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A Phase II Study of Single Agent MEK162 in Patients With Advanced Melanoma

Sponsor
Pfizer (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT01320085
Collaborator
(none)
183
Enrollment
21
Locations
3
Arms
135.2
Anticipated Duration (Months)
8.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study will assess the safety and efficacy of single-agent MEK162 in adult patients with locally advanced and unresectable or metastatic malignant cutaneous melanoma, harboring BRAFV600E or NRAS mutations.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
183 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II, Open-label Study to Assess the Safety and Efficacy of Oral MEK162 in Adults With Locally Advanced and Unresectable or Metastatic Malignant Cutaneous Melanoma, Harboring BRAFV600 or NRAS Mutations
Actual Study Start Date :
Mar 24, 2011
Actual Primary Completion Date :
Jan 7, 2014
Anticipated Study Completion Date :
Jun 29, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: BRAFV600 mutant, 45mg bid MEK162

BRAFV600 mutant, 45mg bid MEK162

Drug: MEK162
Experimental: NRAS mutant, 45mg bid MEK162

NRAS mutant, 45mg bid MEK162

Drug: MEK162
Experimental: BRAFV600 mutant, 60mg bid MEK162

BRAFV600 mutant, 60mg bid MEK162

Drug: MEK162

Outcome Measures

Primary Outcome Measures

  1. Percentage of Participants With Objective Response (OR) [From date of randomization or date of start of treatment until date of first documentation of PD or death due to any cause, whichever occurred first (maximum duration of up to 33 months)]

    Objective response as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.0, was defined as participants with a best overall response of complete response (CR) or partial response (PR), were recorded from date of randomization or date of start of treatment until date of first documentation of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target and non-target lesions, and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

  1. Progression-Free Survival (PFS) [From date of randomization or date of start of treatment until date of first documentation of PD or date of death due to any cause or date of data censoring, whichever occurred first (maximum duration of up to 33 months)]

    PFS as assessed by investigator per RECIST v1.0, was defined as time (in months) from date of randomization or date of start of treatment to first documentation of PD or date of death due to any cause or data censoring date, whichever occurred first. PD was defined for target disease as at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study), sum also demonstrated absolute increase of greater than or equal to (>=) 5 mm, or appearance of >=1 new lesions. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. If a participant did not had an event, data censoring was done at the date of last adequate tumor assessment. Analysis was performed using Kaplan-Meier method.

  2. Overall Survival (OS) [From date of randomization or date of start of treatment to date of death due to any cause or date of censoring, whichever occurred first (maximum duration of up to 33 months)]

    Overall survival was defined as the time (in months) from the date of randomization or date of start of treatment to the date of death due to any cause or data censoring date, whichever occurred first. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.

  3. Duration of Response (DOR) [From first documentation of CR or PR until first documentation of tumor progression or death due to any cause or data censoring date, whichever occurred first (maximum duration of up to 33 months)]

    DOR:time from first documentation of OR(confirmed CR or PR) to first documentation of PD/death due to any cause/data censoring date,whichever occurred first. As per RECIST v1.0, CR:disappearance of all target(T) and non-target(Non-T) lesions sustained for =>4 weeks. Any pathological lymph nodes(T or non-T) reduced in short axis to <10mm. PR:>=30% decrease in sum of diameters(SOD) of T lesions, taking as reference baseline SOD. PD for T lesions:at least a 20% increase in sum of diameters of T lesions, taking as reference smallest sum on study treatment, with absolute increase of >=5 mm, or appearance of >=1 new lesions.PD for Non-T lesions:unequivocal progression of pre-existing lesions/increase in overall tumor burden leading to discontinuation of therapy/appearance of new unequivocal malignant lesion.Data was censored on date of last adequate tumor assessment for participants without an event,who started new anti-cancer treatment prior to assessment,who missed >=2 tumor assessments.

  4. Time to Response (TTR) [From the date of randomization or date of start of treatment to the first documentation of objective response (CR or PR) or data censoring date, whichever occurred first (maximum duration of up to 33 months)]

    TTR as assessed by investigator according to RECIST v1.0, was defined as the time (in months) from date of randomization or date of start of treatment until first documented response (CR or PR) or data censoring date, whichever occurred first. CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to <10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival.

