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Clinical Trial Results:
A phase III, multicenter, randomized, open-label study of oral LDK378 versus standard chemotherapy in adult patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer who have been treated previously with chemotherapy (platinum doublet) and crizotinib

Summary
EudraCT number	2012-005637-36
Trial protocol	DE IT ES FR NL GB IE BE PT
Global end of trial date	10 Nov 2023

Results information
Results version number	v2(current)
This version publication date	28 Mar 2025
First version publication date	21 Nov 2024
Other versions	v1
Version creation reason

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

CLDK378A2303

ISRCTN number

US NCT number

NCT01828112

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

Novartis Campus, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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

10 Nov 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Nov 2023

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to compare the antitumor activity of LDK378 versus reference chemotherapy, as measured by progression-free survival (PFS) determined by blinded independent review committee (BIRC) per response evaluation criteria in solid tumors (RECIST) 1.1. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

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

28 Jun 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Germany: 13

Country: Number of subjects enrolled

Hong Kong: 5

Country: Number of subjects enrolled

Ireland: 6

Country: Number of subjects enrolled

Israel: 5

Country: Number of subjects enrolled

Italy: 42

Country: Number of subjects enrolled

Japan: 29

Country: Number of subjects enrolled

Korea, Republic of: 21

Country: Number of subjects enrolled

Lebanon: 2

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Portugal: 1

Country: Number of subjects enrolled

Russian Federation: 9

Country: Number of subjects enrolled

Singapore: 5

Country: Number of subjects enrolled

Spain: 21

Country: Number of subjects enrolled

Switzerland: 7

Country: Number of subjects enrolled

Türkiye: 9

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

United States: 14

Worldwide total number of subjects

231

EEA total number of subjects

111

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)

178

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Enrollment in countries (with number of sites): Belgium (4), Canada (1), France (9), Germany (8), Hong Kong (3), Ireland (2), Israel (2), Italy (10), Japan (12), Republic of Korea (5), Lebanon (1), Netherlands (2), Portugal (1), Russia (3), Singapore (2), Spain (11), Switzerland (2), Turkey (3), United Kingdom (5), United States (13).

Screening details

In the treatment phase, patients were randomized 1:1 to one of the treatment arms (ceritinib or chemotherapy). In the extension treatment phase, only patients randomized to the chemotherapy arm were allowed to crossover to receive ceritinib therapy after BIRC-confirmed, RECIST-defined disease progression.

Period 1 title

Treatment Phase (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Ceritinib

Arm description

Ceritinib 750 mg

Arm type

Experimental

Investigational medicinal product name

Ceritinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Ceritinib was supplied as 150 mg hard gelatin capsules and was administered orally, fasting, once daily at a dose of 750 mg on a continuous dosing schedule (5 x 150 mg capsules).

Chemotherapy

Arm description

Chemotherapy as determined by BIRC

Arm type

Active comparator

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Docetaxel, a reconstituted solution, was intravenously administered over 1 hour, at 75 mg/m^2 every 21 days.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Pemetrexed, a reconstituted solution, was intravenously administered over 10 minutes at 500 mg/m^2 every 21 days.

Number of subjects in period 1	Ceritinib	Chemotherapy
Started	115	116
Safety Set	115	113
Completed	0	0
Not completed	115	116
Adverse event, serious fatal	9	5
Physician decision	6	7
Adverse event, non-fatal	7	8
No longer required treatment	-	1
Pregnancy	1	-
Study terminated by sponsor	1	-
Progressive disease	79	87
Subject/guardian decision	12	8

Baseline characteristics

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Reporting group title

Ceritinib

Reporting group description

Ceritinib 750 mg

Reporting group title

Chemotherapy

Reporting group description

Chemotherapy as determined by BIRC

Reporting group values	Ceritinib	Chemotherapy	Total
Number of subjects	115	116	231
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	89	89	178
From 65-84 years	26	27	53
85 years and over	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	53.1 ( 11.96 )	54.4 ( 11.61 )	-
Sex: Female, Male
Units:
Female	68	61	129
Male	47	55	102
Race/Ethnicity, Customized
Units: Subjects
Asian	30	38	68
Black	0	1	1
Caucasian	81	68	149
Other	2	4	6
Unknown	2	5	7

End points

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Reporting group title

Ceritinib

Reporting group description

Ceritinib 750 mg

Reporting group title

Chemotherapy

Reporting group description

Chemotherapy as determined by BIRC

Subject analysis set title

Chemotherapy/Ceritinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Patients randomized to chemotherapy who crossed over to ceritinib at the extension treatment phase

Primary: Progression Free Survival (PFS) per Blinded Independent Review Committee (BIRC)

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End point title

Progression Free Survival (PFS) per Blinded Independent Review Committee (BIRC)

End point description

PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.

End point type

Primary

End point timeframe

From the date of randomization to the date of first radiologically documented disease progression or death due to any cause up to approximately 24 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	115	116
Units: months
median (confidence interval 95%)	5.4 (4.1 to 6.9)	1.6 (1.4 to 2.8)

Statistical Analysis

Comparison groups

Ceritinib v Chemotherapy

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

0.67

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS was defined as time from date of randomization to date of death due to any cause.

End point type

Secondary

End point timeframe

Up to approximately 114 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	115	116
Units: months
median (confidence interval 95%)	17.7 (14.2 to 23.7)	20.1 (11.9 to 31.2)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) per Investigator Assessment

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End point title

Progression Free Survival (PFS) per Investigator Assessment

End point description

PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.

