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Clinical Trial Results:
The LOGIC 2 Trial A Phase II, Multi-Center, Open-Label Study Of Sequential LGX818/MEK162 Combination Followed By A Rational Combination With Targeted Agents After Progression, To Overcome Resistance In Adult Patients With Locally Advanced Or Metastatic BRAF V600 Melanoma

Summary
EudraCT number	2013-004552-38
Trial protocol	NL GB ES IT
Global end of trial date	13 Jan 2023

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

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

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Trial information

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Sponsor protocol code

CLGX818X2109 (C4221013)

ISRCTN number

US NCT number

NCT02159066

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 East 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

12 Jul 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Jan 2023

Was the trial ended prematurely?

Main objective of the trial

To assess the anti-tumor activity of LGX818/MEK162 in combination with third targeted agents after progression on LGX818/MEK162 combination therapy.

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 Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Jul 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 11

Country: Number of subjects enrolled

Canada: 28

Country: Number of subjects enrolled

Germany: 37

Country: Number of subjects enrolled

Italy: 4

Country: Number of subjects enrolled

Netherlands: 7

Country: Number of subjects enrolled

Spain: 11

Country: Number of subjects enrolled

Switzerland: 38

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

United States: 12

Worldwide total number of subjects

158

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)

118

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study had 2 parts. In Part I, 158 subjects were enrolled and treated with encorafenib/ binimetinib (LGX818/MEK162) combination. In Part II, 58 subjects received tailored combination treatment.

Screening details

In Part I, subjects were treated until disease progression (PD). Based on the genetic assessment of a tumor biopsy obtained at PD, subjects from Part I entered Part II. Part II combination treatment were: encorafenib/ binimetinib + buparlisib (BKM120), infigratinib (BGJ398), capmatinib (INC280) or ribociclib (LEE011).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Part I: Encorafenib + Binimetinib (naive)

Arm description

Subjects naive to selective V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase (MEK) inhibitors, received encorafenib 450 milligram (mg) once a day and binimetinib 45 mg twice a day until disease progression or no clinical benefit. No dose reduction below 150 mg for encorafenib and 15 mg for binimetinib was permitted for this study. Treatment cycle for encorafenib and binimetinib was defined as 21 days of daily continuous treatment.

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

450 mg once a day. No dose reduction below 150 mg.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Part I: Encorafenib + Binimetinib (non-naive)

Arm description

Subjects non-naive to selective BRAF and MEK inhibitors, received encorafenib 450 mg once a day and binimetinib 45 mg twice a day until disease progression or no clinical benefit. No dose reduction below 150 mg for encorafenib and 15 mg for binimetinib was permitted for this study. Treatment cycle for both drugs was defined as 21 days of daily continuous treatment.

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

450 mg once a day. No dose reduction below 150 mg.

Part II: Encorafenib + Binimetinib + Ribociclib

Arm description

Subejcts received encorafenib 200 mg (starting dose) once a day, binimetinib 45 mg (starting dose) twice a day and ribociclib 100 mg (starting dose) once a day until disease progression or no clinical benefit. No dose reduction below 50 mg for encorafenib and 15 mg for binimetinib was permitted for this study. For ribociclib dose escalation was allowed till 600 mg and dose reduction was permitted till 50 mg. Ribociclib was taken for 21 consecutive days followed by a 7-day planned break.

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

200 mg (starting dose) once a day. No dose reduction below 50 mg.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg (starting dose) once a day. Dose escalation was allowed till 600 mg and dose reduction was permitted till 50 mg.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Part II: Encorafenib + Binimetinib + Infigratinib

Arm description

Subjects received encorafenib 450 mg (starting dose) once a day, binimetinib 45 mg (starting dose) twice a day and infigratinib 75 mg (starting dose) once a day until disease progression or no clinical benefit. No dose reduction below 150 mg for encorafenib and 15 mg for binimetinib was permitted for this study. For infigratinib dose escalation was allowed till 125 mg and dose reduction was permitted till 25 mg. Infigratinib was taken for 21 consecutive days followed by a 7-day planned break.

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

450 mg once a day. No dose reduction below 150 mg.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Investigational medicinal product name

Infigratinib

Investigational medicinal product code

BGJ398

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

75 mg (starting dose) once a day. Dose escalation was allowed till 125 mg and dose reduction was permitted till 25 mg.

Part II: Encorafenib + Binimetinib + Capmatinib

Arm description

Subjects received encorafenib 200 mg (starting dose) once a day, binimetinib 45 mg (starting dose) twice a day and capmatinib 200 mg (starting dose) capsule or 400 mg (starting dose) tablet twice a day until disease progression or no clinical benefit. No dose reduction below 50 mg for encorafenib and 15 mg for binimetinib was permitted for this study. For capmatinib dose escalation was allowed till 600 mg and dose reduction was permitted till 50 mg. Treatment cycle for encorafenib, binimetinib and capmatinib was defined as 21 days of daily continuous treatment.

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

200 mg (starting dose) once a day. No dose reduction below 50 mg.

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

200 mg (starting dose) capsule or 400 mg (starting dose) tablet twice a day. Dose escalation was allowed till 600 mg and dose reduction was permitted till 50 mg.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Part II: Encorafenib + Binimetinib + Buparlisib

Arm description

Subjects received encorafenib 450 mg (starting dose) once a day, binimetinib 45 mg (starting dose) twice a day and buparlisib 60 mg (starting dose) once a day until disease progression or no clinical benefit. No dose reduction below 150 mg for encorafenib and 15 mg for binimetinib was permitted for this study. For buparlisib dose escalation was allowed till 100 mg and dose reduction was permitted till 30 mg. Treatment cycle for encorafenib, binimetinib and buparlisib was defined as 21 days of daily continuous treatment.

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

450 mg once a day. No dose reduction below 150 mg.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Investigational medicinal product name

Buparlisib

Investigational medicinal product code

BKM120

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

60 mg (starting dose) once a day. Dose escalation was allowed till 100 mg and dose reduction was permitted till 30 mg.

Number of subjects in period 1	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Started	75	83	38	1	13	6
Completed	0	4	0	0	0	0
Not completed	75	79	38	1	13	6
Adverse event, serious fatal	11	9	1	-	2	1
Physician decision	2	9	1	-	-	-
Subjects/Guardian Decision	9	3	-	-	2	-
Adverse event, non-fatal	7	5	1	-	1	1
Progressive Disease	37	46	35	1	7	4
Missing Data	1	-	-	-	-	-
Study Terminated by Sponsor	3	3	-	-	-	-
New Therapy for Study Indication	5	4	-	-	1	-

Baseline characteristics

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Reporting group title

Part I: Encorafenib + Binimetinib (naive)

Reporting group description

Reporting group title

Part I: Encorafenib + Binimetinib (non-naive)

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Ribociclib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Infigratinib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Capmatinib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Buparlisib

Reporting group description

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: In Part I, 158 subjects were enrolled and out of these, 58 subjects entered Part II of the study.

Reporting group values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib	Total
Number of subjects	75	83	38	1	13	6	216
Age categorical
Subject in Infigratinib arm has been reported under "Not disclosed" category to avoid risk of identification of the subject.
Units: Subjects
18-44 years	14	24	9	0	0	1	48
45-64 years	43	37	19	0	7	4	110
65 years and over	18	22	10	0	6	1	57
Not disclosed	0	0	0	1	0	0	1
Age Continuous
"0" suggests that age of subject has been masked in Infigratinib arm to avoid risk of identification of the subject. "99999" suggests no standard deviation estimated as there was only 1 evaluable subject.
Units: years
arithmetic mean (standard deviation)	55.3 ± 12.91	53.9 ± 13.81	54.6 ± 13.85	0 ± 99999	63.5 ± 8.84	50.5 ± 10.50	-
Sex: Female, Male
Subject in Infigratinib arm has been reported under "Not disclosed" category to avoid risk of identification of the subject.
Units: Subjects
Female	28	39	22	0	5	1	95
Male	47	44	16	0	8	5	120
Not disclosed	0	0	0	1	0	0	1
Ethnicity (NIH/OMB)
Subject in Infigratinib arm has been reported under "Not disclosed" category to avoid risk of identification of the subject.
Units: Subjects
Hispanic or Latino	3	7	1	0	0	0	11
Not Hispanic or Latino	72	76	37	0	13	6	204
Not disclosed	0	0	0	1	0	0	1
Race, Customized
Race is reported. Subject in Infigratinib arm has been reported under "Not disclosed" category to avoid risk of identification of the subject.
Units: Subjects
Caucasian	74	82	37	0	13	6	212
Asian	1	1	1	0	0	0	3
Not disclosed	0	0	0	1	0	0	1

End points

Top of page

Reporting group title

Part I: Encorafenib + Binimetinib (naive)

Reporting group description

Reporting group title

Part I: Encorafenib + Binimetinib (non-naive)

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Ribociclib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Infigratinib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Capmatinib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Buparlisib

Reporting group description

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + buparlisib 60 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + buparlisib 90 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + infigratinib 75 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + capmatinib 200 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + capmatinib 300 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + capmatinib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects in received encorafenib 100 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subejcts in received encorafenib 200 mg/ binimetinib 30 mg + ribociclib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects in received encorafenib 200 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects in received encorafenib 200 mg/ binimetinib 45 mg + ribociclib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + buparlisib 60 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + buparlisib 90 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + infigratinib 75 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 100 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 30 mg + ribociclib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + ribociclib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 300 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 300 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + capmatinib 300 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + capmatinib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + buparlisib 90 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 300 mg/binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Primary: Overall Response Rate (ORR): Part II

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End point title

Overall Response Rate (ORR): Part II ^[1] ^[2]

End point description

ORR: percentage of subjects with confirmed complete response (CR) and partial response (PR). Response evaluation criteria in solid tumors (RECIST) v1.1: a) CR: disappearance of all non-nodal target lesions. Any pathological lymph nodes assigned as target lesions that had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. All lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis); b) PR: at least a 30 percent (%) decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters. Any radiological assessments taken >30 days after last dose of study therapy or after antineoplastic agents other than study treatments taken by subjects was excluded from the best overall response derivation. Confirmation of CR or PR was to be at least 4 weeks apart from previous radiological assessment. Full analysis set (FAS) for Part II evaluated.

End point type

Primary

End point timeframe

From the start of the treatment until disease/clinical progression or death or early study discontinuation, whichever happened earlier (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be evaluated.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Percentage of subjects
number (confidence interval 95%)	2.6 (0.1 to 13.8)	0 (0 to 0)	0 (0.0 to 24.7)	0 (0.0 to 45.9)

No statistical analyses for this end point

Secondary: Number of Subjects With Adverse Events (AEs) and Serious AEs (SAEs): Part I

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End point title

Number of Subjects With Adverse Events (AEs) and Serious AEs (SAEs): Part I ^[3]

End point description

An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occurred after subjects signed informed consent has been obtained. An SAE was an AE resulting in any of the following outcomes: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Safety set included all subjects who received at least 1 dose of encorafenib or binimetinib for Part I and had at least 1 valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

Day 1 up to 30 days after last dose (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
AEs	75	78
SAEs	47	37

No statistical analyses for this end point

Secondary: Number of Subjects With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II

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End point title

Number of Subjects With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II ^[4]

End point description

DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first cycle (first 21 days for infigratinib and capmatinib; 28 days for ribociclib and buparlisib) of treatment initiation and met the defined criteria for study. Dose-determining analysis set (DDS) consisted of all subjects from the safety set for Part II who met the minimum requirements for safety evaluation and minimum exposure or experienced DLT during the first cycle of the assigned triple combination treatment. No subjects were included in the dose-determining analysis set in the encorafenib/binimetinib+ infigratinib or buparlisib arm, hence no subjects analyzed for these reporting arms for this endpoint.

End point type

Secondary

End point timeframe

Cycle 1 (21 days following the first dose of the combination treatment with infigratinib and capmatinib; 28 days for the combination with ribociclib and buparlisib)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	34	0 ^[5]	12	0 ^[6]
Units: Subjects	1		0

Notes
[5] - No subjects were included in the dose-determining analysis set.
[6] - No subjects were included in the dose-determining analysis set.

No statistical analyses for this end point

Secondary: Number of Subjects With AEs and SAEs: Part II

Top of page

End point title

Number of Subjects With AEs and SAEs: Part II ^[7]

End point description

An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occurred after subjects signed informed consent has been obtained. An SAE was an AE resulting in any of the following outcomes: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Safety set included all subjects who received at least 1 dose of 3rd combination agent for Part II and had at least 1 valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

Day 1 up to 30 days after last dose (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
AEs	37	1	12	6
SAEs	19	0	6	4

No statistical analyses for this end point

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part I

Top of page

End point title

Number of Subjects With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part I ^[8]

End point description

Parameters evaluated were: Activated partial thromboplastin time (APTT) (seconds [sec]) - CTCAE graded high, fibrinogen (gram per liter [g/L]) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded high, prothrombin international normalized ratio (PINR) - CTCAE graded high, lymphocytes (10^9/L) - CTCAE graded low, lymphocytes (10^9/L) - CTCAE graded high, neutrophils (10^9/L) - CTCAE graded low, platelets (10^9/L) - CTCAE graded low, leukocytes (10^9/L) - CTCAE graded low, leukocytes (10^9/L) - CTCAE graded high. CTCAE version 4.03 was used: grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening consequences; grade 0 = values not meeting any of the criteria for grade 1 or higher. Safety set for Part I evaluated. In results reported below: post-baseline has been abbreviated as PB, graded high as GH and graded low as GL.

End point type

Secondary

End point timeframe

Baseline up to last dose (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
APTT-CTCAE GH Worst PB value Grade 0	46	54
Fibrinogen-CTCAE GL Worst PB value Grade 0	28	36
Hemoglobin-CTCAE GL Worst PB value Grade 0	21	17
Hemoglobin-CTCAE GH Worst PB value Grade 0	70	80
PINR -CTCAE GH Worst PB value Grade 0	44	34
Lymphocytes-CTCAE GL Worst PB value Grade 0	23	27
Lymphocytes-CTCAE GH Worst PB value Grade 0	61	68
Neutrophils-CTCAE GL Worst PB value Grade 0	52	62
Platelets-CTCAE GL Worst PB value Grade 0	59	71
Leukocytes-CTCAE GL Worst PB value Grade 0	52	61
Leukocytes-CTCAE GH Worst PB value Grade 0	66	78
APTT-CTCAE GH Worst PB value Grade 1	1	4
Fibrinogen-CTCAE GL Worst PB value Grade 1	8	9
Hemoglobin-CTCAE GL Worst PB value Grade 1	28	39
Hemoglobin-CTCAE GH Worst PB value Grade 1	4	2
PINR -CTCAE GH Worst PB value Grade 1	0	2
Lymphocytes-CTCAE GL Worst PB value Grade 1	22	24
Lymphocytes-CTCAE GH Worst PB value Grade 1	0	0
Neutrophils-CTCAE GL Worst PB value Grade 1	4	6
Platelets-CTCAE GL Worst PB value Grade 1	14	11
Leukocytes-CTCAE GL Worst PB value Grade 1	11	14
Leukocytes-CTCAE GH Worst PB value Grade 1	0	0
APTT -CTCAE GH Worst PB value Grade 2	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 2	5	7
Hemoglobin-CTCAE GL Worst PB value Grade 2	18	20
Hemoglobin-CTCAE GH Worst PB value Grade 2	0	0
PINR-CTCAE GH Worst PB value Grade 2	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 2	13	12
Lymphocytes-CTCAE GH Worst PB value Grade 2	2	6
Neutrophils-CTCAE GL Worst PB value Grade 2	5	4
Platelets-CTCAE GL Worst PB value Grade 2	2	0
Leukocytes-CTCAE GL Worst PB value Grade 2	3	3
Leukocytes-CTCAE GH Worst PB value Grade 2	0	0
APTT-CTCAE GH Worst PB value Grade 3	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 3	4	1
Hemoglobin-CTCAE GL Worst PB value Grade 3	8	6
Hemoglobin-CTCAE GH Worst PB value Grade 3	1	0
PINR -CTCAE GH Worst PB value Grade 3	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 3	6	10
Lymphocytes-CTCAE GH Worst PB value Grade 3	1	0
Neutrophils-CTCAE GL Worst PB value Grade 3	3	1
Platelets-CTCAE GL Worst PB value Grade 3	0	0
Leukocytes-CTCAE GL Worst PB value Grade 3	0	0
Leukocytes-CTCAE GH Worst PB value Grade 3	0	0
APTT -CTCAE GH Worst PB value Grade 4	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 4	0	0
Hemoglobin-CTCAE GL Worst PB value Grade 4	0	0
Hemoglobin-CTCAE GH Worst PB value Grade 4	0	0
PINR-CTCAE GH Worst PB value Grade 4	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 4	0	1
Lymphocytes-CTCAE GH Worst PB value Grade 4	0	0
Neutrophils-CTCAE GL Worst PB value Grade 4	0	0
Platelets-CTCAE GL Worst PB value Grade 4	0	0
Leukocytes-CTCAE GL Worst PB value Grade 4	0	0
Leukocytes-CTCAE GH Worst PB value Grade 4	0	0
APTT -CTCAE GH Worst PB value Missing	28	25
Fibrinogen-CTCAE GL Worst PB value Missing	30	30
Hemoglobin-CTCAE GL Worst PB value Missing	0	1
Hemoglobin-CTCAE GH Worst PB value Missing	0	1
PINR -CTCAE GH Worst PB value Missing	31	47
Lymphocytes-CTCAE GL Worst PB value Missing	11	9
Lymphocytes-CTCAE GH Worst PB value Missing	11	9
Neutrophils-CTCAE GL Worst PB value Missing	11	10
Platelets-CTCAE GL Worst PB value Missing	0	1
Leukocytes-CTCAE GL Worst PB value Missing	9	5
Leukocytes-CTCAE GH Worst PB value Missing	9	5

No statistical analyses for this end point

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on CTCAE Grade: Part II

Top of page

End point title

Number of Subjects With Worst Post-baseline Hematology Results Based on CTCAE Grade: Part II ^[9]

End point description

Parameters evaluated were: APTT (sec) - CTCAE graded high, fibrinogen (g/L) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded high, PINR - CTCAE graded high, lymphocytes (10^9/L) - CTCAE graded low, lymphocytes (10^9/L) - CTCAE graded high, neutrophils (10^9/L) - CTCAE graded low, platelets (10^9/L) - CTCAE graded low, leukocytes (10^9/L) - CTCAE graded low, leukocytes (10^9/L) - CTCAE graded high. CTCAE version 4.03 was used: grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening consequences; grade 0 = values not meeting any of the criteria for grade 1 or higher. Safety set included all subjects who received at least 1 dose of 3rd combination agent for Part II and had at least 1 valid post-baseline safety assessment. In results reported below: post-baseline has been abbreviated as PB, graded high as GH and graded low as GL