  5. Number of Participants With Grade 3 or 4 Treatment-Emergent Adverse Reactions Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.0 [Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months)]

    An adverse drug reaction (ADR) was any untoward medical occurrence attributed to study drug in participants who received study drug. As per NCI-CTCAE v4.0, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4:life-threatening consequence, urgent intervention indicated; Grade 5:death related to study drug. Treatment-emergent ADRs are between first dose of study drug and up to 30 days after last dose of study drug, that were absent before treatment or that worsened relative to pretreatment state. Number of participants with any Grade 3 or 4 treatment-emergent ADR were reported in this outcome measure.

  6. Number of Participants With Serious Adverse Reactions [Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months)]

    A serious ADR was an ADR resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening experience (immediate risk of dying); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly, important medical event.

  7. Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Hematology) [Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)]

    Hematology per NCI-CTCAE included, Lymphocyte count decreased-(G1:<0.8, G2:<0.8-0.5, G3:<0.5-0.2, G4:<0.2[*10^9/L]); Lymphocyte count increased-(G2:>4-20, G3:>20[*10^9/L]); Neutrophil count decreased-(G1:<1.5, G2:<1.5-1.0, G3:<1.0-0.5, G4:<0.5[*10^9/L]); Activated partial thromboplastin time prolonged (seconds)-(G1:>1.5*upper limit normal (ULN), G2:>1.5-2.5*ULN, G3:>2.5*ULN); Platelet count decreased-(G1:<75.0, G2:<75.0-50.0, G3:<50.0-25.0, G4:<25.0[*10^9/L]); Fibrinogen decreased-(G1:<1.0-0.75*lower limit normal (LLN), G2:<0.75-0.5*LLN, G3:<0.5-0.25*LLN G4:<0.25*LLN); Anemia-(G1:<LLN-100, G2:<100-80, G3:<80 [g/L], G4:Life-threatening, G5:death); Hemoglobin increased-(G1:>0-2 g/dL above ULN, G2:>2-4 g/dL above ULN, G3:>4 g/dL above ULN); Prothrombin time (INR) increased-(G1:>1-1.5, G2:>1.5-2.5, G3:>2.5[*ULN]); WBC decreased-(G1:<3.0*10^9/L, G2:<3.0-2.0*10^9/L, G3:<2.0-1.0*10^9/L, G4:<1.0*10^9/L); WBC increased-(G3:>100,000/mm3, G4:Clinical manifestations of increase in WBC, G5:death).

  8. Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Chemistries) [Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)]

    Albumin(G1:<30,G2:<30-20,G3:<20[g/L], G4:life-threatening, G5:death);Alkaline phosphatase(G1:>2.5,G2:>2.5-5.0,G3:>5.0-20.0, G4:>20.0[*ULN]);Creatine kinase(G1:>2.5,G2:>2.5-5,G3:>5-10,G4:>10[*ULN]);Creatinine(CT) clearance(G1:<LLN-60,G2:59-30,G3:29-15,G3:<15[ml/min/1.73m^2], G5:death);CT (G1:>1.5,G2:>1.5-3.0,G3:>3.0-6.0,G4:>6.0[*ULN]);Hypomagnesemia(G1:<0.5,G2:<0.5-0.4,G3:<0.4-0.3,G4:<0.3[mmol/L],G5:death);Hypermagnesemia(G1:>1.23,G3:>1.23-3.30, G4:>3.30[mmol/L],G5:death);Hypophosphatemia(G1:<0.8,G2:<0.8-0.6,G3:<0.6-0.3,G4:<0.3[mmol/L], G5:death);Hypokalemia(G1:<3.0,G2:<3.0,G3:<3.0-2.5,G4:<2.5[mmol/L],G5:death);Hyperkalemia(G1:>5.5,G2:>5.5-6.0,G3:>6.0-7.0, G4:>7.0[mmol/L],G5:death);AST(G1:>3.0,G2:>3.0-5.0,G3:>5.0-20.0,G4:>20.0[*ULN]); ALT(G1:>3.0,G2:>3.0-5.0,G3:>5.0-20.0,G4:>20.0[*ULN]);Hyponatremia(G1:<130,G3:<130-120,G4:<120[mmol/L],G5:death);Hypernatremia(G1:150,G2:>150-155,G3:>155-160,G4:>160[mmol/L],G5:death);High blood bilirubin (G1:>1.5,G2:>1.5-3.0,G3:>3.0-10.0,G4:>10.0[*ULN]).

  9. Number of Participants With Shift From Baseline in Vital Signs Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Blood Pressure) [Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)]

    Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP).

  10. Number of Participants With Markedly Abnormal Vital Sign Values: Sitting Pulse Rate [Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)]

    Pre-defined criteria of markedly abnormal vital signs abnormalities was defined as increase or decrease from baseline (>=15 beats per minute) in pulse rate of >=120 beats per minute or less than or equal to (<=) 50 beats per minute.

