Download PDF

Clinical Trial Results:
A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-Mutant Melanoma Brain Metastasis

Summary
EudraCT number	2018-004555-21
Trial protocol	BE NL IT
Global end of trial date	02 Jun 2021

Results information
Results version number	v1(current)
This version publication date	15 Jan 2023
First version publication date	15 Jan 2023
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

C4221006

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Other trial identifiers

Alias ID: ARRAY-818-201

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

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

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, 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

05 Jul 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Jun 2021

Was the trial ended prematurely?

Yes

Main objective of the trial

Safety Lead-in: Evaluate the safety of a high-dose regimen of encorafenib + binimetinib combination therapy in subjects with BRAFV600-mutant melanoma who had asymptomatic brain metastasis. Phase 2: 1) If the high-dose regimen was determined to be safe based on results of the Safety Lead-in phase, then evaluate the antitumor activity in brain metastases of the standard and high dose regimens of encorafenib + binimetinib combination therapy in subjects with BRAFV600-mutant melanoma who had asymptomatic brain metastasis; 2) If the high-dose regimen was determined not to be safe based on the results of the Safety Lead-in phase, then evaluate the antitumor activity in brain metastases of the standard dosing regimen of encorafenib + binimetinib combination in subjects with BRAFV600-mutant melanoma who have asymptomatic brain metastasis.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Apr 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 2

Country: Number of subjects enrolled

Australia: 1

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Italy: 1

Country: Number of subjects enrolled

United States: 8

Worldwide total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Study had 2 parts, Safety lead-in (SLI) and Phase 2. In Phase 2, subjects would be randomised either to the standard-dose or high-dose treatment, only if high dose was determined to be safe in safety lead-in.

Screening details

Pfizer and the Steering Committee reviewed safety lead-in data and decided not to evaluate high dose combination of encorafenib + binimetinib in Phase 2 of the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID

Arm description

Subjects diagnosed with BRAFV600-mutant melanoma brain metastasis received combination therapy of encorafenib (300 milligram [mg] orally, twice daily [BID]) and binimetinib (45 mg orally, BID) in 28-day cycles and continued until disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent anticancer therapy, or death, whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

Arm type

Experimental

Investigational medicinal product name

Encorafenib + Binimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received Encorafenib 300 mg BID and Binimetinib 45 mg BID in 28 days cycle.

Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID

Arm description

Subjects diagnosed with BRAFV600-mutant melanoma brain metastasis received standard combination therapy of encorafenib (450 mg orally, once daily [QD]) and binimetinib (45 mg orally, BID) in 28-day cycles and subjects who were able to tolerate the encorafenib 450 mg dose further received 600 mg QD after 4 Weeks. Subjects were followed up to 30 days after last dose of study drug.

Arm type

Experimental

Investigational medicinal product name

Encorafenib + Binimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received Encorafenib 450 mg QD and Binimetinib 45 mg BID in 28 days cycle.

Number of subjects in period 1	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Started	10	3
Completed	0	0
Not completed	10	3
Death	7	3
Unspecified	1	-
Study termination by sponsor	2	-

Baseline characteristics

Top of page

Reporting group title

SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID

Reporting group description

Reporting group title

Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID

Reporting group description

Reporting group values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID	Total
Number of subjects	10	3	13
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	5	3	8
From 65-84 years	5	0	5
85 years and over	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	63.2 ( 12.94 )	45.7 ( 5.86 )	-
Sex: Female, Male
Units: Subjects
Female	2	1	3
Male	8	2	10
Race
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	0	0
White	9	3	12
More than one race	0	0	0
Unknown or Not Reported	1	0	1
Ethnicity
Units: Subjects
Hispanic or Latino	2	1	3
Not Hispanic or Latino	8	2	10
Unknown or Not Reported	0	0	0

End points

Top of page

Reporting group title

SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID

Reporting group description

Reporting group title

Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID

Reporting group description

Primary: Number of Subjects With Dose Limiting Toxicities (DLTs): Safety Lead-in (SLI) Phase

Top of page

End point title

Number of Subjects With Dose Limiting Toxicities (DLTs): Safety Lead-in (SLI) Phase ^[1] ^[2]

End point description

DLT: any adverse event (AE) or laboratory abnormality not explained by underlying disease/disease progression/intercurrent illness/concomitant therapies/resulting in inability to tolerate 75% of planned dose of binimetinib or encorafenib during Cycle 1. LVEF >10%, Grade (G)>=3 cardiac disorders; G3/4 hypertension vascular disorders; G3/4 rash,hand foot skin reaction, photosensitivity; G3/4 diarrhea, nausea/vomiting; Total bilirubin (TBL) G>=3 (>3.0*upper limit of normal [ULN)]);AST/ALT>5-8*ULN>5 days,>8*ULN,>3*ULN concurrent TBL>2*ULN;G>=3 serum creatinine, CK elevation, ECG QTcF prolonged,G3 troponin, electrolyte>72 hours,G3/4 amylase/lipase.G4 ANC, platelet count>7 days;G3/4 platelet count, other AE except lymphopenia. G>=3 retinopathy, other disorder>21 days; G2 uveitis/eye pain/blurred vision/decreased visual acuity; G4 other disorder; Other hematologic/non hematologic G>=3 AE. This endpoint was planned to be analysed in SLI phase only. Dose-determining set included.

End point type

Primary

End point timeframe

Cycle 1 of safety lead-in phase (up to 28 days)

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 analysed for this endpoint.
[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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	9
Units: Subjects	3

No statistical analyses for this end point

Primary: Number of Subjects With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase

Top of page

End point title

Number of Subjects With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase ^[3] ^[4]

End point description

AE:any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship.TEAEs: events between 1st dose of study drug up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state or start of subsequent anticancer drug therapy-1 day, whichever occurred first. Grades by NCI CTCAE v.4.03: G1=asymptomatic or mild ,clinical or diagnostic observations only,intervention not indicated; G2=moderate,minimal,local/noninvasive intervention indicated,limiting age-appropriate instrumental activities of daily life (ADL); G3=severe or medically significant but not immediately life-threatening,hospitalisation or prolongation of existing hospitalisation indicated,disabling,limiting self-care ADL; G4=life-threatening consequence,urgent intervention indicated; G5=death related to AE. Subjects with AEs per maximum grades were reported.Safety set:all subjects who received at least 1 dose of any study drug.

End point type

Primary

End point timeframe

Day 1 of dosing up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analysed for this endpoint.
[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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	10
Units: Subjects
Grade 1	1
Grade 2	3
Grade 3	5
Grade 4	1
Grade 5	0

No statistical analyses for this end point

Primary: Number of Subjects With Hepatology Laboratory Test Abnormalities: SLI Phase

Top of page

End point title

Number of Subjects With Hepatology Laboratory Test Abnormalities: SLI Phase ^[5] ^[6]

End point description

Hepatology laboratory abnormalities included following parameters: alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT or AST greater than or equal to (>=) 3*upper limit normal (ULN), >=5*ULN, >=10*ULN, >=20*ULN; total bilirubin (TBILI): >=2*ULN; ALT >=3*ULN and TBILI >=2*ULN; AST >=3*ULN and TBILI >=2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN and ALP >2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN and ALP <=2*ULN or missing. Only those laboratory test parameters in which at least 1 subject had data were reported. The safety set included all subjects who received at least 1 dose of any study drug. This endpoint was planned to be analysed in SLI phase only.