End point type

Secondary

End point timeframe

Up to approximately 84 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	115	116
Units: months
median (confidence interval 95%)	6.2 (4.4 to 7.9)	1.6 (1.4 to 2.6)

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) per BIRC

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End point title

Overall Response Rate (ORR) per BIRC

End point description

ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

Up to approximately 54 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	115	116
Units: percentage of participants
number (confidence interval 95%)	40.9 (31.8 to 50.4)	6.9 (3.0 to 13.1)

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) per Investigator Assessment

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End point title

Overall Response Rate (ORR) per Investigator Assessment

End point description

ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 1.1. CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

Up to approximately 93 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	115	116
Units: percentage of participants
number (confidence interval 95%)	44.3 (35.1 to 53.9)	6.9 (3.0 to 13.1)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) per BIRC

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End point title

Duration of Response (DOR) per BIRC

End point description

DOR defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer. CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

Up to approximately 54 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	47	8
Units: months
median (confidence interval 95%)	7.6 (5.4 to 8.3)	10.4 (3.5 to 999)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) per Investigator Assessment

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End point title

Duration of Response (DOR) per Investigator Assessment

End point description

End point type

Secondary

End point timeframe

Up to approximately 93 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	51	8
Units: months
median (confidence interval 95%)	6.7 (5.5 to 8.3)	8.3 (2.8 to 69.9)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR) per BIRC

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End point title

Disease Control Rate (DCR) per BIRC

End point description

DCR was defined as the percentage of participants with best overall response of CR, PR, or stable disease (SD). CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

End point type

Secondary

End point timeframe

Up to approximately 54 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	115	116
Units: percentage of participants
number (confidence interval 95%)	76.5 (67.7 to 83.9)	37.9 (29.1 to 47.4)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR) per Investigator Assessment

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End point title

Disease Control Rate (DCR) per Investigator Assessment

End point description

End point type

Secondary

End point timeframe

Up to approximately 93 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	115	116
Units: percentage of participants
number (confidence interval 95%)	80.0 (71.5 to 86.9)	39.7 (30.7 to 49.2)

No statistical analyses for this end point

Secondary: Time to Response (TTR) per BIRC

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End point title

Time to Response (TTR) per BIRC

End point description

TTR was defined as the time from date of randomization to date of first documented response (CR or PR). CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

Up to approximately 52 weeks

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	47	8
Units: weeks
median (full range (min-max))	6.71 (4.9 to 52.3)	9.64 (5.4 to 43.3)

No statistical analyses for this end point

Secondary: Time to response (TTR) per Investigator Assessment

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End point title

Time to response (TTR) per Investigator Assessment

End point description

End point type

Secondary

End point timeframe

Up to approximately 45 weeks

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	47	8
Units: weeks
median (full range (min-max))	6.43 (4.9 to 45.4)	14.71 (6.3 to 36.4)

No statistical analyses for this end point

Secondary: Overall Intracranial Response Rate (OIRR) per BIRC

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End point title

Overall Intracranial Response Rate (OIRR) per BIRC

End point description

OIRR was defined as the ORR based on lesions in brain (target, nontarget lesions (and new lesions, if applicable) and calculated as the percentage of patients with a best overall confirmed response of CR or PR in the brain per modified RECIST 1.1 as assessed by BIRC neuroradiologist. CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

Up to approximately 18 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	66	67
Units: percentage of participants
number (confidence interval 95%)	10.6 (4.4 to 20.6)	3.0 (0.4 to 10.4)

No statistical analyses for this end point

Secondary: Intracranial Disease Control Rate (IDCR) per BIRC

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End point title

Intracranial Disease Control Rate (IDCR) per BIRC

End point description

IDCR was defined as the DCR based on lesions in brain (target, non-target lesions (and new lesions, if applicable) and calculated as the proportion of patients with a best overall response of CR or PR or SD (or non-CR/nonPD) in the brain per modified RECIST 1.1 as assessed by BIRC neuro-radiologist. CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

End point type

Secondary

End point timeframe

Up to approximately 18 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	66	67
Units: percentage of participants
number (confidence interval 95%)	71.2 (58.7 to 81.7)	53.7 (41.1 to 66.0)

No statistical analyses for this end point

Secondary: Duration of Intracranial Response (DOIR) per BIRC

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End point title

Duration of Intracranial Response (DOIR) per BIRC

End point description

DOIR was defined as the DOR based on lesions in brain (target, non-target lesions (and new lesions, if applicable) and calculated from the time of first documented response of CR or PR to the date of the first documented disease progression in the brain or death due to any cause per modified RECIST 1.1 as assessed by BIRC neuro-radiologist. CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

Up to approximately 18 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	6	1
Units: months
median (confidence interval 95%)	8.3 (2.7 to 999)	16.7 (0.999 to 999)

No statistical analyses for this end point

Secondary: Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer’s Core Quality of Life Questionnaire (EORTC-QLQC30)

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End point title

Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer’s Core Quality of Life Questionnaire (EORTC-QLQC30)

End point description

The EORTC QLQ-C30 questionnaire contained 30 items and was composed of both multi-item scales and single item measures. These included five functional scales (physical, role, emotional, cognitive, and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and a global health status/quality of life (QoL) scale. All of the scales and single items ranged from 0 to 100. A high scale score represented a higher response level. Thus, a high score for a functional scale indicated a high/healthy level of functioning, a high score for the QoL indicated high QoL, but a high score for a symptom scale/single item indicated a high level of symptomatology/problems. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.