  11. Number of Participants With Markedly Abnormal Vital Sign Values: Weight [Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)]

    Vital signs included assessment of body weight. Body weight (in kilograms) measurements included high and low. Pre-defined criteria of markedly abnormal vital signs abnormalities was defined as increase or decrease from baseline in weight of >=10%.

  12. Number of Participants With Notable Electrocardiogram (ECG) Values [Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)]

    ECG findings included maximum value of >450 millisecond (msec), >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval corrected using Fridericia's formula (QTcF); maximum value of >450 msec, >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval corrected using Bazett's formula (QTcB); maximum value of >450 msec, >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval; RR decrease >25% and to a VR >100, RR increase >25% and to a VR <50 beats per minute for VR interval; an increase >25% and to a value >200 msec for PR interval; an increase >25% and to a value >110 msec for QRS interval.

  13. Number of Participants With Change From Baseline in Abnormal Ophthalmoscopy Values- by Fundoscopy [Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months)]

    Fundoscopy examination included an examination of the retina, vitreous, macula, optic nerve, optic nerve pallor, choroid and other new abnormalities in either or both eyes. New abnormalities were identified where the baseline assessment showed no abnormalities in a particular eye, but at the post-dose time point an abnormality was observed. New abnormalities at any time point were reported and included unscheduled assessments.

  14. Number of Participants With Change From Baseline in Abnormal Ophthalmoscopy Values- by Slit Lamp Examination [Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months)]

    Slit lamp examination included an examination of the conjunctiva, cornea, iris, lens, anterior chamber, lids and other new abnormalities in either or both eyes. New abnormalities were identified where the baseline assessment showed no abnormalities in a particular eye, but at the post-dose time point an abnormality was observed. New abnormalities at any time point were reported and included unscheduled assessments.

  15. Area Under the Curve From Time Zero to End of Dosing Interval at Steady-State (AUCtau) of Binimetinib [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

  16. Maximum Plasma Concentration (Cmax) of Binimetinib [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

  17. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Binimetinib [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

  18. Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-last) of Binimetinib [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

  19. The Last Time Point of the Last Quantifiable Concentration (Tlast) of Binimetinib [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

  20. Trough Plasma Concentration (Ctrough) of Binimetinib [Pre-dose (0 hour) on Day 15 of Cycle 1]

    Ctrough refers to plasma concentration of Binimetinib observed just before treatment administration.

  21. Apparent Total Body Clearance (CL/F) of Binimetinib [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

    Drug clearance was defined as a quantitative measure of the rate at which a drug substance was removed from the plasma. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed.

  22. Area Under the Curve From Time Zero to End of Dosing Interval at Steady-State (AUCtau) of Binimetinib's Metabolite [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

  23. Maximum Plasma Concentration (Cmax) of Binimetinib's Metabolite [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

  24. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Binimetinib's Metabolite [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

  25. Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-last) of Binimetinib's Metabolite [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

  26. The Last Time Point of the Last Quantifiable Concentration (Tlast) of Binimetinib's Metabolite [Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1]

  27. Trough Plasma Concentration (Ctrough) of Binimetinib's Metabolite [Pre-dose (0 hour) on Day 15 of Cycle 1]

    Ctrough refers to plasma concentration of Binimetinib's metabolite observed just before treatment administration.

  28. Percent Change From Baseline in Histological Score (H-score) for Phosphorylated Extracellular Signal-Regulated Kinase (pERK) From Tumor Samples of Cytoplasmic and Nuclear Cellular Compartment [Baseline up to maximum duration of up to 33 months]

    Percent change from baseline in H-score for pERK from tumor samples was assessed and summarized. The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors.

  29. Percent Change From Baseline in Delta CT Values for Dual Specificity Phosphatase 6 (DUSP6) Expression From Tumor Samples [Baseline up to maximum duration of up to 33 months]

    The percentage change in DUSP6 gene expression was derived from the Relative Expression Ratio (RER) computed via the Delta Ct method. DUSP6, a protein coding gene was used as a biomarker of inhibition of the mitogen-activated protein kinase (MEK) pathway.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

  • Locally advanced or metastatic cutaneous melanoma AJCC Stage IIIB to IV, not potentially curable with surgery

  • BRAF or NRAS mutation in tumor tissue

  • All patients enrolled should provide sufficient fresh or archival tumor sample at baseline to enable confirmation of BRAF or NRAS mutations and the additional analyses described in the protocol