End point type

Secondary

End point timeframe

Baseline up to last dose (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
APTT-CTCAE GH Worst PB value Grade 0	27	1	9	4
Fibrinogen-CTCAE GL Worst PB value Grade 0	13	0	6	3
Hemoglobin-CTCAE GL Worst PB value Grade 0	4	0	4	2
Hemoglobin-CTCAE GH Worst PB value Grade 0	37	1	11	6
PINR-CTCAE GH Worst PB value Grade 0	14	1	8	1
Lymphocytes -CTCAE GL Worst PB value Grade 0	5	0	4	2
Lymphocytes-CTCAE GH Worst PB value Grade 0	29	0	11	6
Neutrophils-CTCAE GL Worst PB value Grade 0	10	0	11	6
Platelets-CTCAE GL Worst PB value Grade 0	33	1	11	6
Leukocytes-CTCAE GL Worst PB value Grade 0	8	0	11	6
Leukocytes-CTCAE GH Worst PB value Grade 0	31	0	11	6
APTT-CTCAE GH Worst PB value Grade 1	0	0	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 1	3	1	1	0
Hemoglobin-CTCAE GL Worst PB value Grade 1	15	1	5	1
Hemoglobin-CTCAE GH Worst PB value Grade 1	0	0	1	0
PINR-CTCAE GH Worst PB value Grade 1	0	0	0	0
Lymphocytes -CTCAE GL Worst PB value Grade 1	7	0	4	3
Lymphocytes-CTCAE GH Worst PB value Grade 1	0	0	0	0
Neutrophils-CTCAE GL Worst PB value Grade 1	9	0	0	0
Platelets-CTCAE GL Worst PB value Grade 1	4	0	1	0
Leukocytes-CTCAE GL Worst PB value Grade 1	8	0	0	0
Leukocytes-CTCAE GH Worst PB value Grade 1	0	0	0	0
APTT-CTCAE GH Worst PB value Grade 2	0	0	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 2	2	0	1	0
Hemoglobin-CTCAE GL Worst PB value Grade 2	14	0	2	1
Hemoglobin-CTCAE GH Worst PB value Grade 2	0	0	0	0
PINR-CTCAE GH Worst PB value Grade 2	0	0	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 2	9	0	3	1
Lymphocytes-CTCAE GH Worst PB value Grade 2	0	0	0	0
Neutrophils-CTCAE GL Worst PB value Grade 2	6	0	0	0
Platelets-CTCAE GL Worst PB value Grade 2	0	0	0	0
Leukocytes-CTCAE GL Worst PB value Grade 2	12	0	0	0
Leukocytes-CTCAE GH Worst PB value Grade 2	0	0	0	0
APTT-CTCAE GH Worst PB value Grade 3	0	0	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 3	1	0	0	0
Hemoglobin-CTCAE GL Worst PB value Grade 3	4	0	1	2
Hemoglobin-CTCAE GH Worst PB value Grade 3	0	0	0	0
PINR-CTCAE GH Worst PB value Grade 3	0	0	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 3	7	0	0	0
Lymphocytes-CTCAE GH Worst PB value Grade 3	0	0	0	0
Neutrophils-CTCAE GL Worst PB value Grade 3	1	0	0	0
Platelets-CTCAE GL Worst PB value Grade 3	0	0	0	0
Leukocytes-CTCAE GL Worst PB value Grade 3	3	0	0	0
Leukocytes-CTCAE GH Worst PB value Grade 3	0	0	0	0
APTT-CTCAE GH Worst PB value Grade 4	0	0	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 4	0	0	0	0
Hemoglobin-CTCAE GL Worst PB value Grade 4	0	0	0	0
Hemoglobin-CTCAE GH Worst PB value Grade 4	0	0	0	0
PINR-CTCAE GH Worst PB value Grade 4	0	0	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 4	1	0	0	0
Lymphocytes-CTCAE GH Worst PB value Grade 4	0	0	0	0
Neutrophils-CTCAE GL Worst PB value Grade 4	1	0	0	0
Platelets-CTCAE GL Worst PB value Grade 4	0	0	0	0
Leukocytes-CTCAE GL Worst PB value Grade 4	0	0	0	0
Leukocytes-CTCAE GH Worst PB value Grade 4	0	0	0	0
APTT-CTCAE GH Worst PB value Missing	11	0	4	2
Fibrinogen-CTCAE GL Worst PB value Missing	19	0	5	3
Hemoglobin-CTCAE GL Worst PB value Missing	1	0	1	0
Hemoglobin-CTCAE GH Worst PB value Missing	1	0	1	0
PINR-CTCAE GH Worst PB value Missing	24	0	5	5
Lymphocytes-CTCAE GL Worst PB value Missing	9	1	2	0
Lymphocytes-CTCAE GH Worst PB value Missing	9	1	2	0
Neutrophils-CTCAE GL Worst PB value Missing	11	1	2	0
Platelets-CTCAE GL Worst PB value Missing	1	0	1	0
Leukocytes-CTCAE GL Worst PB value Missing	7	1	2	0
Leukocytes-CTCAE GH Worst PB value Missing	7	1	2	0

No statistical analyses for this end point

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part I

Top of page

End point title

Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part I ^[10]

End point description

Albumin (g/L)-CTCAE graded low, alkaline phosphatase (units per liter [U/L])-CTCAE graded high, alanine aminotransferase (AT) (U/L)-CTCAE graded high, amylase (U/L)-CTCAE graded high, aspartate AT (U/L)-CTCAE graded high, bilirubin (micromole per liter [umol/L])-CTCAE graded high, creatinine (umol/L)-CTCAE graded high, creatine kinase (U/L)-CTCAE graded high, gamma glutamyl transferase (GT) (U/L)-CTCAE graded high, glucose (millimole per liter [mmol/L])-CTCAE graded low, high, potassium (mmol/L)-CTCAE graded low, potassium (mmol/L)-CTCAE graded high, magnesium (mmol/L)-CTCAE graded low, high, phosphate (mmol/L)- CTCAE graded low, sodium (mmol/L)-CTCAE graded low, sodium (mmol/L)-CTCAE graded high, urate (umol/L)-CTCAE graded high. Grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences; grade 0=values not meeting any of the criteria for >=grade 1. Safety set for Part I evaluated. In rows below, graded low=GL, graded high=GH, post-baseline value=PBV

End point type

Secondary

End point timeframe

Baseline up to last dose (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
Albumin-CTCAE GL Worst PBV Grade 0	32	40
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 0	39	43
Alanine AT-CTCAE GH Worst PBV Grade 0	38	51
Amylase-CTCAE GH Worst PBV Grade 0	53	52
Aspartate AT-CTCAE GH Worst PBV Grade 0	38	50
Bilirubin-CTCAE GH Worst PBV Grade 0	73	81
Creatine Kinase-CTCAE GH Worst PBV Grade 0	22	56
Creatinine-CTCAE GH Worst PBV Grade 0	2	4
Gamma GT-CTCAE GH Worst PBV Grade 0	20	33
Glucose-CTCAE GL Worst PBV Grade 0	55	67
Glucose-CTCAE GH Worst PBV Grade 0	56	60
Potassium-CTCAE GL Worst PBV Grade 0	65	74
Potassium-CTCAE GH Worst PBV Grade 0	54	66
Magnesium-CTCAE GL Worst PBV Grade 0	66	68
Magnesium-CTCAE GH Worst PBV Grade 0	74	79
Phosphate-CTCAE GL Worst PBV Grade 0	40	62
Sodium-CTCAE GL Worst PBV Grade 0	54	53
Sodium-CTCAE GH Worst PBV Grade 0	66	75
Urate-CTCAE GH Worst PBV Grade 0	75	82
Albumin-CTCAE GL Worst PBV Grade 1	35	29
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 1	28	31
Alanine AT-CTCAE GH Worst PBV Grade 1	27	28
Amylase-CTCAE GH Worst PBV Grade 1	14	6
Aspartate AT-CTCAE GH Worst PBV Grade 1	30	29
Bilirubin-CTCAE GH Worst PBV Grade 1	1	0
Creatine Kinase-CTCAE GH Worst PBV Grade 1	30	15
Creatinine-CTCAE GH Worst PBV Grade 1	57	56
Gamma GT-CTCAE GH Worst PBV Grade 1	19	18
Glucose-CTCAE GL Worst PBV Grade 1	15	7
Glucose-CTCAE GH Worst PBV Grade 1	4	10
Potassium-CTCAE GL Worst PBV Grade 1	7	5
Potassium-CTCAE GH Worst PBV Grade 1	18	15
Magnesium-CTCAE GL Worst PBV Grade 1	8	14
Magnesium-CTCAE GH Worst PBV Grade 1	1	3
Phosphate-CTCAE GL Worst PBV Grade 1	3	3
Sodium-CTCAE GL Worst PBV Grade 1	21	24
Sodium-CTCAE GH Worst PBV Grade 1	9	6
Urate-CTCAE GH Worst PBV Grade 1	0	0
Albumin-CTCAE GL Worst PBV Grade 2	8	12
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 2	5	5
Alanine AT-CTCAE GH Worst PBV Grade 2	5	2
Amylase-CTCAE GH Worst PBV Grade 2	5	2
Aspartate AT-CTCAE GH Worst PBV Grade 2	4	2
Bilirubin-CTCAE GH Worst PBV Grade 2	1	0
Creatine Kinase-CTCAE GH Worst PBV Grade 2	18	8
Creatinine-CTCAE GH Worst PBV Grade 2	14	22
Gamma GT-CTCAE GH Worst PBV Grade 2	14	13
Glucose-CTCAE GL Worst PBV Grade 2	1	1
Glucose-CTCAE GH Worst PBV Grade 2	3	0
Potassium-CTCAE GL Worst PBV Grade 2	0	0
Potassium-CTCAE GH Worst PBV Grade 2	2	0
Magnesium-CTCAE GL Worst PBV Grade 2	0	0
Magnesium-CTCAE GH Worst PBV Grade 2	0	0
Phosphate-CTCAE GL Worst PBV Grade 2	24	12
Sodium-CTCAE GL Worst PBV Grade 2	0	0
Sodium-CTCAE GH Worst PBV Grade 2	0	1
Urate-CTCAE GH Worst PBV Grade 2	0	0
Albumin-CTCAE GL Worst PBV Grade 3	0	1
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 3	3	3
Alanine AT-CTCAE GH Worst PBV Grade 3	5	0
Amylase-CTCAE GH Worst PBV Grade 3	2	2
Aspartate AT-CTCAE GH Worst PBV Grade 3	3	1
Bilirubin-CTCAE GH Worst PBV Grade 3	0	1
Creatine Kinase-CTCAE GH Worst PBV Grade 3	4	2
Creatinine-CTCAE GH Worst PBV Grade 3	2	0
Gamma GT-CTCAE GH Worst PBV Grade 3	20	15
Glucose-CTCAE GL Worst PBV Grade 3	0	0
Glucose-CTCAE GH Worst PBV Grade 3	7	5
Potassium-CTCAE GL Worst PBV Grade 3	3	3
Potassium-CTCAE GH Worst PBV Grade 3	1	0
Magnesium-CTCAE GL Worst PBV Grade 3	1	0
Magnesium-CTCAE GH Worst PBV Grade 3	0	0
Phosphate-CTCAE GL Worst PBV Grade 3	8	4
Sodium-CTCAE GL Worst PBV Grade 3	0	5
Sodium-CTCAE GH Worst PBV Grade 3	0	0
Urate-CTCAE GH Worst PBV Grade 3	0	0
Albumin-CTCAE GL Worst PBV Grade 4	0	0
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 4	0	0
Alanine AT-CTCAE GH Worst PBV Grade 4	0	0
Amylase-CTCAE GH Worst PBV Grade 4	0	1
Aspartate AT-CTCAE GH Worst PBV Grade 4	0	0
Bilirubin-CTCAE GH Worst PBV Grade 4	0	0
Creatine Kinase-CTCAE GH Worst PBV Grade 4	1	1
Creatinine-CTCAE GH Worst PBV Grade 4	0	0
Gamma GT-CTCAE GH Worst PBV Grade 4	2	3
Glucose-CTCAE GL Worst PBV Grade 4	0	0
Glucose-CTCAE GH Worst PBV Grade 4	1	0
Potassium-CTCAE GL Worst PBV Grade 4	0	0
Potassium-CTCAE GH Worst PBV Grade 4	0	1
Magnesium-CTCAE GL Worst PBV Grade 4	0	0
Magnesium-CTCAE GH Worst PBV Grade 4	0	0
Phosphate-CTCAE GL Worst PBV Grade 4	0	1
Sodium-CTCAE GL Worst PBV Grade 4	0	0
Sodium-CTCAE GH Worst PBV Grade 4	0	0
Urate-CTCAE GH Worst PBV Grade 4	0	0
Albumin-CTCAE GL Worst PBV Missing	0	1
Alkaline Phosphatase-CTCAE GH Worst PBV Missing	0	1
Alanine AT-CTCAE GH Worst PBV Missing	0	2
Amylase-CTCAE GH Worst PBV Missing	1	20
Aspartate AT-CTCAE GH Worst PBV Missing	0	1
Bilirubin-CTCAE GH Worst PBV Missing	0	1
Creatine Kinase-CTCAE GH Worst PBV Missing	0	1
Creatinine-CTCAE GH Worst PBV Missing	0	1
Gamma GT-CTCAE GH Worst PBV Missing	0	1
Glucose-CTCAE GL Worst PBV Missing	4	8
Glucose-CTCAE GH Worst PBV Missing	4	8
Potassium-CTCAE GL Worst PBV Missing	0	1
Potassium-CTCAE GH Worst PBV Missing	0	1
Magnesium-CTCAE GL Worst PBV Missing	0	1
Magnesium-CTCAE GH Worst PBV Missing	0	1
Phosphate-CTCAE GL Worst PBV Missing	0	1
Sodium-CTCAE GL Worst PBV Missing	0	1
Sodium-CTCAE GH Worst PBV Missing	0	1
Urate-CTCAE GH Worst PBV Missing	0	1

No statistical analyses for this end point

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part II

Top of page

End point title

Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part II ^[11]

End point description

Albumin (g/L)- CTCAE graded low, alkaline phosphatase (U/L)- CTCAE graded high, alanine AT (U/L)- CTCAE graded high, amylase (U/L) - CTCAE graded high, aspartate AT (U/L)- CTCAE graded high, bilirubin (umol/L)- CTCAE graded high, creatinine (umol/L) - CTCAE graded high, creatine kinase (U/L)- CTCAE graded high, gamma GT (U/L)- CTCAE graded high, glucose (mmol/L)- CTCAE graded low, high, potassium (mmol/L)- CTCAE graded low, potassium (mmol/L)- CTCAE graded high, magnesium (mmol/L)- CTCAE graded low, high, phosphate (mmol/L)- CTCAE graded low, sodium (mmol/L)- CTCAE graded low, sodium (mmol/L)- CTCAE graded high, urate (umol/L)- CTCAE graded high. Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening consequences; Grade 0= values not meeting any of the criteria for >=grade 1. Safet set for Part II evaluated. In rows below, graded low=GL, graded high=GH, post-baseline value=PBV.

End point type

Secondary

End point timeframe

Baseline up to last dose (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
Albumin-CTCAE GL Worst PBV Grade 0	16	1	1	3
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 0	22	1	7	1
Alanine AT-CTCAE GH Worst PBV Grade 0	27	1	9	4
Amylase-CTCAE GH Worst PBV Grade 0	27	1	9	1
Aspartate AT-CTCAE GH Worst PBV Grade 0	27	1	8	3
Bilirubin-CTCAE GH Worst PBV Grade 0	37	1	12	6
Creatine Kinase-CTCAE GH Worst PBV Grade 0	20	0	6	3
Creatinine-CTCAE GH Worst PBV Grade 0	1	0	0	1
Gamma GT-CTCAE GH Worst PBV Grade 0	20	1	5	0
Glucose -CTCAE GL Worst PBV Grade 0	24	0	11	5
Glucose-CTCAE GH Worst PBV Grade 0	26	1	10	4
Potassium -CTCAE GL Worst PBV Grade 0	34	1	11	5
Potassium-CTCAE GH Worst PBV Grade 0	32	1	9	3
Magnesium -CTCAE GL Worst PBV Grade 0	35	1	10	4
Magnesium-CTCAE GH Worst PBV Grade 0	36	1	12	5
Phosphate -CTCAE GL Worst PBV Grade 0	25	1	7	4
Sodium-CTCAE GL Worst PBV Grade 0	28	1	10	3
Sodium-CTCAE GH Worst PBV Grade 0	35	1	12	4
Urate-CTCAE GH Worst PBV Grade 0	37	1	12	5
Albumin-CTCAE GL Worst PBV Grade 1	13	0	6	0
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 1	10	0	3	4
Alanine AT-CTCAE GH Worst PBV Grade 1	6	0	2	1
Amylase-CTCAE GH Worst PBV Grade 1	1	0	2	0
Aspartate AT-CTCAE GH Worst PBV Grade 1	6	0	4	2
Bilirubin-CTCAE GH Worst PBV Grade 1	0	0	0	0
Creatine Kinase-CTCAE GH Worst PBV Grade 1	14	1	4	2
Creatinine-CTCAE GH Worst PBV Grade 1	25	1	4	3
Gamma GT-CTCAE GH Worst PBV Grade 1	9	0	2	1
Glucose -CTCAE GL Worst PBV Grade 1	6	1	1	0
Glucose-CTCAE GH Worst PBV Grade 1	2	0	1	1
Potassium-CTCAE GL Worst PBV Grade 1	3	0	1	0
Potassium-CTCAE GH Worst PBV Grade 1	4	0	3	2
Magnesium -CTCAE GL Worst PBV Grade 1	2	0	2	1
Magnesium-CTCAE GH Worst PBV Grade 1 1	1	0	0	0
Phosphate -CTCAE GL Worst PBV Grade 1	2	0	1	1
Sodium-CTCAE GL Worst PBV Grade 1	7	0	2	2
Sodium-CTCAE GH Worst PBV Grade 1	2	0	0	1
Urate-CTCAE GH Worst PBV Grade 1	0	0	0	0
Albumin-CTCAE GL Worst PBV Grade 2	7	0	3	1
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 2	3	0	2	1
Alanine AT-CTCAE GH Worst PBV Grade 2	2	0	0	0
Amylase-CTCAE GH Worst PBV Grade 2	0	0	0	1
Aspartate AT-CTCAE GH Worst PBV Grade 2	3	0	0	0
Bilirubin-CTCAE GH Worst PBV Grade 2	0	0	0	0
Creatine Kinase-CTCAE GH Worst PBV Grade 2	3	0	0	0
Creatinine-CTCAE GH Worst PBV Grade 2	11	0	8	1
Gamma GT-CTCAE GH Worst PBV Grade 2	1	0	2	2
Glucose -CTCAE GL Worst PBV Grade 2	0	0	0	0
Glucose-CTCAE GH Worst PBV Grade 2	0	0	0	0
Potassium -CTCAE GL Worst PBV Grade 2	0	0	0	0
Potassium-CTCAE GH Worst PBV Grade 2	1	0	0	0
Magnesium -CTCAE GL Worst PBV Grade 2	0	0	0	0
Magnesium-CTCAE GH Worst PBV Grade 2	0	0	0	0
Phosphate -CTCAE GL Worst PBV Grade 2	7	0	3	0
Sodium-CTCAE GL Worst PBV Grade 2	0	0	0	0
Sodium-CTCAE GH Worst PBV Grade 2	0	0	0	0
Urate-CTCAE GH Worst PBV Grade 2	0	0	0	0
Albumin-CTCAE GL Worst PBV Grade 3	1	0	2	1
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 3	2	0	0	0
Alanine AT-CTCAE GH Worst PBV Grade 3	1	0	1	0
Amylase-CTCAE GH Worst PBV Grade 3	0	0	0	0
Aspartate AT-CTCAE GH Worst PBV Grade 3	1	0	0	1
Bilirubin-CTCAE GH Worst PBV Grade 3	0	0	0	0
Creatine Kinase-CTCAE GH Worst PBV Grade 3	0	0	2	0
Creatinine-CTCAE GH Worst PBV Grade 3	0	0	0	0
Gamma GT-CTCAE GH Worst PBV Grade 3	7	0	3	3
Glucose -CTCAE GL Worst PBV Grade 3	0	0	0	0
Glucose-CTCAE GH Worst PBV Grade 3	1	0	1	0
Potassium -CTCAE GL Worst PBV Grade 3	0	0	0	0
Potassium-CTCAE GH Worst PBV Grade 3	0	0	0	0
Magnesium -CTCAE GL Worst PBV Grade 3	0	0	0	0
Magnesium-CTCAE GH Worst PBV Grade 3	0	0	0	0
Phosphate -CTCAE GL Worst PBV Grade 3	1	0	1	0
Sodium-CTCAE GL Worst PBV Grade 3	2	0	0	0
Sodium-CTCAE GH Worst PBV Grade 3	0	0	0	0
Urate-CTCAE GH Worst PBV Grade 3	0	0	0	0
Albumin-CTCAE GL Worst PBV Grade 4	0	0	0	0
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 4	0	0	0	0
Alanine AT-CTCAE GH Worst PBV Grade 4	1	0	0	1
Amylase-CTCAE GH Worst PBV Grade 4	2	0	0	0
Aspartate AT-CTCAE GH Worst PBV Grade 4	0	0	0	0
Bilirubin-CTCAE GH Worst PBV Grade 4	0	0	0	0
Creatine Kinase-CTCAE GH Worst PBV Grade 4	0	0	0	0
Creatinine-CTCAE GH Worst PBV Grade 4	0	0	0	0
Gamma GT-CTCAE GH Worst PBV Grade 4	0	0	0	0
Glucose-CTCAE GL Worst PBV Grade 4	0	0	0	0
Glucose-CTCAE GH Worst PBV Grade 4	1	0	0	0
Potassium-CTCAE GL Worst PBV Grade 4	0	0	0	0
Potassium-CTCAE GH Worst PBV Grade 4	0	0	0	0
Magnesium-CTCAE GL Worst PBV Grade 4	0	0	0	0
Magnesium-CTCAE GH Worst PBV Grade 4	0	0	0	0
Phosphate-CTCAE GL Worst PBV Grade 4	2	0	0	0
Sodium-CTCAE GL Worst PBV Grade 4	0	0	0	0
Sodium-CTCAE GH Worst PBV Grade 4	0	0	0	0
Urate-CTCAE GH Worst PBV Grade 4	0	0	0	0
Albumin-CTCAE GL Worst PBV Missing	1	0	1	1
Alkaline Phosphatase-CTCAE GH Worst PBV Missing	1	0	1	0
Alanine AT-CTCAE GH Worst PBV Missing	1	0	1	0
Amylase-CTCAE GH Worst PBV Missing	8	0	2	4
Aspartate AT-CTCAE GH Worst PBV Missing	1	0	1	0
Bilirubin-CTCAE GH Worst PBV Missing	1	0	1	0
Creatine Kinase-CTCAE GH Worst PBV Missing	1	0	1	1
Creatinine-CTCAE GH Worst PBV Missing	1	0	1	1
Gamma GT-CTCAE GH Worst PBV Missing	1	0	1	0
Glucose-CTCAE GL Worst PBV Missing	8	0	1	1
Glucose-CTCAE GH Worst PBV Missing	8	0	1	1
Potassium-CTCAE GL Worst PBV Missing	1	0	1	1
Potassium-CTCAE GH Worst PBV Missing	1	0	1	1
Magnesium-CTCAE GL Worst PBV Missing	1	0	1	1
Magnesium-CTCAE GH Worst PBV Missing	1	0	1	1
Phosphate-CTCAE GL Worst PBV Missing	1	0	1	1
Sodium-CTCAE GL Worst PBV Missing	1	0	1	1
Sodium-CTCAE GH Worst PBV Missing	1	0	1	1
Urate-CTCAE GH Worst PBV Missing	1	0	1	1

