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Clinical Trial Results:
A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination with MEK162 in Adult Subjects with BRAF V600 - Dependent Advanced Solid Tumors.

Summary
EudraCT number	2011-005875-17
Trial protocol	ES IT BE FR
Global end of trial date	09 Mar 2023

Results information
Results version number	v1(current)
This version publication date	19 Mar 2024
First version publication date	19 Mar 2024
Other versions

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

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Trial information

Top of page

Sponsor protocol code

C4221005

ISRCTN number

US NCT number

NCT01543698

WHO universal trial number (UTN)

Other trial identifiers

CMEK162X2110: Study id

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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

23 Jun 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Mar 2023

Was the trial ended prematurely?

Main objective of the trial

Phase 1b: To estimate the MTD(s) and/or RP2D(s) of oral LGX818 in combination with oral MEK162 and of oral LGX818 combination with oral MEK162 and oral LEE011 in patients with BRAF V600-dependent advanced solid tumors. Phase 2: To assess clinical efficacy of the LGX818 and MEK162 dual combination and LGX818 and MEK162 and LEE011 triple combination in the respective Phase 2 populations.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

28 May 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 18

Country: Number of subjects enrolled

Belgium: 8

Country: Number of subjects enrolled

Canada: 17

Country: Number of subjects enrolled

France: 8

Country: Number of subjects enrolled

Italy: 50

Country: Number of subjects enrolled

Singapore: 5

Country: Number of subjects enrolled

Spain: 18

Country: Number of subjects enrolled

Switzerland: 21

Country: Number of subjects enrolled

United States: 44

Worldwide total number of subjects

189

EEA total number of subjects

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)

149

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Phase1b:subjects with V-raf murine sarcoma viral oncogene homolog B1(BRAF)V600-dependent advanced solid tumors.Phase2:BRAF V600 mutant metastatic colorectal cancer(mCRC)[Arm1,dual];BRAF V600 mutant melanoma:progressed after prior selective BRAF inhibitor [Arm 2,dual];metastatic BRAF mutant melanoma:naïve to BRAF inhibitor [Arm3,dual]/[ArmA,triple].

Screening details

189 subjects were enrolled. Phase1b:47 subjects for dual and 21 for triple combo. Phase2: a) Dual combo- Arm1(mCRC)=11; Arm2 (prior BRAFi melanoma) =26; Arm3 (BRAFi-naïve melanoma)=42 subjects b) Triple combo-ArmA (BRAFi-naïve melanoma) =42 subjects. Dual combo of LGX818 (enco) and MEK162 (bini) and triple combo of LGX818, MEK162 and LEE011 (ribo).

Period 1 title

Baseline Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg

Arm description

Subjects received Encorafenib 50 milligram (mg) once daily (QD) and Binimetinib 45 mg twice a daily (BID) orally 4 weeks till sponsor/investigator determined the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 50 mg was administered orally.

Phase 1b: Enco 100 mg+ Bini 45 mg

Arm description

Subjects received Encorafenib 100 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 100 mg was administered orally.

Phase 1b: Enco 200 mg+Bini 45 mg

Arm description

Subjects received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Phase 1b: Enco 400 mg+Bini 45 mg

Arm description

Subjects received Encorafenib 400 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 400 mg was administered orally.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Phase 1b: Enco 450 mg+Bini 45 mg

Arm description

Subjects received Encorafenib 450 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 450 mg was administered orally

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Phase 1b: Enco 600 mg+Bini 45 mg

Arm description

Subjects received Encorafenib 600 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 600 mg was administered orally.

Phase 1b: Enco 800 mg+Bini 45 mg

Arm description

Subjects received Encorafenib 800 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 800 mg was administered orally.

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg

Arm description

Subjects received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 100 mg BID orally for 3 weeks on, 1 week off schedule, till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ribociclib 100 mg was administered orally.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg

Arm description

Subjects received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 200 mg BID orally for 3 weeks on, 1 week off schedule, till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ribociclib 200 mg was administered orally.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg

Arm description

Subjects received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 400 mg BID orally for 3 weeks on, 1 week off schedule, till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ribociclib 400 mg was administered orally.

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg

Arm description

Subjects received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 600 mg BID orally for 3 weeks on, 1 week off schedule, till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ribociclib 600 mg was administered orally.

Phase 2: Arm1(mCRC):Enco+Bini

Arm description

Subjects received Encorafenib at MTD (600 mg QD, permitted dose reduction to 450 mg QD) and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 450,600 mg was administered orally.

Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 450,600 mg was administered orally.

Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Capsule, Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 450,600 mg was administered orally.

Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo

Arm description

Subjects received Encorafenib 200 mg QD (MTD), Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 600 mg QD orally for 3 weeks on, 1 week off schedule until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ribociclib 600 mg was administered orally.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Number of subjects in period 1	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg	Phase 2: Arm1(mCRC):Enco+Bini	Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini	Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini	Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo
Started	6	5	4	5	13	8	6	4	5	6	6	11	26	42	42
Completed	6	5	4	5	13	8	6	4	5	6	6	11	26	42	42

Period 2 title

Phase 1b

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg

Arm description

Participants received Encorafenib 50 milligram (mg) once daily (QD) and Binimetinib 45 mg twice a daily (BID) orally 4 weeks till sponsor/investigator determined the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 50 mg was administered orally.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Phase 1b: Enco 100 mg+ Bini 45 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 100 mg was administered orally.

Phase 1b: Enco 200 mg+Bini 45 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Phase 1b: Enco 400 mg+Bini 45 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 400 mg was administered orally.

Phase 1b: Enco 450 mg+Bini 45 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 450 mg was administered orally

Phase 1b: Enco 600 mg+Bini 45 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 600 mg was administered orally.

Phase 1b: Enco 800 mg+Bini 45 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 800 mg was administered orally.

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ribociclib 100 mg was administered orally.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ribociclib 200 mg was administered orally.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Ribociclib 400 mg was administered orally.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ribociclib 600 mg was administered orally.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Number of subjects in period 2 ^[1]	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Started	6	5	4	5	13	8	6	4	5	6	6
Completed	0	0	0	0	0	0	0	0	0	0	0
Not completed	6	5	4	5	13	8	6	4	5	6	6
Adverse event, serious fatal	-	-	1	1	-	-	-	-	-	-	1
Consent withdrawn by subject	-	1	-	1	-	-	1	-	-	-	-
Disease progression	2	4	3	2	10	6	5	3	4	5	1
Adverse event, non-fatal	1	-	-	1	2	2	-	-	1	1	2
Administrative problems	1	-	-	-	1	-	-	1	-	-	2
Protocol deviation	2	-	-	-	-	-	-	-	-	-	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Only participants enrolled in Phase 1b was included in this period.

Period 3 title

Phase 2

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Phase 2: Arm1 (mCRC):Enco+Bini

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 450,600 mg was administered orally.

Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 450,600 mg was administered orally.

Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini

Arm description

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 450,600 mg was administered orally.

Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo

Arm description

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib 200 mg was administered orally.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ribociclib 600 mg was administered orally.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Binimetinib 45 mg was administered orally.

Number of subjects in period 3	Phase 2: Arm1 (mCRC):Enco+Bini	Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini	Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini	Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo
Started	11	26	42	42
Completed	0	0	0	0
Not completed	11	26	42	42
Adverse event, serious fatal	-	1	1	1
Consent withdrawn by subject	-	-	3	1
Disease progression	10	21	30	25
Adverse event, non-fatal	1	3	5	14
Administrative problems	-	-	3	1
Protocol deviation	-	1	-	-

Baseline characteristics

Top of page

Reporting group title

Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 100 mg+ Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 400 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 450 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 600 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 800 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg

Reporting group description

Reporting group title

Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg

Reporting group description

Reporting group title

Phase 2: Arm1(mCRC):Enco+Bini

Reporting group description

Reporting group title

Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini

Reporting group description

Reporting group title

Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini

Reporting group description

Reporting group title

Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo

Reporting group description

Reporting group values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg	Phase 2: Arm1(mCRC):Enco+Bini	Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini	Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini	Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo	Total
Number of subjects	6	5	4	5	13	8	6	4	5	6	6	11	26	42	42	189
Age Categorical
Units: Subjects
<=18 years	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Between 18 and 65 years	3	4	4	4	10	6	5	4	4	3	6	9	22	33	32	149
>=65 years	3	1	0	1	3	2	1	0	1	3	0	2	4	9	10	40
Age continuous
Units: years
arithmetic mean (standard deviation)	55.5 ± 18.17	55.2 ± 6.91	44.0 ± 14.05	49.0 ± 16.39	52.2 ± 17.69	52.0 ± 16.90	55.5 ± 14.71	48.5 ± 6.76	51.4 ± 19.24	58.0 ± 13.45	42.3 ± 9.58	55.3 ± 9.18	52.0 ± 14.23	54.7 ± 13.96	52.0 ± 15.70	-
Sex: Female, Male
Units: Subjects
Female	2	3	4	1	5	3	4	1	4	1	4	3	11	12	19	77
Male	4	2	0	4	8	5	2	3	1	5	2	8	15	30	23	112
Race/Ethnicity, Customized
Units: Subjects
Caucasian	4	5	2	5	12	8	6	4	5	6	6	11	24	37	42	177
Asian	2	0	2	0	1	0	0	0	0	0	0	0	1	0	0	6
Other- Race	0	0	0	0	0	0	0	0	0	0	0	0	1	5	0	6
Race/Ethnicity, Customized
Units: Subjects
Hispanic/Latino	0	0	0	0	0	0	0	0	0	0	0	0	2	1	1	4
Chinese	2	0	2	0	1	0	0	0	0	0	0	0	0	0	0	5
Other- Ethnicity	4	5	2	5	12	8	6	4	5	6	6	11	24	41	41	180

End points

Top of page

Reporting group title

Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 100 mg+ Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 400 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 450 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 600 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 800 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg

Reporting group description

Reporting group title

Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg

Reporting group description

Reporting group title

Phase 2: Arm1(mCRC):Enco+Bini

Reporting group description

Reporting group title

Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini

Reporting group description

Reporting group title

Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini

Reporting group description

Reporting group title

Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo

Reporting group description

Reporting group title

Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 100 mg+ Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 400 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 450 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 600 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 800 mg+Bini 45 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg

Reporting group description

Reporting group title

Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg

Reporting group description

Reporting group title

Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg

Reporting group description

Reporting group title

Phase 2: Arm1 (mCRC):Enco+Bini

Reporting group description

Reporting group title

Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini

Reporting group description

Reporting group title

Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini

Reporting group description

Reporting group title

Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo

Reporting group description

Primary: Number of Subjects With Dose Limiting Toxicities (DLTs): Phase 1b

Top of page

End point title

Number of Subjects With Dose Limiting Toxicities (DLTs): Phase 1b ^[1]

End point description

DLT was defined as an adverse event or abnormal laboratory value assessed as at least possibly related to the study medication, as clinically relevant, as unrelated to disease, disease progression, inter-current illness, or concomitant medications, which occurred (less than equal to) <=28 days following the first dose of LGX818 and MEK162 or LGX818 and MEK162 and LEE011 (cycle 1) and met the defined criteria for the study. Dose Determining Set (DDS) included all Phase 1b subjects from the safety set who either completed a minimum exposure requirement and had sufficient safety evaluations or discontinued prematurely due to a DLT. All subjects reported under "Number of Subjects Analyzed" contributed data to this endpoint measure.