End point type

Secondary

End point timeframe

Screening and treatment phase up to 92 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	107	86
Units: score on a scale
least squares mean (standard error)
Global Health Status/QoL n=106,85	62.9 ( 1.13 )	63.2 ( 1.74 )
Physical Functioning n=107,86	80.5 ( 1.04 )	75.4 ( 1.52 )
Emotional Functioning n=106,86	82.4 ( 1.01 )	80.7 ( 1.54 )
Social Functioning n=106,86	76.7 ( 1.56 )	71.6 ( 2.31 )
Cognitive Functioning n=106,86	86.7 ( 0.91 )	84.5 ( 1.40 )
Role Functioning n=107,86	72.6 ( 1.30 )	68.7 ( 1.98 )
Fatigue n=107,86	31.1 ( 1.10 )	36.1 ( 1.69 )
Nausea and Vomiting n=107,86	17.2 ( 1.08 )	9.4 ( 1.69 )
Pain n=107,86	21.4 ( 1.22 )	24.2 ( 1.85 )
Dyspnea n=107,86	17.4 ( 1.03 )	24.0 ( 1.62 )
Insomnia n=107,86	18.9 ( 1.33 )	25.6 ( 2.05 )
Appetite Loss n=107,86	21.2 ( 1.33 )	13.9 ( 2.07 )
Constipation n=107,86	15.0 ( 1.31 )	15.0 ( 2.00 )
Diarrhea n=106,86	29.3 ( 1.29 )	11.4 ( 2.02 )
Financial Difficulties n=104,85	15.5 ( 1.41 )	19.7 ( 2.10 )

No statistical analyses for this end point

Secondary: EORTC QLQ-LC13 Time to Definitive Deterioration

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End point title

EORTC QLQ-LC13 Time to Definitive Deterioration

End point description

The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) was used in conjunction with the EORTC QLQ-C30 and provided information on an additional 13 items specifically related to lung cancer. The lung cancer module incorporated one multi-item scale to assess dyspnea, and 9 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All of the domain scores ranged from 0 to 100. A high score indicated a high level of symptoms. QLQ-LC13 time to definitive deterioration was defined as the time from randomization to the earliest date a patient shows a 10 point or higher increase from baseline in any of the ALCLC13 scores related to pain in chest, cough, or dyspnea (with no later change below this threshold), or death due to any cause. Each cycle was 21 days.

End point type

Secondary

End point timeframe

Screening and treatment phase up to 92 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	115	116
Units: months
median (confidence interval 95%)	13.4 (8.4 to 16.7)	2.8 (1.0 to 5.6)

No statistical analyses for this end point

Secondary: Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS)

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End point title

Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS)

End point description

The LCSS patient scale uses a 24-hour recall period and contains nine items: six measuring major symptoms for lung cancer (appetite loss, fatigue, cough, dyspnea, hemoptysis, pain), and three summary items related to total symptom distress, normal activity status, and overall quality of life. The total scale used is a 100 mm visual analog scale to measure the intensity of patient responses, with zero corresponding to the lowest rating (best status) and 100 representing the highest rating (worst status). The total score was calculated as the mean of the 9 items. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.

End point type

Secondary

End point timeframe

Screening and treatment phase up to 92 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	107	85
Units: millimeters
least squares mean (standard error)
LCSS Total Score n=106,82	22.0 ( 0.87 )	26.3 ( 1.33 )
Appetite Loss n=107,85	28.0 ( 1.26 )	26.6 ( 1.99 )
Fatigue n=107,84	34.6 ( 1.33 )	39.2 ( 2.06 )
Cough n=107,84	11.5 ( 1.01 )	18.4 ( 1.56 )
Shortness of Breath n=107,85	18.2 ( 0.99 )	24.8 ( 1.56 )
Hemoptysis n=107,85	1.8 ( 0.34 )	2.2 ( 0.55 )
Pain n=107,85	18.2 ( 1.25 )	24.3 ( 1.92 )
Total Symptom Distress n=107,85	20.7 ( 1.26 )	24.6 ( 1.92 )
Normal Activity Status n=107,85	31.3 ( 1.47 )	36.8 ( 2.21 )
Overall Quality of Life n=106,84	33.1 ( 1.27 )	36.4 ( 1.94 )
LCSS Average Symptom Burden Index n=107,83	18.8 ( 0.77 )	22.9 ( 1.20 )

No statistical analyses for this end point

Secondary: Least Squares Mean Scores on the EQ-5D-5L Index

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End point title

Least Squares Mean Scores on the EQ-5D-5L Index

End point description

The EQ-5D descriptive classification consists of five dimensions of health: mobility, self-care, usual activities, anxiety/depression and pain/discomfort. Patients are requested to select the statement which best describes their condition on that day for each dimension. EQ-5D-5L index scores can range from −0.59 to 1, where 1 is the best possible health state. Each cycle was 21 days. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.

End point type

Secondary

End point timeframe

Screening and treatment phase up to 92 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	107	88
Units: score on a scale
least squares mean (standard error)	0.7837 ( 0.01039 )	0.7108 ( 0.01533 )

No statistical analyses for this end point

Secondary: Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS)

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End point title

Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS)

End point description

The EQ-5D descriptive classification consists of five dimensions of health: mobility, self-care, usual activities, anxiety/depression and pain/discomfort. Patients are requested to select the statement which best describes their condition on that day for each dimension. EQ VAS scores can range from 0 to 100, where 100 is the best possible health state. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.

End point type

Secondary

End point timeframe

Screening and treatment phase up to 92 months

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	106	86
Units: score on a scale
least squares mean (standard error)	71.8 ( 0.98 )	69.0 ( 1.45 )

No statistical analyses for this end point

Secondary: Cmax for Ceritinib

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End point title

Cmax for Ceritinib

End point description

The observed maximum plasma concentration following administration

End point type

Secondary

End point timeframe

Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, and 8 hours post-dose. Each cycle was 21 days.

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	4	0 ^[1]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 n=4,0	90.4 ( 49.8 )	( )
Cycle 2, Day 1 n=2,0	1170 ( 17.7 )	( )

Notes
[1] - Data for this endpoint are reported for patients with available data.

No statistical analyses for this end point

Secondary: Tmax for Ceritinib

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End point title

Tmax for Ceritinib

End point description

The time to reach peak or maximum concentration

End point type

Secondary

End point timeframe

Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, and 8 hours post-dose. Each cycle was 21 days.