  • Evidence of measurable tumor disease as per RECIST

  • WHO performance status of 0-2

  • Adequate organ function and laboratory parameters

Exclusion Criteria:

  • History or evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or any eye condition that would be considered a risk factor for CSR or RVO

  • Patients with unstable CNS metastasis

  • Prior treatment with a MEK- inhibitor

  • Impaired cardiovascular function

  • HIV, active Hepatitis B, and/or active Hepatitis C infection

  • Pregnant or nursing (lactating) women

  • Women of child-bearing potential UNLESS they comply with protocol contraceptive requirements

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Highlands Oncology Group Fayetteville Arkansas United States 72703-4005
2 H. Lee Moffitt Cancer Center & Research Institute, Inc. Tampa Florida United States 33612
3 OHSU Knight Cancer Institute Portland Oregon United States 97201
4 OHSU Center for Health and Healing Portland Oregon United States 97239
5 OHSU Research Phamacy Services, Drug Storage Portland Oregon United States 97239
6 Oregon Health and Science University Portland Oregon United States 97239
7 Cancer Care Associates Medical Oncology Allentown Pennsylvania United States 18104
8 St. Luke's Cancer Center - Allentown Campus Allentown Pennsylvania United States 18104
9 Cancer Care Associates Medical Oncology Bethlehem Pennsylvania United States 18015
10 St. Luke's University Health Network Bethlehem Pennsylvania United States 18015
11 St. Luke's Hospital - Quakertown Campus Quakertown Pennsylvania United States 18951
12 LMU Klinikum der Universität München München Bayern Germany 80337
13 Universitätsklinikum Essen Essen Nordrhein-westfalen Germany 45122
14 Universitatsklinikum Schleswig-Holstein Luebeck Schleswig-holstein Germany 23562
15 Istituto Nazionale per lo studio e la cura dei tumori Fondazione Giovanni Pascale Napoli Campania Italy 80131
16 Istituto nazionale Per la Ricerca sul Cancro Genova Italy 16132
17 Radboud University Nijmegen Medical Centre Nijmegen Gelderland Netherlands 6525 GA
18 Maastricht University Medical Center Maastricht Limburg Netherlands 6229 HX
19 Het Nederlands Kanker Instituut Antoni Van Leeuwenhoek Ziekenhuis Amsterdam Noord-holland Netherlands 1066 CX
20 Slotervaartziekenhuis Amsterdam Noord-holland Netherlands 1066 EC
21 Universitätsspital Zürich Zürich (de) Switzerland 08091

Sponsors and Collaborators

  • Pfizer

Investigators

  • Study Director: Pfizer Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT01320085
Other Study ID Numbers:
  • CMEK162X2201
  • C4211001
  • 2010-023412-13
First Posted:
Mar 22, 2011
Last Update Posted:
Nov 22, 2021
Last Verified:
Nov 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Pfizer
Metastatic melanoma,
BRAF-mutant,
NRAS-mutant
Additional relevant MeSH terms:
Melanoma

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail This study included only those participants for whom the presence of a v-raf murine sarcoma viral oncogene homolog B1 (BRAFV600) or Neuroblastoma RAS viral oncogene homolog (NRAS) gene mutation in the tumor tissue was determined. Data in this result summary have been reported at primary completion date (07 January 2014).
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Period Title: Overall Study
STARTED 41 117 25
COMPLETED 0 0 0
NOT COMPLETED 41 117 25

Baseline Characteristics

Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF Total
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Total of all reporting groups
Overall Participants 41 117 25 183
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]
53.7
(14.59)
59.6
(13.74)
51.3
(9.81)
57.1
(13.82)
Sex: Female, Male (Count of Participants)
Female
19
46.3%
33
28.2%
17
68%
69
37.7%
Male
22
53.7%
84
71.8%
8
32%
114
62.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
0
0%
10
8.5%
0
0%
10
5.5%
Not Hispanic or Latino
41
100%
107
91.5%
25
100%
173
94.5%
Unknown or Not Reported
0
0%
0
0%
0
0%
0
0%
Race/Ethnicity, Customized (Count of Participants)
Caucasian
41
100%
117
100%
25
100%
183
100%

Outcome Measures

1. Primary Outcome
Title Percentage of Participants With Objective Response (OR)
Description Objective response as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.0, was defined as participants with a best overall response of complete response (CR) or partial response (PR), were recorded from date of randomization or date of start of treatment until date of first documentation of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target and non-target lesions, and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame From date of randomization or date of start of treatment until date of first documentation of PD or death due to any cause, whichever occurred first (maximum duration of up to 33 months)