End point type

Primary

End point timeframe

Phase 1b: Cycle 1 (28 days following the first dose of LGX818 and MEK162 or LGX818 and MEK162 and LEE011)

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: Only descriptive analysis was planned for this endpoint.

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	2	4	13	8	6	4	5	5	5
Units: Subjects	0	0	0	0	0	0	1	0	0	0	0

No statistical analyses for this end point

Primary: Disease Control Rate (DCR) at Week 16: Phase 2, Arm 1 (mCRC Subjects)

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End point title

Disease Control Rate (DCR) at Week 16: Phase 2, Arm 1 (mCRC Subjects) ^[2]

End point description

DCR was defined as percentage of subjects with a best overall response of complete response (CR), partial response (PR) or stable disease (SD). As per Response Evaluation Criteria in Solid tumors Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis less than (<)10 millimeter [mm]). PR was defined as more than equal to (>=) 30 percent (%) decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD). Full Analysis Set (FAS) included all subjects who received at least one dose of LGX818 or MEK162 or LEE011.

End point type

Primary

End point timeframe

Phase 2: Week 16

Notes
[2] - 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: Only descriptive analysis was planned for this endpoint.

End point values	Phase 2: Arm1 (mCRC):Enco+Bini
Number of subjects analysed	11
Units: Percentage of subjects
number (confidence interval 95%)	63.6 (30.8 to 89.1)

No statistical analyses for this end point

Primary: Objective Response Rate (ORR): Phase 2, Arms 2, 3 and A

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End point title

Objective Response Rate (ORR): Phase 2, Arms 2, 3 and A ^[3]

End point description

ORR was defined as the percentage of subjects with a best overall response of CR or PR. As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis <10 mm. PR was defined as >= 30% decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. FAS included all subjects who received at least one dose of LGX818 or MEK162 or LEE011.

End point type

Primary

End point timeframe

Phase 2: From Day 1 of dosing till complete response or partial response achieved (maximum exposure of treatment for Phase 2 was 111.5 months)

Notes
[3] - 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: Only descriptive analysis was planned for this endpoint.

End point values	Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini	Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini	Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo
Number of subjects analysed	26	42	42
Units: Percentage of subjects
number (confidence interval 95%)	42.3 (23.4 to 63.1)	66.7 (50.5 to 80.4)	59.5 (43.3 to 74.4)

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs): Overall Grades and AEs of Grade 3/4: Phase 1b

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End point title

Number of Subjects With Treatment Emergent Adverse Events (TEAEs): Overall Grades and AEs of Grade 3/4: Phase 1b

End point description

An adverse event (AE) was any untoward medical occurrence in a subject or clinical study subject, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those events with onset dates occurring during the on-treatment period (the time from the Day 1 up to 30 days after last dose). AEs were graded according to CTCAE version 4.03 as Grade 1 indicates Mild AE, Grade 2 indicates Moderate AE, Grade 3 indicates severe AE, and grade 4 indicates life-threatening consequences; urgent intervention indicated. Grade 5 indicates death related to AE. Safety set included all subjects who received at least one dose of LGX818 or MEK162 or LEE011 and had at least one valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

Phase 1b: Day 1 up to 30 days after last dose (maximum treatment exposure for Phase 1b was 118.3 months)

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: Subjects
Overall Grades	6	5	4	5	13	8	6	4	5	6	6
Grade 3/4	5	2	2	4	8	6	6	4	4	6	6

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity With Extrapolation of the Terminal Phase (AUCinf) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Top of page

End point title

Area Under the Concentration-time Curve From Time Zero to Infinity With Extrapolation of the Terminal Phase (AUCinf) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

End point description

AUCinf was reported in unit of measure as hour*nanogram per millilitre (h*ng/mL). FAS evaluated. All subjects reported under "Number of Subjects Analyzed" contributed data to the table; however, may not have evaluable data for every category. Here, “Number Analyzed” signifies number of subjects evaluable for specified categories.99999 signifies data could not be calculated as only 1 subject was evaluable.

End point type

Secondary

End point timeframe

Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hours (hr) post dose on Day 1 of Cycle 1

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: h*ng/mL
arithmetic mean (standard deviation)
Encorafenib; n=6,5,4,4,13,7,5,4,4,3,5	3740 ± 2350	11700 ± 6200	22000 ± 9790	42000 ± 23600	36700 ± 19400	57400 ± 27100	40200 ± 12100	15000 ± 7360	9960 ± 5940	18900 ± 9900	17400 ± 9480
Binimetinib; n=5,4,3,3,11,7,4,4,4,3,4	2190 ± 1350	1930 ± 529	3730 ± 2250	1960 ± 1140	2750 ± 1490	3090 ± 1600	2340 ± 462	2160 ± 1580	3000 ± 932	3110 ± 1450	2970 ± 458
Ribociclib;n=0,0,0,0,0,0,0,4,5,4,4	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	1040 ± 665	3030 ± 1600	7930 ± 5180	18200 ± 10400
Metabolite of Binimetinib;n=5,3,2,3,9,5,4,3,4,0,4	321 ± 225	271 ± 28.9	631 ± 296	275 ± 121	361 ± 184	449 ± 302	361 ± 78.1	173 ± 55.6	337 ± 29.2	99999 ± 99999	239 ± 79.1
Metabolite of Ribociclib;n=0,0,0,0,0,0,0,1,3,1,0	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	194 ± 99999	601 ± 225	1340 ± 99999	2160 ± 99999

No statistical analyses for this end point

Secondary: Number of Subjects With TEAEs: Overall Grades and AEs of Grade 3/4: Phase 2

Top of page

End point title

Number of Subjects With TEAEs: Overall Grades and AEs of Grade 3/4: Phase 2

End point description

An AE was any untoward medical occurrence in a subject or clinical study subject, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those events with onset dates occurring during the on-treatment period (the time from the Day 1 up to 30 days after last dose). AEs were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 as Grade 1 indicates Mild AE, Grade 2 indicates Moderate AE, Grade 3 indicates severe AE, and grade 4 indicates life-threatening consequences; urgent intervention indicated. Grade 5 indicates death related to AE. Safety set included all subjects who received at least one dose of LGX818 or MEK162 or LEE011 and had at least one valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

Phase 2: Day 1 up to 30 days after last dose (maximum treatment exposure for Phase 2 was 111.5 months)

End point values	Phase 2: Arm1 (mCRC):Enco+Bini	Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini	Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini	Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo
Number of subjects analysed	11	26	42	42
Units: Subjects
Overall Grades	11	26	42	42
Grade 3/4	5	15	27	34

No statistical analyses for this end point

Secondary: Area Under the Concentration-Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Top of page

End point title

Area Under the Concentration-Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

End point description

FAS evaluated. All subjects reported under "Number of Subjects Analyzed" contributed data to the table; however, may not have evaluable data for every category. Here, “Number Analyzed” signifies number of subjects evaluable for specified categories.

End point type

Secondary

End point timeframe

Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: h*ng/mL
arithmetic mean (standard deviation)
Encorafenib; n=6,5,4,4,13,7,6,4,5,6,6	3690 ± 2340	11500 ± 6070	22000 ± 9750	40200 ± 21700	36100 ± 19300	57000 ± 26800	38100 ± 11800	11400 ± 4530	9280 ± 4190	12700 ± 5020	15800 ± 7160
Binimetinib; n=6,5,3,4,13,7,4,4,5,6,6	1990 ± 1130	1990 ± 715	3300 ± 1990	1870 ± 867	2330 ± 1220	2790 ± 1480	2120 ± 478	1520 ± 663	2470 ± 878	2020 ± 843	2320 ± 635
Ribociclib; n=0,0,0,0,0,0,0,4,5,6,6	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	806 ± 549	2550 ± 1280	6700 ± 3720	14500 ± 7490
Metabolite of Binimetinib;n=6,5,3,4,13,7,4,4,5,6,6	276 ± 184	280 ± 50.5	372 ± 320	241 ± 82.5	287 ± 122	340 ± 244	307 ± 78.4	156 ± 53.8	259 ± 54.3	168 ± 109	161 ± 81.9
Metabolite of Ribociclib; n=0,0,0,0,0,0,0,4,5,6,6	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	81.4 ± 41.0	397 ± 145	758 ± 231	1200 ± 320

No statistical analyses for this end point

Secondary: AUClast at Steady State (AUClast,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Top of page

End point title

AUClast at Steady State (AUClast,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

End point description

FAS evaluated. All subjects reported under "Number of Subjects Analyzed" contributed data to the table; however, may not have evaluable data for every category.