End point type

Primary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Notes
[5] - 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 analysed for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	10
Units: Subjects
ALT: >=3*ULN	3
ALT: >=5*ULN	1
AST: >=3*ULN	3
ALT or AST: >=3*ULN	3
ALT or AST: >=5*ULN	1

No statistical analyses for this end point

Primary: Number of Subjects With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase

Top of page

End point title

Number of Subjects With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase ^[7] ^[8]

End point description

Hematology and coagulation laboratory test included: activated partial thromboplastin time prolonged (APTTP), anemia, hemoglobin (Hg) increased (inc), international normalised ratio (INR) increased, leukocytosis (Lkc), lymphocyte count decreased (LCD), lymphocyte count increased (LCI), neutrophil count decreased (NCD), platelet count decreased (PCD), and white blood cell decreased (WBCD). Laboratory results were categorically summarised according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Number of subjects with shift from baseline for hematology and coagulation laboratory test were assessed. Only those laboratory test parameters in which at least 1 subject had data were reported. The safety set included all subjects who received at least 1 dose of any study drug. Here, "n" signifies subjects evaluable for specified rows.

End point type

Primary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Notes
[7] - 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 analysed for this endpoint.
[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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	10
Units: Subjects
APTTP: G0 (baseline) to G0 (post-baseline), n=6	5
APTTP: G0 (baseline) to G1 (post-baseline), n=6	1
Anemia: G0 (baseline) to G0 (post-baseline), n=10	2
Anemia: G0 (baseline) to G1 (post-baseline), n=10	7
Anemia: G0 (baseline) to G2 (post-baseline), n=10	1
Hg inc: G0 (baseline) to G0 (post-baseline), n=10	10
INR inc: G0 (baseline) to G0 (post-baseline), n=10	10
Lkc: G0 (baseline) to G0 (post-baseline), n=10	10
LCD: G0 (baseline) to G0 (post-baseline), n=9	2
LCD: G0 (baseline) to G1 (post-baseline), n=9	2
LCD: G0 (baseline) to G2 (post-baseline), n=9	2
LCD: G0 (baseline) to G3 (post-baseline), n=9	3
LCI: G0 (baseline) to G0 (post-baseline), n=9	8
LCI: G0 (baseline) to G2 (post-baseline), n=9	1
NCD: G0 (baseline) to G0 (post-baseline), n=9	8
NCD: G0 (baseline) to G2 (post-baseline), n=9	1
PCD: G0 (baseline) to G0 (post-baseline), n=10	7
PCD: G0 (baseline) to G1 (post-baseline), n=10	3
WBCD: G0 (baseline) to G0 (post-baseline), n=10	8
WBCD: G0 (baseline) to G2 (post-baseline), n=10	2

No statistical analyses for this end point

Primary: Number of Subjects With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase

Top of page

End point title

Number of Subjects With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase ^[9] ^[10]

End point description

Biochemistry laboratory test included:alanine aminotransferase increased (AAI),alkaline phosphatase increased (API),aspartate aminotransferase increased (AsAI),blood bilirubin increased (BBI),creatine kinase increased (CKI), creatinine increased (CrI),hypercalcemia (hypercal),hyperglycemia (hypergly),hyperkalemia (hyperkal),hypermagnesemia (hypermag),hypernatremia (hypernat),hypoalbuminemia (hypoalb),hypocalcemia (hypocal),hypoglycemia (hypogly),hypokalemia (hypokal),hypomagnesemia (hypomag),hyponatremia (hyponat),hypophosphatemia (hypophos),lipase increased (LI), and serum amylase increased (SMI).Laboratory results were categorically summarised according to the NCI-CTCAE criteria v4.03.G1= mild;G2= moderate;G3= severe,G4= life-threatening or disabling.Number of subjects with shift from baseline for biochemistry lab test were assessed. Only those lab test parameters in which at least 1 subject had data were reported.Safety set included. Here, n=subjects evaluable for specified rows.

End point type

Primary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Notes
[9] - 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 analysed for this endpoint.
[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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	10
Units: Subjects
AAI: G0 (baseline) to G0 (post-baseline), n=8	2
AAI: G0 (baseline) to G1 (post-baseline), n=8	3
AAI: G0 (baseline) to G2 (post-baseline), n=8	2
AAI: G0 (baseline) to G3 (post-baseline), n=8	1
AAI: G1 (baseline) to G1 (post-baseline), n=2	2
API: G0 (baseline) to G0 (post-baseline), n=8	5
API: G0 (baseline) to G1 (post-baseline), n=8	3
API: G1 (baseline) to G0 (post-baseline), n=2	2
AsAI: G0 (baseline) to G0 (post-baseline), n=8	4
AsAI: G0 (baseline) to G1 (post-baseline), n=8	2
AsAI: G0 (baseline) to G2 (post-baseline), n=8	2
AsAI: G1 (baseline) to G0 (post-baseline), n=2	1
AsAI: G1 (baseline) to G1 (post-baseline), n=2	1
BBI: G0 (baseline) to G0 (post-baseline), n=10	10
CKI: G0 (baseline) to G0 (post-baseline), n=10	6
CKI: G0 (baseline) to G1 (post-baseline), n=10	3
CKI: G0 (baseline) to G4 (post-baseline), n=10	1
CrI: G0 (baseline) to G1 (post-baseline), n=10	9
CrI: G0 (baseline) to G2 (post-baseline), n=10	1
Hypercal: G0(baseline) to G0(post-baseline),n=10	10
Hypergly:G0(baseline) to G0 (post-baseline),n=8	5
Hypergly: G0(baseline) to G1(post-baseline),n=8	1
Hypergly: G0(baseline) to G3(post-baseline),n=8	2
Hypergly:Baseline to post-baseline,n=2	1
Hypergly:Missing(baseline)toG1 (post-baseline)n=2	1
Hyperkal:G0(baseline) to G0(post-baseline),n=10	10
Hypermag:G0(baseline) to G0(post-baseline),n=10	9
Hypermag:G0(baseline) to G1(post-baseline),n=10	1
Hypernat:G0(baseline) to G0(post-baseline),n=10	10
Hypoalb:G0(baseline) to G0(post-baseline),n=9	6
Hypoalb:G0(baseline) to G1(post-baseline),n=9	3
Hypoalb:G2(baseline) to G2(post-baseline),n=1	1
Hypocal:G0(baseline) to G0(post-baseline),n=10	8
Hypocal:G0(baseline) to G1(post-baseline),n=10	2
Hypogly:G0(baseline) to G0(post-baseline),n=10	10
Hypokal:G0(baseline) to G0(post-baseline),n=10	10
Hypomag:G0(baseline) to G0(post-baseline),n=10	10
Hyponat:G0(baseline) to G0(post-baseline),n=8	3
Hyponat:G0(baseline) to G1(post-baseline),n=8	2
Hyponat:G0(baseline) to G3(post-baseline),n=8	3
Hyponat:G1(baseline) to G0(post-baseline),n=2	1
Hyponat:G1(baseline) to G3(post-baseline),n=2	1
Hypophos:G0(baseline)toG0(post-baseline),n=7	6
Hypophos:G0(baseline)toG2(post-baseline),n=7	1
Hypophos:Missing(baseline)toG0(post-baseline),n=2	1
Hypophos:Missing(baseline)toG2(post-baseline),n=2	1
LI: G0(baseline) to G0(post-baseline), n=10	7
LI: G0(baseline) to G1(post-baseline), n=10	3
SMI: G0(baseline) to G0(post-baseline), n=10	10

No statistical analyses for this end point

Primary: Number of Subjects With Notable Abnormal Vital Signs: SLI Phase

Top of page

End point title

Number of Subjects With Notable Abnormal Vital Signs: SLI Phase ^[11] ^[12]

End point description

Vital signs:systolic & diastolic blood pressure (BP),pulse rate,weight & temperature.Systolic & diastolic BP was measured in millimeters of mercury (mmHg) based on criteria: High Systolic BP:>=160 mmHg & increase>=20 mmHg from baseline; High Diastolic BP:>=100 mmHg & increase>=15 mmHg from baseline; Low Systolic BP:<=90 mmHg with decrease from baseline of >=20 mmHg; Low Diastolic BP:<=50 mmHg with decrease from baseline of >=15 mmHg; Pulse rate was measured in beats per minute (bpm) based on criteria:High pulse rate>=120 bpm with increase from baseline of >=15 bpm;Low pulse rate <=50 bpm with decrease from baseline of >=15 bpm;Weight was measured in in kilogram (kg) based on criteria:Increase from baseline of >=10%,:>=20% decrease from baseline; Temperature was measured in degree Celsius (C) based on criteria:High body temperature>=37.5 degree C,Low body temperature<=36 degree C.Only those vital signs parameters in which at least 1 subject had data were reported.Safety set included.