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	4	0 ^[2]
Units: hours
median (full range (min-max))
Cycle 1, Day 1 n=4,0	6.03 (4.17 to 23.6)	( to )
Cycle 2, Day 1 n=2,0	7.15 (6.17 to 8.13)	( to )

Notes
[2] - Data for this endpoint are reported for patients with available data.

No statistical analyses for this end point

Secondary: Tlast for Ceritinib

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End point title

Tlast for Ceritinib

End point description

The time to last quantifiable concentration

End point type

Secondary

End point timeframe

Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	4	0 ^[3]
Units: hours
median (full range (min-max))
Cycle 1, Day 1 n=4,0	24 (23.6 to 24.1)	( to )
Cycle 2, Day 1 n=2,0	23.9 (23.7 to 24.2)	( to )

Notes
[3] - Data for this endpoint are reported for patients with available data.

No statistical analyses for this end point

Secondary: AUC0-24h for Ceritinib

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End point title

AUC0-24h for Ceritinib

End point description

The area under the plasma concentration-time curve calculated from time zero to 24 hours

End point type

Secondary

End point timeframe

Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	4	0 ^[4]
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 n=4,0	1470 ( 65.1 )	( )
Cycle 2, Day 1 n=2,0	25000 ( 19.0 )	( )

Notes
[4] - Data for this endpoint are reported for patients with available data.

No statistical analyses for this end point

Secondary: Mean Accumulation Ratio (Racc) for Ceritinib

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End point title

Mean Accumulation Ratio (Racc) for Ceritinib

End point description

Accumulation ratio calculated using AUC0-24 values obtained from a dosing interval at steady-state (Cycle 2, Day 1) divided by AUC0-24 on Cycle 1, Day 1.

End point type

Secondary

End point timeframe

Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	1	0 ^[5]
Units: ratio
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 n=0,0	999 ( 999 )	( )
Cycle 2, Day 1 n=1,0	15.5 ( 999 )	( )

Notes
[5] - Data for this endpoint are reported for patients with available data.

No statistical analyses for this end point

Secondary: Clearance Rate at Steady State (CLss/F) for Ceritinib

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End point title

Clearance Rate at Steady State (CLss/F) for Ceritinib

End point description

The apparent total body clearance from plasma. CLss/F is calculated from AUC0-24 assuming steady state (CLss/F=Dose/AUC0-24).

End point type

Secondary

End point timeframe

Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.

End point values	Ceritinib	Chemotherapy
Number of subjects analysed	2	0 ^[6]
Units: L/h
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 n=0,0	999 ( 999 )	( )
Cycle 2, Day 1 n=2,0	30 ( 19.0 )	( )

Notes
[6] - Data for this endpoint are reported for patients with available data.

No statistical analyses for this end point

Secondary: Post-Hoc: All Collected Deaths

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End point title

Post-Hoc: All Collected Deaths

End point description

Pre-treatment deaths: from day of patient’s informed consent to the day before first dose of study treatment. On-treatment deaths: from first dose of study treatment to 30 days following the last dose of study treatment at the end of treatment phase. For crossover patients, from first dose of ceritinib at the extension treatment phase to 30 days following the last dose. Survival Follow-up deaths: from Day 31 after last dose of study treatment to the data cut-off date.

End point type

Secondary

End point timeframe

Pre-treatment and on-treatment deaths: Up to approximately 8 years. Post-treatment survival follow-up deaths: Up to an additional 2.5 years.

End point values	Ceritinib	Chemotherapy	Chemotherapy/Ceritinib
Number of subjects analysed	115	116	78
Units: Participants
Pre-treatment deaths	0	2	0
On-treatment deaths	16	5	19
Survival follow-up deaths	86	18	44
All deaths	102	25	63

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from day of first dose of study medication to last dose of study medication plus 30 days, up to approximately 8 years.

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

26.1

Reporting group title

Ceritinib

Reporting group description

Ceritinib 750 mg

Reporting group title

Chemotherapy/Ceritinib

Reporting group description

Patients randomized to chemotherapy who crossed over to ceritinib at the extension treatment phase