End point type

Secondary

End point timeframe

Phase 1b: Pre dose,0.5,1.5, 2.5, 4, 6, 8 and 24 hr post dose on Day 15 of Cycle 1

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: h*ng/mL
arithmetic mean (standard deviation)
Encorafenib;n=6,5,2,3,11,6,6,4,5,5,5	2620 ± 1260	5510 ± 1280	4620 ± 1640	10200 ± 2280	15900 ± 8730	27300 ± 17900	25300 ± 7240	6310 ± 2340	8210 ± 2550	11800 ± 7000	15700 ± 6060
Binimetinib;n=6,5,2,4,11,6,5,4,4,5,5	2950 ± 1380	2610 ± 873	2660 ± 1900	2110 ± 1220	2550 ± 901	2590 ± 1640	2540 ± 529	2180 ± 1180	2820 ± 954	2740 ± 1230	2970 ± 1180
Ribociclib;n=0,0,0,0,0,0,0,4,5,5,5	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	462 ± 129	1520 ± 979	5620 ± 3730	10100 ± 2970
Metabolite of Binimetinib;n=6,5,2,4,11,6,5,4,4,5,5	147 ± 152	173 ± 125	118 ± 70.7	119 ± 96.5	157 ± 104	132 ± 142	190 ± 79.8	149 ± 136	210 ± 68.4	176 ± 92.5	169 ± 48.5
Metabolite of Ribociclib;n=0,0,0,0,0,0,0,4,5,5,5	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	255 ± 131	729 ± 267	2150 ± 399	3260 ± 891

No statistical analyses for this end point

Secondary: Area Under the Concentration-Time Curve From Time Zero to Tau After First Dose (AUCtau) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

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End point title

Area Under the Concentration-Time Curve From Time Zero to Tau After First Dose (AUCtau) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

End point description

FAS evaluated. All subjects reported under "Number of Subjects Analyzed" contributed data to the table; however, may not have evaluable data for every category.

End point type

Secondary

End point timeframe

Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: h*ng/mL
arithmetic mean (standard deviation)
Encorafenib;n=6,5,4,4,13,7,5,4,4,3,5	3700 ± 2320	11500 ± 6070	22000 ± 9750	40200 ± 21700	36300 ± 19000	57000 ± 26800	40000 ± 12100	14800 ± 7140	9940 ± 5900	18700 ± 9730	17300 ± 9300
Binimetinib;n=5,4,3,3,11,7,4,4,4,3,4	2130 ± 1330	1860 ± 532	3600 ± 2160	1890 ± 1110	2650 ± 1410	3010 ± 1560	2280 ± 477	1790 ± 979	2900 ± 939	2860 ± 1320	2900 ± 453
Ribociclib;n=0,0,0,0,0,0,0,4,5,6,6	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	845 ± 504	2550 ± 1280	6700 ± 3720	14500 ± 7490
Metabolite of Binimetinib;n=5,3,2,3,9,5,4,3,4,0,4	307 ± 222	265 ± 27.9	585 ± 304	257 ± 109	338 ± 162	430 ± 291	344 ± 82.0	152 ± 32.3	322 ± 23.5	99999 ± 99999	230 ± 79.1
Metabolite of Ribociclib;n=0,0,0,0,0,0,0,3,5,6,6	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	98.9 ± 25.9	397 ± 145	758 ± 231	1200 ± 320

No statistical analyses for this end point

Secondary: AUCtau at Steady State (AUCtau,ss) of Encorafenib, Binimetinib and Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

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End point title

AUCtau at Steady State (AUCtau,ss) of Encorafenib, Binimetinib and Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

End point description

End point type

Secondary

End point timeframe

Phase 1b: Pre dose,0.5,1.5, 2.5, 4, 6, 8 and 24 hr post dose on Day 15 of Cycle 1

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: h*ng/mL
arithmetic mean (standard deviation)
Encorafenib;n=6,5,2,3,11,6,6,4,5,5,5	2620 ± 1260	5510 ± 1280	4620 ± 1640	10200 ± 2280	15900 ± 8730	27300 ± 17900	25300 ± 7240	6310 ± 2340	8210 ± 2550	11800 ± 7000	15700 ± 6060
Binimetinib;n=6,5,2,4,11,6,5,4,4,5,5	2950 ± 1380	2610 ± 873	2660 ± 1900	2110 ± 1220	2550 ± 901	2590 ± 1640	2540 ± 529	2180 ± 1180	2820 ± 954	2740 ± 1230	2970 ± 1180
Ribociclib;n=0,0,0,0,0,0,0,4,5,5,5	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	462 ± 129	1520 ± 979	5620 ± 3730	10100 ± 2970
Metabolite of Binimetinib;n=3,3,2,2,7,2,4,2,4,4,5	261 ± 136	237 ± 107	126 ± 59.5	194 ± 75.8	221 ± 83.5	304 ± 77.7	225 ± 25.1	265 ± 33.4	219 ± 71.5	207 ± 69.7	175 ± 52.8
Metabolite of Ribociclib;n=0,0,0,0,0,0,0,4,5,5,5	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	255 ± 131	729 ± 267	2150 ± 399	3260 ± 891

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b

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End point title

Maximum Observed Plasma Concentration (Cmax) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b

End point description

End point type

Secondary

End point timeframe

Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: ng/mL
arithmetic mean (standard deviation)
Encorafenib;n=6,5,4,4,13,7,6,4,5,6,6	855 ± 480	1930 ± 652	3820 ± 1550	6930 ± 1950	7620 ± 3350	10300 ± 3170	7880 ± 2910	2920 ± 499	3190 ± 1010	3450 ± 1140	4200 ± 1020
Binimetinib;n=6,5,3,4,13,7,4,4,5,6,6	635 ± 402	587 ± 147	986 ± 771	532 ± 227	807 ± 398	901 ± 480	621 ± 160	462 ± 85.6	867 ± 232	560 ± 213	703 ± 222
Ribociclib;n=0,0,0,0,0,0,0,4,5,6,6	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	74.2 ± 37.5	219 ± 95.2	554 ± 251	1220 ± 701
Metabolite of Binimetinib;n=6,5,3,4,13,7,4,4,5,6,6	79.3 ± 55.3	75.3 ± 10.7	90.8 ± 88.0	67.9 ± 32.0	85.1 ± 34.9	93.5 ± 67.0	81.1 ± 32.4	41.8 ± 13.2	83.2 ± 28.2	40.2 ± 22.3	45.0 ± 25.4
Metabolite of Ribociclib;n=0,0,0,0,0,0,0,4,5,6,6	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	5.90 ± 1.73	28.7 ± 7.82	58.0 ± 39.6	73.8 ± 24.3

No statistical analyses for this end point

Secondary: Cmax at Steady State (Cmax,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

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End point title

Cmax at Steady State (Cmax,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

End point description

End point type

Secondary

End point timeframe

Phase 1b: Pre dose,0.5,1.5, 2.5,4, 6,8 and 24 hr post dose on Day 15 of Cycle 1

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: ng/mL
arithmetic mean (standard deviation)
Encorafenib;n=6,5,2,3,11,6,6,4,5,5,5	587 ± 321	1190 ± 409	1060 ± 194	3760 ± 1380	4320 ± 2260	11100 ± 14100	7320 ± 2700	1670 ± 453	2320 ± 779	2480 ± 1090	2590 ± 929
Binimetinib;n=6,5,2,4,11,6,5,4,4,5,5	693 ± 283	568 ± 233	616 ± 438	553 ± 336	638 ± 283	716 ± 321	726 ± 206	584 ± 181	778 ± 160	563 ± 262	609 ± 261
Ribociclib;n=0,0,0,0,0,0,0,4,5,5,5	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	43.7 ± 16.1	146 ± 111	493 ± 258	752 ± 304
Metabolite of Binimetinib;n=6,5,2,4,11,6,5,4,4,5,5	39.7 ± 43.7	36.0 ± 25.9	27.3 ± 12.6	31.7 ± 25.9	38.8 ± 21.8	35.0 ± 25.3	47.3 ± 19.5	38.3 ± 25.4	55.1 ± 26.5	33.2 ± 16.7	33.7 ± 12.8
Metabolite of Ribociclib;n=0,0,0,0,0,0,0,4,5,5,5	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	16.8 ± 9.77	49.7 ± 19.5	155 ± 30.5	195 ± 56.3

No statistical analyses for this end point

Secondary: Elimination Half-life (t1/2) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

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End point title

Elimination Half-life (t1/2) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

End point description

End point type

Secondary

End point timeframe

Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: Hour
arithmetic mean (standard deviation)
Encorafenib;n=6,5,4,4,13,7,5,4,4,3,5	3.68 ± 0.605	3.65 ± 0.351	2.88 ± 0.121	4.19 ± 2.13	3.47 ± 0.402	3.21 ± 0.550	3.04 ± 0.0935	3.25 ± 0.375	2.10 ± 0.451	2.95 ± 1.13	2.59 ± 0.567
Binimetinib;n=5,4,3,3,11,7,4,4,4,3,4	2.36 ± 0.427	2.37 ± 0.704	2.10 ± 0.522	2.51 ± 0.472	2.22 ± 0.439	2.12 ± 0.314	1.99 ± 0.601	3.73 ± 1.78	2.45 ± 1.19	3.11 ± 1.01	1.98 ± 0.523
Ribociclib;n=0,0,0,0,0,0,0,4,5,4,4	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	8.71 ± 2.32	7.97 ± 1.24	10.3 ± 3.94	7.71 ± 0.408
Metabolite of Binimetinib;n=5,3,2,3,9,5,4,3,4,0,4	2.82 ± 0.757	2.00 ± 0.0542	2.95 ± 0.739	2.58 ± 0.737	2.64 ± 0.604	2.28 ± 0.546	2.37 ± 0.517	3.39 ± 1.57	2.49 ± 0.528	99999 ± 99999	2.32 ± 0.455
Metabolite of Ribociclib;n=0,0,0,0,0,0,0,1,3,1,1	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	23.2 ± 99999	15.4 ± 6.92	7.99 ± 99999	15.9 ± 99999

No statistical analyses for this end point

Secondary: t1/2 at Steady State (t1/2,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

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End point title

t1/2 at Steady State (t1/2,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

End point description

End point type

Secondary

End point timeframe

Phase 1b: Pre dose,0.5,1.5, 2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: Hour
arithmetic mean (standard deviation)
Encorafenib;n=5,4,2,3,11,6,6,4,5,5,4	4.74 ± 1.18	4.47 ± 0.380	4.32 ± 1.25	4.21 ± 0.724	3.57 ± 0.688	3.40 ± 0.223	3.37 ± 0.511	3.98 ± 0.331	3.24 ± 0.776	4.00 ± 0.922	3.52 ± 0.237
Binimetinib;n=2,4,1,4,9,0,3,3,3,4,4	4.74 ± 1.43	4.80 ± 1.40	3.28 ± 99999	4.20 ± 1.36	3.61 ± 1.14	99999 ± 99999	2.91 ± 0.157	4.04 ± 2.03	2.67 ± 1.40	3.69 ± 1.16	5.21 ± 1.75
Ribociclib;n=0,0,0,0,0,0,0,4,4,4,3	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	13.2 ± 2.26	11.4 ± 6.07	8.49 ± 2.80	10.3 ± 5.32
Metabolite of Binimetinib;n=2,2,1,1,5,2,3,1,3,2,2	4.51 ± 1.23	7.23 ± 5.44	2.07 ± 99999	4.61 ± 99999	2.79 ± 1.23	4.06 ± 0.195	3.33 ± 0.524	5.12 ± 99999	2.58 ± 0.626	3.44 ± 0.115	4.38 ± 2.14
Metabolite of Ribociclib;n=0,0,0,0,0,0,0,4,4,2,2	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	18.3 ± 3.23	15.7 ± 6.62	15.0 ± 6.27	18.6 ± 2.76

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS): Phase 2

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End point title

Progression Free Survival (PFS): Phase 2

End point description

PFS was defined as the time from the start of study treatment to the date of the event defined as the first documented progression or death due to any cause. If a subject did not have an event, PFS was censored at the date of last adequate tumor assessment. Per RECIST 1.1, PD= At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm^2. Unequivocal progression of existing non-target lesions. Kaplan-Meier method was used for analysis. FAS included all subjects who received at least one dose of LGX818 or MEK162 or LEE011.

