (4.55%)	2 / 31 (6.45%)	4 / 34 (11.76%)
occurrences all number	2	0	1	1	2	4
Pain In Extremity
subjects affected / exposed	2 / 28 (7.14%)	4 / 35 (11.43%)	0 / 3 (0.00%)	1 / 22 (4.55%)	1 / 31 (3.23%)	4 / 34 (11.76%)
occurrences all number	2	4	0	2	1	4
Infections and infestations
Conjunctivitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	2 / 22 (9.09%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences all number	0	0	0	2	1	0
Influenza
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	3 / 31 (9.68%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	3	1
Nasopharyngitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	1 / 3 (33.33%)	1 / 22 (4.55%)	4 / 31 (12.90%)	1 / 34 (2.94%)
occurrences all number	0	0	1	1	6	3
Respiratory Tract Infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 35 (0.00%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	0	0	0	0	2
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 28 (0.00%)	2 / 35 (5.71%)	0 / 3 (0.00%)	2 / 22 (9.09%)	4 / 31 (12.90%)	1 / 34 (2.94%)
occurrences all number	0	2	0	4	6	2
Urinary Tract Infection
subjects affected / exposed	1 / 28 (3.57%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences all number	1	2	0	0	1	0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	17 / 28 (60.71%)	15 / 35 (42.86%)	1 / 3 (33.33%)	8 / 22 (36.36%)	10 / 31 (32.26%)	12 / 34 (35.29%)
occurrences all number	17	17	1	9	15	15
Dehydration
subjects affected / exposed	1 / 28 (3.57%)	1 / 35 (2.86%)	0 / 3 (0.00%)	1 / 22 (4.55%)	1 / 31 (3.23%)	3 / 34 (8.82%)
occurrences all number	1	1	0	1	1	3
Hyperglycaemia
subjects affected / exposed	1 / 28 (3.57%)	0 / 35 (0.00%)	1 / 3 (33.33%)	0 / 22 (0.00%)	1 / 31 (3.23%)	1 / 34 (2.94%)
occurrences all number	1	0	1	0	1	1
Hypokalaemia
subjects affected / exposed	2 / 28 (7.14%)	2 / 35 (5.71%)	0 / 3 (0.00%)	2 / 22 (9.09%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences all number	3	5	0	2	2	0
Hypomagnesaemia
subjects affected / exposed	1 / 28 (3.57%)	2 / 35 (5.71%)	0 / 3 (0.00%)	0 / 22 (0.00%)	0 / 31 (0.00%)	1 / 34 (2.94%)
occurrences all number	1	3	0	0	0	1
Hyponatraemia
subjects affected / exposed	2 / 28 (7.14%)	4 / 35 (11.43%)	0 / 3 (0.00%)	0 / 22 (0.00%)	1 / 31 (3.23%)	0 / 34 (0.00%)
occurrences all number	2	4	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

11 Feb 2011

This amendment was issued 14 months after study start (09 Nov 2010) and after the inclusion of 116 patients, introduced the following changes: The main purpose of this amendment was to add an additional fifth stratum that would enroll 30 patients with EGFR activating mutations (i.e. exon 18 21), who were less heavily pretreated than patients in the current EGFR stratum (up to two prior lines in comparison to four prior therapies). Preliminary data from the ongoing trial had shown evidence of activity in patients with EGFR activating mutations that had been previously treated with EGFR TKIs. As of 15-Nov-2011, 5/22 evaluable patients had a partial response (four confirmed, one unconfirmed). Because of the efficacy trend observed in the EGFR mutant cohort, 30 additional patients with EGFR mutation were to be enrolled to further assess AUY922 activity in this patient population. In contrast to the previous EGFR mutant stratum, patients enrolled to this new stratum were less heavily pretreated (up to two prior lines), would have no history of CNS metastasis, and would have a performance status of 0 to 1. The reason to enroll less heavily pretreated patients with EGFR mutations was due to the observation that a high number of EGFR mutant patients, nine patients in total, discontinued study participation due to early disease progression prior to completing first radiological assessment (6 ±1weeks), reflecting the fact that most patients had advanced disease, brain metastasis, and had received multiple previous lines of therapies; In addition, all patients to be enrolled to the fifth EGFR mutation stratum were required to undergo baseline biopsy prior to study enrollment in order to understand resistance mechanism to EGFR TKI, as pre-clinical data suggested that HSP90 inhibition may have different sensitivity based on the mutated EGFR, such as T790M (Shimamura et al 2005);

12 Jan 2012

This amendment was issued 14 months after study start (09 Nov 2010) and after the inclusion of 116 patients, introduced the following changes: The main purpose of this amendment was to add an additional fifth stratum that would enroll 30 patients with EGFR activating mutations (i.e. exon 18 21), who were less heavily pretreated than patients in the current EGFR stratum (up to two prior lines in comparison to four prior therapies). Preliminary data from the ongoing trial had shown evidence of activity in patients with EGFR activating mutations that had been previously treated with EGFR TKIs. As of 15-Nov-2011, 5/22 evaluable patients had a partial response (four confirmed, one unconfirmed). Because of the efficacy trend observed in the EGFR mutant cohort, 30 additional patients with EGFR mutation were to be enrolled to further assess AUY922 activity in this patient population. In contrast to the previous EGFR mutant stratum, patients enrolled to this new stratum were less heavily pretreated (up to two prior lines), would have no history of CNS metastasis, and would have a performance status of 0 to 1. The reason to enroll less heavily pretreated patients with EGFR mutations was due to the observation that a high number of EGFR mutant patients, nine patients in total, discontinued study participation due to early disease progression prior to completing first radiological assessment (6 ±1weeks), reflecting the fact that most patients had advanced disease, brain metastasis, and had received multiple previous lines of therapies; In addition, all patients to be enrolled to the fifth EGFR mutation stratum were required to undergo baseline biopsy prior to study enrollment in order to understand resistance mechanism to EGFR TKI, as pre-clinical data suggested that HSP90 inhibition may have different sensitivity based on the mutated EGFR, such as T790M (Shimamura et al 2005);

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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