Reporting group title

Chemotherapy

Reporting group description

Chemotherapy as determined by BIRC

Serious adverse events	Ceritinib	Chemotherapy/Ceritinib	Chemotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	57 / 115 (49.57%)	45 / 78 (57.69%)	35 / 113 (30.97%)
number of deaths (all causes)	16	19	5
number of deaths resulting from adverse events	1	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour flare
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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 / 115 (0.00%)	2 / 78 (2.56%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Metastases to central nervous system
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Vascular disorders
Lymphoedema
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Deep vein thrombosis
subjects affected / exposed	1 / 115 (0.87%)	1 / 78 (1.28%)	0 / 113 (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
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Asthenia
subjects affected / exposed	2 / 115 (1.74%)	2 / 78 (2.56%)	3 / 113 (2.65%)
occurrences causally related to treatment / all	0 / 2	2 / 2	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 2
Condition aggravated
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
General physical health deterioration
subjects affected / exposed	7 / 115 (6.09%)	1 / 78 (1.28%)	2 / 113 (1.77%)
occurrences causally related to treatment / all	2 / 7	0 / 2	1 / 2
deaths causally related to treatment / all	1 / 5	0 / 1	0 / 0
Fatigue
subjects affected / exposed	2 / 115 (1.74%)	1 / 78 (1.28%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Non-cardiac chest pain
subjects affected / exposed	2 / 115 (1.74%)	3 / 78 (3.85%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pyrexia
subjects affected / exposed	4 / 115 (3.48%)	1 / 78 (1.28%)	2 / 113 (1.77%)
occurrences causally related to treatment / all	0 / 4	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Acute respiratory failure
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pneumonitis
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pneumothorax
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Pulmonary embolism
subjects affected / exposed	0 / 115 (0.00%)	2 / 78 (2.56%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Respiratory distress
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	3 / 115 (2.61%)	2 / 78 (2.56%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0
Pleural effusion
subjects affected / exposed	5 / 115 (4.35%)	5 / 78 (6.41%)	2 / 113 (1.77%)
occurrences causally related to treatment / all	1 / 5	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Interstitial lung disease
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Dyspnoea
subjects affected / exposed	8 / 115 (6.96%)	4 / 78 (5.13%)	5 / 113 (4.42%)
occurrences causally related to treatment / all	1 / 8	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 3	0 / 2	0 / 1
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hallucination
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
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 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anxiety disorder
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Anxiety
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Product issues
Device failure
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Aspartate aminotransferase increased
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
C-reactive protein increased
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Electrocardiogram T wave inversion
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Neutrophil count decreased
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Tracheal obstruction
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	2 / 115 (1.74%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Pericardial effusion
subjects affected / exposed	4 / 115 (3.48%)	1 / 78 (1.28%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Pericarditis
subjects affected / exposed	1 / 115 (0.87%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Coordination abnormal
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Cognitive disorder
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Cerebellar infarction
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Brain oedema
subjects affected / exposed	1 / 115 (0.87%)	1 / 78 (1.28%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Aphasia
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Intracranial mass
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	2 / 115 (1.74%)	0 / 78 (0.00%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Seizure
subjects affected / exposed	1 / 115 (0.87%)	2 / 78 (2.56%)	2 / 113 (1.77%)
occurrences causally related to treatment / all	0 / 1	0 / 9	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Petit mal epilepsy
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Partial seizures
subjects affected / exposed	1 / 115 (0.87%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Parkinsonism
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Paraparesis
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Syncope
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Febrile neutropenia
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
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
Lenticular opacities
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Visual field defect
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 115 (1.74%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 115 (0.87%)	1 / 78 (1.28%)	0 / 113 (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
Faecaloma
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Gastric perforation
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Vomiting
subjects affected / exposed	6 / 115 (5.22%)	5 / 78 (6.41%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	3 / 6	3 / 5	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Nausea
subjects affected / exposed	8 / 115 (6.96%)	4 / 78 (5.13%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	6 / 9	4 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Haematemesis
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal toxicity
subjects affected / exposed	1 / 115 (0.87%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal perforation