End point type

Secondary

End point timeframe

Phase 2: From start of study drug until documented PD or death due to any cause or censoring date (maximum exposure of treatment in Phase 2 was 111.5 months)

End point values	Phase 2: Arm1 (mCRC):Enco+Bini	Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini	Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini	Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo
Number of subjects analysed	11	26	42	42
Units: Months
median (confidence interval 95%)	5.4 (2.1 to 9.0)	3.8 (3.4 to 9.3)	7.5 (5.7 to 12.2)	9.0 (5.6 to 11.1)

No statistical analyses for this end point

Secondary: Accumulation Ratio (RA) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b

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End point title

Accumulation Ratio (RA) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b

End point description

Accumulation ratio was calculated as AUCtau,ss/AUCtau. FAS evaluated. All subjects reported under "Number of Subjects Analyzed" contributed data to the table; however, may not have evaluable data for every category. Here, “Number Analyzed” signifies number of subjects evaluable for specified categories. 99999 signifies data could not be calculated as only 1 subject was evaluable.

End point type

Secondary

End point timeframe

Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 and 15 of Cycle 1

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: Ratio
arithmetic mean (standard deviation)
Encorafenib;n=6,5,2,3,11,6,5,4,4,3,4	0.857 ± 0.351	0.601 ± 0.322	0.298 ± 0.0682	0.348 ± 0.125	0.458 ± 0.188	0.473 ± 0.215	0.690 ± 0.291	0.460 ± 0.134	0.841 ± 0.178	0.833 ± 0.463	0.806 ± 0.393
Binimetinib;n=5,4,2,4,9,6,4,4,3,2,4	1.51 ± 0.248	1.26 ± 0.152	1.07 ± 0.142	0.989 ± 0.353	1.03 ± 0.339	0.969 ± 0.297	1.19 ± 0.472	1.29 ± 0.572	0.778 ± 0.102	1.19 ± 0.324	1.08 ± 0.316
Ribociclib;n=0,0,0,0,0,0,0,4,5,5,5	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	0.640 ± 0.282	0.734 ± 0.404	1.11 ± 0.753	0.712 ± 0.168
Metabolite of Binimetinib;n=3,1,1,2,4,1,3,1,3,0,4	0.899 ± 0.542	0.588 ± 99999	0.285 ± 99999	0.954 ± 0.0302	0.546 ± 0.300	0.499 ± 99999	0.569 ± 0.0381	1.56 ± 99999	0.726 ± 0.194	99999 ± 99999	0.910 ± 0.195
Metabolite of Ribociclib;n=0,0,0,0,0,0,0,3,5,5,5	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	2.81 ± 0.619	1.93 ± 0.684	2.73 ± 0.517	2.97 ± 0.548

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR): Phase 1b

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End point title

Objective Response Rate (ORR): Phase 1b

End point description

ORR was defined as the percentage of subjects with a best overall response of CR or PR. As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis <10 mm. PR was defined as >= 30 % decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. FAS included all subjects who received at least one dose of LGX818 or MEK162 or LEE011.

End point type

Secondary

End point timeframe

Phase 1b: From Day 1 of dosing till complete response or partial response achieved (maximum exposure of treatment in Phase 1b was 118.3 months)

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: Percentage of subjects
number (confidence interval 95%)	66.7 (22.3 to 95.7)	40.0 (5.3 to 85.3)	25.0 (0.6 to 80.6)	40.0 (5.3 to 85.3)	53.8 (25.1 to 80.8)	25.0 (3.2 to 65.1)	50.0 (11.8 to 88.2)	75.0 (19.4 to 99.4)	60.0 (14.7 to 94.7)	66.7 (22.3 to 95.7)	66.7 (22.3 to 95.7)

No statistical analyses for this end point

Secondary: Time to Response (TTR): Phase 2

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End point title

Time to Response (TTR): Phase 2

End point description

TTR was defined as the time from the first dose of study treatment to the first documentation of objective tumor response documented in subject with confirmed objective response (CR or PR). As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis <10 mm. PR was defined as >= 30 % decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. Kaplan-Meier method was used for analysis. Here "Number of Subjects Analyzed" signifies the number of subjects who were confirmed responders and were evaluable for this endpoint measure.

End point type

Secondary

End point timeframe

Phase 2: From date of start of treatment until date of first documentation of objective tumor response (maximum exposure of treatment in Phase 2 was 111.5 months)

End point values	Phase 2: Arm1 (mCRC):Enco+Bini	Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini	Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini	Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo
Number of subjects analysed	2	11	28	25
Units: Months
median (confidence interval 95%)	2.6 (1.6 to 3.6)	1.8 (1.0 to 5.6)	1.0 (1.0 to 1.8)	1.9 (1.8 to 2.1)

No statistical analyses for this end point

Secondary: Duration of Response (DOR): Phase 2

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End point title

Duration of Response (DOR): Phase 2

End point description

DOR was defined as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to underlying cancer, whichever occurred first in subjects with confirmed objective response (CR or PR). As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis <10 mm. PR was defined as >= 30 % decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. Kaplan-Meier method was used for analysis. FAS evaluated. Here "Number of Subjects Analyzed" signifies the number of subjects who were confirmed responders and were evaluable for this endpoint measure. 99999 signifies data could not be calculated due to insufficient number of subjects.

End point type

Secondary

End point timeframe

Phase 2: From date of first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to underlying cancer, whichever occurred first (maximum exposure of treatment in Phase 2 was 111.5 months)

End point values	Phase 2: Arm1 (mCRC):Enco+Bini	Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini	Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini	Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo
Number of subjects analysed	2	11	28	25
Units: Months
median (confidence interval 95%)	7.1 (3.8 to 99999)	3.8 (2.9 to 12.9)	10.9 (6.5 to 19.5)	7.5 (5.6 to 25.8)

No statistical analyses for this end point

Secondary: Overall Survival (OS): Phase 2

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End point title

Overall Survival (OS): Phase 2

End point description

OS was defined as the time from date of randomization/start of treatment to date of death due to any cause. If a subject was not known to have died, survival was censored at the date of last contact. Analysis was performed using Kaplan-Meier method. FAS included all subjects who received at least one dose of LGX818 or MEK162 or LEE011. 99999 signifies data could not be calculated due to insufficient number of subjects.

End point type

Secondary

End point timeframe

Phase 2: From date of start of study treatment until date of death or censoring date (maximum exposure of treatment in Phase 2 was 111.5 months)

End point values	Phase 2: Arm1 (mCRC):Enco+Bini	Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini	Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini	Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo
Number of subjects analysed	11	26	42	42
Units: Months
median (confidence interval 95%)	9.5 (7.7 to 27.2)	11.4 (5.9 to 20.7)	23.1 (17.3 to 99999)	21.8 (14.8 to 35.7)

No statistical analyses for this end point

Secondary: Number of Subjects With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 1b

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End point title

Number of Subjects With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 1b

End point description

Molecular alterations of tumor tissues was determined using the following potential predictive markers: Biomarkers like V-raf murine sarcoma viral oncogene homolog B1 (BRAF),V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), Phosphatase and tensin homolog (PTEN), Phosphatidylinositol 3' kinase catalytic alphapolypeptide (PIK3CA), Epidermal growth factor receptor (EGFR). FAS included all subjects who received at least one dose of LGX818 or MEK162 or LEE011.

End point type

Secondary

End point timeframe

Phase 1b: Baseline

End point values	Phase 1b: Encorafenib 50 mg+Binimetinib 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg	Phase 1b: Enco 400 mg+Bini 45 mg	Phase 1b: Enco 450 mg+Bini 45 mg	Phase 1b: Enco 600 mg+Bini 45 mg	Phase 1b: Enco 800 mg+Bini 45 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 100 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 200 mg	Phase 1b:Enco 200 mg+Bini 45 mg+Ribo 400 mg	Phase 1b: Enco 200 mg+Bini 45 mg+Ribo 600 mg
Number of subjects analysed	6	5	4	5	13	8	6	4	5	6	6
Units: Subjects
BRAF	5	4	3	4	7	7	3	3	4	5	4
KRAS	1	0	0	0	0	0	0	0	0	0	0
PTEN	0	1	0	0	1	2	1	0	0	0	1
PIK3CA	0	1	0	0	0	1	0	0	0	0	0
EGFR	0	0	0	0	2	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers:Phase 2

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End point title

Number of Subjects With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers:Phase 2

End point description

Molecular alterations of tumor tissues was determined using the following potential predictive markers: BRAF, HRAS, KRAS, Neuroblastoma RAS viral oncogene homolog (NRAS), PTEN, PIK3CA, Mitogen-activated protein kinase 1 (MAP2K1), Mitogen-activated protein kinase 2 (MAP2K2), EGFR.FAS included all subjects who received at least one dose of LGX818 or MEK162 or LEE011.