End point type

Primary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Notes
[11] - 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 analysed for this endpoint.
[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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	10
Units: Subjects
High systolic BP	2
Low diastolic BP	1
High pulse rate	1
Low pulse rate	1
Increased body weight	2
High body temperature	1
Low body temperature	3

No statistical analyses for this end point

Primary: Number of Subjects With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase

Top of page

End point title

Number of Subjects With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase ^[13] ^[14]

End point description

In this endpoint, number of subjects with notable abnormal ECG values included: Fridericia's Correction Formula (QTcF) values in millisecond (msec) based on following criteria: 1) Increase from baseline >30 msec; 2) Increase from baseline >60 msec; 3) New >450 msec; 4) New >480 msec; and 5) New >500 msec; heart rate (HR) values in bpm based on following criteria: 1) Increase from baseline >25% and to a value >100; 2) Decrease from baseline >25% and to a value <50. Only those ECG parameters in which at least 1 subject had data were reported. The safety set included all subjects who received at least 1 dose of any study drug. This endpoint was planned to be analysed in phase 2 only.

End point type

Primary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Notes
[13] - 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 analysed for this endpoint.
[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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	10
Units: Subjects
QTcF: New >450 msec	6
QTcF:Increase from baseline >30 msec	5
HR:Increase from baseline >25% & to a value >100	1

No statistical analyses for this end point

Primary: Number of Subjects With Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to AEs: SLI Phase

Top of page

End point title

Number of Subjects With Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to AEs: SLI Phase ^[15] ^[16]

End point description

An AE is any untoward medical occurrence in clinical investigation subject administered a product or medical device; event need not necessarily to have a causal relationship with treatment or usage. In this endpoint, number of subjects with incidence of dose interruptions, dose modifications and discontinuations due to AEs were reported. The safety set included all subjects who received at least 1 dose of any study drug. This endpoint was planned to be analysed in SLI phase only.

End point type

Primary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Notes
[15] - 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 analysed for this endpoint.
[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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	10
Units: Subjects
Dose interruptions due to AE	6
Dose modifications due to AE	4
Discontinuations due to AE	1

No statistical analyses for this end point

Primary: Brain Metastasis Response Rate (BMRR) Based on Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST v1.1): Phase 2

Top of page

End point title

Brain Metastasis Response Rate (BMRR) Based on Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST v1.1): Phase 2 ^[17] ^[18]

End point description

BMRR was reported in terms of percentage of subjects who achieved a confirmed best overall response (BOR) of confirmed complete response (CR) or partial response (PR) in brain metastasis per mRECIST v1.1 from date of first dose until disease progression, death due to any cause, or start of subsequent anticancer therapy, whichever occurred first. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have absolute increase of at least 5 mm. The safety set included all subjects who received at least 1 dose of any study drug.

End point type

Primary

End point timeframe

From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in Phase 2 (approximately up to 8.3 months)

Notes
[17] - 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 analysed for this endpoint.
[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: Only Phase 2 arm was planned to be analysed for this endpoint.

End point values	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	3
Units: Percentage of subjects
number (confidence interval 95%)	66.7 (9.4 to 99.2)

No statistical analyses for this end point

Secondary: Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2

Top of page

End point title

Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2

End point description

Extracranial response rate was defined as the percentage of subjects with a BOR of confirmed CR or confirmed PR in extracranial lesions by investigator assessment per RECIST v1.1. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have absolute increase of at least 5 mm. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The safety set included all subjects who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	10	3
Units: Percentage of subjects
number (confidence interval 95%)	60.0 (26.2 to 87.8)	100 (29.2 to 100)

No statistical analyses for this end point

Secondary: Global Response Rate: SLI Phase and Phase 2

Top of page

End point title

Global Response Rate: SLI Phase and Phase 2

End point description

Global response rate was defined as the percentage of subjects with a BOR of confirmed CR or confirmed PR by investigator assessment in brain metastasis and extracranial lesions per combined mRECIST v1.1 and RECIST v1.1, respectively. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. Any pathological lymph nodes must be <10 mm on the short axis. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline). PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have absolute increase of at least 5 mm. The safety set included all subjects who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	10	3
Units: Percentage of subjects
number (confidence interval 95%)	50.0 (18.7 to 81.3)	100 (29.2 to 100)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2

Top of page

End point title

Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2

End point description

DCR was defined as the percentage of subjects with a BOR of CR, PR or stable disease (SD) by investigator assessment per mRECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started. The safety set included all subjects who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	10	3
Units: Percentage of subjects
number (confidence interval 95%)	100 (69.2 to 100)	100 (29.2 to 100)

No statistical analyses for this end point

Secondary: DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2

Top of page

End point title

DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2

End point description

DCR was defined as the percentage of subjects with a BOR of CR, PR or SD by Investigator assessment per RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum demonstrates an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. The safety set included all subjects who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	10	3
Units: Percentage of subjects
number (confidence interval 95%)	70.0 (34.8 to 93.3)	100 (29.2 to 100)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2

Top of page

End point title

Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2

End point description

DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have absolute increase of at least 5 mm. DOR (months)=(date of event or censoring – date of first CR or PR + 1)/30.4375. If subject with CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, subject was censored on date of last adequate tumor assessment that documented no progression. Safety set included all subjects who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

From date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	10	3
Units: Months
median (confidence interval 95%)	3.3 (2.8 to 8.5)	5.6 (5.0 to 6.2)

No statistical analyses for this end point

Secondary: DCR for Global Response: SLI Phase and Phase 2

Top of page

End point title

DCR for Global Response: SLI Phase and Phase 2

End point description

DCR was defined as the percentage of subjects with a BOR of CR, PR or SD by Investigator assessment per RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must be <10 mm on the short axis. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline). SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to quality for PD. PD: at least a 20% increase in the sum of the diameters of target lesions, taking as a reference the smallest sum of diameters recorded since the treatment started (i.e., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of at least 5 mm. The safety set included all subjects who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	10	3
Units: Percentage of subjects
number (confidence interval 95%)	90.0 (55.5 to 99.7)	100 (29.2 to 100)

No statistical analyses for this end point

Secondary: DOR for Global Response: SLI Phase and Phase 2

Top of page

End point title

DOR for Global Response: SLI Phase and Phase 2

End point description

DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have absolute increase of at least 5 mm. DOR (months) = (date of event or censoring – date of first CR or PR + 1)/30.4375. If a subject with CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, subject was censored on date of last adequate tumor assessment that documented no progression. Safety set included all subjects who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	10	3
Units: Months
median (confidence interval 95%)	2.9 (2.8 to 8.5)	5.0 (3.9 to 6.2)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2

Top of page

End point title

Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2

End point description

PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression (PD) by Investigator assessment, or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase of at least 5 mm. If a subject did not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. Data for this endpoint was not evaluated, due to limited number of subjects who had event.

End point type

Secondary

End point timeframe

From date of first dose of study treatment to the earliest documented disease progression by investigator assessment, or death due to any cause, whichever occurs first in SLI (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	0 ^[19]	0 ^[20]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[19] - Data was not evaluated, due to limited number of subjects who had event.
[20] - Data was not evaluated, due to limited number of subjects who had event.

No statistical analyses for this end point

Secondary: DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2

Top of page

End point title

DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2

End point description

DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have absolute increase of at least 5 mm. DOR (months) = (date of event or censoring – date of first CR or PR + 1)/30.4375. If a subject with CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, subject was censored on date of last adequate tumor assessment that documented no progression. Data for this endpoint was not evaluated, due to limited number of subjects who had event.