Outcome Measure Data

Analysis Population Description
The full analysis set included all randomized participants who received at least one dose of study drug.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
Number (95% Confidence Interval) [percentage of participants]
4.9
12%
14.5
12.4%
12.0
48%
2. Secondary Outcome
Title Progression-Free Survival (PFS)
Description PFS as assessed by investigator per RECIST v1.0, was defined as time (in months) from date of randomization or date of start of treatment to first documentation of PD or date of death due to any cause or data censoring date, whichever occurred first. PD was defined for target disease as at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study), sum also demonstrated absolute increase of greater than or equal to (>=) 5 mm, or appearance of >=1 new lesions. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. If a participant did not had an event, data censoring was done at the date of last adequate tumor assessment. Analysis was performed using Kaplan-Meier method.
Time Frame From date of randomization or date of start of treatment until date of first documentation of PD or date of death due to any cause or date of data censoring, whichever occurred first (maximum duration of up to 33 months)

Outcome Measure Data

Analysis Population Description
The full analysis set included all randomized participants who received at least one dose of study drug.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
Median (95% Confidence Interval) [months]
3.5
3.6
1.8
3. Secondary Outcome
Title Overall Survival (OS)
Description Overall survival was defined as the time (in months) from the date of randomization or date of start of treatment to the date of death due to any cause or data censoring date, whichever occurred first. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.
Time Frame From date of randomization or date of start of treatment to date of death due to any cause or date of censoring, whichever occurred first (maximum duration of up to 33 months)

Outcome Measure Data

Analysis Population Description
The full analysis set included all randomized participants who received at least one dose of study drug.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
Median (95% Confidence Interval) [months]
NA
NA
16.6
4. Secondary Outcome
Title Duration of Response (DOR)
Description DOR:time from first documentation of OR(confirmed CR or PR) to first documentation of PD/death due to any cause/data censoring date,whichever occurred first. As per RECIST v1.0, CR:disappearance of all target(T) and non-target(Non-T) lesions sustained for =>4 weeks. Any pathological lymph nodes(T or non-T) reduced in short axis to <10mm. PR:>=30% decrease in sum of diameters(SOD) of T lesions, taking as reference baseline SOD. PD for T lesions:at least a 20% increase in sum of diameters of T lesions, taking as reference smallest sum on study treatment, with absolute increase of >=5 mm, or appearance of >=1 new lesions.PD for Non-T lesions:unequivocal progression of pre-existing lesions/increase in overall tumor burden leading to discontinuation of therapy/appearance of new unequivocal malignant lesion.Data was censored on date of last adequate tumor assessment for participants without an event,who started new anti-cancer treatment prior to assessment,who missed >=2 tumor assessments.
Time Frame From first documentation of CR or PR until first documentation of tumor progression or death due to any cause or data censoring date, whichever occurred first (maximum duration of up to 33 months)

Outcome Measure Data

Analysis Population Description
The full analysis set included all randomized participants who received at least one dose of study drug. Here "Overall number of participants analyzed" signifies participants evaluable for this outcome measure.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 2 17 3
Median (95% Confidence Interval) [months]
3.6
4.0
NA
5. Secondary Outcome
Title Time to Response (TTR)
Description TTR as assessed by investigator according to RECIST v1.0, was defined as the time (in months) from date of randomization or date of start of treatment until first documented response (CR or PR) or data censoring date, whichever occurred first. CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to <10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival.
Time Frame From the date of randomization or date of start of treatment to the first documentation of objective response (CR or PR) or data censoring date, whichever occurred first (maximum duration of up to 33 months)