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Gastrointestinal obstruction
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Gastritis
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Hepatobiliary disorders
Jaundice
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Hepatic lesion
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Hepatic failure
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute hepatic failure
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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 and urinary disorders
Urinary retention
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Urinary bladder rupture
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Renal failure
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	2 / 115 (1.74%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mobility decreased
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Back pain
subjects affected / exposed	1 / 115 (0.87%)	1 / 78 (1.28%)	2 / 113 (1.77%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Biliary tract infection
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Bacterial pyelonephritis
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic infection
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Pseudomembranous colitis
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Respiratory tract infection
subjects affected / exposed	3 / 115 (2.61%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	6 / 115 (5.22%)	6 / 78 (7.69%)	4 / 113 (3.54%)
occurrences causally related to treatment / all	1 / 8	1 / 8	3 / 4
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0
Oropharyngeal candidiasis
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Oral herpes
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Typhoid fever
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Nasopharyngitis
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Mucosal infection
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	0 / 113 (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
Lower respiratory tract infection
subjects affected / exposed	1 / 115 (0.87%)	1 / 78 (1.28%)	0 / 113 (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
Localised infection
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Infection
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Neutropenic sepsis
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	2 / 113 (1.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Urosepsis
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Dehydration
subjects affected / exposed	2 / 115 (1.74%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 115 (0.87%)	1 / 78 (1.28%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 115 (0.87%)	1 / 78 (1.28%)	0 / 113 (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
Hyperglycaemia
subjects affected / exposed	1 / 115 (0.87%)	3 / 78 (3.85%)	0 / 113 (0.00%)
occurrences causally related to treatment / all	0 / 1	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 115 (0.00%)	1 / 78 (1.28%)	0 / 113 (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
Decreased appetite
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	1 / 113 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
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	Ceritinib	Chemotherapy/Ceritinib	Chemotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	114 / 115 (99.13%)	76 / 78 (97.44%)	111 / 113 (98.23%)
Vascular disorders
Hypertension
subjects affected / exposed	4 / 115 (3.48%)	5 / 78 (6.41%)	4 / 113 (3.54%)
occurrences all number	4	5	4
General disorders and administration site conditions
Asthenia
subjects affected / exposed	29 / 115 (25.22%)	13 / 78 (16.67%)	19 / 113 (16.81%)
occurrences all number	46	18	32
Fatigue
subjects affected / exposed	34 / 115 (29.57%)	17 / 78 (21.79%)	32 / 113 (28.32%)
occurrences all number	47	23	39
Malaise
subjects affected / exposed	7 / 115 (6.09%)	7 / 78 (8.97%)	5 / 113 (4.42%)
occurrences all number	8	7	6
Non-cardiac chest pain
subjects affected / exposed	16 / 115 (13.91%)	11 / 78 (14.10%)	4 / 113 (3.54%)
occurrences all number	22	15	4
Oedema peripheral
subjects affected / exposed	6 / 115 (5.22%)	5 / 78 (6.41%)	11 / 113 (9.73%)
occurrences all number	6	5	12
Pain
subjects affected / exposed	8 / 115 (6.96%)	5 / 78 (6.41%)	2 / 113 (1.77%)
occurrences all number	8	7	2
Pyrexia
subjects affected / exposed	19 / 115 (16.52%)	14 / 78 (17.95%)	16 / 113 (14.16%)
occurrences all number	32	25	25
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	2 / 115 (1.74%)	7 / 78 (8.97%)	4 / 113 (3.54%)
occurrences all number	2	15	8
Oropharyngeal pain
subjects affected / exposed	5 / 115 (4.35%)	4 / 78 (5.13%)	4 / 113 (3.54%)
occurrences all number	5	4	4
Epistaxis
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	6 / 113 (5.31%)
occurrences all number	0	0	6
Dyspnoea
subjects affected / exposed	18 / 115 (15.65%)	13 / 78 (16.67%)	18 / 113 (15.93%)
occurrences all number	19	17	20
Cough
subjects affected / exposed	20 / 115 (17.39%)	13 / 78 (16.67%)	20 / 113 (17.70%)
occurrences all number	24	19	22
Rhinorrhoea
subjects affected / exposed	2 / 115 (1.74%)	2 / 78 (2.56%)	6 / 113 (5.31%)
occurrences all number	2	2	6
Productive cough
subjects affected / exposed	7 / 115 (6.09%)	6 / 78 (7.69%)	7 / 113 (6.19%)
occurrences all number	8	6	7
Psychiatric disorders
Insomnia
subjects affected / exposed	11 / 115 (9.57%)	6 / 78 (7.69%)	13 / 113 (11.50%)
occurrences all number	13	6	13
Anxiety
subjects affected / exposed	4 / 115 (3.48%)	7 / 78 (8.97%)	5 / 113 (4.42%)
occurrences all number	4	8	5
Investigations
Alanine aminotransferase increased
subjects affected / exposed	52 / 115 (45.22%)	29 / 78 (37.18%)	10 / 113 (8.85%)
occurrences all number	97	55	11
Amylase increased
subjects affected / exposed	7 / 115 (6.09%)	5 / 78 (6.41%)	3 / 113 (2.65%)
occurrences all number	20	7	3
Aspartate aminotransferase increased
subjects affected / exposed	44 / 115 (38.26%)	25 / 78 (32.05%)	5 / 113 (4.42%)
occurrences all number	76	51	6
Blood alkaline phosphatase increased
subjects affected / exposed	28 / 115 (24.35%)	12 / 78 (15.38%)	1 / 113 (0.88%)
occurrences all number	35	13	2
Blood creatinine increased
subjects affected / exposed	24 / 115 (20.87%)	21 / 78 (26.92%)	1 / 113 (0.88%)