No statistical analyses for this end point

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part I

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End point title

Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part I ^[12]

End point description

Vital signs evaluated were: Low/high systolic blood pressure (BP) (millimeter of Mercury [mmHg]): less than or equal to (<=) 90 mmHg with decrease from baseline of >=20 mmHg / >=160 mmHg with increase from baseline of >=20 mmHg; low/high diastolic BP [mmHg]: <=50 mmHg with decrease from baseline of >=15 mmHg / >=100 mmHg with increase from baseline of >=15 mmHg; low/high pulse rate (beats per minute [bpm]): <=50 bpm with decrease from baseline of >=15 bpm / >=120 bpm with increase from baseline of >=15 bpm; low/high weight (kilogram [kg]): >=20% decrease/increase from baseline; and low/high body temperature (degree Celsius [C]): <=36 C / >= 37.5 C. Safety set for Part I evaluated. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, "n" signifies number of subjects evaluable for specified rows.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
Sitting Pulse Rate: High (n= 75, 79)	2	8
Sitting Pulse Rate: Low (n= 75, 80)	5	4
Sitting Systolic BP: High (n= 74, 80)	18	5
Sitting Systolic BP: Low (n= 75, 78)	3	2
Sitting Diastolic BP: High (n= 75, 79)	11	4
Sitting Diastolic BP: Low (n= 74, 80)	5	3
Weight: High (n= 74, 71)	0	2
Weight: Low (n= 74, 71)	0	0
Body temperature: High (n= 74, 79)	14	14
Body temperature: Low (n= 60, 71)	44	36

No statistical analyses for this end point

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part II

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End point title

Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part II ^[13]

End point description

Vital signs evaluated were: Low/high systolic BP (mmHg): <=90 mmHg with decrease from baseline of >=20 mmHg / >=160 mmHg with increase from baseline of >=20 mmHg; low/high diastolic BP [mmHg]: <=50 mmHg with decrease from baseline of >=15 mmHg / >=100 mmHg with increase from baseline of >=15 mmHg; low/high pulse rate (bpm): <=50 bpm with decrease from baseline of >=15 bpm / >=120 bpm with increase from baseline of >=15 bpm; low/high weight (kg): >=20% decrease/increase from baseline; and low/high body temperature (C): <=36 C / >= 37.5 C. Safety set for Part II evaluated. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, "n" signifies number of subjects evaluable for specified rows.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
Sitting Pulse Rate: High (n= 37, 1, 13, 6)	2	0	0	1
Sitting Pulse Rate: Low (n= 37, 1, 13, 6)	1	0	0	0
Sitting Systolic BP: High (n= 37, 1, 11, 6)	2	0	4	0
Sitting Systolic BP: Low (n= 37, 1, 13, 6)	0	0	0	0
Sitting Diastolic BP: High (n= 37, 1, 13, 6)	2	0	1	0
Sitting Diastolic BP: Low (n= 37, 1, 13, 6)	1	0	0	0
Weight: High (n= 36, 1, 13, 5)	0	0	0	0
Weight: Low (n= 36, 1, 13, 5)	1	0	0	0
Body temperature: High (n= 36, 1, 13, 6)	3	0	1	1
Body temperature: Low (n= 30, 1, 11, 5)	14	1	6	3

No statistical analyses for this end point

Secondary: Number of Subjects With Notable Electrocardiograms (ECG) Values: Part I

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End point title

Number of Subjects With Notable Electrocardiograms (ECG) Values: Part I ^[14]

End point description

Abnormality categories were: Heart rate (HR): increase from baseline >25% and to a value >100 bpm, decrease from baseline >25% and to a value <60 bpm; PR: increase from baseline >25% and to a value >200 millisecond (ms); QRS: increase from baseline >25% and to a value >110 ms; QT: increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms; and Corrected QT interval by Fridericia (QTcF): increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms. New = newly occurred post-baseline value. Safety set for Part I evaluated. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, "n" signifies number of subjects evaluable for specified rows. In results reported below, increase from baseline has been abbreviated as IFB, and decrease from baseline as DFB.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
HR: IFB >25% & to a value >100 bpm (n = 74, 80)	10	5
HR: DFB>25% & to a value <60 bpm (n = 74, 80)	37	23
PR: IFB >25% & to a value >200 ms (n = 72, 80)	5	1
QRS: IFB >25% & to a value >110 ms (n = 75, 80)	3	0
QT: IFB >30 ms (n = 75, 80)	61	48
QT: IFB >60 ms (n = 75, 80)	29	15
QT: New Interval >450 ms (n = 75, 78)	24	4
QT: New Interval >480 ms (n = 75, 80)	5	3
QT: New Interval >500 ms (n = 75, 80)	3	0
QTcF: IFB >30 ms (n = 75, 80)	46	31
QTcF: IFB >60 ms (n = 75, 80)	4	2
QTcF: New Interval >450 ms (n = 74, 77)	28	15
QTcF: New Interval >480 ms (n = 75, 80)	4	0
QTcF: New Interval >500 ms (n = 75, 80)	1	0

No statistical analyses for this end point

Secondary: Number of Subjects With Notable ECG Values: Part II

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End point title

Number of Subjects With Notable ECG Values: Part II ^[15]

End point description

Abnormality categories were: HR: increase from baseline >25% and to a value >100 bpm, decrease from baseline >25% and to a value <60 bpm; PR: increase from baseline >25% and to a value >200 ms; QRS: increase from baseline >25% and to a value >110 ms; QT: increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms; and QTcF: increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms. New = newly occurred post-baseline value. Safety set for Part II evaluated. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, "n" signifies number of subjects evaluable for specified rows. In results reported below, increase from baseline has been abbreviated as IFB, and decrease from baseline as DFB. Here “99999” = data not available as there was no subject evaluable.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
HR: IFB>25% & to a value >100 bpm (n=38, 1, 13, 6)	3	0	2	1
HR: DFB>25% & to a value <60 bpm (n=38, 1, 13, 6)	14	0	7	0
PR: IFB>25% & to a value >200 ms (n=37, 1, 13, 6)	1	0	2	0
QRS: IFB>25% & to a value >110 ms (n=38, 1, 13, 6)	0	0	0	0
QT: IFB>30 ms (n=38, 1, 13, 6)	24	0	9	0
QT: IFB>60 ms (n=38, 1, 13, 6)	2	0	0	0
QT: New Interval >450 ms (n=37, 0, 13, 6)	3	99999	3	0
QT: New Interval >480 ms (n=38, 1, 13, 6)	1	0	0	0
QT: New Interval >500 ms (n=38, 1, 13, 6)	0	0	0	0
QTcF: IFB>30 ms (n=38, 1, 13, 6)	11	0	2	1
QTcF: IFB>60 ms (n=38, 1, 13, 6)	0	0	0	0
QTcF: New Interval >450 ms (n=37, 1, 13, 5)	14	0	3	0
QTcF: New Interval >480 ms (n=38, 1, 13, 6)	0	0	0	0
QTcF: New Interval >500 ms (n=38, 1, 13, 6)	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With At least One Dose Interruption: Part I

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End point title

Number of Subjects With At least One Dose Interruption: Part I ^[16]

End point description

In this endpoint, number of subjects with at least 1 dose interruption for encorafenib and binimetinib, respectively were reported. Safety set included all subjects who received at least 1 dose of encorafenib or binimetinib for Part I and had at least 1 valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
Encorafenib	46	40
Binimetinib	44	41

No statistical analyses for this end point

Secondary: Number of Subjects With At least One Dose Interruption: Part II

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End point title

Number of Subjects With At least One Dose Interruption: Part II ^[17]

End point description

In this endpoint, number of subjects with at least 1 dose interruption for encorafenib, binimetinib, and each third combination agent were reported. Safety set included all subjects who received at least 1 dose of 3rd combination agent for Part II and had at least 1 valid post-baseline safety assessment. Here, "n" signifies number of subjects evaluable for specified drug. Here “99999” signifies that data not available as there was no subject evaluable.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
Encorafenib (n =38, 1, 13, 6)	14	0	4	2
Binimetinib (n =38, 1, 13, 6)	13	0	5	3
Ribociclib (n =38, 0, 0, 0)	11	99999	99999	99999
Infigratinib (n =0, 1, 0, 0)	99999	0	99999	99999
Capmatinib (n =0, 0, 13, 0)	99999	99999	5	99999
Buparlisib (n =0, 0, 0, 6)	99999	99999	99999	2

No statistical analyses for this end point

Secondary: Number of Subjects With At least One Dose Reduction: Part I

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End point title

Number of Subjects With At least One Dose Reduction: Part I ^[18]

End point description

In this endpoint, number of subjects with at least 1 dose reduction for encorafenib and binimetinib, respectively were reported. Safety set included all subjects who received at least 1 dose of encorafenib or binimetinib for Part I and had at least 1 valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
Encorafenib	9	14
Binimetinib	32	28

No statistical analyses for this end point

Secondary: Number of Subjects With At least One Dose Reduction: Part II

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End point title

Number of Subjects With At least One Dose Reduction: Part II ^[19]

End point description

In this endpoint, number of subjects with at least 1 dose reduction for encorafenib, binimetinib, and each third combination agent were reported. Safety set included all subjects who received at least 1 dose of 3rd combination agent for Part II and had at least 1 valid post-baseline safety assessment. Here, "n" signifies number of subjects evaluable for specified drug. Here “99999” signifies that data not available as there was no subject evaluable.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
Encorafenib (n = 38, 1, 13, 6)	1	0	0	1
Binimetinib (n = 38, 1, 13, 6)	11	0	5	3
Ribociclib (n = 38, 0, 0, 0)	1	99999	99999	99999
Infigratinib (n = 0, 1, 0, 0)	99999	0	99999	99999
Capmatinib (n = 0, 0, 13, 0)	99999	99999	7	99999
Buparlisib (n = 0, 0, 0, 6)	99999	99999	99999	1

No statistical analyses for this end point

Secondary: Actual Dose Intensity: Part I

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End point title

Actual Dose Intensity: Part I ^[20]

End point description

Dose intensity across all cycles = cumulative dose/duration of exposure. Safety set included all subjects who received at least 1 dose of encorafenib or binimetinib for Part I and had at least 1 valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Milligram per day
arithmetic mean (standard deviation)
Encorafenib	425.311 ± 53.5392	408.711 ± 65.5297
Binimetinib	81.920 ± 13.0994	82.083 ± 10.9117

No statistical analyses for this end point

Secondary: Actual Dose Intensity: Part II

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End point title

Actual Dose Intensity: Part II ^[21]

End point description

Dose intensity across all cycles = cumulative dose/duration of exposure. Safety set included all subjects who received at least 1 dose of 3rd combination agent for Part II and had at least 1 valid post-baseline safety assessment. Here, "n" signifies number of subjects evaluable for specified drug. Here “99999” signifies: 1) that data (both mean and standard deviation) is not available as there was no subject evaluable or 2) standard deviation not available as only 1 subject was evaluable.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Milligram per day
arithmetic mean (standard deviation)
Encorafenib (n =38, 1, 13, 6)	197.856 ± 42.6637	450.000 ± 99999	195.945 ± 8.4015	405.014 ± 102.5218
Binimetinib (n =38, 1, 13, 6)	79.749 ± 14.7267	90.000 ± 99999	87.373 ± 3.6593	78.791 ± 20.1538
Ribociclib (n =38, 0, 0, 0)	486.628 ± 79.4485	99999 ± 99999	99999 ± 99999	99999 ± 99999
Infigratinib (n =0, 1, 0, 0)	99999 ± 99999	60.227 ± 99999	99999 ± 99999	99999 ± 99999
Capmatinib (n =0, 0, 13, 0)	99999 ± 99999	99999 ± 99999	579.519 ± 259.1157	99999 ± 99999
Buparlisib (n =0, 0, 0, 6)	99999 ± 99999	99999 ± 99999	99999 ± 99999	72.206 ± 15.7019

No statistical analyses for this end point

Secondary: PFS: Part II

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End point title

PFS: Part II ^[22]

End point description

PFS : time from the start date of study drug in Part II until documented PD or death due to any cause. All subjects who had not progressed or died at the time of the data cut-off were censored at the date of last tumor assessment (other than those who were unknown or missing) prior to cut-off date or start date of new anti-neoplastic therapy, whichever is earlier. 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. FAS for Part II evaluated. Here “99999” signifies: 1) 95% CI not available as only 1 subject was evaluable and 2) Upper limit of 95% CI could not be estimated as there were insufficient number of subjects with events.

End point type

Secondary

End point timeframe

From start of study drug until documented PD or death due to any cause (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Months
median (confidence interval 95%)	2.1 (1.7 to 2.1)	2.1 (-99999 to 99999)	2.1 (1.0 to 3.7)	1.4 (0.4 to 99999)

No statistical analyses for this end point

Secondary: Duration of Response (DOR): Part I

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End point title

Duration of Response (DOR): Part I ^[23]

End point description

DOR: time between date of first documented response (CR or PR) and date of first documented progression or death due to underlying cancer. If there was no progression or death due to underlying cancer, then the subject was censored at the date of last tumor assessment other than unknown. CR: disappearance of all non-nodal target lesions (TLs). Any pathological lymph nodes assigned as TLs must have had a reduction in short axis to <10 mm. Disappearance of all non-TLs. All lymph nodes assigned a non-TL must be non-pathological in size (<10 mm short axis). PR: at least a 30% decrease in sum of diameter of all TLs, taking as reference baseline sum of diameters. PD: at least a 20% increase in sum of diameter of all measured TLs, taking as the reference the smallest sum of diameter of all TLs recorded at or after baseline. Sum must also demonstrate an absolute increase of at least 5 mm. FAS for Part I was evaluated. Here, "Number of Subjects Analyzed" signifies confirmed responders.

End point type

Secondary

End point timeframe

From date of first documented response (CR or PR) till the date of first documented progression or death due to underlying cancer or censoring date (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	55	21
Units: Months
median (confidence interval 95%)	10.9 (8.1 to 14.1)	5.6 (3.9 to 13.0)

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS): Part I

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End point title

Progression-Free Survival (PFS): Part I ^[24]

End point description

PFS was defined as the time from the start date of study drug in Part I until documented PD or death due to any cause. All subjects who had not progressed or died at the time of the data cut-off were censored at the date of last tumor assessment (other than those who were unknown or missing) prior to cut-off date or start date of new anti-neoplastic therapy, whichever is earlier. 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. For Part I, FAS consisted of all subjects who received at least 1 dose (partial or full) of encorafenib or binimetinib.

End point type

Secondary

End point timeframe

From start of study drug until documented PD or death due to any cause (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Months
median (confidence interval 95%)	11.1 (8.1 to 15.0)	3.3 (2.1 to 4.7)

No statistical analyses for this end point

Secondary: TTR: Part II

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End point title

TTR: Part II ^[25]

End point description

TTR was defined as the time between the start date of study drug in Part II and first documented response (CR or PR). RECIST v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis) and b) PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameter. For Part II, FAS consisted of all subjects who received at least 1 dose of encorafenib or binimetinib or the assigned third agent following the assignment of the triple combination treatment. Here, "Number of Subjects Analyzed" signifies subjects evaluable for this endpoint who were responders. Here “99999” signifies: 95% CI not available as only 1 subject was evaluable.

End point type

Secondary

End point timeframe

From start date of study drug till first documented response (CR or PR) (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	1	0 ^[26]	0 ^[27]	0 ^[28]
Units: Months
median (confidence interval 95%)	4.1 (-99999 to 99999)	( to )	( to )	( to )

Notes
[26] - Subject was not a responder.
[27] - None of the subjects were responders.
[28] - None of the subjects were responders.