Outcome Measure Data

Analysis Population Description
The full analysis set included all randomized participants who received at least one dose of study drug. Here "Overall number of participants analyzed" signifies participants evaluable for this outcome measure.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 2 17 3
Median (95% Confidence Interval) [months]
2.2
1.9
1.8
6. Secondary Outcome
Title Number of Participants With Grade 3 or 4 Treatment-Emergent Adverse Reactions Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.0
Description An adverse drug reaction (ADR) was any untoward medical occurrence attributed to study drug in participants who received study drug. As per NCI-CTCAE v4.0, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4:life-threatening consequence, urgent intervention indicated; Grade 5:death related to study drug. Treatment-emergent ADRs are between first dose of study drug and up to 30 days after last dose of study drug, that were absent before treatment or that worsened relative to pretreatment state. Number of participants with any Grade 3 or 4 treatment-emergent ADR were reported in this outcome measure.
Time Frame Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who had received at least one dose of study drug and had at least one valid post-baseline safety assessment.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
Count of Participants [Participants]
19
46.3%
50
42.7%
13
52%
7. Secondary Outcome
Title Number of Participants With Serious Adverse Reactions
Description A serious ADR was an ADR resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening experience (immediate risk of dying); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly, important medical event.
Time Frame Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who had received at least one dose of study drug and had at least one valid post-baseline safety assessment.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
Count of Participants [Participants]
2
4.9%
9
7.7%
4
16%
8. Secondary Outcome
Title Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Hematology)
Description Hematology per NCI-CTCAE included, Lymphocyte count decreased-(G1:<0.8, G2:<0.8-0.5, G3:<0.5-0.2, G4:<0.2[*10^9/L]); Lymphocyte count increased-(G2:>4-20, G3:>20[*10^9/L]); Neutrophil count decreased-(G1:<1.5, G2:<1.5-1.0, G3:<1.0-0.5, G4:<0.5[*10^9/L]); Activated partial thromboplastin time prolonged (seconds)-(G1:>1.5*upper limit normal (ULN), G2:>1.5-2.5*ULN, G3:>2.5*ULN); Platelet count decreased-(G1:<75.0, G2:<75.0-50.0, G3:<50.0-25.0, G4:<25.0[*10^9/L]); Fibrinogen decreased-(G1:<1.0-0.75*lower limit normal (LLN), G2:<0.75-0.5*LLN, G3:<0.5-0.25*LLN G4:<0.25*LLN); Anemia-(G1:<LLN-100, G2:<100-80, G3:<80 [g/L], G4:Life-threatening, G5:death); Hemoglobin increased-(G1:>0-2 g/dL above ULN, G2:>2-4 g/dL above ULN, G3:>4 g/dL above ULN); Prothrombin time (INR) increased-(G1:>1-1.5, G2:>1.5-2.5, G3:>2.5[*ULN]); WBC decreased-(G1:<3.0*10^9/L, G2:<3.0-2.0*10^9/L, G3:<2.0-1.0*10^9/L, G4:<1.0*10^9/L); WBC increased-(G3:>100,000/mm3, G4:Clinical manifestations of increase in WBC, G5:death).
Time Frame Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who had received at least one dose of study drug and had at least one valid post-baseline safety assessment.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
Absolute Lymphocytes decreased: Grade 0 baseline to Grade 0 post-baseline
28
68.3%
63
53.8%
10
40%
Absolute Lymphocytes decreased: Grade 0 baseline to Grade 1 post-baseline
1
2.4%
8
6.8%
1
4%
Absolute Lymphocytes decreased: Grade 0 baseline to Grade 2 post-baseline
1
2.4%
7
6%
0
0%
Absolute Lymphocytes decreased: Grade 0 baseline to Grade 3 post-baseline
0
0%
0
0%
1
4%
Absolute Lymphocytes decreased: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Absolute Lymphocytes decreased: Grade 1 baseline to Grade 0 post-baseline
2
4.9%
6
5.1%
3
12%
Absolute Lymphocytes decreased: Grade 1 baseline to Grade 1 post-baseline
3
7.3%
12
10.3%
3
12%