End point type

Secondary

End point timeframe

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	0 ^[21]	0 ^[22]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[21] - Data was not evaluated, due to limited number of subjects who had event.
[22] - Data was not evaluated, due to limited number of subjects who had event.

No statistical analyses for this end point

Secondary: PFS for Global Tumor Assessment: SLI Phase and Phase 2

Top of page

End point title

PFS for Global Tumor Assessment: SLI Phase and Phase 2

End point description

PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression (PD) by Investigator assessment, or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of the diameters of target lesions, taking as a reference the smallest sum of diameters recorded since the treatment started (i.e., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of at least 5 mm. Global tumor assessment consists of brain metastasis and extracranial lesions. If a subject did not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. Data for this outcome measure was not evaluated, due to limited number of subjects who had event.

End point type

Secondary

End point timeframe

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	0 ^[23]	0 ^[24]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[23] - Data was not evaluated, due to limited number of subjects who had event.
[24] - Data was not evaluated, due to limited number of subjects who had event.

No statistical analyses for this end point

Secondary: BMRR Based on mRECIST v1.1: SLI Phase

Top of page

End point title

BMRR Based on mRECIST v1.1: SLI Phase ^[25]

End point description

BMRR: percentage of subjects who achieved a confirmed best overall response (BOR) of confirmed CR or PR in brain metastasis per mRECIST v1.1 from date of first dose until disease progression, death due to any cause, or start of subsequent anticancer therapy, whichever occurs first. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: Disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters (e.g., percent change from baseline). The safety set included all subjects who received at least 1 dose of any study drug. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months)

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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	10
Units: Percentage of subjects
number (confidence interval 95%)	60.0 (26.2 to 87.8)

No statistical analyses for this end point

Secondary: Overall Survival: Safety Lead-in Phase and Phase 2

Top of page

End point title

Overall Survival: Safety Lead-in Phase and Phase 2

End point description

Overall survival (OS) was defined as the time from date of the first dose of study treatment to the date of death due to any cause. If a death was not observed by the date of the analysis cutoff, OS was censored at the date of last contact. OS (months) = (date of death or censoring – date of first dose +1)/30.4375. Data for this endpoint was not evaluated, due to limited number of subjects who had event.

End point type

Secondary

End point timeframe

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	0 ^[26]	0 ^[27]
Units: Months
arithmetic mean (standard deviation)	( )	( )

Notes
[26] - Data was not evaluated, due to limited number of subjects who had event.
[27] - Data was not evaluated, due to limited number of subjects who had event.

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2

Top of page

End point title

Number of Subjects With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2 ^[28]

End point description

AE: any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. TEAEs: event between 1st dose of study drug up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state or start of subsequent anticancer drug therapy 1 day, whichever occurred first. Grades by NCI CTCAE v.4.03: G1=asymptomatic or mild, clinical or diagnostic observations only,intervention not indicated;G2=moderate, minimal,local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL); G3=severe or medically significant but not immediately life-threatening, hospitalisation or prolongation of existing hospitalisation indicated,disabling,limiting self-care ADL; G4=life-threatening consequence,urgent intervention indicated; G5=death related to AE. Only those categories in which at least 1 subject had data were reported. Safety set:all subjects who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

Day 1 of dosing up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

Notes
[28] - 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: Only Phase 2 arm was planned to be analysed for this endpoint.

End point values	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	3
Units: Subjects
Grade 2	2
Grade 4	1

No statistical analyses for this end point

Secondary: Number of Subjects With Hepatology Laboratory Test Abnormalities: Phase 2

Top of page

End point title

Number of Subjects With Hepatology Laboratory Test Abnormalities: Phase 2 ^[29]

End point description

Hepatology laboratory abnormalities included following parameters: ALT, AST, ALT or AST >=3*ULN, >=5*ULN, >=10*ULN, >=20*ULN; TBILI: >=2*ULN; ALT >=3*ULN and TBILI >=2*ULN; AST >=3*ULN and TBILI >=2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN and ALP >2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN and ALP <=2*ULN or missing. Only those laboratory test parameters in which at least 1 subject had data were reported. The safety set included all subjects who received at least 1 dose of any study drug. This endpoint was planned to be analysed in phase 2 only.

End point type

Secondary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

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: Only Phase 2 arm was planned to be analysed for this endpoint.

End point values	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	3
Units: Subjects
ALT: >=3*ULN	2
ALT: >=5*ULN	1
ALT: >=10*ULN	1
ALT: >=20*ULN	1
AST: >=3*ULN	1
AST: >=5*ULN	1
AST: >=10*ULN	1
ALT or AST: >=3*ULN	2
ALT or AST: >=5*ULN	1
ALT or AST: >=10*ULN	1
ALT or AST: >=20*ULN	1

No statistical analyses for this end point

Secondary: Number of Subjects With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2

Top of page

End point title

Number of Subjects With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 ^[30]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

Notes
[30] - 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: Only Phase 2 arm was planned to be analysed for this endpoint.

End point values	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	3
Units: Subjects
APTTP: G0 (baseline) to G0 (post-baseline), n=1	1
Anemia: G0 (baseline) to G1 (post-baseline), n=2	1
Anemia: G0 (baseline) to G2 (post-baseline), n=2	1
Anemia: G1 (baseline) to G1 (post-baseline), n=1	1
Hg inc: G0 (baseline) to G0 (post-baseline), n=3	3
INR inc: G0 (baseline) to G0 (post-baseline), n=1	1
Lkc: G0 (baseline) to G0 (post-baseline), n=3	3
LCD: G0 (baseline) to G0 (post-baseline), n=3	2
LCD: G0 (baseline) to G1 (post-baseline), n=3	1
LCI: G0 (baseline) to G0 (post-baseline), n=3	3
NCD: G0 (baseline) to G0 (post-baseline), n=3	2
NCD: G0 (baseline) to G2 (post-baseline), n=3	1
PCD: G0 (baseline) to G0 (post-baseline), n=3	2
PCD: G0 (baseline) to G1 (post-baseline), n=3	1
WBCD: G0 (baseline) to G0 (post-baseline), n=3	2
WBCD: G0 (baseline) to G1 (post-baseline), n=3	1

No statistical analyses for this end point

Secondary: Number of Subjects With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2

Top of page

End point title

Number of Subjects With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 ^[31]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

Notes
[31] - 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: Only Phase 2 arm was planned to be analysed for this endpoint.

End point values	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	3
Units: Subjects
AAI: G0 (baseline) to G2 (post-baseline), n=1	1
AAI: G1 (baseline) to G0 (post-baseline), n=2	1
AAI: G1 (baseline) to G4 (post-baseline), n=2	1
API: G0 (baseline) to G0 (post-baseline), n=2	1
API: G0 (baseline) to G1 (post-baseline), n=2	1
API: G2 (baseline) to G2 (post-baseline), n=1	1
AsAI: G0 (baseline) to G1 (post-baseline), n=2	1
AsAI: G0 (baseline) to G3 (post-baseline), n=2	1
AsAI: G1 (baseline) to G0 (post-baseline), n=1	1
BBI: G0 (baseline) to G0 (post-baseline), n=3	3
CK inc: G0 (baseline) to G1 (post-baseline), n=3	2
CK inc: G0 (baseline) to G2 (post-baseline), n=3	1
CrI: G0 (baseline) to G1 (post-baseline), n=3	1
CrI: G0 (baseline) to G2 (post-baseline), n=3	2
Hypercal: G0 (baseline) to G0 (post-baseline), n=3	3
Hypergly: G0 (baseline) to G0 (post-baseline), n=3	3
Hyperkal: G0 (baseline) to G0 (post-baseline), n=3	3
Hypermag: G0 (baseline) to G0 (post-baseline), n=3	3
Hypernat: G0 (baseline) to G0 (post-baseline), n=3	3
Hypoalb: G0 (baseline) to G0 (post-baseline), n=2	2
Hypoalb: G1 (baseline) to G0 (post-baseline), n=1	1
Hypocal: G0 (baseline) to G0 (post-baseline), n=3	1
Hypocal: G0 (baseline) to G1 (post-baseline), n=3	2
Hypogly: G0 (baseline) to G0 (post-baseline), n=3	3
Hypokal: G0 (baseline) to G0 (post-baseline), n=3	2
Hypokal: G0 (baseline) to G1 (post-baseline), n=3	1
Hypomag: G0 (baseline) to G0 (post-baseline), n=3	3
Hyponat: G0 (baseline) to G0 (post-baseline), n=3	3
Hypophos: G0 (baseline) to G0 (post-baseline), n=3	3
LI: G0 (baseline) to G0 (post-baseline), n=3	2
LI: G0 (baseline) to G1 (post-baseline), n=3	1
SAI: G0 (baseline) to G0 (post-baseline), n=3	2
SAI: G0 (baseline) to G1 (post-baseline), n=3	1