End point type

Secondary

End point timeframe

Phase 2: Baseline

End point values	Phase 2: Arm1 (mCRC):Enco+Bini	Phase 2: Arm 2 (prior BRAFi melanoma):Enco+Bini	Phase 2: Arm 3 (BRAFi-naïve melanoma):Enco+Bini	Phase 2: Arm A (BRAFi-naïve melanoma):Enco+Bini+Ribo
Number of subjects analysed	11	26	42	42
Units: Subjects
BRAF	4	15	20	30
HRAS	0	0	0	0
KRAS	2	0	0	0
NRAS	0	2	0	0
PTEN	1	6	5	5
PIK3CA	2	0	0	2
MAP2K1	0	3	1	0
MAP2K2	0	0	0	0
ARAF	0	0	0	0
EGFR	0	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Day 1 of dosing up to 30 days after last dose (maximum treatment exposure for Phase 1b was 118.3 months, Phase 2 was 111.5 months)

Adverse event reporting additional description

Same event may appear as both non-SAE and SAE, but what is presented are distinct events. An event may be categorised as serious in 1 subject and non-serious in other subject, or a subject may have experienced both SAE and non-SAE. Safety analysis set was evaluated.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Phase 1b: Enco 800 mg + Bini 45 mg

Reporting group description

Subjects received Encorafenib 800 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Reporting group title

Phase 1b: Enco 600 mg + Bini 45 mg

Reporting group description

Subjects received Encorafenib 600 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Reporting group title

Phase 1b: Enco 450 mg+ Bini 45 mg

Reporting group description

Subjects received Encorafenib 450 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Reporting group title

Phase 1b: Enco 400 mg + Bini 45 mg

Reporting group description

Subjects received Encorafenib 400 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Reporting group title

Phase 1b: Enco 200 mg + Bini 45 mg

Reporting group description

Subjects received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Reporting group title

Phase 1b: Enco 100 mg+ Bini 45 mg

Reporting group description

Subjects received Encorafenib 100 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Reporting group title

Phase 1b: Enco 50 mg + Bini 45 mg

Reporting group description

Subjects received Encorafenib 50 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Reporting group title

Phase 1b: Enco 200 mg+ Bini 45 mg + Ribo 600 mg

Reporting group description

Subjects received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 600 mg QD orally for 3 weeks on, 1 week off schedule.

Reporting group title

Phase 1b: Enco 200 mg+ Bini 45 mg+ Ribo 400 mg

Reporting group description

Subjects received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 400 mg QD orally for 3 weeks on, 1 week off schedule.

Reporting group title

Phase 1b: Enco 200 mg+ Bini 45 mg+ Ribo 200 mg

Reporting group description

Subjects received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 200 mg QD orally for 3 weeks on, 1 week off schedule.

Reporting group title

Phase 1b: Enc 200 mg+ Bini 45 mg+ Ribo 100 mg

Reporting group description

Subjects received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 100 mg QD orally for 3 weeks on, 1 week off schedule.

Reporting group title

Phase 2: Arm 3 (BRAFi-naïve melanoma): Enco+ Bini

Reporting group description

Subjects received Encorafenib at MTD (600 mg QD, permitted dose reduction to 450 mg QD) and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks.

Reporting group title

Phase 2: Arm 2 (prior BRAFi melanoma): Enco+ Bini

Reporting group description

Subjects received Encorafenib at MTD (600 mg QD, permitted dose reduction to 450 mg QD) and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks.

Reporting group title

Phase 2: Arm A (BRAFi-naïve melanoma): Enco+ Bini+ Ribo

Reporting group description

Subjects received Encorafenib 200 mg QD (MTD), Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 600 mg QD orally for 3 weeks on, 1 week off schedule.

Reporting group title

Phase 2: Arm 1 (mCRC): Enco+ Bini

Reporting group description

Subjects received Encorafenib at MTD (600 mg QD, permitted dose reduction to 450 mg QD) and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks.

Phase 1b: Enco 800 mg + Bini 45 mg

Phase 1b: Enco 600 mg + Bini 45 mg

Phase 1b: Enco 450 mg+ Bini 45 mg

Phase 1b: Enco 400 mg + Bini 45 mg

Phase 1b: Enco 200 mg + Bini 45 mg

Phase 1b: Enco 100 mg+ Bini 45 mg

Phase 1b: Enco 50 mg + Bini 45 mg

Phase 1b: Enco 200 mg+ Bini 45 mg + Ribo 600 mg

Phase 1b: Enco 200 mg+ Bini 45 mg+ Ribo 400 mg

Phase 1b: Enco 200 mg+ Bini 45 mg+ Ribo 200 mg

Phase 1b: Enc 200 mg+ Bini 45 mg+ Ribo 100 mg

Phase 2: Arm 3 (BRAFi-naïve melanoma): Enco+ Bini

Phase 2: Arm 2 (prior BRAFi melanoma): Enco+ Bini

Phase 2: Arm A (BRAFi-naïve melanoma): Enco+ Bini+ Ribo

Phase 2: Arm 1 (mCRC): Enco+ Bini

Total subjects affected by serious adverse events

subjects affected / exposed

4 / 6 (66.67%)

4 / 8 (50.00%)

5 / 13 (38.46%)

2 / 5 (40.00%)

2 / 4 (50.00%)

2 / 5 (40.00%)

4 / 6 (66.67%)

2 / 6 (33.33%)

3 / 6 (50.00%)

3 / 5 (60.00%)

2 / 4 (50.00%)

18 / 42 (42.86%)

13 / 26 (50.00%)

21 / 42 (50.00%)

5 / 11 (45.45%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Cancer pain

subjects affected / exposed

0 / 6 (0.00%)

1 / 8 (12.50%)

1 / 13 (7.69%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Chronic myeloid leukaemia

subjects affected / exposed

0 / 6 (0.00%)

1 / 8 (12.50%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Malignant melanoma in situ

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tumour pain

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Uterine leiomyoma

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intracranial tumour haemorrhage

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lung adenocarcinoma

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Malignant melanoma

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

1 / 4 (25.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metastases to central nervous system

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metastases to lung

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Aortic stenosis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Surgical and medical procedures

Lymphadenectomy

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Pyrexia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

1 / 13 (7.69%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

3 / 42 (7.14%)

2 / 26 (7.69%)

2 / 42 (4.76%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

1 / 3

1 / 2

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Axillary pain

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Chills

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General physical health deterioration

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

2 / 42 (4.76%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Disease progression

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Haemothorax

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

1 / 13 (7.69%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cough

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

1 / 11 (9.09%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Dyspnoea

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

2 / 42 (4.76%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory distress

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acute pulmonary oedema

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pleural effusion

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Suicide attempt

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Troponin increased

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Alanine aminotransferase increased

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Mediastinoscopy

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aspartate aminotransferase increased

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Fall

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Femur fracture

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pubis fracture

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rib fracture

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

1 / 13 (7.69%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Traumatic haematoma

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper limb fracture

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tendon rupture

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Intracardiac mass

subjects affected / exposed

0 / 6 (0.00%)

1 / 8 (12.50%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tachycardia

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myocardial infarction

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pericarditis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Atrial fibrillation

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ventricular tachycardia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Balance disorder

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cerebral infarction

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

1 / 13 (7.69%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dizziness

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

2 / 6 (33.33%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Encephalopathy

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haemorrhage intracranial

subjects affected / exposed

0 / 6 (0.00%)

1 / 8 (12.50%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hemiparesis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nerve root compression

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Seizure

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

1 / 4 (25.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Transient ischaemic attack

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ataxia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Headache

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

2 / 42 (4.76%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Loss of consciousness

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tremor

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Polyneuropathy

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Epilepsy

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Leukopenia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neutropenia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Ear and labyrinth disorders

Vertigo positional

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

1 / 13 (7.69%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

Retinal detachment

subjects affected / exposed

0 / 6 (0.00%)

1 / 8 (12.50%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Retinal vein occlusion

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Retinopathy hypertensive

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

1 / 13 (7.69%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blindness

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eye pain

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Iritis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Visual impairment

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

1 / 11 (9.09%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Macular oedema

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Detachment of retinal pigment epithelium

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Dysphagia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal haemorrhage

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haematemesis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intestinal obstruction

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

1 / 4 (25.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

2 / 11 (18.18%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Melaena

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

2 / 42 (4.76%)

3 / 26 (11.54%)

2 / 42 (4.76%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 3

1 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Small intestinal obstruction

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

2 / 42 (4.76%)

3 / 26 (11.54%)

3 / 42 (7.14%)

1 / 11 (9.09%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

0 / 2

0 / 3

1 / 4

1 / 1

deaths causally related to treatment / all

0 / 0

Abdominal pain

subjects affected / exposed

0 / 6 (0.00%)

1 / 8 (12.50%)

0 / 13 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal pain upper

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea haemorrhagic

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

1 / 42 (2.38%)

1 / 11 (9.09%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

2 / 2

1 / 1

deaths causally related to treatment / all

0 / 0

Rectal haemorrhage

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal obstruction

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

1 / 4 (25.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastric ulcer

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Inguinal hernia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pancreatitis acute

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Cholecystitis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatic haemorrhage

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Skin lesion

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rash maculo-papular

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dermatitis bullous

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

1 / 11 (9.09%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Hydronephrosis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal failure

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

2 / 42 (4.76%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Bone disorder

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal chest pain

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

1 / 13 (7.69%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Back pain

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

1 / 11 (9.09%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pain in extremity

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Polyarthritis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Pharyngeal abscess

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Post procedural infection

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyelonephritis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

1 / 11 (9.09%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Septic shock

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin infection

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Streptococcal bacteraemia

subjects affected / exposed

1 / 6 (16.67%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bacteraemia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cellulitis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Erysipelas

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lung infection

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

1 / 11 (9.09%)

occurrences causally related to treatment / all

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Abdominal abscess

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Dermo-hypodermitis

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypercreatininaemia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

1 / 26 (3.85%)

0 / 42 (0.00%)

1 / 11 (9.09%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 42 (2.38%)

2 / 26 (7.69%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Tumour lysis syndrome

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 42 (0.00%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Type 2 diabetes mellitus

subjects affected / exposed

0 / 6 (0.00%)

0 / 8 (0.00%)

0 / 13 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 42 (2.38%)