No statistical analyses for this end point

Secondary: DOR: Part II

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End point title

DOR: Part II ^[29]

End point description

DOR: time between date of first documented response (CR or PR) & date of first documented progression or death due to underlying cancer. If there was no progression or death due to underlying cancer, then the subject was censored at the date of last tumor assessment other than unknown. CR: disappearance of all non-nodal TLs. Any pathological lymph nodes assigned as TLs must have had a reduction in short axis to <10mm. Disappearance of all non-TLs. All lymph nodes assigned a non-TL must be non-pathological in size (<10mm short axis). PR: at least 30% decrease in sum of diameter of all TLs, taking as reference baseline sum of diameters. PD: at least 20% increase in sum of diameter of all measured TLs, taking as reference the smallest sum of diameter of all TLs recorded at or after baseline. Sum must also demonstrate an absolute increase of at least 5mm. FAS Part II was evaluated. "Number of Subjects Analyzed"=confirmed responders; “99999”=95%CI unavailable as only 1 subject evaluable.

End point type

Secondary

End point timeframe

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	1	0 ^[30]	0 ^[31]	0 ^[32]
Units: Months
median (confidence interval 95%)	2.1 (-99999 to 99999)	( to )	( to )	( to )

Notes
[30] - Subject was not a confirmed responder.
[31] - None of the subjects were confirmed responders.
[32] - None of the subjects were confirmed responders.

No statistical analyses for this end point

Secondary: Time to Response (TTR): Part I

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End point title

Time to Response (TTR): Part I ^[33]

End point description

TTR was defined as the time between the start date of study drug in Part I and first documented response (CR or PR). RECIST v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis) and b) PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. For Part I, FAS consisted of all subjects who received at least 1 dose (partial or full) of encorafenib or binimetinib. Here, ‘Number of Subjects Analyzed’ signifies subjects evaluable for this endpoint who were responders.

End point type

Secondary

End point timeframe

From start date of study drug till first documented response (CR or PR) (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	52	16
Units: Months
median (confidence interval 95%)	1.4 (1.38 to 1.41)	0.72 (0.72 to 0.82)

No statistical analyses for this end point

Secondary: Overall Survival (OS): Part II

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End point title

Overall Survival (OS): Part II ^[34]

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 known date subject alive. For Part II, FAS consisted of all subjects who received at least 1 dose of encorafenib or binimetinib or the assigned third agent following the assignment of the triple combination treatment. Here “99999” signifies: 1) Upper limit was not estimable due to insufficient number of subjects with events, and 2) 95% CI not available as only 1 subject was evaluable.

End point type

Secondary

End point timeframe

From date of randomization/start of treatment to date of death due to any cause or censoring date (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Months
median (confidence interval 95%)	10.4 (6.0 to 16.7)	20.8 (-99999 to 99999)	5.6 (1.7 to 99999)	2.5 (0.4 to 99999)

No statistical analyses for this end point

Secondary: DCR: Part II

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End point title

DCR: Part II ^[35]

End point description

DCR = percentage of subjects with a best overall response of CR or PR or SD. CR = disappearance of all non-nodal TLs. Any pathological lymph nodes assigned as TLs had a reduction in short axis to <10 mm. Disappearance of all non-TLs. All lymph nodes assigned a non-TL must be non-pathological in size (<10 mm short axis). PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD = neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. 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 TLs 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. FAS for Part II evaluated. Here “99999” signifies: 95% CI not available as only 1 subject was evaluable.

End point type

Secondary

End point timeframe

From start date of study drug till first documented response (CR or PR or SD) (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Percentage of subjects
number (confidence interval 95%)	26.3 (13.4 to 43.1)	0 (-99999 to 99999)	15.4 (1.9 to 45.4)	16.7 (0.4 to 64.1)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR): Part I

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End point title

Disease Control Rate (DCR): Part I ^[36]

End point description

DCR = percentage of subjects with a best overall response of CR or PR or SD. CR = disappearance of all non-nodal TLs. Any pathological lymph nodes assigned as TLs had a reduction in short axis to <10 mm. Disappearance of all non-TLs. All lymph nodes assigned a non-TL must be non-pathological in size (<10 mm short axis). PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD = neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. 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 TLs 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. For Part I, FAS consisted of all subjects who received at least 1 dose (partial or full) of encorafenib or binimetinib.

End point type

Secondary

End point timeframe

From start date of study drug till first documented response (CR or PR or SD) (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Percentage of subjects
number (confidence interval 95%)	92.0 (83.4 to 97.0)	42.2 (31.4 to 53.5)

No statistical analyses for this end point

Secondary: Summary of Genomic Biomarkers From Tumor Samples: Part I

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End point title

Summary of Genomic Biomarkers From Tumor Samples: Part I ^[37]

End point description

Number of subjects with multiple alterations in genomic biomarkers like biomarker BRAF, CCND1, CDK4, EGFR, FGFR1, FGFR4, KRAS, MET, NRAS, PIK3CA, and PTEN were reported and alterations included copy number variant/copy number ratio (CNV/CNR), rearrangement, short variant. It was not necessary that all biomarkers had all alterations. For Part I, FAS consisted of all subjects who received at least 1 dose (partial or full) of encorafenib or binimetinib. In results reported below, Rearrangement/Genomic Position has been abbreviated as R/GP and baseline as B.

End point type

Secondary

End point timeframe

Baseline up to end of treatment (EOT) (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
BRAF: CNV/CNR at B	4	9
BRAF: CNV/CNR at EOT	2	3
BRAF: R/GP at B chr7:140482508-140482692	0	1
BRAF: R/GP at B chr7:140487121-140487285	0	1
BRAF: R/GP at B chr7:140487916-140488167	0	1
BRAF: R/GP at B chr7:140488878-140489055	0	1
BRAF: R/GP at B cchr7:140489413-140489576	0	1
BRAF: R/GP at B chr7:140490446-140490656	0	1
BRAF: R/GP at B chr7:140491528-140491878	0	1
BRAF: R/GP at B chr7:140491580-140491878	0	1
BRAF: R/GP at B chr7:140492969-140493301	0	1
BRAF: R/GP at EOT chr7:140481691-140482150	1	0
BRAF: R/GP at EOT chr7:140482057-140482467	0	1
BRAF: R/GP at EOT chr7:140482081-140482482	1	0
BRAF: R/GP at EOT chr7:140482088-140482296	0	1
BRAF: R/GP at EOT chr7:140482167-140482382	1	0
BRAF: R/GP at EOT chr7:140482495-140482731	0	1
BRAF: R/GP at EOT chr7:140482644-140482867	0	1
BRAF: R/GP at EOT chr7:140483058-140483257	1	0
BRAF: R/GP at EOT chr7:140486136-140486408	1	0
BRAF: R/GP at EOT chr7:140486274-140486561	0	1
BRAF: R/GP at EOT chr7:140489019-140489575	0	1
BRAF: R/GP at EOT chr7:140489219-140489431	1	0
BRAF: R/GP at EOT chr7:140489830-140490002	0	1
BRAF: R/GP at EOT chr7:140491411-140491879	0	1
BRAF: R/GP at EOT chr7:140492091-140492240	1	0
BRAF: R/GP at EOT chr7:140492379-140492708	0	1
BRAF: R/GP at EOT chr7:140492714-140492997	0	1
BRAF: R/GP at EOT chr7:140493601-140493951	0	1
BRAF: R/GP at EOT chr7:140493858-140494232	1	0
BRAF: Short variant/amino acid change at B V600E	46	53
BRAF: Short variant/amino acid change at B V600G	1	0
BRAF: Short variant/amino acid change at B V600K	4	7
BRAF: Short variant/amino acid change at B V600R	1	0
BRAF: Short variant/amino acid change at EOT V600E	18	19
BRAF: Short variant/amino acid change at EOT V600K	0	4
BRAF: Short variant/amino acid change at EOT V600R	1	0
CCND1: CNV/CNR at B	1	0
CDK4: CNV/CNR at B	3	2
EGFR: CNV/CNR at B	1	3
EGFR: CNV/CNR at EOT	1	1
FGFR1: CNV/CNR at B	1	0
FGFR1: CNV/CNR at EOT	1	0
FGFR4: CNV/CNR at B	1	0
KRAS: CNV/CNR at B	2	0
MET: CNV/CNR at B	4	6
MET: CNV/CNR at EOT	3	5
MET: R/GP at EOT chr7:116321020-116321260	1	0
NRAS: CNV/CNR at B	0	1
PIK3CA: CNV/CNR at B	1	0
PTEN: CNV/CNR at B	4	13
PTEN: CNV/CNR at EOT	5	10
PTEN: R/GP at EOT chr10:89720538-89720776	0	1

No statistical analyses for this end point

Secondary: Plasma Concentration for Encorafenib (LGX): Part I

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End point title

Plasma Concentration for Encorafenib (LGX): Part I ^[38]

End point description

In results reported below, following abbreviations have been used: Cycle 1 (C1), Day 1 (D1), Day 8 (D8), Day 15 (D15), Day 21 (D21), Cycle 2 (C2), Cycle 3 (C3), Cycle 4 (C4), Cycle 5 (C5) and end of treatment (EOT). Maximum treatment exposure for Part I was of 403.7 weeks. Pharmacokinetic analysis set (PAS) consisted of all subjects who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, “n” signifies number of subjects evaluable for specified time points.

End point type

Secondary

End point timeframe

C1 (1.5 hrs post-dose on D1; pre-dose, 1.5 hrs post-dose on D15); C2 (pre-dose on D8 and D21); C3 pre-dose on D15; C4 pre-dose on D15; C5 pre-dose on D15; EOT

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	78
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
C1 D1, 1.5 hr (n = 59, 55)	4820 ± 114.2	4480 ± 124.4
C1 D15, Pre-dose (n= 68, 59)	10.0 ± 81.6	13.8 ± 104.4
C1 D15, 1.5 hr (n = 52, 54)	2470 ± 116.7	2910 ± 91.6
C2 D8, Pre-dose (n =69, 48)	9.96 ± 81.7	14.7 ± 117.5
C2 D21, Pre-dose (n =62, 41)	9.04 ± 84.2	15.6 ± 156.3
C3 D15, Pre-dose (n =68, 41)	8.43 ± 82.3	11.2 ± 114.3
C4 D15, Pre-dose (n =63, 30)	9.21 ± 100.3	12.3 ± 108.9
C5 D15, Pre-dose (n = 56, 30)	8.84 ± 59.4	11.9 ± 72.7
EOT (n = 35, 47)	19.6 ± 399.9	34.5 ± 890.3

No statistical analyses for this end point

Secondary: Plasma Concentration for Encorafenib (LGX): Part II

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End point title

Plasma Concentration for Encorafenib (LGX): Part II

End point description

In results reported below, following abbreviations have been used: Cycle 1 (C1), Day 1 (D1), Day 8 (D8), Day 15 (D15), Day 16 (D16), Day 21 (D21), Cycle 2 (C2), Cycle 3 (C3), Cycle 4 (C4), Cycle 5 (C5). Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. Here, “n” signifies number of subjects evaluable for specified time points. In results reported below, “99999” suggests that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable and where subjects evaluable were 2: dispersion not available as out of 2 subjects, 1 subject had BLQ value; b) no geometric mean and geometric coefficient of variation: below limit of the quantitation (BLQ) value.

End point type

Secondary

End point timeframe

C1 (1.5, 4 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg	Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg
Number of subjects analysed	3	3	1	5	1	5	1	1	3	1	29
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
C1 D1: 1.5 hrs (n=0,2,1,2,1,3,1,1,2,0,22)	99999 ± 99999	3430 ± 17.6	1860 ± 99999	1130 ± 3.8	3750 ± 99999	1770 ± 62.9	878 ± 99999	2030 ± 99999	847 ± 28.1	99999 ± 99999	1600 ± 85.6
C1 D1: 4 hrs (n=0,0,0,0,0,0,1,1,3,0,24)	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	238 ± 99999	297 ± 99999	626 ± 65.7	99999 ± 99999	596 ± 51.1
C1 D8: Pre-dose (n=3,2,1,3,1,4,1,1,2,1,23)	8.97 ± 89.0	21.3 ± 150.6	12.4 ± 99999	10.3 ± 54.4	6.21 ± 99999	11.7 ± 56.4	12.5 ± 99999	15.2 ± 99999	9.39 ± 15.9	7.15 ± 99999	16.2 ± 116.1
C1 D15: Pre-dose (n=3,2,1,4,1,4,1,1,2,0,22)	11.2 ± 106.3	18.6 ± 159.4	7.74 ± 99999	9.95 ± 40.1	7.95 ± 99999	13.5 ± 35.0	9.28 ± 99999	10.3 ± 99999	7.75 ± 37.3	99999 ± 99999	20.9 ± 188.5
C1 D15: 0.5 hr (n=3,2,1,5,1,4,1,1,2,0,22)	437 ± 228.2	625 ± 19.5	1690 ± 99999	262 ± 345.5	139 ± 99999	127 ± 216.1	8.55 ± 99999	601 ± 99999	473 ± 1248.5	99999 ± 99999	175 ± 252.7
C1 D15: 1.5 hrs (n=3,2,1,5,1,4,1,1,2,0,22)	3050 ± 59.6	2150 ± 54.6	2100 ± 99999	1550 ± 62.4	2890 ± 99999	2500 ± 27.9	366 ± 99999	1960 ± 99999	1450 ± 3.9	99999 ± 99999	1850 ± 69.7
C1 D15: 2.5 hrs (n=3,2,1,5,0,4,1,1,1,0,22)	1420 ± 39.6	1320 ± 30.0	1020 ± 99999	808 ± 55.0	99999 ± 99999	1550 ± 34.4	622 ± 99999	981 ± 99999	686 ± 99999	99999 ± 99999	1510 ± 48.2
C1 D15: 4 hrs (n=3,2,1,4,1,4,1,0,2,0,23)	649 ± 37.5	770 ± 6.2	397 ± 99999	453 ± 24.3	1160 ± 99999	667 ± 20.4	389 ± 99999	99999 ± 99999	478 ± 39.6	99999 ± 99999	1020 ± 34.3
C1 D15: 6 hrs (n=3,2,1,5,1,4,1,1,2,0,19)	246 ± 94.6	433 ± 45.0	211 ± 99999	165 ± 68.8	266 ± 99999	317 ± 26.8	209 ± 99999	199 ± 99999	203 ± 11.1	99999 ± 99999	567 ± 51.5
C1 D15: 8 hrs (n=3,2,0,5,1,3,1,1,2,0,20)	180 ± 94.5	276 ± 103.8	99999 ± 99999	115 ± 55.4	257 ± 99999	217 ± 34.5	142 ± 99999	132 ± 99999	109 ± 2.6	99999 ± 99999	412 ± 62.3
C1 D16: 24 hrs (n=3,2,1,4,1,4,1,1,2,0,24)	11.3 ± 45.3	25.1 ± 2066.8	6.76 ± 99999	8.10 ± 43.1	5.20 ± 99999	15.0 ± 20.9	10.7 ± 99999	7.85 ± 99999	10.8 ± 106.1	99999 ± 99999	22.8 ± 199.0
C1 D21: Pre-dose (n=0,0,1,0,0,0,1,1,2,1,20)	99999 ± 99999	99999 ± 99999	10.4 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	13.6 ± 99999	13.9 ± 99999	12.4 ± 60.4	20.3 ± 99999	17.5 ± 106.4
C2 D1: Pre-dose (n=3,2,1,5,1,3,1,1,2,1,18)	13.5 ± 193.0	32.6 ± 202.9	12.7 ± 99999	19.9 ± 210.5	2.91 ± 99999	14.0 ± 30.3	8.50 ± 99999	82.5 ± 99999	8.19 ± 42.2	19.2 ± 99999	11.9 ± 100.9
C2 D15: Pre-dose (n=1,1,1,4,0,4,1,1,2,1,14)	41.3 ± 99999	15.6 ± 99999	13.9 ± 99999	9.68 ± 36.5	99999 ± 99999	8.49 ± 70.5	11.1 ± 99999	16.5 ± 99999	12.3 ± 24.3	8.95 ± 99999	21.3 ± 115.3
C3 D1: Pre-dose (n=1,0,1,2,0,4,0,1,0,0,15)	13.9 ± 99999	99999 ± 99999	20.5 ± 99999	23.2 ± 33.1	99999 ± 99999	10.1 ± 72.1	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	9.34 ± 125.7
C4 D1: Pre-dose (n=1,0,0,0,0,2,1,1,0,0,6)	30.2 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	12.5 ± 11.4	5.95 ± 99999	7.28 ± 99999	99999 ± 99999	99999 ± 99999	13.1 ± 21.8
C5 D1: Pre-dose (n=1,0,0,0,0,0,1,1,0,0,5)	749 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	10.7 ± 99999	9.84 ± 99999	99999 ± 99999	99999 ± 99999	9.15 ± 44.0
EOT (n =2,1,1,3,1,4,1,1,2,1,22)	1.77 ± 99999	99999 ± 99999	14.3 ± 99999	99999 ± 99999	99999 ± 99999	13.9 ± 66.6	8.24 ± 99999	6.81 ± 99999	24.5 ± 259.8	99999 ± 99999	16.6 ± 265.0

No statistical analyses for this end point

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part I

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End point title

Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part I ^[39]

End point description

AR00426032 is metabolite of binimetinib. Maximum treatment exposure for Part I was of 403.7 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified time points.

End point type

Secondary

End point timeframe

C1 (1.5 hrs post-dose on D1; pre-dose, 1.5 hrs post-dose on D15); C2 (pre-dose on D8 and D21); C3 pre-dose on D15; C4 pre-dose on D15; C5 pre-dose on D15; EOT

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	78
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
Binimetinib: C1 D1, 1.5 hr (n =58, 60)	551 ± 88.8	482 ± 73.4
Binimetinib: C1 D15, Pre-dose (n =66, 56)	40.3 ± 63.5	43.3 ± 72.9
Binimetinib: C1 D15, 1.5 hr (n =53, 54)	461 ± 70.2	451 ± 50.2
Binimetinib: C2 D8, Pre-dose (n =69, 46)	39.9 ± 58.8	44.8 ± 73.0
Binimetinib: C2 D21, Pre-dose (n =62, 39)	38.9 ± 54.9	53.1 ± 78.2
Binimetinib: C3 D15, Pre-dose (n =65, 41)	41.9 ± 60.4	38.7 ± 94.6
Binimetinib: C4 D15, Pre-dose (n =61, 30)	36.2 ± 68.6	38.8 ± 57.4
Binimetinib: C5 D15, Pre-dose (n =56, 30)	41.3 ± 55.7	39.2 ± 76.1
Binimetinib: EOT (n =35, 47)	33.2 ± 179.4	52.8 ± 180.4
AR00426032: C1 D1, 1.5 hr (n =58, 60)	57.6 ± 93.5	47.5 ± 101.6
AR00426032: C1 D15, Pre-dose (n =66, 56)	4.13 ± 70.8	4.50 ± 64.0
AR00426032: C1 D15, 1.5 hr (n =52, 54)	30.6 ± 110.9	31.9 ± 84.0
AR00426032: C2 D8, Pre-dose (n =69, 46)	3.63 ± 60.2	4.17 ± 88.1
AR00426032: C2 D21, Pre-dose (n =62, 39)	4.11 ± 61.0	4.39 ± 80.2
AR00426032: C3 D15, Pre-dose (n =64, 41)	3.71 ± 59.5	3.90 ± 60.6
AR00426032: C4 D15, Pre-dose (n =61, 30)	3.48 ± 65.8	3.81 ± 56.9
AR00426032: C5 D15, Pre-dose (n =56, 30)	3.77 ± 66.9	3.36 ± 67.3
AR00426032: EOT (n =33, 47)	4.09 ± 90.8	5.88 ± 118.0

No statistical analyses for this end point

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part II

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End point title

Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part II

End point description

AR00426032 is metabolite of binimetinib. Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified time points. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable and where subjects evaluable were 2: dispersion not available as out of 2 subjects, 1 subject had BLQ value; b) no geometric mean and geometric coefficient of variation: no subject evaluable, or if subjects were evaluable then all BLQ values. In results reported below, binimetinib is abbreviated as BI, AR00426032 is abbreviated as AR and pre-dose as PD.