No statistical analyses for this end point

Secondary: Number of Subjects With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2

Top of page

End point title

Number of Subjects With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2 ^[32]

End point description

Vital signs: systolic & diastolic BP, pulse rate, weight & temperature. Systolic & diastolic BP was measured in mmHg based on criteria: High Systolic BP:>=160 mmHg & increase>=20 mmHg from baseline; High Diastolic BP:>=100 mmHg & increase>=15 mmHg from baseline; Low Systolic BP:<=90 mmHg with decrease from baseline of >=20 mmHg; Low Diastolic BP:<=50 mmHg with decrease from baseline of >=15 mmHg; Pulse rate was measured in bpm based on criteria: High pulse rate>=120 bpm with increase from baseline of >=15 bpm; Low pulse rate <=50 bpm with decrease from baseline of >=15 bpm; Weight was measured in in kg based on criteria: Increase from baseline of >=10%,:>=20% decrease from baseline; Temperature was measured in degree C based on criteria: High body temperature>=37.5 degree C, Low body temperature<=36 degree C. Only those vital signs parameters in which at least 1 subject had data were reported. Safety set included.

End point type

Secondary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

Notes
[32] - 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: Only Phase 2 arm was planned to be analysed for this endpoint.

End point values	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	3
Units: Subjects
Increased body weight	1
Low body temperature	2

No statistical analyses for this end point

Secondary: Number of Subjects With Notable Abnormal Electrocardiogram (ECG) Values: Phase 2

Top of page

End point title

Number of Subjects With Notable Abnormal Electrocardiogram (ECG) Values: Phase 2 ^[33]

End point description

In this end point, number of subjects with notable abnormal ECG values included: QTcF values in msec based on following criteria: 1) increase from baseline >30 msec; 2) increase from baseline >60 msec; 3) new >450 msec; 4) new >480 msec; and 5) new >500 msec; heart rate values in bpm based on following criteria: 1) Increase from baseline >25% and to a value >100; 2) Decrease from baseline >25% and to a value <50. Only those vital ECG parameters in which at least 1 subject had data were reported. The safety set included all subjects who received at least 1 dose of any study drug. This endpoint was planned to be analysed in phase 2 only.

End point type

Secondary

End point timeframe

Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

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: Only Phase 2 arm was planned to be analysed for this endpoint.

End point values	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID
Number of subjects analysed	3
Units: Subjects
QTcF: Increase from baseline >30	1

No statistical analyses for this end point

Secondary: Plasma Concentrations of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Plasma Concentrations of Encorafenib and its Metabolite LHY746: SLI Phase ^[34]

End point description

In this end point, plasma concentrations (in nanogram per milliliter [ng/mL]) of encorafenib and its metabolite LHY746 at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), Cycle 2 Day 1 (C2D1), and Cycle 3 Day 1 (C3D1) at different time points were reported. The pharmacokinetic (PK) analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose, Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose, Cycle 2, Cycle 3 Day 1: Pre-dose

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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: ng/mL
geometric mean (geometric coefficient of variation)
Encorafenib C1D1: 0.5 hrs post dose, n=8	65.5 ( 328.8 )
Encorafenib C1D1: 1.5 hrs post dose, n=8	1830 ( 325.5 )
Encorafenib C1D1: 3 hrs post dose, n=8	2120 ( 36.3 )
Encorafenib C1D1: 6 hrs post dose, n=7	1170 ( 67.7 )
Encorafenib C1D15: pre-dose, n=6	92.3 ( 87.9 )
Encorafenib C1D15: 0.5 hrs post dose, n=6	182 ( 243.5 )
Encorafenib C1D15: 1.5 hrs post dose, n=6	745 ( 132.7 )
Encorafenib C1D15: 3 hrs post dose, n=6	953 ( 50.0 )
Encorafenib C1D15: 6 hrs post dose, n=6	332 ( 61.0 )
Encorafenib C2D1: pre-dose, n=4	59.7 ( 65.7 )
Encorafenib C3D1: pre-dose, n=5	50.1 ( 47.8 )
LHY746 C1D1: 0.5 hrs post dose, n=8	6.46 ( 114.1 )
LHY746 C1D1: 1.5 hrs post dose, n=8	123 ( 345.5 )
LHY746 C1D1: 3 hrs post dose, n=6	296 ( 46.7 )
LHY746 C1D1: 6 hrs post dose, n=7	277 ( 62.7 )
LHY746 C1D15: pre-dose, n=6	892 ( 101.1 )
LHY746 C1D15: 0.5 hrs post dose, n=6	941 ( 88.2 )
LHY746 C1D15: 1.5 hrs post dose, n=6	1040 ( 93.4 )
LHY746 C1D15: 3 hrs post dose, n=8	1690 ( 64.3 )
LHY746 C1D15: 6 hrs post dose, n=6	1520 ( 59.0 )
LHY746 C2D1: pre-dose, n=4	655 ( 91.3 )
LHY746 C3D1: pre-dose, n=5	256 ( 2956.0 )

No statistical analyses for this end point

Secondary: Plasma Concentrations of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

Plasma Concentrations of Binimetinib and its Metabolite AR00426032: SLI Phase ^[35]

End point description

In this end point, plasma concentrations of binimetinib and its metabolite AR00426032 at C1D1, C1D15, C2D1, and C3D1 at different time points were reported. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose: Cycle 2, Cycle 3 Day 1: Pre-dose

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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: ng/mL
geometric mean (geometric coefficient of variation)
Binimetinib C1D1: 0.5 hrs post dose, n=8	86.6 ( 567.4 )
Binimetinib C1D1: 1.5 hrs post dose, n=8	297 ( 341.9 )
Binimetinib C1D1: 3 hrs post dose, n=8	233 ( 83.2 )
Binimetinib C1D1: 6 hrs post dose, n=7	151 ( 91.6 )
Binimetinib C1D15: pre-dose, n=6	47.7 ( 71.8 )
Binimetinib C1D15: 0.5 hrs post dose, n=6	151 ( 67.8 )
Binimetinib C1D15: 1.5 hrs post dose, n=6	232 ( 121.1 )
Binimetinib C1D15: 3 hrs post dose, n=6	215 ( 55.2 )
Binimetinib C1D15: 6 hrs post dose, n=6	79.9 ( 56.6 )
Binimetinib C2D1: pre-dose, n=4	42.0 ( 47.8 )
Binimetinib C3D1: pre-dose, n=5	30.0 ( 65.3 )
AR00426032 C1D1: 0.5 hrs post dose, n=8	8.10 ( 132.4 )
AR00426032 C1D1: 1.5 hrs post dose, n=8	30.3 ( 345.7 )
AR00426032 C1D1: 3 hrs post dose, n=8	31.7 ( 60.1 )
AR00426032 C1D1: 6 hrs post dose, n=7	21.9 ( 36.6 )
AR00426032 C1D15: pre-dose, n=6	3.13 ( 53.0 )
AR00426032 C1D15: 0.5 hrs post dose, n=6	5.89 ( 136.9 )
AR00426032 C1D15: 1.5 hrs post dose, n=6	10.6 ( 56.8 )
AR00426032 C1D15: 3 hrs post dose, n=6	12.5 ( 58.0 )
AR00426032 C1D15: 6 hrs post dose, n=6	4.71 ( 62.8 )
AR00426032 C2D1: pre-dose, n=4	2.97 ( 29.6 )
AR00426032 C3D1: pre-dose, n=5	1.57 ( 42.2 )