0 / 11 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Phase 1b: Enco 800 mg + Bini 45 mg	Phase 1b: Enco 600 mg + Bini 45 mg	Phase 1b: Enco 450 mg+ Bini 45 mg	Phase 1b: Enco 400 mg + Bini 45 mg	Phase 1b: Enco 200 mg + Bini 45 mg	Phase 1b: Enco 100 mg+ Bini 45 mg	Phase 1b: Enco 50 mg + Bini 45 mg	Phase 1b: Enco 200 mg+ Bini 45 mg + Ribo 600 mg	Phase 1b: Enco 200 mg+ Bini 45 mg+ Ribo 400 mg	Phase 1b: Enco 200 mg+ Bini 45 mg+ Ribo 200 mg	Phase 1b: Enc 200 mg+ Bini 45 mg+ Ribo 100 mg	Phase 2: Arm 3 (BRAFi-naïve melanoma): Enco+ Bini	Phase 2: Arm 2 (prior BRAFi melanoma): Enco+ Bini	Phase 2: Arm A (BRAFi-naïve melanoma): Enco+ Bini+ Ribo	Phase 2: Arm 1 (mCRC): Enco+ Bini
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	8 / 8 (100.00%)	13 / 13 (100.00%)	5 / 5 (100.00%)	4 / 4 (100.00%)	5 / 5 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	5 / 6 (83.33%)	5 / 5 (100.00%)	4 / 4 (100.00%)	39 / 42 (92.86%)	26 / 26 (100.00%)	42 / 42 (100.00%)	11 / 11 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	1 / 26 (3.85%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	1	0	0
Basal cell carcinoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	1 / 26 (3.85%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	1	0	0
Cancer pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 13 (7.69%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	0	2	2	0	0	0	0	0	0	0	0
Seborrhoeic keratosis
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	2	0	0	0	4	0	0	0	0	0	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	3 / 13 (23.08%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	3 / 6 (50.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	9 / 42 (21.43%)	1 / 26 (3.85%)	9 / 42 (21.43%)	1 / 11 (9.09%)
occurrences all number	0	1	9	0	0	4	5	0	0	0	0	26	7	27	1
Flushing
subjects affected / exposed	0 / 6 (0.00%)	2 / 8 (25.00%)	1 / 13 (7.69%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	2	1	2	0	0	0	0	0	0	0	0	0	0	0
Hot flush
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	3	1	0	0	0	0	0	0	0	0	0	0	0	0
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0	0	2	0	0	0	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 13 (7.69%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	2 / 5 (40.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	3 / 26 (11.54%)	9 / 42 (21.43%)	7 / 11 (63.64%)
occurrences all number	1	1	1	2	0	1	0	7	1	3	0	5	3	22	10
Fatigue
subjects affected / exposed	3 / 6 (50.00%)	3 / 8 (37.50%)	7 / 13 (53.85%)	2 / 5 (40.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	4 / 6 (66.67%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 5 (20.00%)	2 / 4 (50.00%)	12 / 42 (28.57%)	10 / 26 (38.46%)	14 / 42 (33.33%)	2 / 11 (18.18%)
occurrences all number	7	7	16	7	0	4	6	5	1	2	2	23	12	26	2
Oedema peripheral
subjects affected / exposed	1 / 6 (16.67%)	2 / 8 (25.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 4 (25.00%)	7 / 42 (16.67%)	4 / 26 (15.38%)	3 / 42 (7.14%)	0 / 11 (0.00%)
occurrences all number	2	2	2	0	0	1	4	6	1	0	3	9	4	5	0
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	4 / 42 (9.52%)	2 / 26 (7.69%)	3 / 42 (7.14%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	4	2	4	0
Chills
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	3 / 13 (23.08%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 4 (0.00%)	7 / 42 (16.67%)	5 / 26 (19.23%)	4 / 42 (9.52%)	2 / 11 (18.18%)
occurrences all number	1	2	6	1	0	0	1	0	1	0	0	10	5	6	2
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	4 / 13 (30.77%)	1 / 5 (20.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	4 / 6 (66.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	3 / 5 (60.00%)	2 / 4 (50.00%)	14 / 42 (33.33%)	4 / 26 (15.38%)	12 / 42 (28.57%)	6 / 11 (54.55%)
occurrences all number	0	1	16	3	1	0	7	1	3	5	2	24	4	18	12
Peripheral swelling
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 13 (7.69%)	1 / 5 (20.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 42 (4.76%)	1 / 26 (3.85%)	0 / 42 (0.00%)	1 / 11 (9.09%)
occurrences all number	2	0	1	1	1	2	1	0	0	0	0	2	1	0	1
Chest pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	4 / 42 (9.52%)	0 / 26 (0.00%)	0 / 42 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	0	0	0	2	0	0	0	0	4	0	0	2
Respiratory, thoracic and mediastinal disorders
Productive cough
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 42 (2.38%)	2 / 26 (7.69%)	0 / 42 (0.00%)	3 / 11 (27.27%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	2	0	5
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 42 (4.76%)	0 / 26 (0.00%)	0 / 42 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	1	2	0	0	2	0	0	0	0	0	2	0	0	3
Dyspnoea
subjects affected / exposed	1 / 6 (16.67%)	3 / 8 (37.50%)	1 / 13 (7.69%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	7 / 42 (16.67%)	1 / 26 (3.85%)	5 / 42 (11.90%)	0 / 11 (0.00%)
occurrences all number	1	3	1	1	0	1	2	1	0	0	2	8	1	6	0
Cough
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 13 (15.38%)	2 / 5 (40.00%)	0 / 4 (0.00%)	3 / 5 (60.00%)	4 / 6 (66.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	11 / 42 (26.19%)	6 / 26 (23.08%)	3 / 42 (7.14%)	3 / 11 (27.27%)
occurrences all number	1	1	5	4	0	5	17	1	0	2	0	15	6	3	3
Wheezing
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	1 / 26 (3.85%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	1	0	0
Nasal congestion
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	2	2	0	0	0	0	0	0	0	0	0	0	0	0
Respiratory tract congestion
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 13 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	1	0	0	0	0	0	0	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	1 / 26 (3.85%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	3	1	0	0
Insomnia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	4 / 13 (30.77%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	4 / 42 (9.52%)	1 / 26 (3.85%)	0 / 42 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	5	0	1	0	1	0	0	0	0	8	1	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 6 (33.33%)	3 / 8 (37.50%)	2 / 13 (15.38%)	2 / 5 (40.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 5 (20.00%)	1 / 4 (25.00%)	11 / 42 (26.19%)	5 / 26 (19.23%)	11 / 42 (26.19%)	1 / 11 (9.09%)
occurrences all number	3	17	4	7	3	0	1	6	3	2	1	40	16	52	3
Lipase increased
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	3 / 13 (23.08%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 4 (0.00%)	14 / 42 (33.33%)	1 / 26 (3.85%)	4 / 42 (9.52%)	1 / 11 (9.09%)
occurrences all number	1	1	6	0	0	0	5	0	1	0	0	28	1	13	1
Haemoglobin decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 5 (40.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	2	0	0	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)	0 / 4 (0.00%)	7 / 42 (16.67%)	1 / 26 (3.85%)	9 / 42 (21.43%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	21	0	0	11	1	16	3
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 13 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	3 / 6 (50.00%)	2 / 6 (33.33%)	3 / 6 (50.00%)	3 / 5 (60.00%)	1 / 4 (25.00%)	15 / 42 (35.71%)	6 / 26 (23.08%)	11 / 42 (26.19%)	0 / 11 (0.00%)
occurrences all number	2	1	0	1	0	11	74	9	28	35	4	64	24	20	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	3 / 8 (37.50%)	1 / 13 (7.69%)	2 / 5 (40.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 5 (20.00%)	1 / 4 (25.00%)	12 / 42 (28.57%)	6 / 26 (23.08%)	10 / 42 (23.81%)	1 / 11 (9.09%)
occurrences all number	3	11	1	8	2	0	1	8	4	2	1	34	11	29	3
Neutrophil count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	4 / 42 (9.52%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	15	0
Weight increased
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 13 (15.38%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	6 / 42 (14.29%)	1 / 26 (3.85%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	9	8	17	3	0	0	14	0	0	0	0	35	1	0	0
Ejection fraction decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	1 / 26 (3.85%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	9	2	0	0
Amylase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	6 / 42 (14.29%)	1 / 26 (3.85%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	10	3	0	0
White blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	2 / 26 (7.69%)	4 / 42 (9.52%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	9	2	7	0
Platelet count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	4 / 42 (9.52%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	6	0
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 13 (7.69%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	0	0	3	0	0	0	0	0	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	5 / 42 (11.90%)	1 / 26 (3.85%)	0 / 42 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	6	2	0	5
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	2	2	0	0	0	0	0	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	5 / 6 (83.33%)	2 / 8 (25.00%)	3 / 13 (23.08%)	2 / 5 (40.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 4 (25.00%)	8 / 42 (19.05%)	1 / 26 (3.85%)	10 / 42 (23.81%)	1 / 11 (9.09%)
occurrences all number	12	7	5	4	1	1	4	25	0	1	1	11	1	15	1
Dysgeusia
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	2 / 13 (15.38%)	1 / 5 (20.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 42 (4.76%)	1 / 26 (3.85%)	6 / 42 (14.29%)	1 / 11 (9.09%)
occurrences all number	1	0	2	1	1	0	3	1	0	0	0	2	1	7	1
Dizziness
subjects affected / exposed	2 / 6 (33.33%)	2 / 8 (25.00%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	9 / 42 (21.43%)	1 / 26 (3.85%)	0 / 42 (0.00%)	2 / 11 (18.18%)
occurrences all number	3	2	4	0	0	1	4	0	0	0	0	13	1	0	2
Paraesthesia
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 13 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	5 / 42 (11.90%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	1	0	2	0	0	0	0	5	0	0	0
Visual field defect
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	1 / 26 (3.85%)	0 / 42 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	1	0	2
Hypoaesthesia
subjects affected / exposed	2 / 6 (33.33%)	0 / 8 (0.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	0	3	0	0	1	3	0	0	0	0	0	0	0	0
Memory impairment
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	1	0	0	0	1	0	0	0	0	0	0	0	0
Migraine
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 13 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	1	0	4	0	0	0	0	0	0	0	0
Syncope
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 13 (7.69%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	1	1	0	1	0	0	0	0	0	0	0	0	0
Somnolence
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	1	0	0	0	0	0	0	0	0	0	0	0	0
Presyncope
subjects affected / exposed	2 / 6 (33.33%)	2 / 8 (25.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	2	0	0	0	1	1	0	0	0	0	0	0	0	0
Disturbance in attention
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 13 (7.69%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	2	0	0	1	0	0	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	3 / 8 (37.50%)	1 / 13 (7.69%)	1 / 5 (20.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 6 (33.33%)	1 / 5 (20.00%)	1 / 4 (25.00%)	7 / 42 (16.67%)	6 / 26 (23.08%)	11 / 42 (26.19%)	1 / 11 (9.09%)
occurrences all number	0	7	1	1	2	8	5	5	3	1	1	23	19	30	10
Lymphopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	3 / 42 (7.14%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	6	0
Leukopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	3 / 42 (7.14%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	16	0	0	0	0	0	11	0
Neutropenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	17 / 42 (40.48%)	0 / 11 (0.00%)
occurrences all number	0	0	5	0	0	1	1	51	0	2	0	0	0	114	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	0	0	3	0	0	0	0	0	0	0	0
Eye disorders
Detachment of retinal pigment epithelium
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	2 / 5 (40.00%)	3 / 4 (75.00%)	5 / 42 (11.90%)	7 / 26 (26.92%)	2 / 42 (4.76%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	4	2	3	4	9	10	2	0
Retinopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	6 / 42 (14.29%)	4 / 26 (15.38%)	9 / 42 (21.43%)	7 / 11 (63.64%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	10	4	14	13
Photophobia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	2 / 26 (7.69%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	3	2	0	0
Chorioretinopathy
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 42 (4.76%)	3 / 26 (11.54%)	0 / 42 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	1	3	0	0	0	2	0	0	0	0	2	5	0	3
Retinal detachment
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	5 / 42 (11.90%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	1	2	0	0	0	6	0
Macular oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 5 (40.00%)	3 / 4 (75.00%)	3 / 42 (7.14%)	4 / 26 (15.38%)	5 / 42 (11.90%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	6	5	9	5	15	6	7	1
Subretinal fluid
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	4 / 13 (30.77%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 5 (40.00%)	1 / 4 (25.00%)	9 / 42 (21.43%)	4 / 26 (15.38%)	3 / 42 (7.14%)	0 / 11 (0.00%)
occurrences all number	4	6	12	1	0	0	0	3	5	3	1	21	4	5	0
Vision blurred
subjects affected / exposed	3 / 6 (50.00%)	2 / 8 (25.00%)	1 / 13 (7.69%)	1 / 5 (20.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	3 / 6 (50.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	12 / 42 (28.57%)	5 / 26 (19.23%)	0 / 42 (0.00%)	1 / 11 (9.09%)