occurrences all number	46	39	1
Electrocardiogram QT prolonged
subjects affected / exposed	14 / 115 (12.17%)	8 / 78 (10.26%)	0 / 113 (0.00%)
occurrences all number	25	14	0
Gamma-glutamyltransferase increased
subjects affected / exposed	27 / 115 (23.48%)	18 / 78 (23.08%)	3 / 113 (2.65%)
occurrences all number	31	21	3
Lipase increased
subjects affected / exposed	1 / 115 (0.87%)	5 / 78 (6.41%)	0 / 113 (0.00%)
occurrences all number	9	8	0
Neutrophil count decreased
subjects affected / exposed	1 / 115 (0.87%)	0 / 78 (0.00%)	8 / 113 (7.08%)
occurrences all number	5	0	14
Weight decreased
subjects affected / exposed	37 / 115 (32.17%)	13 / 78 (16.67%)	7 / 113 (6.19%)
occurrences all number	42	13	7
White blood cell count decreased
subjects affected / exposed	2 / 115 (1.74%)	0 / 78 (0.00%)	7 / 113 (6.19%)
occurrences all number	4	0	9
Nervous system disorders
Tremor
subjects affected / exposed	6 / 115 (5.22%)	7 / 78 (8.97%)	0 / 113 (0.00%)
occurrences all number	6	8	0
Somnolence
subjects affected / exposed	5 / 115 (4.35%)	5 / 78 (6.41%)	3 / 113 (2.65%)
occurrences all number	5	6	3
Paraesthesia
subjects affected / exposed	3 / 115 (2.61%)	0 / 78 (0.00%)	6 / 113 (5.31%)
occurrences all number	3	0	7
Neuropathy peripheral
subjects affected / exposed	2 / 115 (1.74%)	1 / 78 (1.28%)	9 / 113 (7.96%)
occurrences all number	3	1	9
Headache
subjects affected / exposed	28 / 115 (24.35%)	16 / 78 (20.51%)	18 / 113 (15.93%)
occurrences all number	43	20	21
Dizziness
subjects affected / exposed	13 / 115 (11.30%)	10 / 78 (12.82%)	8 / 113 (7.08%)
occurrences all number	16	12	8
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	3 / 115 (2.61%)	6 / 78 (7.69%)	9 / 113 (7.96%)
occurrences all number	5	8	17
Febrile neutropenia
subjects affected / exposed	0 / 115 (0.00%)	0 / 78 (0.00%)	6 / 113 (5.31%)
occurrences all number	0	0	6
Anaemia
subjects affected / exposed	7 / 115 (6.09%)	8 / 78 (10.26%)	20 / 113 (17.70%)
occurrences all number	8	13	22
Neutropenia
subjects affected / exposed	6 / 115 (5.22%)	6 / 78 (7.69%)	25 / 113 (22.12%)
occurrences all number	11	6	34
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	29 / 115 (25.22%)	20 / 78 (25.64%)	10 / 113 (8.85%)
occurrences all number	44	27	11
Nausea
subjects affected / exposed	73 / 115 (63.48%)	46 / 78 (58.97%)	27 / 113 (23.89%)
occurrences all number	119	72	40
Stomatitis
subjects affected / exposed	8 / 115 (6.96%)	5 / 78 (6.41%)	15 / 113 (13.27%)
occurrences all number	11	6	23
Vomiting
subjects affected / exposed	61 / 115 (53.04%)	37 / 78 (47.44%)	9 / 113 (7.96%)
occurrences all number	144	61	10
Dyspepsia
subjects affected / exposed	6 / 115 (5.22%)	2 / 78 (2.56%)	1 / 113 (0.88%)
occurrences all number	8	2	1
Diarrhoea
subjects affected / exposed	84 / 115 (73.04%)	57 / 78 (73.08%)	21 / 113 (18.58%)
occurrences all number	180	100	31
Constipation
subjects affected / exposed	25 / 115 (21.74%)	20 / 78 (25.64%)	15 / 113 (13.27%)
occurrences all number	35	24	26
Abdominal pain upper
subjects affected / exposed	22 / 115 (19.13%)	11 / 78 (14.10%)	5 / 113 (4.42%)
occurrences all number	26	15	5
Dysphagia
subjects affected / exposed	3 / 115 (2.61%)	4 / 78 (5.13%)	3 / 113 (2.65%)
occurrences all number	3	4	3
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	14 / 115 (12.17%)	6 / 78 (7.69%)	7 / 113 (6.19%)
occurrences all number	15	8	8
Dry skin
subjects affected / exposed	6 / 115 (5.22%)	4 / 78 (5.13%)	2 / 113 (1.77%)
occurrences all number	7	5	2
Alopecia
subjects affected / exposed	6 / 115 (5.22%)	2 / 78 (2.56%)	24 / 113 (21.24%)
occurrences all number	6	2	24
Rash
subjects affected / exposed	15 / 115 (13.04%)	15 / 78 (19.23%)	13 / 113 (11.50%)
occurrences all number	20	18	16
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 115 (0.00%)	4 / 78 (5.13%)	2 / 113 (1.77%)
occurrences all number	0	4	2
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	8 / 115 (6.96%)	4 / 78 (5.13%)	7 / 113 (6.19%)
occurrences all number	10	5	7
Neck pain
subjects affected / exposed	8 / 115 (6.96%)	1 / 78 (1.28%)	2 / 113 (1.77%)
occurrences all number	10	1	2
Myalgia
subjects affected / exposed	6 / 115 (5.22%)	6 / 78 (7.69%)	14 / 113 (12.39%)
occurrences all number	6	8	16
Musculoskeletal chest pain
subjects affected / exposed	11 / 115 (9.57%)	3 / 78 (3.85%)	4 / 113 (3.54%)
occurrences all number	12	3	4
Arthralgia
subjects affected / exposed	23 / 115 (20.00%)	13 / 78 (16.67%)	16 / 113 (14.16%)
occurrences all number	31	15	21
Back pain
subjects affected / exposed	27 / 115 (23.48%)	10 / 78 (12.82%)	9 / 113 (7.96%)
occurrences all number	36	14	10
Muscular weakness
subjects affected / exposed	4 / 115 (3.48%)	5 / 78 (6.41%)	5 / 113 (4.42%)
occurrences all number	4	6	5
Infections and infestations
Bronchitis
subjects affected / exposed	4 / 115 (3.48%)	4 / 78 (5.13%)	4 / 113 (3.54%)
occurrences all number	9	6	5
Cystitis
subjects affected / exposed	0 / 115 (0.00%)	4 / 78 (5.13%)	0 / 113 (0.00%)
occurrences all number	0	4	0
Influenza
subjects affected / exposed	7 / 115 (6.09%)	2 / 78 (2.56%)	1 / 113 (0.88%)
occurrences all number	8	3	1
Nasopharyngitis
subjects affected / exposed	13 / 115 (11.30%)	6 / 78 (7.69%)	2 / 113 (1.77%)
occurrences all number	16	14	2
Oral candidiasis
subjects affected / exposed	6 / 115 (5.22%)	1 / 78 (1.28%)	3 / 113 (2.65%)
occurrences all number	7	1	3
Pneumonia
subjects affected / exposed	6 / 115 (5.22%)	5 / 78 (6.41%)	1 / 113 (0.88%)
occurrences all number	14	6	1
Respiratory tract infection
subjects affected / exposed	7 / 115 (6.09%)	3 / 78 (3.85%)	1 / 113 (0.88%)
occurrences all number	9	3	2
Upper respiratory tract infection
subjects affected / exposed	3 / 115 (2.61%)	5 / 78 (6.41%)	4 / 113 (3.54%)
occurrences all number	4	6	4
Urinary tract infection
subjects affected / exposed	1 / 115 (0.87%)	6 / 78 (7.69%)	4 / 113 (3.54%)
occurrences all number	1	7	18
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	50 / 115 (43.48%)	25 / 78 (32.05%)	23 / 113 (20.35%)
occurrences all number	62	27	24
Hyperglycaemia
subjects affected / exposed	9 / 115 (7.83%)	5 / 78 (6.41%)	3 / 113 (2.65%)
occurrences all number	12	5	3
Hypoalbuminaemia
subjects affected / exposed	4 / 115 (3.48%)	5 / 78 (6.41%)	2 / 113 (1.77%)
occurrences all number	5	5	2
Hypokalaemia
subjects affected / exposed	12 / 115 (10.43%)	7 / 78 (8.97%)	1 / 113 (0.88%)
occurrences all number	20	8	1