Absolute Lymphocytes decreased: Grade 1 baseline to Grade 2 post-baseline
1
2.4%
4
3.4%
1
4%
Absolute Lymphocytes decreased: Grade 1 baseline to Grade 3 post-baseline
1
2.4%
0
0%
0
0%
Absolute Lymphocytes decreased: Grade 2 baseline to Grade 0 post-baseline
1
2.4%
4
3.4%
0
0%
Absolute Lymphocytes decreased: Grade 2 baseline to Grade 1 post-baseline
2
4.9%
2
1.7%
0
0%
Absolute Lymphocytes decreased: Grade 2 baseline to Grade 2 post-baseline
0
0%
4
3.4%
4
16%
Absolute Lymphocytes decreased: Grade 2 baseline to Grade 3 post-baseline
0
0%
3
2.6%
1
4%
Absolute Lymphocytes decreased: Grade 3 baseline to Grade 2 post-baseline
0
0%
2
1.7%
0
0%
Absolute Lymphocytes decreased: Grade 3 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Absolute Lymphocytes decreased: 'Missing' baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Absolute Lymphocytes increased: Grade 0 baseline to Grade 0 post-baseline
36
87.8%
110
94%
22
88%
Absolute Lymphocytes increased: Grade 0 baseline to Grade 2 post-baseline
4
9.8%
6
5.1%
2
8%
Absolute Lymphocytes increased: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Absolute Lymphocytes increased: 'Missing' baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Absolute Neutrophils (Segmented and Bands): Grade 0 baseline to Grade 0 post-baseline
38
92.7%
100
85.5%
21
84%
Absolute Neutrophils (Segmented and Bands): Grade 0 baseline to Grade 1 post-baseline
0
0%
2
1.7%
0
0%
Absolute Neutrophils (Segmented and Bands): Grade 0 baseline to Grade 3 post-baseline
0
0%
0
0%
2
8%
Absolute Neutrophils (Segmented and Bands): Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Absolute Neutrophils (Segmented and Bands): Grade 1 baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Absolute Neutrophils (Segmented and Bands): Grade 1 baseline to Grade 1 post-baseline
0
0%
2
1.7%
0
0%
Absolute Neutrophils (Segmented and Bands): Grade 1 baseline to Grade 2 post-baseline
0
0%
1
0.9%
0
0%
Absolute Neutrophils (Segmented and Bands): Grade 1 baseline to Grade 3 post-baseline
1
2.4%
0
0%
0
0%
Absolute Neutrophils (Segmented and Bands): Grade 2 baseline to Grade 1 post-baseline
0
0%
1
0.9%
0
0%
Absolute Neutrophils (Segmented and Bands): Grade 2 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Absolute Neutrophils (Segmented and Bands): Grade 3 baseline to Grade 1 post-baseline
1
2.4%
0
0%
0
0%
Absolute Neutrophils (Segmented and Bands): Grade 3 baseline to Grade 3 post-baseline
0
0%
0
0%
1
4%
Absolute Neutrophils (Segmented and Bands): Grade 4 baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Absolute Neutrophils (Segmented and Bands): 'Missing' baseline to Grade 0 post-baseline
0
0%
4
3.4%
0
0%
Absolute Neutrophils (Segmented and Bands): 'Missing' baseline to 'Missing' post-baseline
0
0%
4
3.4%
0
0%
Activated partial thromboplastin time: Grade 0 baseline to Grade 0 post-baseline
31
75.6%
96
82.1%
19
76%
Activated partial thromboplastin time: Grade 0 baseline to Grade 1 post-baseline
3
7.3%
14
12%
2
8%
Activated partial thromboplastin time: Grade 0 baseline to Grade 2 post-baseline
0
0%
1
0.9%
1
4%
Activated partial thromboplastin time: Grade 0 baseline to Grade 3 post-baseline
1
2.4%
0
0%
0
0%
Activated partial thromboplastin time: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Activated partial thromboplastin time: Grade 1 baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Activated partial thromboplastin time: Grade 1 baseline to Grade 1 post-baseline
1
2.4%
3
2.6%
1
4%
Activated partial thromboplastin time: Grade 1 baseline to Grade 2 post-baseline
1
2.4%
1
0.9%
0
0%
Activated partial thromboplastin time: Grade 2 baseline to Grade 2 post-baseline
0
0%
1
0.9%
0
0%
Activated partial thromboplastin time: 'Missing' baseline to Grade 0 post-baseline
2
4.9%
0
0%
1
4%
Activated partial thromboplastin time: 'Missing' baseline to 'Missing' post-baseline
1
2.4%
0
0%
0
0%
Platelet count (Direct): Grade 0 baseline to Grade 0 post-baseline
36
87.8%
97
82.9%
21
84%
Platelet count (Direct): Grade 0 baseline to Grade 1 post-baseline
2
4.9%