occurrences all number	3	2	1	1	2	2	5	0	0	0	0	12	7	0	3
Dry eye
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	3 / 13 (23.08%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	3	0	1	0	1	0	0	0	0	0	0	0	0
Cataract
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	3 / 6 (50.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	9	0	0	0	0	0	0	0	0
Visual impairment
subjects affected / exposed	1 / 6 (16.67%)	2 / 8 (25.00%)	1 / 13 (7.69%)	2 / 5 (40.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 5 (20.00%)	2 / 4 (50.00%)	3 / 42 (7.14%)	4 / 26 (15.38%)	6 / 42 (14.29%)	0 / 11 (0.00%)
occurrences all number	1	5	1	3	0	0	1	4	0	3	2	3	5	7	0
Retinal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	2 / 8 (25.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	2	3	0	0	0	0	0	0	0	0	0	0	0	0
Retinal degeneration
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	2	2	0	0	0	0	0	0	0	0	0	0	0	0
Vitreous detachment
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	1	0	0	1	0	0	0	0	0	0	0	0	0
Vitreous floaters
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	1	2	0	0	0	0	0	0	0	0	0	0	0	0
Uveitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	4 / 42 (9.52%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	2	0	0	0	9	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	4 / 6 (66.67%)	7 / 8 (87.50%)	7 / 13 (53.85%)	2 / 5 (40.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	4 / 6 (66.67%)	4 / 6 (66.67%)	3 / 6 (50.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	20 / 42 (47.62%)	14 / 26 (53.85%)	18 / 42 (42.86%)	8 / 11 (72.73%)
occurrences all number	11	12	18	3	1	2	5	5	9	1	0	65	23	49	14
Constipation
subjects affected / exposed	4 / 6 (66.67%)	3 / 8 (37.50%)	4 / 13 (30.77%)	2 / 5 (40.00%)	2 / 4 (50.00%)	3 / 5 (60.00%)	3 / 6 (50.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 5 (0.00%)	2 / 4 (50.00%)	13 / 42 (30.95%)	5 / 26 (19.23%)	12 / 42 (28.57%)	4 / 11 (36.36%)
occurrences all number	4	8	5	2	3	6	7	1	1	0	3	21	6	20	6
Abdominal pain upper
subjects affected / exposed	3 / 6 (50.00%)	1 / 8 (12.50%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	5 / 42 (11.90%)	0 / 11 (0.00%)
occurrences all number	3	1	1	0	0	1	1	0	0	0	0	0	0	6	0
Abdominal pain
subjects affected / exposed	3 / 6 (50.00%)	2 / 8 (25.00%)	4 / 13 (30.77%)	2 / 5 (40.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	3 / 6 (50.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)	0 / 5 (0.00%)	1 / 4 (25.00%)	11 / 42 (26.19%)	2 / 26 (7.69%)	6 / 42 (14.29%)	0 / 11 (0.00%)
occurrences all number	5	2	6	2	0	4	6	3	5	0	2	23	2	8	0
Dry mouth
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	3 / 13 (23.08%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 5 (40.00%)	0 / 4 (0.00%)	4 / 42 (9.52%)	1 / 26 (3.85%)	4 / 42 (9.52%)	0 / 11 (0.00%)
occurrences all number	2	0	3	0	0	2	2	1	1	2	0	4	1	4	0
Dyspepsia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 13 (7.69%)	0 / 5 (0.00%)	1 / 4 (25.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	7 / 42 (16.67%)	1 / 26 (3.85%)	2 / 42 (4.76%)	0 / 11 (0.00%)
occurrences all number	0	1	1	0	1	3	0	2	0	0	4	8	1	2	0
Flatulence
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	4 / 42 (9.52%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	0	0	2	0	0	0	0	4	0	0	0
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 13 (7.69%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 42 (2.38%)	3 / 26 (11.54%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	1	1	0	1	1	0	0	0	0	1	3	0	0
Vomiting
subjects affected / exposed	1 / 6 (16.67%)	3 / 8 (37.50%)	7 / 13 (53.85%)	2 / 5 (40.00%)	4 / 4 (100.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 4 (0.00%)	14 / 42 (33.33%)	9 / 26 (34.62%)	16 / 42 (38.10%)	7 / 11 (63.64%)
occurrences all number	5	5	14	4	6	3	4	4	0	5	0	24	16	30	15
Nausea
subjects affected / exposed	3 / 6 (50.00%)	5 / 8 (62.50%)	7 / 13 (53.85%)	2 / 5 (40.00%)	2 / 4 (50.00%)	4 / 5 (80.00%)	3 / 6 (50.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	2 / 5 (40.00%)	2 / 4 (50.00%)	20 / 42 (47.62%)	11 / 26 (42.31%)	17 / 42 (40.48%)	6 / 11 (54.55%)
occurrences all number	17	8	13	7	4	6	6	4	0	2	4	38	19	30	11
Abdominal discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	2	0	0	1	0	0	0	0	0	0	0	0	0
Mouth ulceration
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	2	0	0	0	0	0	0	0	0	0
Stomatitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	1	0	1	0	0	0	0	0	0	0	0
Skin and subcutaneous tissue disorders
Photosensitivity reaction
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	3 / 42 (7.14%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	3	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	4 / 42 (9.52%)	0 / 11 (0.00%)
occurrences all number	4	3	1	0	0	0	0	0	1	1	0	0	0	8	0
Hyperkeratosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	5 / 42 (11.90%)	3 / 26 (11.54%)	5 / 42 (11.90%)	1 / 11 (9.09%)
occurrences all number	0	0	4	0	0	2	0	0	0	0	0	9	3	5	1
Dry skin
subjects affected / exposed	3 / 6 (50.00%)	0 / 8 (0.00%)	2 / 13 (15.38%)	1 / 5 (20.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	11 / 42 (26.19%)	4 / 26 (15.38%)	5 / 42 (11.90%)	1 / 11 (9.09%)
occurrences all number	3	0	2	3	2	1	1	2	0	0	0	12	5	9	1
Pruritus
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	12 / 42 (28.57%)	3 / 26 (11.54%)	4 / 42 (9.52%)	0 / 11 (0.00%)
occurrences all number	2	4	2	0	0	0	5	3	0	1	0	16	4	4	0
Alopecia
subjects affected / exposed	2 / 6 (33.33%)	0 / 8 (0.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	2 / 4 (50.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 4 (0.00%)	8 / 42 (19.05%)	1 / 26 (3.85%)	3 / 42 (7.14%)	1 / 11 (9.09%)
occurrences all number	2	0	1	0	2	3	0	2	1	1	0	8	1	3	1
Erythema
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	2	0	0	0	0	0	0	0	0	0	0	0	0
Hyperhidrosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	4 / 42 (9.52%)	2 / 26 (7.69%)	0 / 42 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	3	0	1
Hair texture abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	1 / 26 (3.85%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	3	1	0	0
Rash
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	3 / 13 (23.08%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	2 / 4 (50.00%)	8 / 42 (19.05%)	9 / 26 (34.62%)	7 / 42 (16.67%)	0 / 11 (0.00%)
occurrences all number	2	1	5	0	3	0	2	0	0	2	2	12	10	11	0
Palmoplantar keratoderma
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 13 (23.08%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0	0	0	0	0	0	0	0
Skin lesion
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	1	0	0	0	2	0	0	0	0	0	0	0	0
Vitiligo
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 13 (23.08%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	4	0	0	0	0	0	0	0	0	0	0	0	0
Actinic keratosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 13 (23.08%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	5	0	0	2	0	0	0	0	0	0	0	0	0
Dermatitis acneiform
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	2	2	0	0	0	0	0	0	0	0	0	0	0	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	3 / 13 (23.08%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	3	0	0	0	2	0	0	0	0	0	0	0	0
Dysuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	0 / 26 (0.00%)	0 / 42 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	0	0	2
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 42 (2.38%)	2 / 26 (7.69%)	0 / 42 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	3	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 5 (60.00%)	3 / 6 (50.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	3 / 5 (60.00%)	2 / 4 (50.00%)	15 / 42 (35.71%)	7 / 26 (26.92%)	6 / 42 (14.29%)	4 / 11 (36.36%)
occurrences all number	7	6	4	0	0	3	7	3	0	4	3	27	11	8	5
Back pain
subjects affected / exposed	1 / 6 (16.67%)	2 / 8 (25.00%)	2 / 13 (15.38%)	1 / 5 (20.00%)	1 / 4 (25.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	8 / 42 (19.05%)	5 / 26 (19.23%)	7 / 42 (16.67%)	4 / 11 (36.36%)
occurrences all number	1	5	2	1	2	6	1	1	0	1	0	12	5	13	7
Muscular weakness
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 42 (4.76%)	2 / 26 (7.69%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	1	0	3	0	0	0	0	2	2	0	0
Pain in extremity
subjects affected / exposed	3 / 6 (50.00%)	1 / 8 (12.50%)	2 / 13 (15.38%)	1 / 5 (20.00%)	2 / 4 (50.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 4 (50.00%)	5 / 42 (11.90%)	5 / 26 (19.23%)	8 / 42 (19.05%)	1 / 11 (9.09%)
occurrences all number	6	2	2	1	3	1	4	1	0	0	2	11	5	12	1
Myalgia
subjects affected / exposed	3 / 6 (50.00%)	2 / 8 (25.00%)	2 / 13 (15.38%)	2 / 5 (40.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 5 (60.00%)	2 / 4 (50.00%)	7 / 42 (16.67%)	2 / 26 (7.69%)	4 / 42 (9.52%)	1 / 11 (9.09%)
occurrences all number	3	2	2	3	0	0	1	0	0	4	2	13	2	6	1
Musculoskeletal pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	3 / 13 (23.08%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	4 / 42 (9.52%)	1 / 26 (3.85%)	3 / 42 (7.14%)	0 / 11 (0.00%)
occurrences all number	1	0	4	0	1	0	1	0	0	1	0	4	1	4	0
Arthritis
subjects affected / exposed	2 / 6 (33.33%)	0 / 8 (0.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 6 (0.00%)	2 / 8 (25.00%)	3 / 13 (23.08%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 4 (50.00%)	7 / 42 (16.67%)	0 / 26 (0.00%)	4 / 42 (9.52%)	1 / 11 (9.09%)
occurrences all number	0	4	3	0	3	0	2	2	0	0	2	12	0	6	2
Flank pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 8 (25.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	2	1	0	0	0	2	0	0	0	0	0	0	0	0
Joint stiffness
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	1	0	0	0	1	1	0	0	0	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	0	1	2	0	0	0	0	0	0	0	0
Infections and infestations
Oral herpes
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	3 / 42 (7.14%)	0 / 11 (0.00%)
occurrences all number	2	4	0	0	0	2	0	0	0	0	1	0	0	4	0
Conjunctivitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	4 / 42 (9.52%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	5	0
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 13 (15.38%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	2 / 42 (4.76%)	0 / 11 (0.00%)
occurrences all number	0	1	2	1	0	3	2	1	0	0	1	0	0	5	0
Influenza
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	0	2	4	0	0	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 42 (4.76%)	4 / 26 (15.38%)	0 / 42 (0.00%)	4 / 11 (36.36%)
occurrences all number	2	1	3	0	0	0	2	0	0	0	0	2	5	0	5
Nasopharyngitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 13 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	2 / 5 (40.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 42 (4.76%)	1 / 26 (3.85%)	0 / 42 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	1	0	0	1	3	4	0	0	0	0	3	1	0	1
Metabolism and nutrition disorders
Hypertriglyceridaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 4 (25.00%)	3 / 42 (7.14%)	1 / 26 (3.85%)	3 / 42 (7.14%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	2	3	6	1	4	0
Hyperkalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 4 (0.00%)	4 / 42 (9.52%)	1 / 26 (3.85%)	3 / 42 (7.14%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	7	1	6	0
Decreased appetite
subjects affected / exposed	3 / 6 (50.00%)	1 / 8 (12.50%)	0 / 13 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 4 (25.00%)	4 / 42 (9.52%)	1 / 26 (3.85%)	8 / 42 (19.05%)	4 / 11 (36.36%)
occurrences all number	3	2	0	1	0	0	1	0	0	1	1	4	1	11	6
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 13 (15.38%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	1 / 26 (3.85%)	0 / 42 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	2	3	0	0	0	0	0	0	0	0	3	1	0	1
Hypercholesterolaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	6 / 42 (14.29%)	2 / 26 (7.69%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	8	2	0	0
Hypercreatininaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 42 (0.00%)	1 / 26 (3.85%)	0 / 42 (0.00%)	3 / 11 (27.27%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	6
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 13 (15.38%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	1 / 26 (3.85%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	22	1	0	0	0	0	0	0	0	6	1	0	0
Hyperphosphataemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 42 (2.38%)	3 / 26 (11.54%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	4	0	0
Hypocalcaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 42 (4.76%)	3 / 26 (11.54%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	3	0	0
Hypokalaemia
subjects affected / exposed	2 / 6 (33.33%)	0 / 8 (0.00%)	1 / 13 (7.69%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	2 / 42 (4.76%)	2 / 26 (7.69%)	5 / 42 (11.90%)	1 / 11 (9.09%)
occurrences all number	2	0	1	1	0	1	0	0	0	1	0	2	2	5	6
Hypomagnesaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 13 (7.69%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	4 / 42 (9.52%)	3 / 26 (11.54%)	0 / 42 (0.00%)	2 / 11 (18.18%)
occurrences all number	2	0	1	0	0	0	1	0	0	0	0	5	5	0	4
Hyponatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 13 (7.69%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	2 / 26 (7.69%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	0	1	1	0	0	0	0	5	2	0	0
Iron deficiency
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 13 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 42 (7.14%)	2 / 26 (7.69%)	0 / 42 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	3	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