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and its Metabolite LHY746: SLI Phase ^[36]

End point description

In this end point, area under the plasma concentration-time curve from zero to 6 hours (AUC 0-6) after administration of encorafenib and its metabolite LHY746 in nanogram*hour per milliliter (ng*hr/mL) at C1D1, and C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	7
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Encorafenib: C1D1, n=7	9530 ( 50.6 )
Encorafenib: C1D15, n=6	3930 ( 52.8 )
LHY746: C1D1, n=7	1230 ( 60.1 )
LHY746: C1D15, n=6	8160 ( 67.7 )

No statistical analyses for this end point

Secondary: AUC0-6 of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

AUC0-6 of Binimetinib and its Metabolite AR00426032: SLI Phase ^[37]

End point description

In this end point, area under the plasma concentration-time curve from zero to 6 hours (AUC 0-6) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	7
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Binimetinib: C1D1n =7	1410 ( 85.5 )
Binimetinib: C1D15, n=6	1050 ( 39.7 )
AR00426032: C1D1, n=7	159 ( 65.9 )
AR00426032: C1D15, n=6	53.9 ( 48.6 )

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to last Time Point (AUClast) of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Area Under the Plasma Concentration-Time Curve From Time Zero to last Time Point (AUClast) of Encorafenib and its Metabolite LHY746: SLI Phase ^[38]

End point description

In this end point, area under the plasma concentration-time curve from zero to the last measurable time point (AUClast) after administration of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Encorafenib: C1D1, n=8	9190 ( 47.8 )
Encorafenib: C1D15, n=6	7490 ( 52.8 )
LHY746: C1D1, n=8	1180 ( 56.9 )
LHY746: C1D15, n=6	29600 ( 73.0 )

No statistical analyses for this end point

Secondary: AUClast of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

AUClast of Binimetinib and its Metabolite AR00426032: SLI Phase ^[39]

End point description

In this end point, area under the plasma concentration-time curve from zero to the last measurable time point (AUClast) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Binimetinib: C1D1, n=8	1350 ( 79.1 )
Binimetinib: C1D15, n=6	1440 ( 43.9 )
AR00426032: C1D1, n=8	156 ( 60.6 )
AR00426032: C1D15, n=6	77.9 ( 49.7 )

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to Tau (AUCtau) of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Area Under the Plasma Concentration-Time Curve From Time Zero to Tau (AUCtau) of Encorafenib and its Metabolite LHY746: SLI Phase ^[40]

End point description

In this end point, area under the plasma concentration-time curve from time zero to the last measurable time point Tau (AUCtau) of encorafenib and its metabolite LHY746 over a dosing interval (6 hours as appropriate) of C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[40] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Encorafenib, n=6	7490 ( 52.8 )
LHY746, n=6	29600 ( 73.0 )

No statistical analyses for this end point

Secondary: AUCtau of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

AUCtau of Binimetinib and its Metabolite AR00426032: SLI Phase ^[41]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[41] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Binimetinib, n=6	1440 ( 43.9 )
AR00426032, n=6	77.9 ( 49.7 )

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and its Metabolite LHY746: SLI Phase ^[42]

End point description

In this end point, maximum observed plasma concentration (Cmax) after administration of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[42] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: ng/mL
geometric mean (geometric coefficient of variation)
Encorafenib: C1D1, n=8	3210 ( 47.7 )
Encorafenib: C1D15, n=6	1370 ( 79.3 )
LHY746: C1D1, n=8	340 ( 47.2 )
LHY746: C1D15, n=6	1720 ( 65.3 )

No statistical analyses for this end point

Secondary: Cmax of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

Cmax of Binimetinib and its Metabolite AR00426032: SLI Phase ^[43]

End point description

In this end point, maximum observed plasma concentration (Cmax) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[43] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: ng/mL
geometric mean (geometric coefficient of variation)
Binimetinib: C1D1, n=8	506 ( 85.5 )
Binimetinib: C1D15, n=6	359 ( 40.5 )
AR00426032: C1D1, n=8	53.9 ( 77.8 )
AR00426032: C1D15, n=6	16.9 ( 54.0 )

No statistical analyses for this end point

Secondary: Minimum Observed Plasma Concentration (Cmin) at the end of a Dosing Interval at Steady State of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Minimum Observed Plasma Concentration (Cmin) at the end of a Dosing Interval at Steady State of Encorafenib and its Metabolite LHY746: SLI Phase ^[44]

End point description

In this end point, minimum observed plasma concentration (Cmin) after administration of encorafenib and its metabolite LHY746 at C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[44] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Encorafenib, n=6	91.1 ( 88.3 )
LHY746, n=6	829 ( 99.3 )

No statistical analyses for this end point

Secondary: Cmin of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

Cmin of Binimetinib and its Metabolite AR00426032: SLI Phase ^[45]

End point description

In this end point, minimum observed plasma concentration (Cmin) after administration of binimetinib and its metabolite AR00426032 at C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[45] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Binimetinib, n=6	47.7 ( 71.8 )
AR00426032, n=6	3.04 ( 47.8 )

No statistical analyses for this end point

Secondary: Ctrough of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Ctrough of Encorafenib and its Metabolite LHY746: SLI Phase ^[46]

End point description

In this end point, measured concentration at the end of a dosing interval (Ctrough) of encorafenib and its metabolite LHY746 at C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[46] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Encorafenib, n=6	332 ( 61.0 )
LHY746, n=6	1520 ( 59.0 )

No statistical analyses for this end point

Secondary: Ctrough of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

Ctrough of Binimetinib and its Metabolite AR00426032: SLI Phase ^[47]

End point description

In this end point, measured concentration at the end of a dosing interval (Ctrough) of binimetinib and its metabolite AR00426032 at C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[47] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Binimetinib, n=6	79.9 ( 56.6 )
AR00426032, n=6	4.71 ( 62.8 )

No statistical analyses for this end point

Secondary: Time to Reach Maximum Concentration (Tmax) of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Time to Reach Maximum Concentration (Tmax) of Encorafenib and its Metabolite LHY746: SLI Phase ^[48]

End point description

In this end point, time to reach maximum concentration (Tmax) of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[48] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: hours
median (full range (min-max))
Encorafenib: C1D1, n=8	1.53 (1.47 to 3.00)
Encorafenib: C1D15, n=6	1.55 (0.43 to 3.00)
LHY746: C1D1, n=8	4.33 (1.47 to 6.00)
LHY746: C1D15, n=6	3.00 (2.92 to 5.73)

No statistical analyses for this end point

Secondary: Tmax of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

Tmax of Binimetinib and its Metabolite AR00426032: SLI Phase ^[49]

End point description

In this end point, time to reach maximum concentration (Tmax) of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[49] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: hours
median (full range (min-max))
Binimetinib: C1D1, n=8	1.50 (1.45 to 6.08)
Binimetinib: C1D15, n=6	1.55 (0.43 to 2.98)
AR00426032: C1D1, n=8	1.53 (1.47 to 6.08)
AR00426032: C1D15, n=6	1.58 (0.43 to 3.07)