End point type

Secondary

End point timeframe

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Ribociclib 600mg

Number of subjects analysed

Units: Nanogram per milliliter

geometric mean (geometric coefficient of variation)

BI,C1 D1: 1.5 hrs(n=0,2,1,2,1,3,1,1,2,0,21,1,1)

99999 ± 99999

410 ± 48.8

416 ± 99999

313 ± 25.6

1100 ± 99999

508 ± 130.2

396 ± 99999

649 ± 99999

273 ± 24.6

99999 ± 99999

446 ± 59.8

522 ± 99999

1230 ± 99999

BI, C1 D1: 4 hrs(n=0,0,0,0,0,0,1,1,3,0,24,1,0)

99999 ± 99999

152 ± 99999

106 ± 99999

129 ± 25.8

99999 ± 99999

215 ± 44.5

99.5 ± 99999

99999 ± 99999

BI, C1 D8: PD (n=3,2,1,3,1,4,1,1,2,1,21,1,0)

41.6 ± 21.7

51.1 ± 9.7

46.0 ± 99999

74.6 ± 34.5

27.2 ± 99999

67.4 ± 63.1

63.0 ± 99999

31.5 ± 99999

25.1 ± 1.7

27.2 ± 99999

51.0 ± 67.8

37.3 ± 99999

99999 ± 99999

BI, C1 D15: PD (n=3,2,1,4,1,4,1,1,2,0,22,1,0)

32.0 ± 17.1

39.1 ± 57.4

33.9 ± 99999

85.6 ± 53.7

47.3 ± 99999

50.9 ± 34.4

54.3 ± 99999

28.3 ± 99999

21.1 ± 23.7

99999 ± 99999

48.2 ± 70.0

36.2 ± 99999

99999 ± 99999

BI, C1 D15: 0.5 hr (n=3,2,1,5,1,4,1,1,2,0,22,0,0)

150 ± 36.1

143 ± 496.2

315 ± 99999

430 ± 26.8

401 ± 99999

180 ± 91.5

229 ± 99999

389 ± 99999

161 ± 54.7

99999 ± 99999

158 ± 90.1

99999 ± 99999

BI, C1 D15:1.5 hrs (n=3,2,1,5,1,4,1,1,2,0,22,0,0)

386 ± 41.1

187 ± 351.0

413 ± 99999

489 ± 27.1

797 ± 99999

734 ± 45.6

261 ± 99999

520 ± 99999

313 ± 15.9

99999 ± 99999

437 ± 46.5

99999 ± 99999

BI, C1 D15:2.5 hrs (n=3,2,1,5,0,4,1,1,1,0,22,1,0)

250 ± 17.1

143 ± 172.4

235 ± 99999

295 ± 29.7

99999 ± 99999

491 ± 38.0

207 ± 99999

331 ± 99999

154 ± 99999

99999 ± 99999

380 ± 31.2

178 ± 99999

99999 ± 99999

BI, C1 D15: 4 hrs (n=3,2,1,4,1,4,1,0,2,0,23,0,0)

147 ± 21.4

125 ± 62.1

98.0 ± 99999

166 ± 48.9

264 ± 99999

266 ± 32.5

130 ± 99999

99999 ± 99999

98.0 ± 60.0

99999 ± 99999

241 ± 28.6

99999 ± 99999

BI, C1 D15: 6 hrs (n=3,2,1,5,1,4,1,1,2,0,20,0,0)

79.0 ± 36.1

97.3 ± 32.8

55.8 ± 99999

106 ± 53.3

112 ± 99999

141 ± 15.1

167 ± 99999

77.4 ± 99999

53.3 ± 36.2

99999 ± 99999

134 ± 46.5

99999 ± 99999

BI, C1 D15: 8 hrs (n=3,2,0,5,1,3,1,1,2,0,20,0,0)

74.9 ± 34.7

59.7 ± 12.6

99999 ± 99999

107 ± 40.9

132 ± 99999

102 ± 12.4

116 ± 99999

65.5 ± 99999

42.2 ± 39.2

99999 ± 99999

109 ± 54.8

99999 ± 99999

BI, C1 D16: 24 hrs (n=3,2,1,5,1,4,1,1,2,0,23,1,0)

44.1 ± 19.1

30.2 ± 59.2

42.1 ± 99999

63.2 ± 64.0

17.6 ± 99999

55.9 ± 54.0

78.3 ± 99999

29.8 ± 99999

23.1 ± 5.2

99999 ± 99999

55.2 ± 66.0

40.5 ± 99999

99999 ± 99999

BI, C1 D21: PD (n=0,0,1,0,0,0,1,1,2,1,19,1,1)

99999 ± 99999

34.0 ± 99999

99999 ± 99999

40.4 ± 99999

38.8 ± 99999

13.6 ± 80.7

19.6 ± 99999

63.2 ± 51.0

35.3 ± 99999

8.91 ± 99999

BI, C2 D1: PD (n=3,2,1,5,1,3,1,1,2,1,16,1,1)

38.8 ± 62.5

42.7 ± 27.8

40.5 ± 99999

118 ± 120.1

24.6 ± 99999

54.2 ± 32.4

58.3 ± 99999

174 ± 99999

23.3 ± 20.2

58.3 ± 99999

46.0 ± 71.2

22.4 ± 99999

54.1 ± 99999

BI, C2 D15: PD (n=1,1,1,4,1,4,1,1,2,1,14,1,1)

63.7 ± 99999

73.0 ± 99999

63.9 ± 99999

40.9 ± 50.8

18.9 ± 99999

49.8 ± 21.2

63.1 ± 99999

19.4 ± 99999

15.2 ± 18.2

14.1 ± 99999

58.4 ± 68.3

27.3 ± 99999

34.9 ± 99999

BI, C3 D1: PD (n=1,0,1,2,0,4,1,1,0,0,16,1,0)

50.0 ± 99999

99999 ± 99999

47.2 ± 99999

37.8 ± 189.6

99999 ± 99999

41.9 ± 49.0

53.4 ± 99999

4.82 ± 99999

99999 ± 99999

45.0 ± 91.8

42.0 ± 99999

99999 ± 99999

BI, C4D1: PD (n=1,0,0,0,0,3,1,1,0,0,4,0,0)

46.1 ± 99999

99999 ± 99999

53.8 ± 10.6

63.6 ± 99999

40.9 ± 99999

99999 ± 99999

77.5 ± 32.1

99999 ± 99999

BI, C5D1: PD (n=1,0,0,0,0,0,1,1,0,0,5,0,0)

60.0 ± 99999

99999 ± 99999

42.3 ± 99999

28.5 ± 99999

99999 ± 99999

73.8 ± 25.7

99999 ± 99999

BI, EOT (n=2,1,1,3,1,4,1,1,2,1,21,0,0)

99999 ± 99999

36.3 ± 99999

99999 ± 99999

52.1 ± 18.3

41.0 ± 99999

32.3 ± 99999

13.8 ± 205.5

99999 ± 99999

29.0 ± 179.7

99999 ± 99999

AR,C1 D1: 1.5 hrs(n=0,2,1,2,0,3,0,1,2,0,21,1,1)

99999 ± 99999

22.4 ± 200.6

12.9 ± 99999

11.4 ± 85.7

99999 ± 99999

35.9 ± 274.1

99999 ± 99999

22.1 ± 99999

8.05 ± 68.9

99999 ± 99999

19.4 ± 99.3

16.3 ± 99999

64.6 ± 99999

AR, C1 D1: 4 hrs(n=0,0,0,0,0,0,1,1,3,0,23,1,0)

99999 ± 99999

9.40 ± 99999

4.09 ± 99999

6.71 ± 145.3

99999 ± 99999

12.3 ± 75.3

4.61 ± 99999

99999 ± 99999

AR, C1 D8: PD (n=3,2,1,3,0,4,1,1,2,1,21,1,0)

3.98 ± 31.9

2.95 ± 165.3

1.21 ± 99999

7.10 ± 122.1

99999 ± 99999

6.34 ± 54.5

6.15 ± 99999

1.10 ± 99999

1.73 ± 48.7

2.09 ± 99999

5.50 ± 62.6

2.14 ± 99999

99999 ± 99999

AR, C1 D15: PD (n=3,2,1,4,1,4,1,1,2,0,22,1,0)

3.14 ± 74.5

3.80 ± 111.9

1.21 ± 99999

11.5 ± 39.5

4.36 ± 99999

5.45 ± 42.2

4.16 ± 99999

99999 ± 99999

3.81 ± 99999

99999 ± 99999

4.19 ± 79.2

1.09 ± 99999

99999 ± 99999

AR, C1 D15: 0.5 hr (n=3,2,1,5,1,4,1,1,2,0,22,0,0)

6.66 ± 43.2

7.43 ± 455.1

8.21 ± 99999

13.1 ± 97.8

11.4 ± 99999

9.80 ± 75.7

7.31 ± 99999

4.35 ± 99999

6.16 ± 490.6

99999 ± 99999

7.81 ± 119.0

99999 ± 99999

AR, C1 D15:1.5 hrs (n=3,2,1,5,0,4,1,1,2,0,22,0,0)

24.9 ± 92.2

13.2 ± 1550.1

15.8 ± 99999

27.9 ± 85.6

99999 ± 99999

41.1 ± 25.7

12.9 ± 99999

12.6 ± 99999

16.1 ± 151.9

99999 ± 99999

18.3 ± 135.9

99999 ± 99999

AR, C1 D15:2.5 hrs (n=3,2,1,5,0,4,1,1,1,0,22,1,0)

18.5 ± 77.0

11.3 ± 447.2

7.75 ± 99999

18.5 ± 88.4

99999 ± 99999

34.3 ± 51.3

9.71 ± 99999

8.51 ± 99999

16.2 ± 99999

99999 ± 99999

18.5 ± 81.2

4.73 ± 99999

99999 ± 99999

AR, C1 D15: 4 hrs (n=3,2,1,4,1,4,1,0,2,0,23,0,0)

11.8 ± 40.3

9.98 ± 142.4

3.15 ± 99999

9.46 ± 142.7

22.6 ± 99999

19.3 ± 76.9

6.76 ± 99999

99999 ± 99999

5.21 ± 81.9

99999 ± 99999

12.2 ± 78.7

99999 ± 99999

AR, C1 D15: 6 hrs (n=3,2,1,5,1,4,1,1,2,0,20,0,0)

6.86 ± 61.8

7.66 ± 117.7

1.82 ± 99999

6.90 ± 142.3

8.89 ± 99999

9.66 ± 71.5

5.82 ± 99999

2.52 ± 99999

3.07 ± 95.0

99999 ± 99999

7.41 ± 80.2

99999 ± 99999

AR, C1 D15: 8 hrs (n=3,2,0,5,1,3,1,1,2,0,20,0,0)

5.94 ± 76.7

5.24 ± 70.7

99999 ± 99999

6.49 ± 124.9

8.06 ± 99999

8.87 ± 76.5

5.12 ± 99999

1.95 ± 99999

2.67 ± 72.9

99999 ± 99999

6.73 ± 75.0

99999 ± 99999

AR, C1 D16: 24 hrs (n=3,2,1,5,1,4,1,1,2,0,22,1,0)

3.99 ± 61.8

2.92 ± 159.3

1.27 ± 99999

7.79 ± 87.5

1.44 ± 99999

4.75 ± 25.4

6.53 ± 99999

1.08 ± 99999

3.19 ± 99999

99999 ± 99999

4.70 ± 80.2

1.56 ± 99999

99999 ± 99999

AR, C1 D21: PD (n=0,0,1,0,0,0,1,1,2,1,17,1,1)

99999 ± 99999

3.66 ± 99999

1.47 ± 99999

3.18 ± 99999

1.13 ± 99999

6.64 ± 56.1

1.65 ± 99999

3.11 ± 99999

AR, C2 D1: PD (n=3,2,1,5,0,3,1,1,2,1,15,1,1)

6.23 ± 82.0

3.51 ± 36.8

99999 ± 99999

13.5 ± 116.8

99999 ± 99999

5.71 ± 44.2

4.32 ± 99999

2.06 ± 99999

4.09 ± 99999

3.99 ± 99999

4.03 ± 58.1

99999 ± 99999

17.8 ± 99999

AR, C2 D15: PD (n=1,1,1,4,1,4,1,1,2,1,14,1,1)

9.97 ± 99999

7.52 ± 99999

1.07 ± 99999

3.27 ± 65.1

1.74 ± 99999

4.23 ± 62.5

8.54 ± 99999

1.63 ± 99999

1.99 ± 99999

1.19 ± 99999

5.69 ± 57.0

1.33 ± 99999

3.74 ± 99999

AR, C3 D1: PD (n=1,0,1,2,0,4,1,1,0,0,15,1,0)

9.74 ± 99999

99999 ± 99999

6.15 ± 99999

99999 ± 99999

4.35 ± 42.3

4.50 ± 99999

1.09 ± 99999

99999 ± 99999

4.46 ± 70.2

1.73 ± 99999

99999 ± 99999

AR, C4D1: PD (n=1,0,0,0,0,3,1,1,0,0,4,0,0)

7.10 ± 99999

99999 ± 99999

5.70 ± 11.8

5.43 ± 99999

2.78 ± 99999

99999 ± 99999

5.78 ± 83.0

99999 ± 99999

AR, C5D1: PD (n=1,0,0,0,0,0,1,1,0,0,5,0,0)

6.05 ± 99999

99999 ± 99999

8.89 ± 99999

1.36 ± 99999

99999 ± 99999

6.11 ± 67.8

99999 ± 99999

AR, EOT (n=2,1,1,3,1,4,1,1,2,1,20,0,0)

99999 ± 99999

6.68 ± 80.1

3.77 ± 99999

1.48 ± 99999

3.65 ± 99999

99999 ± 99999

4.24 ± 85.5

99999 ± 99999

No statistical analyses for this end point

Secondary: Plasma Concentration for Ribociclib (LEE) and its Metabolite: Part II

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End point title

Plasma Concentration for Ribociclib (LEE) and its Metabolite: Part II

End point description

LEQ803 is metabolite of ribociclib. Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified time points. “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

End point values	Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Ribociclib 600mg	Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg
Number of subjects analysed	1	1	3	1	29	1	1
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
Ribociclib, C1 D1: 1.5 hrs(n=1,1,2,0,21,1,1)	220 ± 99999	117 ± 99999	107 ± 40.6	99999 ± 99999	230 ± 119.7	784 ± 99999	185 ± 99999
Ribociclib, C1 D1: 4 hrs(n=1,1,3,0,24,1,0)	213 ± 99999	84.5 ± 99999	205 ± 96.0	99999 ± 99999	354 ± 58.5	99999 ± 99999	268 ± 99999
Ribociclib, C1 D8: Pre-dose(n=1,1,2,0,22,1,1)	77.4 ± 99999	32.3 ± 99999	30.7 ± 33.5	99999 ± 99999	100 ± 49.9	127 ± 99999	80.5 ± 99999
Ribociclib, C1 D15: Pre-dose(n=1,1,2,0,25,1,0)	98.4 ± 99999	28.2 ± 99999	30.7 ± 24.9	99999 ± 99999	104 ± 54.2	99999 ± 99999	64.7 ± 99999
Ribociclib, C1 D15: 0.5 hr(n=1,1,2,0,24,0,0)	86.1 ± 99999	59.7 ± 99999	35.4 ± 66.6	99999 ± 99999	179 ± 65.0	99999 ± 99999	99999 ± 99999
Ribociclib, C1 D15: 1.5 hrs(n=1,1,2,0,24,0,0)	204 ± 99999	95.9 ± 99999	200 ± 240.3	99999 ± 99999	508 ± 95.2	99999 ± 99999	99999 ± 99999
Ribociclib, C1 D15: 2.5 hrs(n=1,1,1,0,24,1,0)	321 ± 99999	126 ± 99999	718 ± 99999	99999 ± 99999	627 ± 68.3	99999 ± 99999	393 ± 99999
Ribociclib, C1 D15: 4 hrs(n=1,0,2,0,25,0,0)	368 ± 99999	99999 ± 99999	341 ± 42.9	99999 ± 99999	707 ± 62.2	99999 ± 99999	99999 ± 99999
Ribociclib, C1 D15: 6 hrs(n=1,1,2,0,23,0,0)	434 ± 99999	109 ± 99999	239 ± 37.2	99999 ± 99999	578 ± 55.9	99999 ± 99999	99999 ± 99999
Ribociclib, C1 D15: 8 hrs(n=1,1,2,0,21,0,0)	311 ± 99999	83.6 ± 99999	182 ± 27.1	99999 ± 99999	477 ± 55.2	99999 ± 99999	99999 ± 99999
Ribociclib, C1 D16: 24 hrs(n=1,1,2,0,24,1,0)	94.0 ± 99999	25.6 ± 99999	52.7 ± 90.4	99999 ± 99999	120 ± 64.9	99999 ± 99999	91.8 ± 99999
Ribociclib, C1 D21: Pre-dose(n=1,0,1,0,10,1,1)	105 ± 99999	99999 ± 99999	102 ± 99999	99999 ± 99999	112 ± 75.8	115 ± 99999	69.9 ± 99999
Ribociclib, C2 D1: Pre-dose(n=1,1,1,1,16,0,1)	99999 ± 99999	19.5 ± 99999	1.59 ± 99999	1.07 ± 99999	7.00 ± 377.8	132 ± 99999	99999 ± 99999
Ribociclib, C2 D15: Pre-dose(n=1,1,2,1,15,1,1)	103 ± 99999	41.5 ± 99999	53.7 ± 51.2	36.0 ± 99999	107 ± 59.4	102 ± 99999	113 ± 99999
Ribociclib, C3 D1: Pre-dose(n=1,1,0,0,11,0,0)	1.16 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	4.06 ± 172.4	99999 ± 99999	99999 ± 99999
Ribociclib, C4 D1: Pre-dose(n=1,0,0,0,2,0,0)	1.22 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	1.59 ± 31.6	99999 ± 99999	99999 ± 99999
Ribociclib, C5 D1: Pre-dose(n=0,0,0,0,2,0,0)	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	2.16 ± 35.5	99999 ± 99999	99999 ± 99999
Ribociclib, EOT(n=1,1,2,1,21,0,1)	1.94 ± 99999	60.3 ± 99999	1.49 ± 99999	45.8 ± 99999	29.0 ± 292.1	22.8 ± 99999	99999 ± 99999
LEQ803, C1 D1: 1.5 hrs(n=1,1,2,0,21,1,1)	57.1 ± 99999	70.2 ± 99999	68.2 ± 2.4	99999 ± 99999	47.5 ± 97.4	63.6 ± 99999	59.0 ± 99999
LEQ803, C1 D1: 4 hrs(n=1,1,3,0,24,1,0)	65.2 ± 99999	50.8 ± 99999	73.5 ± 20.4	99999 ± 99999	81.1 ± 55.6	99999 ± 99999	63.2 ± 99999
LEQ803, C1 D8: Pre-dose(n=1,1,2,0,22,1,1)	64.3 ± 99999	49.3 ± 99999	38.1 ± 9.1	99999 ± 99999	53.7 ± 36.5	71.2 ± 99999	47.2 ± 99999
LEQ803, C1 D15: Pre-dose(n=1,1,2,0,25,1,0)	76.0 ± 99999	37.1 ± 99999	32.9 ± 25.7	99999 ± 99999	55.1 ± 33.9	99999 ± 99999	49.2 ± 99999
LEQ803, C1 D15: 0.5 hr(n=1,1,2,0,24,0,0)	75.5 ± 99999	39.5 ± 99999	32.1 ± 0.7	99999 ± 99999	60.8 ± 36.9	99999 ± 99999	99999 ± 99999
LEQ803, C1 D15: 1.5 hrs(n=1,1,2,0,24,0,0)	92.3 ± 99999	72.6 ± 99999	82.7 ± 0.7	99999 ± 99999	112 ± 46.9	99999 ± 99999	99999 ± 99999
LEQ803, C1 D15: 2.5 hrs(n=1,1,1,0,24,1,0)	130 ± 99999	92.5 ± 99999	126 ± 99999	99999 ± 99999	133 ± 45.4	99999 ± 99999	137 ± 99999
LEQ803, C1 D15: 4 hrs(n=1,0,2,0,25,0,0)	138 ± 99999	99999 ± 99999	140 ± 23.4	99999 ± 99999	152 ± 31.2	99999 ± 99999	99999 ± 99999
LEQ803, C1 D15: 6 hrs(n=1,1,2,0,23,0,0)	175 ± 99999	90.2 ± 99999	111 ± 27.6	99999 ± 99999	145 ± 27.2	99999 ± 99999	99999 ± 99999
LEQ803, C1 D15: 8 hrs(n=1,1,2,0,21,0,0)	135 ± 99999	79.8 ± 99999	95.2 ± 50.1	99999 ± 99999	128 ± 27.6	99999 ± 99999	99999 ± 99999
LEQ803, C1 D16: 24 hrs(n=1,1,2,0,24,1,0)	84.5 ± 99999	46.8 ± 99999	42.5 ± 13.8	99999 ± 99999	63.1 ± 36.1	99999 ± 99999	59.6 ± 99999
LEQ803, C1 D21: Pre-dose(n=1,0,1,0,10,1,1)	73.8 ± 99999	99999 ± 99999	43.7 ± 99999	99999 ± 99999	58.1 ± 39.1	80.2 ± 99999	52.9 ± 99999
LEQ803, C2 D1: Pre-dose(n=1,1,1,1,16,0,1)	6.68 ± 99999	14.5 ± 99999	4.10 ± 99999	2.70 ± 99999	8.48 ± 154.5	80.8 ± 99999	99999 ± 99999
LEQ803, C2 D15: Pre-dose(n=1,1,2,1,15,1,1)	90.0 ± 99999	45.6 ± 99999	45.7 ± 6.8	28.0 ± 99999	58.3 ± 42.7	61.1 ± 99999	66.8 ± 99999
LEQ803, C3 D1: Pre-dose(n=1,1,0,0,11,0,0)	7.88 ± 99999	2.75 ± 99999	99999 ± 99999	99999 ± 99999	7.57 ± 61.4	99999 ± 99999	99999 ± 99999
LEQ803, C4 D1: Pre-dose(n=1,0,0,0,2,0,0)	7.19 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	5.72 ± 6.9	99999 ± 99999	99999 ± 99999
LEQ803, C5 D1: Pre-dose(n=0,0,0,0,2,0,0)	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	6.07 ± 28.9	99999 ± 99999	99999 ± 99999
LEQ803, EOT(n=1,1,2,1,21,0,1)	10.4 ± 99999	69.3 ± 99999	5.06 ± 4.6	23.5 ± 99999	20.6 ± 152.2	31.2 ± 99999	99999 ± 99999