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Were there any global substantial amendments to the protocol? Yes

27 Aug 2013

This protocol amendment was implemented to address the availability of new safety data, to amend the eligible study population, and to clarify sections of the protocol where additional guidance was required.

20 May 2014

This protocol amendment was implemented to expand the inclusion criteria to allow for one (as in the prior version of the protocol) or two prior regimens of cytotoxic chemotherapy (one regimen must have included a platinum doublet) for the treatment of locally advanced or metastatic ALK - positive NSCLC and to allow more than one course of prior crizotinib treatment. Additional amendment items included updated safety information and clarification of sections of the protocol where additional guidance was required; updated safety data in the protocol and associated Informed Consent Form (ICF) to be consistent with the Investigator’s Brochure Edition 6 (release 27 November 2013).

23 Apr 2015

This protocol amendment was implemented to delete the requirement for patients randomized to the chemotherapy arm to wait 31 days before crossing over to the crizotinib treatment arm and provide guidance on ceritinib treatment initiation for crossover patients to allow patients to cross over earlier if eligible. The time window for crossover to ceritinib treatment arm was increased from 56 days to 84 days, to allow for resolution of any adverse events (AEs) to grade ≤ 1 (NCI- Common Terminology Criteria for Adverse Events [CTCAE] v 4.03). In addition, patients who had a World Health Organization (WHO) performance status above 2 or a history of interstitial lung disease or interstitial pneumonitis were not allowed to cross over. Removed “start of new anti-cancer therapy” as an allowable reason to stop collecting tumor assessments. Updated the protocol based on currently available safety data. Pancreatic enzyme elevations (lipase and/or amylase) occur in patients treated with ceritinib. Clinical data suggest that a small proportion (<1%) of patients treated with ceritinib can develop clinical pancreatitis, and the causal role of ceritinib in these cases cannot be excluded. Due to this finding, the protocol was amended to include additional eligibility criteria, dose modification, and follow-up monitoring language for patients who may have experienced this safety finding. Added an evaluation of the anticipated benefits and risks to comply with European Union (EU) clinical trial regulations. Included an additional condition for the final analysis of PFS, requiring that all randomized patients completed at least 12 weeks of follow-up or had discontinued earlier.

11 Dec 2015

This protocol amendment was implemented to provide follow-up evaluations for hepatic toxicities and work-up guidelines for potential drug-induced liver injury (DILI) cases in order to optimize patient safety. Other changes: Dose guidance modification for QTcF text was updated to provide clarification on monitoring procedure. The secondary objectives and related endpoints were updated to specify that assessment of the antitumor activity of ceritinib versus reference chemotherapy in the brain, as measured by OIRR, IDCR and DOIR, would be as assessed by BIRC neuro-radiologist per modified RECIST 1.1 to allow selecting up to 5 measurable brain lesions as target lesions. In addition, already present information was clarified, where required.

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.

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

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Clinical trials

Clinical Trial Results: A phase III, multicenter, randomized, open-label study of oral LDK378 versus standard chemotherapy in adult patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer who have been treated previously with chemotherapy (platinum doublet) and crizotinib

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression Free Survival (PFS) per Blinded Independent Review Committee (BIRC)

Primary: Progression Free Survival (PFS) per Blinded Independent Review Committee (BIRC)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Progression Free Survival (PFS) per Investigator Assessment

Secondary: Progression Free Survival (PFS) per Investigator Assessment

Secondary: Overall Response Rate (ORR) per BIRC

Secondary: Overall Response Rate (ORR) per BIRC

Secondary: Overall Response Rate (ORR) per Investigator Assessment

Secondary: Overall Response Rate (ORR) per Investigator Assessment

Secondary: Duration of Response (DOR) per BIRC

Secondary: Duration of Response (DOR) per BIRC

Secondary: Duration of Response (DOR) per Investigator Assessment

Secondary: Duration of Response (DOR) per Investigator Assessment

Secondary: Disease Control Rate (DCR) per BIRC

Secondary: Disease Control Rate (DCR) per BIRC

Secondary: Disease Control Rate (DCR) per Investigator Assessment

Secondary: Disease Control Rate (DCR) per Investigator Assessment

Secondary: Time to Response (TTR) per BIRC

Secondary: Time to Response (TTR) per BIRC

Secondary: Time to response (TTR) per Investigator Assessment

Secondary: Time to response (TTR) per Investigator Assessment

Secondary: Overall Intracranial Response Rate (OIRR) per BIRC

Secondary: Overall Intracranial Response Rate (OIRR) per BIRC

Secondary: Intracranial Disease Control Rate (IDCR) per BIRC

Secondary: Intracranial Disease Control Rate (IDCR) per BIRC

Secondary: Duration of Intracranial Response (DOIR) per BIRC

Secondary: Duration of Intracranial Response (DOIR) per BIRC

Secondary: Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer’s Core Quality of Life Questionnaire (EORTC-QLQC30)

Secondary: Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer’s Core Quality of Life Questionnaire (EORTC-QLQC30)

Secondary: EORTC QLQ-LC13 Time to Definitive Deterioration

Secondary: EORTC QLQ-LC13 Time to Definitive Deterioration

Secondary: Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS)

Secondary: Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS)

Secondary: Least Squares Mean Scores on the EQ-5D-5L Index

Secondary: Least Squares Mean Scores on the EQ-5D-5L Index

Secondary: Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS)

Secondary: Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS)

Secondary: Cmax for Ceritinib

Secondary: Cmax for Ceritinib

Secondary: Tmax for Ceritinib

Secondary: Tmax for Ceritinib

Secondary: Tlast for Ceritinib

Secondary: Tlast for Ceritinib

Secondary: AUC0-24h for Ceritinib

Secondary: AUC0-24h for Ceritinib

Secondary: Mean Accumulation Ratio (Racc) for Ceritinib

Secondary: Mean Accumulation Ratio (Racc) for Ceritinib

Secondary: Clearance Rate at Steady State (CLss/F) for Ceritinib

Secondary: Clearance Rate at Steady State (CLss/F) for Ceritinib

Secondary: Post-Hoc: All Collected Deaths

Secondary: Post-Hoc: All Collected Deaths

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase III, multicenter, randomized, open-label study of oral LDK378 versus standard chemotherapy in adult patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer who have been treated previously with chemotherapy (platinum doublet) and crizotinib