No statistical analyses for this end point

Secondary: Time of Last PK Sample (Tlast) of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Time of Last PK Sample (Tlast) of Encorafenib and its Metabolite LHY746: SLI Phase ^[50]

End point description

In this end point, time of last PK sample (Tlast) of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[50] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: hours
median (full range (min-max))
Encorafenib: C1D1, n=8	5.78 (3.00 to 6.08)
Encorafenib: C1D15, n=6	24.00 (24.00 to 24.00)
LHY746: C1D1, n=8	5.78 (3.00 to 6.08)
LHY746: C1D15, n=6	24.00 (24.00 to 24.00)

No statistical analyses for this end point

Secondary: Tlast of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

Tlast of Binimetinib and its Metabolite AR00426032: SLI Phase ^[51]

End point description

In this end point, time of last PK sample (Tlast) of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[51] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: hours
median (full range (min-max))
Binimetinib: C1D1, n=8	5.78 (3.00 to 6.08)
Binimetinib: C1D15, n=6	12.00 (12.00 to 12.00)
AR00426032: C1D1, n=8	5.78 (3.00 to 6.08)
AR00426032: C1D15, n=6	12.00 (12.00 to 12.00)

No statistical analyses for this end point

Secondary: Accumulation Ratio Between AUClast,ss and AUClast (RAUC) of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Accumulation Ratio Between AUClast,ss and AUClast (RAUC) of Encorafenib and its Metabolite LHY746: SLI Phase ^[52]

End point description

In this end point, accumulation ratio of encorafenib and its metabolite LHY746 calculated as: C1D15 AUC0-6 divided by C1D1 AUC0-6 was assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[52] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	6
Units: ratio
geometric mean (geometric coefficient of variation)
Encorafenib, n=6	0.468 ( 46.0 )
LHY746, n=6	7.25 ( 46.7 )

No statistical analyses for this end point

Secondary: RAUC of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

RAUC of Binimetinib and its Metabolite AR00426032: SLI Phase ^[53]

End point description

In this end point, accumulation ratio of binimetinib and its metabolite AR00426032 calculated as: C1D15 AUC0-6 divided by C1D1 AUC0-6 was assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[53] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	6
Units: ratio
geometric mean (geometric coefficient of variation)
Binimetinib, n=6	0.877 ( 60.4 )
AR00426032, n=6	0.359 ( 93.0 )

No statistical analyses for this end point

Secondary: Accumulation Ratio Between Cmax,ss and Cmax (RCmax) of Encorafenib and its Metabolite LHY746: SLI Phase

Top of page

End point title

Accumulation Ratio Between Cmax,ss and Cmax (RCmax) of Encorafenib and its Metabolite LHY746: SLI Phase ^[54]

End point description

In this endpoint, accumulation ratio of encorafenib and its metabolite LHY746 calculated as: C1D15 Cmax divided by C1D1 Cmax was assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[54] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	6
Units: ratio
geometric mean (geometric coefficient of variation)
Encorafenib, n=6	0.490 ( 71.8 )
LHY746, n=6	5.78 ( 41.7 )

No statistical analyses for this end point

Secondary: Rcmax of Binimetinib and its Metabolite AR00426032: SLI Phase

Top of page

End point title

Rcmax of Binimetinib and its Metabolite AR00426032: SLI Phase ^[55]

End point description

In this end point, accumulation ratio of binimetinib and its metabolite AR00426032 calculated as: C1D15 Cmax divided by C1D1 Cmax was assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[55] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	6
Units: ratio
geometric mean (geometric coefficient of variation)
Binimetinib, n=6	0.818 ( 95.9 )
AR00426032, n=6	0.347 ( 130.9 )

No statistical analyses for this end point

Secondary: Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) of LHY746: SLI Phase

Top of page

End point title

Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) of LHY746: SLI Phase ^[56]

End point description

In this end point, ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, for LHY746/encorafenib at C1D1, and C1D15 was assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[56] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	7
Units: ratio
geometric mean (geometric coefficient of variation)
C1D1, n=7	0.164 ( 21.7 )
C1D15, n=6	2.64 ( 36.0 )

No statistical analyses for this end point

Secondary: MRAUClast of AR00426032: SLI Phase

Top of page

End point title

MRAUClast of AR00426032: SLI Phase ^[57]

End point description

In this end point, ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, for AR00426032/binimetinib at C1D1, and C1D15 was assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[57] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	7
Units: ratio
geometric mean (geometric coefficient of variation)
C1D1, n=7	0.109 ( 54.1 )
C1D15, n=6	0.0494 ( 63.9 )

No statistical analyses for this end point

Secondary: Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) of LHY746: SLI Phase

Top of page

End point title

Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) of LHY746: SLI Phase ^[58]

End point description

In this end point, ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, for LHY746/encorafenib at C1D1, and C1D15 was assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[58] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: ratio
geometric mean (geometric coefficient of variation)
C1D1, n=8	0.135 ( 16.7 )
C1D15, n=6	1.59 ( 47.8 )

No statistical analyses for this end point

Secondary: MRCmax of AR00426032: SLI Phase

Top of page

End point title

MRCmax of AR00426032: SLI Phase ^[59]

End point description

In this end point, ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, for AR00426032/ binimetinib at C1D1, and C1D15 was assessed. PK analysis set included all subjects who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'N' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable for specified rows. This endpoint was planned to be analysed in SLI phase only.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours post-dose: Cycle 1 Day 15: Predose, 0.5, 1.5, 3, 6 hours (hrs.) post-dose

Notes
[59] - 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: Only Safety-Lead in arm was planned to be analysed for this endpoint.

End point values	SLI Phase: Encorafenib 300 mg BID+Binimetinib 45 mg BID
Number of subjects analysed	8
Units: ratio
geometric mean (geometric coefficient of variation)
C1D1, n=8	0.103 ( 49.3 )
C1D15, n=6	0.0453 ( 53.8 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Day 1 of dosing up to 30 days after last dose of study drug in Safety Lead-in Phase (maximum up to 10.4 months) and Phase 2 (maximum up to 8.3 months)

Adverse event reporting additional description

Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorised as serious in 1 subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID

Reporting group description

Subjects diagnosed with BRAFV600-mutant melanoma brain metastasis received standard combination therapy of encorafenib (450 mg orally, QD) and binimetinib (45 mg orally, BID) in 28-day cycles and subjects who were able to tolerate the encorafenib 450 mg dose further received 600 mg QD after 4 Weeks. Subjects were followed up to 30 days after last dose of study drug.

Reporting group title

SLI Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID

Reporting group description

Subjects diagnosed with BRAFV600-mutant melanoma brain metastasis received combination therapy of encorafenib (300 mg orally, BID) and binimetinib (45 mg orally, BID) in 28-day cycles and continued until disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent anticancer therapy, or death, whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