No statistical analyses for this end point

Secondary: Plasma Concentration for Infigratinib (BGJ) and its Metabolites: Part II

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End point title

Plasma Concentration for Infigratinib (BGJ) and its Metabolites: Part II

End point description

BHS697 and CQM157 are metabolites of infigratinib. Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. Here, “n” signifies number of subjects evaluable for specified time points. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable and where subjects were evaluable: BLQ value.

End point type

Secondary

End point timeframe

C1 (1.5 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; EOT

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg
Number of subjects analysed	1
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
Infigratinib, C1 D1: 1.5 hrs (n =1)	15.0 ± 99999
Infigratinib, C1 D8: Pre-dose (n =1)	2.67 ± 99999
Infigratinib, C1 D15: Pre-dose (n =1)	2.49 ± 99999
Infigratinib, C1 D15: 0.5 hr (n =1)	3.39 ± 99999
Infigratinib, C1 D15: 1.5 hrs (n =1)	15.2 ± 99999
Infigratinib, C1 D15: 2.5 hrs (n =1)	27.5 ± 99999
Infigratinib, C1 D15: 4 hrs (n =1)	24.7 ± 99999
Infigratinib, C1 D15: 6 hrs (n =1)	20.5 ± 99999
Infigratinib, C1 D16: 24 hrs (n =0)	99999 ± 99999
Infigratinib, C1 D21: Pre-dose (n =1)	2.05 ± 99999
Infigratinib, C2 D1: Pre-dose (n =1)	99999 ± 99999
Infigratinib, C2 D15: Pre-dose (n =1)	4.65 ± 99999
Infigratinib, C3 D1: Pre-dose (n =1)	99999 ± 99999
Infigratinib, EOT (n =1)	2.42 ± 99999
BHS697, C1 D1: 1.5 hrs (n =1)	4.83 ± 99999
BHS697, C1 D8: Pre-dose (n =1)	2.17 ± 99999
BHS697, C1 D15: Pre-dose (n =1)	1.64 ± 99999
BHS697, C1 D15: 0.5 hr (n =1)	2.14 ± 99999
BHS697, C1 D15: 1.5 hrs (n =1)	6.83 ± 99999
BHS697, C1 D15: 2.5 hrs (n =1)	8.53 ± 99999
BHS697, C1 D15: 4 hrs (n =1)	6.89 ± 99999
BHS697, C1 D15: 6 hrs (n =1)	5.57 ± 99999
BHS697, C1 D16: 24 hrs (n =0)	99999 ± 99999
BHS697, C1 D21: Pre-dose (n =1)	1.37 ± 99999
BHS697, C2 D1: Pre-dose (n =1)	99999 ± 99999
BHS697, C2 D15: Pre-dose (n =1)	2.83 ± 99999
BHS697, C3 D1: Pre-dose (n =1)	99999 ± 99999
BHS697, EOT (n =1)	1.69 ± 99999
CQM157, C1 D1: 1.5 hrs (n =1)	13.0 ± 99999
CQM157, C1 D8: Pre-dose (n =1)	14.1 ± 99999
CQM157, C1 D15: Pre-dose (n =1)	11.1 ± 99999
CQM157, C1 D15: 0.5 hr (n =1)	12.0 ± 99999
CQM157, C1 D15: 1.5 hrs (n =1)	21.3 ± 99999
CQM157, C1 D15: 2.5 hrs (n =1)	28.3 ± 99999
CQM157, C1 D15: 4 hrs (n =1)	25.0 ± 99999
CQM157, C1 D15: 6 hrs (n =1)	32.2 ± 99999
CQM157, C1 D16: 24 hrs (n =0)	99999 ± 99999
CQM157, C1 D21: Pre-dose (n =1)	9.65 ± 99999
CQM157, C2 D1: Pre-dose (n =1)	99999 ± 99999
CQM157, C2 D15: Pre-dose (n =1)	15.5 ± 99999
CQM157, C3 D1: Pre-dose (n =1)	99999 ± 99999
CQM157, EOT (n =1)	11.9 ± 99999

No statistical analyses for this end point

Secondary: Plasma Concentration for Capmatinib (INC): Part II

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End point title

Plasma Concentration for Capmatinib (INC): Part II

End point description

Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified time points.In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable and where subjects were evaluable: BLQ value.

End point type

Secondary

End point timeframe

C1 (1.5 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT

End point values	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg
Number of subjects analysed	5	5	1
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
C1 D1: 1.5 hrs (n =3, 1, 2)	362 ± 268.6	715 ± 133.2	3600 ± 99999
C1 D8: Pre-dose (n =3, 1, 4)	74.3 ± 97.2	129 ± 49.4	44.4 ± 99999
C1 D15: Pre-dose (n =4, 1, 4)	89.3 ± 35.7	173 ± 41.2	71.4 ± 99999
C1 D15: 0.5 hr (n =5, 1, 4)	196 ± 103.8	314 ± 49.0	1880 ± 99999
C1 D15: 1.5 hrs (n =5, 1, 4)	636 ± 78.2	1830 ± 38.3	3670 ± 99999
C1 D15: 2.5 hrs (n =5, 0, 4)	545 ± 81.2	1530 ± 18.4	99999 ± 99999
C1 D15: 4 hrs (n =4, 1, 4)	401 ± 17.3	950 ± 39.1	1230 ± 99999
C1 D15: 6 hrs (n =5, 1, 4)	157 ± 63.2	487 ± 23.3	264 ± 99999
C1 D15: 8 hrs (n =5, 1, 3)	120 ± 50.0	390 ± 10.5	268 ± 99999
C1 D16: 24 hrs (n =5, 1, 4)	79.6 ± 103.1	269 ± 68.7	58.1 ± 99999
C2 D1: Pre-dose (n =5, 1, 3)	151 ± 107.6	227 ± 42.0	38.7 ± 99999
C2 D15: Pre-dose (n =3, 1, 3)	65.2 ± 31.0	166 ± 80.9	50.5 ± 99999
C3 D1: Pre-dose (n =2, 0, 3)	114 ± 113.4	96.5 ± 17.9	99999 ± 99999
C4 D1: Pre-dose (n =0, 0, 3)	99999 ± 99999	175 ± 44.8	99999 ± 99999
C5 D1: Pre-dose (n =0, 1, 0)	99999 ± 99999	99999 ± 99999	41.8 ± 99999
EOT (n =3, 1, 4)	99999 ± 99999	65.4 ± 155.0	99999 ± 99999

No statistical analyses for this end point

Secondary: Plasma Concentration for Buparlisib (BKM): Part II

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End point title

Plasma Concentration for Buparlisib (BKM): Part II

End point description

Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified time points. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable and where subjects were evaluable: BLQ value.

End point type

Secondary

End point timeframe

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg
Number of subjects analysed	3	3
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
C1 D1: 1.5 hrs (n =1, 1)	213 ± 99999	213 ± 99999
C1 D8: Pre-dose (n =3, 2)	45.0 ± 75.2	119 ± 3.6
C1 D15: Pre-dose (n =3, 2)	49.7 ± 115.9	97.3 ± 16.2
C1 D15: 0.5 hr (n =3, 2)	139 ± 13.4	229 ± 21.5
C1 D15: 1.5 hrs (n =3, 2)	266 ± 51.5	312 ± 10.9
C1 D15: 2.5 hrs (n =3, 2)	176 ± 42.2	268 ± 11.9
C1 D15: 4 hrs (n =3, 2)	115 ± 44.0	235 ± 39.4
C1 D15: 6 hrs (n =3, 2)	94.2 ± 40.0	171 ± 26.4
C1 D15: 8 hrs (n =3, 2)	87.4 ± 63.9	111 ± 25.5
C1 D16: 24 hrs (n =3, 2)	41.8 ± 82.9	101 ± 1.4
C2 D1: Pre-dose (n =3, 2)	54.7 ± 134.9	110 ± 51.2
C2 D15: Pre-dose (n =1, 1)	99.3 ± 99999	138 ± 99999
C3 D1: Pre-dose (n =1, 0)	81.2 ± 99999	99999 ± 99999
C4 D1: Pre-dose (n =1, 0)	73.2 ± 99999	99999 ± 99999
C5 D1: Pre-dose (n =1, 0)	122 ± 99999	99999 ± 99999
EOT (n =2, 1)	1.84 ± 53.4	99999 ± 99999

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration at Steady State (Cmax,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

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End point title

Maximum Observed Plasma Concentration at Steady State (Cmax,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

End point description

AR00426032 = binimetinib metabolite, LEQ803 = ribociclib metabolite, BHS697 and CQM157 = infigratinib metabolites. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified drugs. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 (minutes) min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Number of subjects analysed

Units: Nanogram per milliliter

geometric mean (geometric coefficient of variation)

Encorafenib (n=3,2,1,5,1,4,1,1,2,1,25,0)

3060 ± 58.8

2150 ± 54.6

2100 ± 99999

1600 ± 62.0

2890 ± 99999

2570 ± 23.0

622 ± 99999

1960 ± 99999

1860 ± 32.1

2010 ± 99999

2030 ± 40.6

99999 ± 99999

Binimetinib (n=3,2,1,5,1,4,1,1,2,1,24,1)

386 ± 41.1

221 ± 237.6

413 ± 99999

515 ± 17.0

797 ± 99999

858 ± 13.0

261 ± 99999

520 ± 99999

313 ± 15.9

584 ± 99999

489 ± 31.3

291 ± 99999

AR00426032 (n=3,2,1,5,1,4,1,1,2,1,24,1)

24.9 ± 92.2

18.1 ± 591.2

15.8 ± 99999

27.9 ± 85.6

22.6 ± 99999

47.1 ± 29.2

12.9 ± 99999

12.6 ± 99999

16.1 ± 151.9

19.4 ± 99999

23.7 ± 94.1

9.04 ± 99999

Ribociclib (n=0,0,0,0,0,0,1,1,2,1,26,1)

99999 ± 99999

434 ± 99999

126 ± 99999

428 ± 84.2

282 ± 99999

753 ± 70.6

597 ± 99999

LEQ803 (n=0,0,0,0,0,0,1,1,2,1,26,1)

99999 ± 99999

175 ± 99999

93.2 ± 99999

144 ± 19.2

67.5 ± 99999

156 ± 36.2

138 ± 99999

Infigratinib (n=0,0,1,0,0,0,0,0,0,0,0,0)

99999 ± 99999

27.5 ± 99999

99999 ± 99999

BHS697 (n=0,0,1,0,0,0,0,0,0,0,0,0)

99999 ± 99999

8.53 ± 99999

99999 ± 99999

CQM157 (n=0,0,1,0,0,0,0,0,0,0,0,0)

99999 ± 99999

32.2 ± 99999

99999 ± 99999

Capmatinib (n=0,0,0,5,1,4,0,0,0,0,0,0)

99999 ± 99999

722 ± 85.3

3670 ± 99999

1920 ± 31.8

99999 ± 99999

Buparlisib (n=3,2,0,5,1,4,0,0,0,0,0,0)

266 ± 51.5

312 ± 10.9

99999 ± 99999

No statistical analyses for this end point

Secondary: Time to Reach Cmax at Steady State (Tmax, ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

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End point title

Time to Reach Cmax at Steady State (Tmax, ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

End point description

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Number of subjects analysed

Units: Hour

median (full range (min-max))

Encorafenib (n=3,2,1,5,1,4,1,1,2,1,25,0)

1.33 (0.58 to 1.50)

1.54 (1.50 to 1.58)

1.50 (1.50 to 1.50)

1.50 (0.50 to 1.53)

1.50 (1.50 to 1.50)

1.50 (1.50 to 2.50)

2.37 (2.37 to 2.37)

1.47 (1.47 to 1.47)

1.00 (0.50 to 1.50)

1.50 (1.50 to 1.50)

1.58 (0.63 to 6.17)

99999 (-99999 to 99999)

Binimetinib (n=3,2,1,5,1,4,1,1,2,1,24,1)

1.50 (1.33 to 1.67)

2.75 (1.50 to 4.00)

1.50 (1.50 to 1.50)

1.50 (0.50 to 1.58)

1.50 (1.50 to 1.50)

1.50 (1.50 to 2.50)

1.38 (1.38 to 1.38)

1.47 (1.47 to 1.47)

1.50 (1.50 to 1.50)

1.58 (0.50 to 4.08)

1.08 (1.08 to 1.08)

AR00426032 (n=3,2,1,5,1,4,1,1,2,1,24,1)

1.50 (1.33 to 1.67)

2.75 (1.50 to 4.00)

1.50 (1.50 to 1.50)

1.50 (1.50 to 1.58)

4.00 (4.00 to 4.00)

1.92 (1.50 to 2.50)

1.38 (1.38 to 1.38)

1.47 (1.47 to 1.47)

1.50 (1.50 to 1.50)

1.65 (0.67 to 4.08)

1.08 (1.08 to 1.08)

Ribociclib (n=0,0,0,0,0,0,1,1,2,1,26,1)

99999 (-99999 to 99999)

5.92 (5.92 to 5.92)

2.45 (2.45 to 2.45)

3.18 (2.33 to 4.03)

1.50 (1.50 to 1.50)

3.65 (1.50 to 6.00)

0.50 (0.50 to 0.50)

LEQ803 (n=0,0,0,0,0,0,1,1,2,1,26,1)

99999 (-99999 to 99999)

5.92 (5.92 to 5.92)

4.98 (4.98 to 4.98)

3.18 (2.33 to 4.03)

1.50 (1.50 to 1.50)

4.12 (1.55 to 7.00)

1.08 (1.08 to 1.08)

Infigratinib (n=0,0,1,0,0,0,0,0,0,0,0,0)

99999 (-99999 to 99999)

2.50 (2.50 to 2.50)

99999 (-99999 to 99999)

BHS697 (n=0,0,1,0,0,0,0,0,0,0,0,0)

99999 (-99999 to 99999)

2.50 (2.50 to 2.50)

99999 (-99999 to 99999)

CQM157 (n=0,0,1,0,0,0,0,0,0,0,0,0)

99999 (-99999 to 99999)

5.75 (5.75 to 5.75)

99999 (-99999 to 99999)

Capmatinib (n=0,0,0,5,1,4,0,0,0,0,0,0)

99999 (-99999 to 99999)

1.53 (1.50 to 2.58)

1.50 (1.50 to 1.50)

1.50 (1.50 to 2.50)

99999 (-99999 to 99999)

Buparlisib (n=3,2,0,0,0,0,0,0,0,0,0,0)

1.50 (1.33 to 1.67)

1.50 (1.50 to 1.50)

99999 (-99999 to 99999)

99999 (99999 to 99999)

99999 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From Time Zero to Time tau at Steady-State (AUCtau,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II

Top of page

End point title

Area Under the Concentration-time Curve From Time Zero to Time tau at Steady-State (AUCtau,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II

End point description

AR00426032 = binimetinib metabolite, LEQ803 = ribociclib metabolite. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified drugs. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Number of subjects analysed

Units: Hour*nanogram per milliliter

geometric mean (geometric coefficient of variation)

Encorafenib (n=3,2,1,5,1,4,1,1,2,1,23,0)

9080 ± 42.2

10100 ± 18.4

7420 ± 99999

4990 ± 42.6

10800 ± 99999

8570 ± 10.6

3490 ± 99999

6000 ± 99999

5740 ± 7.1

6200 ± 99999

11300 ± 41.1

99999 ± 99999

Binimetinib (n=3,2,1,5,1,4,1,1,2,1,23,1)

1580 ± 17.0

1220 ± 105.7

1260 ± 99999

2180 ± 29.4

3040 ± 99999

2760 ± 4.8

1700 ± 99999

1900 ± 99999

1140 ± 21.1

1740 ± 99999

2270 ± 29.5

99999 ± 99999

AR00426032 (n=3,2,1,5,1,4,1,1,2,1,22,1)

116 ± 66.8

94.4 ± 222.2

42.0 ± 99999

124 ± 113.9

135 ± 99999

182 ± 43.1

81.5 ± 99999

47.0 ± 99999

57.9 ± 128.5

66.9 ± 99999

115 ± 92.6

41.1 ± 99999

Ribociclib (n=0,0,0,0,0,0,1,1,2,1,22,1)

99999 ± 99999

5630 ± 99999

1650 ± 99999

3730 ± 62.5

2320 ± 99999

9230 ± 60.9

5960 ± 99999

LEQ803 (n=0,0,0,0,0,0,1,1,2,1,22,1)