21 May 2012

Amendment 1: Addressed the enhanced safety measures to be implemented in order to minimize risks to subjects to be treated in this study.

26 Jul 2012

Amendment 2: Introduced a third arm in the Phase 2 part of the study to enroll 40 subjects with locally advanced or metastatic BRAF V600 mutant melanoma who were naïve to previous treatment with a selective BRAF inhibitor.

26 Nov 2012

Amendment 3: Production of the original MEK162 tablet used in this study will cease and two new MEK162 tablet variants have been developed. One variant is a modified formulation of the MEK162 drug product and the other variant has the same formulation but contains drug substance from a new manufacturer.

21 May 2013

Amendment 4: To allow for reduction of the MEK162 dose in case of MEK162 related toxicities.

25 Jul 2013

Amendment 5: To add LEE011 to the LGX818 and MEK162 combination treatment in order to explore safety and preliminary efficacy of this triple combination in subjects with BRAF V600-dependent advanced solid tumors.

03 Jan 2014

Amendment 6: To modify existing safety monitoring for visual toxicities.

24 Mar 2014

Amendment 7: Based on Urgent Safety Measures.

30 Sep 2015

Amendment 8: Addressed recently observed safety findings from subjects treated with LEE011 (Ribociclib) in other clinical trials.

15 Nov 2018

Amendment 9: Definition of end of study, disease progression follow-up period, and survival follow-up period and dose limiting toxicities was updated.

15 Mar 2021

Amendment 10: To modify the frequency of assessments to allow for subjects still on treatment to be monitored in a manner that is consistent with local standard-of-care practice.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination with MEK162 in Adult Subjects with BRAF V600 - Dependent Advanced Solid Tumors.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With Dose Limiting Toxicities (DLTs): Phase 1b

Primary: Number of Subjects With Dose Limiting Toxicities (DLTs): Phase 1b

Primary: Disease Control Rate (DCR) at Week 16: Phase 2, Arm 1 (mCRC Subjects)

Primary: Disease Control Rate (DCR) at Week 16: Phase 2, Arm 1 (mCRC Subjects)

Primary: Objective Response Rate (ORR): Phase 2, Arms 2, 3 and A

Primary: Objective Response Rate (ORR): Phase 2, Arms 2, 3 and A

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs): Overall Grades and AEs of Grade 3/4: Phase 1b

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs): Overall Grades and AEs of Grade 3/4: Phase 1b

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity With Extrapolation of the Terminal Phase (AUCinf) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity With Extrapolation of the Terminal Phase (AUCinf) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Number of Subjects With TEAEs: Overall Grades and AEs of Grade 3/4: Phase 2

Secondary: Number of Subjects With TEAEs: Overall Grades and AEs of Grade 3/4: Phase 2

Secondary: Area Under the Concentration-Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Area Under the Concentration-Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: AUClast at Steady State (AUClast,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: AUClast at Steady State (AUClast,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Area Under the Concentration-Time Curve From Time Zero to Tau After First Dose (AUCtau) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Area Under the Concentration-Time Curve From Time Zero to Tau After First Dose (AUCtau) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: AUCtau at Steady State (AUCtau,ss) of Encorafenib, Binimetinib and Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: AUCtau at Steady State (AUCtau,ss) of Encorafenib, Binimetinib and Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Maximum Observed Plasma Concentration (Cmax) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Maximum Observed Plasma Concentration (Cmax) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Cmax at Steady State (Cmax,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Cmax at Steady State (Cmax,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Elimination Half-life (t1/2) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Elimination Half-life (t1/2) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: t1/2 at Steady State (t1/2,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: t1/2 at Steady State (t1/2,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Progression Free Survival (PFS): Phase 2

Secondary: Progression Free Survival (PFS): Phase 2

Secondary: Accumulation Ratio (RA) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Accumulation Ratio (RA) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b

Secondary: Objective Response Rate (ORR): Phase 1b

Secondary: Objective Response Rate (ORR): Phase 1b

Secondary: Time to Response (TTR): Phase 2

Secondary: Time to Response (TTR): Phase 2

Secondary: Duration of Response (DOR): Phase 2

Secondary: Duration of Response (DOR): Phase 2

Secondary: Overall Survival (OS): Phase 2

Secondary: Overall Survival (OS): Phase 2

Secondary: Number of Subjects With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 1b

Secondary: Number of Subjects With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 1b

Secondary: Number of Subjects With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers:Phase 2

Secondary: Number of Subjects With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers:Phase 2

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination with MEK162 in Adult Subjects with BRAF V600 - Dependent Advanced Solid Tumors.