Serious adverse events	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID	SLI Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	4 / 10 (40.00%)
number of deaths (all causes)	3	7
number of deaths resulting from adverse events
Vascular disorders
Air embolism
subjects affected / exposed	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Phase 2: Encorafenib 450 mg QD + Binimetinib 45 mg BID	SLI Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	10 / 10 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2
Neoplasm skin
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Seborrhoeic keratosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Vascular disorders
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Chills
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	3
Facial pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	3
Fatigue
subjects affected / exposed	1 / 3 (33.33%)	6 / 10 (60.00%)
occurrences all number	1	9
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	4 / 10 (40.00%)
occurrences all number	0	4
Respiratory, thoracic and mediastinal disorders
Nasal discomfort
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Wheezing
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Respiratory tract congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Psychiatric disorders
Stress
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	3 / 10 (30.00%)
occurrences all number	0	3
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	2 / 3 (66.67%)	3 / 10 (30.00%)
occurrences all number	3	4
Alanine aminotransferase increased
subjects affected / exposed	2 / 3 (66.67%)	5 / 10 (50.00%)
occurrences all number	6	8
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	4
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	3
Lipase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Lymphocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	5
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2
Transaminases increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2
Troponin T increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2
Disturbance in attention
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Facial paresis
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	3
Headache
subjects affected / exposed	1 / 3 (33.33%)	3 / 10 (30.00%)
occurrences all number	1	5
Lethargy
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Memory impairment
subjects affected / exposed	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	1	1
Neuropathy peripheral
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	3 / 10 (30.00%)
occurrences all number	0	4
Eye disorders
Macular oedema
subjects affected / exposed	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	1	0
Retinopathy
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Vision blurred
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Visual impairment
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2
Abdominal pain
subjects affected / exposed	1 / 3 (33.33%)	5 / 10 (50.00%)
occurrences all number	3	7
Constipation
subjects affected / exposed	0 / 3 (0.00%)	3 / 10 (30.00%)
occurrences all number	0	4
Diarrhoea
subjects affected / exposed	2 / 3 (66.67%)	5 / 10 (50.00%)
occurrences all number	3	9
Dysphagia
subjects affected / exposed	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	1	0
Gastritis
subjects affected / exposed	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Haematochezia
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Haemorrhoids
subjects affected / exposed	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	1	0
Nausea
subjects affected / exposed	2 / 3 (66.67%)	5 / 10 (50.00%)
occurrences all number	3	8
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	4 / 10 (40.00%)
occurrences all number	2	4
Skin and subcutaneous tissue disorders
Actinic keratosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Hyperkeratosis
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2
Erythema
subjects affected / exposed	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	1	0
Dermal cyst
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Melanocytic hyperplasia
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Angioedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Pain of skin
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Papule
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2
Photosensitivity reaction
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Purpura
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Rash
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2
Rash macular
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	4 / 10 (40.00%)
occurrences all number	0	4
Rash pruritic
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Seborrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Vitiligo
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Skin disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	3
Renal impairment
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	3 / 10 (30.00%)
occurrences all number	0	4
Back pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2
Myositis
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Osteoarthritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	1	1
Folliculitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Onychomycosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Otitis media
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Rhinitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	5
Abnormal loss of weight
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	4

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

13 Mar 2020

To revise subject eligibility criteria based on investigator feedback and changes in standard of care for the treatment of asymptomatic brain metastases. Study design was updated to allow for flexibility regarding if the high-dose regimen was not tolerated and to simplify the overall study design.

07 Aug 2020

To evaluate the safety, tolerability and efficacy for subjects with intra-patient dose escalation up to 600 mg QD encorafenib in Phase 2. To include update safety/risk data. Adverse events and serious adverse events revised to align with Pfizer standard operating procedures. Per Pfizer TLF reduction initiative, the safety parameters (body weight, ECOG PS, dermatologic, ECHO/MUGA and ophthalmic examination) were not summarised descriptively in the tables.

04 Jan 2021

1) Clarification of Safety reporting for cardiovascular and death events; 2) Inclusion of Health Canada recommendations for additional ECG criteria that may qualify as serious adverse events.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
02 Jun 2021	Pfizer and the Steering Committee reviewed safety lead-in data and decided not to evaluate high dose combination of encorafenib + binimetinib in Phase 2 of the study.	-

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

Data for pharmacokinetic end points for “Phase 2” was not collected and analysed as sampling was insufficient to support noncompartmental analysis in subjects.

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-Mutant Melanoma Brain Metastasis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With Dose Limiting Toxicities (DLTs): Safety Lead-in (SLI) Phase

Primary: Number of Subjects With Dose Limiting Toxicities (DLTs): Safety Lead-in (SLI) Phase

Primary: Number of Subjects With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase

Primary: Number of Subjects With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase

Primary: Number of Subjects With Hepatology Laboratory Test Abnormalities: SLI Phase

Primary: Number of Subjects With Hepatology Laboratory Test Abnormalities: SLI Phase

Primary: Number of Subjects With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase

Primary: Number of Subjects With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase

Primary: Number of Subjects With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase

Primary: Number of Subjects With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase

Primary: Number of Subjects With Notable Abnormal Vital Signs: SLI Phase

Primary: Number of Subjects With Notable Abnormal Vital Signs: SLI Phase

Primary: Number of Subjects With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase

Primary: Number of Subjects With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase

Primary: Number of Subjects With Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to AEs: SLI Phase

Primary: Number of Subjects With Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to AEs: SLI Phase

Primary: Brain Metastasis Response Rate (BMRR) Based on Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST v1.1): Phase 2

Primary: Brain Metastasis Response Rate (BMRR) Based on Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST v1.1): Phase 2

Secondary: Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2

Secondary: Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2

Secondary: Global Response Rate: SLI Phase and Phase 2

Secondary: Global Response Rate: SLI Phase and Phase 2

Secondary: Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2

Secondary: Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2

Secondary: DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2

Secondary: DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2

Secondary: Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2

Secondary: Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2

Secondary: DCR for Global Response: SLI Phase and Phase 2

Secondary: DCR for Global Response: SLI Phase and Phase 2

Secondary: DOR for Global Response: SLI Phase and Phase 2

Secondary: DOR for Global Response: SLI Phase and Phase 2

Secondary: Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2

Secondary: Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2

Secondary: DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2

Secondary: DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2

Secondary: PFS for Global Tumor Assessment: SLI Phase and Phase 2

Secondary: PFS for Global Tumor Assessment: SLI Phase and Phase 2

Secondary: BMRR Based on mRECIST v1.1: SLI Phase

Secondary: BMRR Based on mRECIST v1.1: SLI Phase

Secondary: Overall Survival: Safety Lead-in Phase and Phase 2

Secondary: Overall Survival: Safety Lead-in Phase and Phase 2

Secondary: Number of Subjects With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2

Secondary: Number of Subjects With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2

Secondary: Number of Subjects With Hepatology Laboratory Test Abnormalities: Phase 2

Secondary: Number of Subjects With Hepatology Laboratory Test Abnormalities: Phase 2

Secondary: Number of Subjects With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2

Secondary: Number of Subjects With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2

Secondary: Number of Subjects With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2

Secondary: Number of Subjects With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2

Secondary: Number of Subjects With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2

Secondary: Number of Subjects With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2

Secondary: Number of Subjects With Notable Abnormal Electrocardiogram (ECG) Values: Phase 2

Secondary: Number of Subjects With Notable Abnormal Electrocardiogram (ECG) Values: Phase 2

Secondary: Plasma Concentrations of Encorafenib and its Metabolite LHY746: SLI Phase

Secondary: Plasma Concentrations of Encorafenib and its Metabolite LHY746: SLI Phase

Secondary: Plasma Concentrations of Binimetinib and its Metabolite AR00426032: SLI Phase

Secondary: Plasma Concentrations of Binimetinib and its Metabolite AR00426032: SLI Phase

Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and its Metabolite LHY746: SLI Phase

Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and its Metabolite LHY746: SLI Phase

Secondary: AUC0-6 of Binimetinib and its Metabolite AR00426032: SLI Phase

Secondary: AUC0-6 of Binimetinib and its Metabolite AR00426032: SLI Phase

Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to last Time Point (AUClast) of Encorafenib and its Metabolite LHY746: SLI Phase

Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to last Time Point (AUClast) of Encorafenib and its Metabolite LHY746: SLI Phase

Secondary: AUClast of Binimetinib and its Metabolite AR00426032: SLI Phase

Secondary: AUClast of Binimetinib and its Metabolite AR00426032: SLI Phase

Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to Tau (AUCtau) of Encorafenib and its Metabolite LHY746: SLI Phase

Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to Tau (AUCtau) of Encorafenib and its Metabolite LHY746: SLI Phase

Secondary: AUCtau of Binimetinib and its Metabolite AR00426032: SLI Phase

Secondary: AUCtau of Binimetinib and its Metabolite AR00426032: SLI Phase

Clinical Trial Results:
A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-Mutant Melanoma Brain Metastasis