99999 ± 99999

1640 ± 99999

1900 ± 24.9

930 ± 99999

2540 ± 31.3

2300 ± 99999

Capmatinib (n=0,0,0,5,1,4,0,0,0,0,0,0)

99999 ± 99999

3070 ± 52.6

12200 ± 99999

8420 ± 22.0

99999 ± 99999

Buparlisib (n=3,2,0,0,0,0,0,0,0,0,0,0)

2130 ± 54.6

3400 ± 18.5

99999 ± 99999

No statistical analyses for this end point

Secondary: Elimination Half-life at Steady State (t1/2, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II

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End point title

Elimination Half-life at Steady State (t1/2, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II

End point description

AR00426032 = binimetinib metabolite, LEQ803 = ribociclib metabolite. Elimination half-life means the time required for the plasma concentration to decline by 50% during the elimination phase. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified drugs. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Number of subjects analysed

Units: Hour

arithmetic mean (standard deviation)

Encorafenib (n=3,2,1,5,1,4,1,1,2,1,20,0)

3.75 ± 0.302

5.89 ± 4.32

3.57 ± 99999

4.18 ± 1.85

3.41 ± 99999

3.96 ± 0.233

4.27 ± 99999

3.75 ± 99999

4.32 ± 1.62

3.83 ± 99999

3.60 ± 0.711

99999 ± 99999

Binimetinib (n=3,2,1,4,0,4,1,1,2,1,22,1)

8.35 ± 3.52

3.48 ± 0.484

1.60 ± 99999

10.3 ± 6.29

99999 ± 99999

5.88 ± 2.77

5.84 ± 99999

3.82 ± 99999

5.38 ± 3.39

10.9 ± 99999

4.13 ± 1.42

99999 ± 99999

AR00426032 (n=3,2,1,2,1,3,0,1,2,1,17,0)

6.35 ± 1.21

4.14 ± 0.683

1.59 ± 99999

7.95 ± 4.03

2.86 ± 99999

5.64 ± 2.49

99999 ± 99999

4.34 ± 99999

6.24 ± 4.43

99999 ± 99999

5.91 ± 3.00

99999 ± 99999

Ribociclib (n=0,0,0,0,0,0,0,1,2,1,18,1)

99999 ± 99999

9.01 ± 99999

8.44 ± 2.21

10.7 ± 99999

7.77 ± 1.95

10.1 ± 99999

LEQ803 (n=0,0,0,0,0,0,0,1,2,1,11,0)

99999 ± 99999

19.9 ± 99999

14.1 ± 4.04

19.2 ± 99999

16.0 ± 4.50

99999 ± 99999

Capmatinib (n=0,0,0,2,1,1,0,0,0,0,0,0)

99999 ± 99999

2.18 ± 0.0599

2.50 ± 99999

2.82 ± 99999

99999 ± 99999

Buparlisib (n=3,0,0,0,0,0,0,0,0,0,0,0)

15.4 ± 4.62

99999 ± 99999

No statistical analyses for this end point

Secondary: Apparent Total Plasma Clearance at Steady State (Cl, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II

Top of page

End point title

Apparent Total Plasma Clearance at Steady State (Cl, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II

End point description

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified drugs. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Number of subjects analysed

Units: Liter per hour

geometric mean (geometric coefficient of variation)

Encorafenib (n =3,2,1,5,1,4,1,1,2,1,20,0)

49.6 ± 42.1

44.7 ± 18.4

60.7 ± 99999

40.1 ± 42.6

18.6 ± 99999

23.4 ± 10.7

28.7 ± 99999

33.3 ± 99999

34.9 ± 6.9

32.2 ± 99999

19.5 ± 44.3

99999 ± 99999

Binimetinib (n =3,2,1,5,1,4,1,1,2,1,23,0)

28.5 ± 14.8

36.9 ± 105.7

35.6 ± 99999

20.8 ± 28.1

15.1 ± 99999

16.3 ± 5.0

17.4 ± 99999

15.8 ± 99999

26.5 ± 22.6

25.9 ± 99999

19.9 ± 29.2

99999 ± 99999

Ribociclib (n =0,0,0,0,0,0,0,1,2,1,19,1)

99999 ± 99999

243 ± 99999

161 ± 61.1

173 ± 99999

62.4 ± 58.5

99.3 ± 99999

Capmatinib (n =0,0,0,5,1,3,0,0,0,0,0,0)

99999 ± 99999

65.9 ± 52.2

24.8 ± 99999

45.7 ± 24.4

99999 ± 99999

Buparlisib (n =3,1,0,0,0,0,0,0,0,0,0,0)

28.2 ± 53.6

23.2 ± 99999

99999 ± 99999

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution at Steady State (Vz, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II

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End point title

Apparent Volume of Distribution at Steady State (Vz, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II

End point description

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution is the apparent volume of distribution at steady-state. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified drugs. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Number of subjects analysed

Units: Liter

geometric mean (geometric coefficient of variation)

Encorafenib (n =3,2,1,5,1,4,1,1,2,1,20,0)

268 ± 45.4

324 ± 69.8

313 ± 99999

226 ± 92.9

91.7 ± 99999

133 ± 13.5

177 ± 99999

180 ± 99999

210 ± 32.3

178 ± 99999

99.3 ± 46.0

99999 ± 99999

Binimetinib (n =3,2,1,4,0,4,1,1,2,1,22,0)

324 ± 58.3

185 ± 83.4

82.5 ± 99999

244 ± 75.9

99999 ± 99999

125 ± 56.1

147 ± 99999

86.8 ± 99999

184 ± 111.8

406 ± 99999

113 ± 48.5

99999 ± 99999

Ribociclib (n =0,0,0,0,0,0,0,1,2,1,18,1)

99999 ± 99999

3160 ± 99999

1930 ± 30.5

2660 ± 99999

677 ± 65.0

1440 ± 99999

Capmatinib (n =0,0,0,2,1,1,0,0,0,0,0,0)

99999 ± 99999

190 ± 30.3

89.5 ± 99999

233 ± 99999

99999 ± 99999

Buparlisib (n =3,0,0,0,0,0,0,0,0,0,0,0)

604 ± 17.4

99999 ± 99999

No statistical analyses for this end point

Secondary: Last Measurable Plasma Concentration at Steady State (Clast, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

Top of page

End point title

Last Measurable Plasma Concentration at Steady State (Clast, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

End point description

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Number of subjects analysed

Units: Nanogram per milliliter

geometric mean (geometric coefficient of variation)

Encorafenib (n =3,2,1,5,1,4,1,1,2,1,25,0)

11.3 ± 45.3

25.1 ± 2066.8

6.76 ± 99999

15.9 ± 315.9

5.20 ± 99999

15.0 ± 20.9

10.7 ± 99999

7.85 ± 99999

10.8 ± 106.1

10.5 ± 99999

33.7 ± 254.3

99999 ± 99999

Binimetinib (n =3,2,1,5,1,4,1,1,2,1,24,1)

44.1 ± 19.1

30.2 ± 59.2

55.8 ± 99999

63.2 ± 64.0

17.6 ± 99999

55.9 ± 54.0

78.3 ± 99999

29.8 ± 99999

23.1 ± 5.2

47.9 ± 99999

58.7 ± 60.2

40.5 ± 99999

AR00426032 (n =3,2,1,5,1,4,1,1,2,1,24,1)

3.99 ± 61.8

2.92 ± 159.3

1.82 ± 99999

5.57 ± 130.2

1.44 ± 99999

4.75 ± 25.4

6.53 ± 99999

1.08 ± 99999

2.31 ± 47.8

3.54 ± 99999

4.68 ± 92.3

1.56 ± 99999

Ribociclib (n =0,0,0,0,0,0,1,1,2,1,26,1)

99999 ± 99999

94.0 ± 99999

25.6 ± 99999

52.7 ± 90.4

34.9 ± 99999

147 ± 71.8

91.8 ± 99999

LEQ803 (n =0,0,0,0,0,0,1,1,2,1,26,1)

99999 ± 99999

84.5 ± 99999

46.8 ± 99999

42.5 ± 13.8

22.8 ± 99999

73.2 ± 49.6

59.6 ± 99999

Infigratinib (n =0,0,1,0,0,0,0,0,0,0,0,0)

99999 ± 99999

20.5 ± 99999

99999 ± 99999

BHS697 (n =0,0,1,0,0,0,0,0,0,0,0,0)

99999 ± 99999

5.57 ± 99999

99999 ± 99999

CQM157 (n =0,0,1,0,0,0,0,0,0,0,0,0)

99999 ± 99999

32.2 ± 99999

99999 ± 99999

Capmatinib (n =0,0,0,5,1,4,0,0,0,0,0,0)

99999 ± 99999

79.6 ± 103.1

58.1 ± 99999

269 ± 68.7

99999 ± 99999

Buparlisib (n =3,2,0,0,0,0,0,0,0,0,0,0)

41.8 ± 82.9

101 ± 1.4

99999 ± 99999

No statistical analyses for this end point

Secondary: Measured Concentration at the end of a Dosing Interval at Steady State (Ctrough, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

Top of page

End point title

Measured Concentration at the end of a Dosing Interval at Steady State (Ctrough, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

End point description

End point type

Secondary

End point timeframe

C1 D15: at the end of a dosing interval at steady-state (24 hour ± 2 hour), taken directly before next administration

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Number of subjects analysed

Units: Nanogram per milliliter

geometric mean (geometric coefficient of variation)

Encorafenib (n =3,2,1,5,1,4,1,1,2,1,24,0)

11.2 ± 106.3

18.6 ± 159.4

7.74 ± 99999

11.6 ± 51.3

7.95 ± 99999

13.5 ± 35.0

9.28 ± 99999

10.3 ± 99999

7.75 ± 37.3

10.4 ± 99999

21.7 ± 185.4

99999 ± 99999

Binimetinib (n =3,2,1,5,1,4,1,1,2,1,23,1)

32.0 ± 17.1

39.1 ± 57.4

33.9 ± 99999

81.2 ± 47.5

47.3 ± 99999

50.9 ± 34.4

54.3 ± 99999

28.3 ± 99999

21.1 ± 23.7

31.5 ± 99999

51.0 ± 76.1

36.2 ± 99999

AR00426032 (n =3,2,1,5,1,4,1,1,2,1,23,1)

3.14 ± 74.5

3.80 ± 111.9

1.21 ± 99999

8.22 ± 84.6

4.36 ± 99999

5.45 ± 42.2

4.16 ± 99999

99999 ± 99999

3.81 ± 99999

1.72 ± 99999

4.34 ± 79.9

1.09 ± 99999

Ribociclib (n =0,0,0,0,0,0,1,1,2,1,25,1)

99999 ± 99999

98.4 ± 99999

28.2 ± 99999

30.7 ± 24.9

36.4 ± 99999

104 ± 54.2

64.7 ± 99999

LEQ803 (n =0,0,0,0,0,0,1,1,2,1,25,1)

99999 ± 99999

76.0 ± 99999

37.1 ± 99999

32.9 ± 25.7

22.8 ± 99999

55.1 ± 33.9

49.2 ± 99999

Infigratinib (n =0,0,1,0,0,0,0,0,0,0,0,0)

99999 ± 99999

2.49 ± 99999

99999 ± 99999

BHS697 (n =0,0,1,0,0,0,0,0,0,0,0,0)

99999 ± 99999

1.64 ± 99999

99999 ± 99999

CQM157 (n =0,0,1,0,0,0,0,0,0,0,0,0)

99999 ± 99999

11.1 ± 99999

99999 ± 99999

Capmatinib (n =0,0,0,5,1,4,0,0,0,0,0,0)

99999 ± 99999

83.9 ± 34.0

71.4 ± 99999

173 ± 41.2

99999 ± 99999

Buparlisib (n =3,2,0,0,0,0,0,0,0,0,0,0)

49.7 ± 115.9

97.3 ± 16.2

99999 ± 99999

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Day 1 up to 30 days after last dose (maximum treatment exposure for Part I was 403.7 weeks and for Part II was 97.0 weeks)

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 categorized as serious in 1 subject and non-serious in other subject, or a subject may have experienced both SAE and non-SAE. Safety set evaluated.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Part I: Encorafenib + Binimetinib (naive)

Reporting group description

Reporting group title

Part I: Encorafenib + Binimetinib (non-naive)

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Buparlisib

Reporting group description

Subjects received encorafenib 450 mg (starting dose) once a day, binimetinib 45 mg (starting dose) twice a day and buparlisib 60 mg starting dose) once a day until disease progression or no clinical benefit. No dose reduction below 150 mg for encorafenib and 15 mg for binimetinib was permitted for this study. For buparlisib dose escalation was allowed till 100 mg and dose reduction was permitted till 30 mg. Treatment cycle for encorafenib, binimetinib and buparlisib was defined as 21 days of daily continuous treatment.

Reporting group title

Part II: Encorafenib + Binimetinib + Infigratinib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Capmatinib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Ribociclib

Reporting group description

Subjects received encorafenib 200 mg (starting dose) once a day, binimetinib 45 mg (starting dose) twice a day and ribociclib 100 mg (starting dose) once a day until disease progression or no clinical benefit. No dose reduction below 50 mg for encorafenib and 15 mg for binimetinib was permitted for this study. For ribociclib dose escalation was allowed till 600 mg and dose reduction was permitted till 50 mg. Ribociclib was taken for 21 consecutive days followed by a 7-day planned break.

Serious adverse events	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)	Part II: Encorafenib + Binimetinib + Buparlisib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Ribociclib
Total subjects affected by serious adverse events
subjects affected / exposed	47 / 75 (62.67%)	37 / 83 (44.58%)	4 / 6 (66.67%)	0 / 1 (0.00%)	6 / 13 (46.15%)	19 / 38 (50.00%)
number of deaths (all causes)	20	29	4	1	8	28
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer recurrent
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to spine
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 75 (0.00%)	2 / 83 (2.41%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic malignant melanoma
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour ulceration
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Shock
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vasculitis
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 75 (0.00%)	4 / 83 (4.82%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	2 / 4	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 75 (1.33%)	4 / 83 (4.82%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 1	1 / 5	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 75 (1.33%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic pain
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hiccups
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary alveolar haemorrhage
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	1 / 75 (1.33%)	1 / 83 (1.20%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 75 (1.33%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intraocular pressure increased
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 75 (0.00%)	2 / 83 (2.41%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Troponin T increased
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Seroma
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pneumothorax
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoradionecrosis
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Periprosthetic fracture
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Embolic cerebral infarction
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	3 / 75 (4.00%)	2 / 83 (2.41%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aphasia
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	2 / 75 (2.67%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paresis
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraparesis
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiplegia
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	2 / 75 (2.67%)	0 / 83 (0.00%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 75 (4.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	2 / 38 (5.26%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo positional
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Vision blurred
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diplopia
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Exophthalmos
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 75 (1.33%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 75 (1.33%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	4 / 75 (5.33%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Terminal ileitis
subjects affected / exposed	2 / 75 (2.67%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 75 (1.33%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	4 / 75 (5.33%)	3 / 83 (3.61%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	1 / 4	4 / 4	0 / 0	0 / 0	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intussusception
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal mass
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 75 (2.67%)	6 / 83 (7.23%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 2	5 / 8	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug eruption
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	2 / 75 (2.67%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenomegaly
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adrenocortical insufficiency acute
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Costochondritis
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibromyalgia
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Groin pain
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myopathy toxic
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Chorioretinitis
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	2 / 75 (2.67%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 75 (1.33%)	3 / 83 (3.61%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	4 / 75 (5.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal infection
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vestibular neuronitis
subjects affected / exposed	1 / 75 (1.33%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	2 / 75 (2.67%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 75 (1.33%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 75 (0.00%)	2 / 83 (2.41%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 75 (0.00%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)	Part II: Encorafenib + Binimetinib + Buparlisib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Ribociclib
Total subjects affected by non serious adverse events
subjects affected / exposed	75 / 75 (100.00%)	73 / 83 (87.95%)	5 / 6 (83.33%)	0 / 1 (0.00%)	11 / 13 (84.62%)	33 / 38 (86.84%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	3 / 38 (7.89%)
occurrences all number	0	0	0	0	0	4
Vascular disorders
Hypertension
subjects affected / exposed	9 / 75 (12.00%)	4 / 83 (4.82%)	1 / 6 (16.67%)	0 / 1 (0.00%)	1 / 13 (7.69%)	1 / 38 (2.63%)
occurrences all number	19	5	1	0	1	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	31 / 75 (41.33%)	27 / 83 (32.53%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	6 / 38 (15.79%)
occurrences all number	44	32	0	0	1	7
Chills
subjects affected / exposed	5 / 75 (6.67%)	7 / 83 (8.43%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	9	8	0	0	0	0
Asthenia
subjects affected / exposed	3 / 75 (4.00%)	6 / 83 (7.23%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	3	6	0	0	0	0
Pyrexia
subjects affected / exposed	13 / 75 (17.33%)	16 / 83 (19.28%)	2 / 6 (33.33%)	0 / 1 (0.00%)	0 / 13 (0.00%)	7 / 38 (18.42%)
occurrences all number	19	21	2	0	0	10
Oedema peripheral
subjects affected / exposed	15 / 75 (20.00%)	10 / 83 (12.05%)	1 / 6 (16.67%)	0 / 1 (0.00%)	3 / 13 (23.08%)	4 / 38 (10.53%)
occurrences all number	15	12	1	0	7	5
Influenza like illness
subjects affected / exposed	6 / 75 (8.00%)	5 / 83 (6.02%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	9	5	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	9 / 75 (12.00%)	9 / 83 (10.84%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	12	10	0	0	0	0
Dyspnoea
subjects affected / exposed	5 / 75 (6.67%)	8 / 83 (9.64%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	6	12	0	0	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	3 / 38 (7.89%)
occurrences all number	0	0	0	0	0	3
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	4 / 75 (5.33%)	5 / 83 (6.02%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	3 / 38 (7.89%)
occurrences all number	10	5	0	0	1	4
Aspartate aminotransferase increased
subjects affected / exposed	9 / 75 (12.00%)	6 / 83 (7.23%)	2 / 6 (33.33%)	0 / 1 (0.00%)	0 / 13 (0.00%)	4 / 38 (10.53%)
occurrences all number	25	7	7	0	0	5
Amylase increased
subjects affected / exposed	7 / 75 (9.33%)	6 / 83 (7.23%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	10	11	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	13 / 75 (17.33%)	8 / 83 (9.64%)	1 / 6 (16.67%)	0 / 1 (0.00%)	1 / 13 (7.69%)	5 / 38 (13.16%)
occurrences all number	46	9	7	0	2	8
Blood creatine increased
subjects affected / exposed	4 / 75 (5.33%)	4 / 83 (4.82%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	5	6	0	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	38 / 75 (50.67%)	10 / 83 (12.05%)	0 / 6 (0.00%)	0 / 1 (0.00%)	2 / 13 (15.38%)	5 / 38 (13.16%)
occurrences all number	138	29	0	0	3	6
Ejection fraction decreased
subjects affected / exposed	6 / 75 (8.00%)	6 / 83 (7.23%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	7	10	0	0	0	0
Blood creatinine increased
subjects affected / exposed	7 / 75 (9.33%)	10 / 83 (12.05%)	0 / 6 (0.00%)	0 / 1 (0.00%)	2 / 13 (15.38%)	4 / 38 (10.53%)
occurrences all number	18	15	0	0	5	5
Electrocardiogram QT prolonged
subjects affected / exposed	7 / 75 (9.33%)	2 / 83 (2.41%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	9	2	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	12 / 75 (16.00%)	8 / 83 (9.64%)	1 / 6 (16.67%)	0 / 1 (0.00%)	2 / 13 (15.38%)	2 / 38 (5.26%)
occurrences all number	21	14	2	0	3	3
Lipase increased
subjects affected / exposed	11 / 75 (14.67%)	7 / 83 (8.43%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	27	18	0	0	0	0
White blood cell count decreased
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	4 / 38 (10.53%)
occurrences all number	0	0	0	0	0	8
Weight increased
subjects affected / exposed	7 / 75 (9.33%)	5 / 83 (6.02%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	9	5	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	8 / 75 (10.67%)	5 / 83 (6.02%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	4 / 38 (10.53%)
occurrences all number	8	5	0	0	0	4
Headache
subjects affected / exposed	14 / 75 (18.67%)	8 / 83 (9.64%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	22	11	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	28 / 75 (37.33%)	16 / 83 (19.28%)	3 / 6 (50.00%)	0 / 1 (0.00%)	3 / 13 (23.08%)	10 / 38 (26.32%)
occurrences all number	44	27	5	0	6	16
Leukopenia
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	5 / 38 (13.16%)
occurrences all number	0	0	0	0	0	17
Neutropenia
subjects affected / exposed	6 / 75 (8.00%)	2 / 83 (2.41%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	13	2	0	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	5 / 75 (6.67%)	5 / 83 (6.02%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	6	6	0	0	0	0
Retinopathy
subjects affected / exposed	22 / 75 (29.33%)	10 / 83 (12.05%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	29	16	0	0	0	0
Subretinal fluid
subjects affected / exposed	9 / 75 (12.00%)	8 / 83 (9.64%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	13	13	0	0	0	0
Visual field defect
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	1 / 6 (16.67%)	0 / 1 (0.00%)	2 / 13 (15.38%)	0 / 38 (0.00%)
occurrences all number	0	0	1	0	3	0
Cataract
subjects affected / exposed	4 / 75 (5.33%)	4 / 83 (4.82%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	5	5	0	0	0	0
Vision blurred
subjects affected / exposed	11 / 75 (14.67%)	8 / 83 (9.64%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	16	8	0	0	0	0
Gastrointestinal disorders
Flatulence
subjects affected / exposed	5 / 75 (6.67%)	3 / 83 (3.61%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	6	3	0	0	0	0
Vomiting
subjects affected / exposed	15 / 75 (20.00%)	22 / 83 (26.51%)	1 / 6 (16.67%)	0 / 1 (0.00%)	1 / 13 (7.69%)	10 / 38 (26.32%)
occurrences all number	28	39	1	0	2	15
Nausea
subjects affected / exposed	30 / 75 (40.00%)	33 / 83 (39.76%)	2 / 6 (33.33%)	0 / 1 (0.00%)	2 / 13 (15.38%)	15 / 38 (39.47%)
occurrences all number	50	52	3	0	2	19
Diarrhoea
subjects affected / exposed	33 / 75 (44.00%)	25 / 83 (30.12%)	1 / 6 (16.67%)	0 / 1 (0.00%)	2 / 13 (15.38%)	9 / 38 (23.68%)
occurrences all number	60	37	1	0	2	15
Constipation
subjects affected / exposed	22 / 75 (29.33%)	13 / 83 (15.66%)	1 / 6 (16.67%)	0 / 1 (0.00%)	1 / 13 (7.69%)	5 / 38 (13.16%)
occurrences all number	29	13	1	0	1	7
Abdominal pain
subjects affected / exposed	14 / 75 (18.67%)	11 / 83 (13.25%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	2 / 38 (5.26%)
occurrences all number	19	16	1	0	0	2
Skin and subcutaneous tissue disorders
Hyperkeratosis
subjects affected / exposed	8 / 75 (10.67%)	2 / 83 (2.41%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	9	2	0	0	0	0
Rash maculo-papular
subjects affected / exposed	5 / 75 (6.67%)	5 / 83 (6.02%)	0 / 6 (0.00%)	0 / 1 (0.00%)	1 / 13 (7.69%)	3 / 38 (7.89%)
occurrences all number	5	6	0	0	1	4
Night sweats
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	2 / 38 (5.26%)
occurrences all number	0	0	1	0	0	2
Alopecia
subjects affected / exposed	11 / 75 (14.67%)	4 / 83 (4.82%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	12	4	0	0	0	0
Dry skin
subjects affected / exposed	7 / 75 (9.33%)	10 / 83 (12.05%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	7	10	0	0	0	0
Rash
subjects affected / exposed	6 / 75 (8.00%)	11 / 83 (13.25%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	9	28	0	0	0	0
Pruritus
subjects affected / exposed	7 / 75 (9.33%)	6 / 83 (7.23%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	9	6	0	0	0	0
Musculoskeletal and connective tissue disorders
Muscle spasms
subjects affected / exposed	16 / 75 (21.33%)	7 / 83 (8.43%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	3 / 38 (7.89%)
occurrences all number	18	8	0	0	0	4
Arthralgia
subjects affected / exposed	26 / 75 (34.67%)	15 / 83 (18.07%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	2 / 38 (5.26%)
occurrences all number	40	34	1	0	0	2
Back pain
subjects affected / exposed	16 / 75 (21.33%)	6 / 83 (7.23%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	4 / 38 (10.53%)
occurrences all number	24	7	1	0	0	4
Pain in extremity
subjects affected / exposed	8 / 75 (10.67%)	9 / 83 (10.84%)	1 / 6 (16.67%)	0 / 1 (0.00%)	1 / 13 (7.69%)	1 / 38 (2.63%)
occurrences all number	12	14	1	0	1	1
Myalgia
subjects affected / exposed	11 / 75 (14.67%)	6 / 83 (7.23%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	12	11	0	0	0	0
Groin pain
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	1 / 6 (16.67%)	0 / 1 (0.00%)	0 / 13 (0.00%)	4 / 38 (10.53%)
occurrences all number	0	0	1	0	0	5
Infections and infestations
Urinary tract infection
subjects affected / exposed	7 / 75 (9.33%)	3 / 83 (3.61%)	0 / 6 (0.00%)	0 / 1 (0.00%)	2 / 13 (15.38%)	3 / 38 (7.89%)
occurrences all number	11	3	0	0	2	3
Upper respiratory tract infection
subjects affected / exposed	11 / 75 (14.67%)	3 / 83 (3.61%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	16	3	0	0	0	0
Nasopharyngitis
subjects affected / exposed	12 / 75 (16.00%)	6 / 83 (7.23%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	28	7	0	0	0	0
Conjunctivitis
subjects affected / exposed	7 / 75 (9.33%)	1 / 83 (1.20%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	7	1	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	5 / 75 (6.67%)	14 / 83 (16.87%)	0 / 6 (0.00%)	0 / 1 (0.00%)	0 / 13 (0.00%)	0 / 38 (0.00%)
occurrences all number	6	14	0	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 75 (0.00%)	0 / 83 (0.00%)	0 / 6 (0.00%)	0 / 1 (0.00%)	3 / 13 (23.08%)	1 / 38 (2.63%)
occurrences all number	0	0	0	0	5	1

More information

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Were there any global substantial amendments to the protocol? Yes

05 May 2014

The reason for the current amendment is to comply with health authority request to better define some DLT criteria by excluding only Grade ≥3 cutaneous squamous cell carcinoma, rather than SCC (squamous cell carcinoma), from the DLT definition. Moreover, Grade ≥3 laboratory abnormalities, which are clearly drug related, will also be considered DLT. In addition, minor changes for consistency and clarification were implemented.

25 Nov 2014

This amendment will allow patients who have received treatment with any BRAF and/or MEK inhibitor to begin the trial with the LGX818 and MEK162 prior to disease progression and will allow patients who received LGX818 and/or MEK162 in other trials to enter LOGIC 2 prior to progression. This amendment will allow patients who have received other BRAF and/or MEK inhibitors, and have not progressed, but are not tolerating their treatment, to receive LGX818/MEK162 combination in this trial. Patients who develop brain metastasis during Part I of the study can continue treatment on Part II of the study at the discretion of the Investigator and the Sponsor Medical Monitor. DDI risk assessments as well as the list of concomitant medications for some study treatments have been updated due to emerging data. Changes and clarifications have been made following health authority requests: Patient minimum age must be 18 years at time of informed consent signature. The end of study definition has been expanded to clarify the End of study will be upon completion of the safety follow-up, disease progression follow-up and survival follow-up (only for Part II), whichever comes later, or if the study is terminated early. The followings clarification have been provided; the exclusion criterion for Enrollment in Part 2, patients who become pregnant must discontinue the study, exclusion criterion 10 to explain that total abstinence should be considered only “when this is in line with the preferred and usual lifestyle of the subject”, the word “non-malignant” was deleted because it is incorrectly associated to Squamous cell carcinoma/keratoacanthoma lesions. Molecular pre-screening was modified to clarify that for patients in the US, for whom BRAF status is assessed during molecular pre-screening, an FDA-approved BRAF assay must be used.

04 Sep 2015

This amendment provides guidance to investigators on management of toxicities for BKM120, INC280 and LEE011, provides additional guidance to investigators around management of liver toxicities for BKM12, and documents a change in study sponsorship from Novartis to Array BioPharma. A decision was taken on 10 July 2015 to halt further recruitment to the BKM120 arm, which was communicated to Health Authorities and sites. Pharmacokinetic analysis of the patients already treated with triple combination LGX818 (encorafenib), MEK162 (binimetinib) and BKM120 has shown a significant drug-drug interaction (DDI) between LGX818 and BKM120. The BKM120 exposure in triple combination was found to be substantially reduced, by up to 80% compared to single agent BKM120 based on the preliminary PK analysis. Based on this observed DDI between LGX818 and BKM120, reaching efficacious exposures of BKM120 is unlikely with the current doses of LGX818 and MEK162. Guidance to investigators for the management of liver toxicities when taking INC280 has also been provided. Based on the preclinical data which suggest photosensitization potential for INC280, precautionary measures against ultraviolet exposure are being included in this amendment. The dose modification guidelines for QTcF prolongation specificity for monitoring and dose adjustment to better manage patient safety in patients taking LEE011 has been updated. The protocol has been amended to update the guidelines for the management of hepatic toxicity for patients treated with LEE011. Patients who do not tolerate triple therapy will be allowed to be rechallenged with dual therapy after discussion with Sponsor Medical Monitor and provides clarification regarding antineoplastic therapy. Concomitant medications to be used with caution, Non-clinical, and clinical PK data have been updated.

02 Feb 2016

This amendment is to provide additional information and guidance to investigators for management of liver toxicities for the INC280 combination. Clarifications in the dose modification guidelines in case of liver toxicity, updated rules with regards to study treatment discontinuation for events that meet the Hy’s Law criteria and specific work-up guidelines for potential drug-induced liver injury (DILI) cases are added in the protocol. Patients with increased AST/ALT and total bilirubin (TBIL) values that may be indicative of potential DILI, should be considered as clinically important events; therefore, specific guidance for actions to be taken on study treatment (e.g. discontinuation) and for monitoring of liver function tests (LFTs) have been implemented and clarified. In addition, this protocol is amended to include the following serious adverse event (SAE): a female patient experienced a serious, unexpected, possibly related adverse event (AE) of abnormal LFTs during treatment with a combination of INC280 and gefitinib while enrolled in the [CINC280X2202] study (Initial Investigator Notification Letter issued 12 March 2015). The investigator assessed the AE as suspected to be related to the combination of INC280 and gefitinib. This AE met the criteria of Hy’s Law and the hepatotoxicity could not be attributed solely to either drug alone or to the combination. This amendment also introduces the use of INC280 tablets with different dosage strengths (100 mg and 200 mg, instead of 50 mg and 200 mg) in order to improve the convenience of study drug administration for patients. Related to this, the protocol also allows for intra-patient crossover from the capsule formulation to the tablet formulation once the capsule formulation is no longer available. The eligibility criteria for amylase and lipase have been updated to be consistent across the different INC280 studies. The list of prohibited and concomitant medications to be used with caution has been updated.

19 Oct 2017

As of 12 September 2017, 27 patients in the CLGX818X2109 study (25 in Part I and 2 in Part II [both on LGX818/ MEK162/LEE011 combination]), were continuing to derive benefit from study treatment. In order to minimize the burden on the patients and to reduce their radiation exposure, this amendment allows the frequency of tumor assessments in all Part I continuing patients to be reduced to every 6-12 weeks based on Investigator discretion. Patients may be transitioned to this less frequent imaging schedule once they have completed ≥ 24 months of study treatment in Part I and the Run-in phase. In addition, this protocol is also being amended to change the frequency and type of ophthalmologic examinations. In a separate Phase 3 study (CMEK162B2301; ClinicalTrials.gov identifier NCT01909453) in patients with BRAF V600-mutant melanoma treated with the combination of LGX818 (450 mg once daily [QD]) plus MEK162 (45 mg twice daily [BID]), the median time to onset of retinopathy excluding retinal vein occlusion (in patients with at least one event) was 0.2 months (95% confidence interval [CI] 0.1, 0.9) and there were no patients with a new onset event after 24 months. Based on these findings, and in order to minimize the burden on patients who continue to derive benefit from study treatment, this amendment allows patients who have been receiving study treatment ≥ 24 months in Part I and the Run-in phase and who have not had a retinal adverse event (AE) to be evaluated only for visual acuity at each scheduled patient visit (Day 15 of all cycles) with a full ophthalmic examination required every 12 weeks (i.e., every 4 cycles) or more frequently if clinically indicated, and at End of Study Treatment visit. Additional revisions have been to sections of the protocol that are specific to the Part II triple combination arm with LEE011 in order to reflect recent clinical development changes pertaining to patient selection and dose modification.

26 Mar 2019

As of the release date of this amendment, 17 patients in the CLGX818X2109 study (16 in Part I and 1 in Part II [LGX818/MEK162/LEE011]) were receiving study treatment. There are no patients ongoing in the Part II triple combination arms with INC280, BGJ398, or BKM120. The protocol is being amended to discontinue enrollment to the triple combination arms containing INC280 and BGJ398 due to the lack of efficacy in these arms and because there is no interest in further clinical development of these combinations. The BKM120 combination was closed on 10 July 2015 due to a significant drug-drug interaction (DDI) between LGX818 and BKM120 (Amendment 3). There have been no responses observed in 13 patients treated in the INC280 arm or in the single patient treated in the BGJ398 arm.

16 Dec 2019

In June 2018, encorafenib (LGX818) 450 mg orally QD, in combination with binimetinib (MEK162) 45 mg orally BID, received marketing approval in the United States and several jurisdictions for the treatment of patients with unresectable or metastatic BRAF V600-mutant melanoma with subsequent regulatory approvals in the European Union and Japan. This approval was based on the randomized Phase 3 COLUMBUS Study (CMEK162B2301). At this stage of development, the toxicity profile of encorafenib in combination with binimetinib has been well established. As all patients who continue to receive encorafenib and binimetinib under this study protocol have been treated for a minimum of 3 years, this protocol has been amended to reduce the frequency of safety assessments to align with study centers’ institutional standards for patients with BRAF V600-mutant locally advanced unresectable or metastatic melanoma. As of the release date of this amendment, 13 patients in the Part I of Study CLGX818X2109 were receiving study treatment with encorafenib and binimetinib. There are no patients receiving treatment in the Part II triple combination arm with LEE011. The protocol has also been amended to discontinue enrollment to the triple combination arm containing LEE011 due to the limited efficacy and minimal interest in further clinical development of this combination. The BKM120 combination was closed on 10 July 2015 due to a significant drug-drug interaction (DDI) between LGX818 and BKM120 (Amendment 03) and the INC280 and BGJ398 arms were closed in Amendment 06 due to the lack of responses observed in the 13 patients treated in the INC280 arm or in the single patient treated in the BGJ398 arm.

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: The LOGIC 2 Trial A Phase II, Multi-Center, Open-Label Study Of Sequential LGX818/MEK162 Combination Followed By A Rational Combination With Targeted Agents After Progression, To Overcome Resistance In Adult Patients With Locally Advanced Or Metastatic BRAF V600 Melanoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall Response Rate (ORR): Part II

Primary: Overall Response Rate (ORR): Part II

Secondary: Number of Subjects With Adverse Events (AEs) and Serious AEs (SAEs): Part I

Secondary: Number of Subjects With Adverse Events (AEs) and Serious AEs (SAEs): Part I

Secondary: Number of Subjects With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II

Secondary: Number of Subjects With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II

Secondary: Number of Subjects With AEs and SAEs: Part II

Secondary: Number of Subjects With AEs and SAEs: Part II

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part I

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part I

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on CTCAE Grade: Part II

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on CTCAE Grade: Part II

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part I

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part I

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part II

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part II

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part I

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part I

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part II

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part II

Secondary: Number of Subjects With Notable Electrocardiograms (ECG) Values: Part I

Secondary: Number of Subjects With Notable Electrocardiograms (ECG) Values: Part I

Secondary: Number of Subjects With Notable ECG Values: Part II

Secondary: Number of Subjects With Notable ECG Values: Part II

Secondary: Number of Subjects With At least One Dose Interruption: Part I

Secondary: Number of Subjects With At least One Dose Interruption: Part I

Secondary: Number of Subjects With At least One Dose Interruption: Part II

Secondary: Number of Subjects With At least One Dose Interruption: Part II

Secondary: Number of Subjects With At least One Dose Reduction: Part I

Secondary: Number of Subjects With At least One Dose Reduction: Part I

Secondary: Number of Subjects With At least One Dose Reduction: Part II

Secondary: Number of Subjects With At least One Dose Reduction: Part II

Secondary: Actual Dose Intensity: Part I

Secondary: Actual Dose Intensity: Part I

Secondary: Actual Dose Intensity: Part II

Secondary: Actual Dose Intensity: Part II

Secondary: PFS: Part II

Secondary: PFS: Part II

Secondary: Duration of Response (DOR): Part I

Secondary: Duration of Response (DOR): Part I

Secondary: Progression-Free Survival (PFS): Part I

Secondary: Progression-Free Survival (PFS): Part I

Secondary: TTR: Part II

Secondary: TTR: Part II

Secondary: DOR: Part II

Secondary: DOR: Part II

Secondary: Time to Response (TTR): Part I

Secondary: Time to Response (TTR): Part I

Secondary: Overall Survival (OS): Part II

Secondary: Overall Survival (OS): Part II

Secondary: DCR: Part II

Secondary: DCR: Part II

Secondary: Disease Control Rate (DCR): Part I

Secondary: Disease Control Rate (DCR): Part I

Secondary: Summary of Genomic Biomarkers From Tumor Samples: Part I

Secondary: Summary of Genomic Biomarkers From Tumor Samples: Part I

Secondary: Plasma Concentration for Encorafenib (LGX): Part I

Secondary: Plasma Concentration for Encorafenib (LGX): Part I

Secondary: Plasma Concentration for Encorafenib (LGX): Part II

Secondary: Plasma Concentration for Encorafenib (LGX): Part II

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part I

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part I

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part II

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part II

Secondary: Plasma Concentration for Ribociclib (LEE) and its Metabolite: Part II

Secondary: Plasma Concentration for Ribociclib (LEE) and its Metabolite: Part II

Secondary: Plasma Concentration for Infigratinib (BGJ) and its Metabolites: Part II

Secondary: Plasma Concentration for Infigratinib (BGJ) and its Metabolites: Part II

Secondary: Plasma Concentration for Capmatinib (INC): Part II

Secondary: Plasma Concentration for Capmatinib (INC): Part II

Clinical Trial Results:
The LOGIC 2 Trial A Phase II, Multi-Center, Open-Label Study Of Sequential LGX818/MEK162 Combination Followed By A Rational Combination With Targeted Agents After Progression, To Overcome Resistance In Adult Patients With Locally Advanced Or Metastatic BRAF V600 Melanoma