14
12%
3
12%
Platelet count (Direct): Grade 0 baseline to Grade 2 post-baseline
0
0%
1
0.9%
0
0%
Platelet count (Direct): Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Platelet count (Direct): Grade 1 baseline to Grade 0 post-baseline
1
2.4%
0
0%
0
0%
Platelet count (Direct): Grade 1 baseline to Grade 1 post-baseline
0
0%
4
3.4%
0
0%
Platelet count (Direct): Grade 1 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Platelet count (Direct): 'Missing' baseline to Grade 0 post-baseline
1
2.4%
0
0%
0
0%
Fibrinogen decreased: Grade 0 baseline to Grade 0 post-baseline
8
19.5%
19
16.2%
8
32%
Fibrinogen decreased: Grade 0 baseline to Grade 1 post-baseline
11
26.8%
52
44.4%
6
24%
Fibrinogen decreased: Grade 0 baseline to Grade 2 post-baseline
10
24.4%
32
27.4%
7
28%
Fibrinogen decreased: Grade 0 baseline to Grade 3 post-baseline
0
0%
8
6.8%
2
8%
Fibrinogen decreased: Grade 0 baseline to Grade 4 post-baseline
2
4.9%
1
0.9%
0
0%
Fibrinogen decreased: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Fibrinogen decreased: Grade 2 baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Fibrinogen decreased: 'Missing' baseline to Grade 0 post-baseline
6
14.6%
4
3.4%
1
4%
Fibrinogen decreased: 'Missing' baseline to 'Missing' post-baseline
3
7.3%
0
0%
0
0%
Haemoglobin decreased: Grade 0 baseline to Grade 0 post-baseline
3
7.3%
22
18.8%
7
28%
Haemoglobin decreased: Grade 0 baseline to Grade 1 post-baseline
10
24.4%
35
29.9%
4
16%
Haemoglobin decreased: Grade 0 baseline to Grade 2 post-baseline
1
2.4%
4
3.4%
1
4%
Haemoglobin decreased: Grade 0 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Haemoglobin decreased: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Haemoglobin decreased: Grade 1 baseline to Grade 0 post-baseline
0
0%
4
3.4%
1
4%
Haemoglobin decreased: Grade 1 baseline to Grade 1 post-baseline
16
39%
27
23.1%
6
24%
Haemoglobin decreased: Grade 1 baseline to Grade 2 post-baseline
5
12.2%
16
13.7%
4
16%
Haemoglobin decreased: Grade 1 baseline to Grade 3 post-baseline
0
0%
3
2.6%
1
4%
Haemoglobin decreased: Grade 2 baseline to Grade 1 post-baseline
2
4.9%
0
0%
0
0%
Haemoglobin decreased: Grade 2 baseline to Grade 2 post-baseline
3
7.3%
3
2.6%
0
0%
Haemoglobin decreased: Grade 2 baseline to Grade 3 post-baseline
0
0%
2
1.7%
0
0%
Haemoglobin increased: Grade 0 baseline to Grade 0 post-baseline
40
97.6%
115
98.3%
24
96%
Haemoglobin increased: Grade 0 baseline to Grade 1 post-baseline
0
0%
2
1.7%
0
0%
Haemoglobin increased: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Prothrombin time: Grade 0 baseline to Grade 0 post-baseline
15
36.6%
40
34.2%
11
44%
Prothrombin time: Grade 0 baseline to Grade 1 post-baseline
20
48.8%
56
47.9%
9
36%
Prothrombin time: Grade 0 baseline to Grade 2 post-baseline
0
0%
2
1.7%
1
4%
Prothrombin time: Grade 0 baseline to Grade 3 post-baseline
1
2.4%
2
1.7%
0
0%
Prothrombin time: Grade 0 baseline to 'Missing' post-baseline
0
0%
0
0%
1
4%
Prothrombin time: Grade 1 baseline to Grade 1 post-baseline
0
0%
5
4.3%
0
0%
Prothrombin time: Grade 1 baseline to Grade 3 post-baseline
0
0%
0
0%
1
4%
Prothrombin time: Grade 2 baseline to Grade 2 post-baseline
1
2.4%
0
0%
0
0%
Prothrombin time: Grade 2 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Prothrombin time: Grade 3 baseline to Grade 3 post-baseline
1
2.4%
0
0%
0
0%
Prothrombin time: 'Missing' baseline to Grade 0 post-baseline
2
4.9%
0
0%
1
4%
Prothrombin time: 'Missing' baseline to 'Missing' post-baseline
1
2.4%
11
9.4%
1
4%
WBC (Total) decreased: Grade 0 baseline to Grade 0 post-baseline
35
85.4%
93
79.5%
20
80%
WBC (Total) decreased: Grade 0 baseline to Grade 1 post-baseline
2
4.9%
10
8.5%
1
4%
WBC (Total) decreased: Grade 0 baseline to Grade 2 post-baseline
0
0%
1
0.9%
0
0%
WBC (Total) decreased: Grade 0 baseline to Grade 3 post-baseline
0
0%
0
0%
1
4%
WBC (Total) decreased: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
WBC (Total) decreased: Grade 1 baseline to Grade 0 post-baseline
2
4.9%
4
3.4%
0
0%
WBC (Total) decreased: Grade 1 baseline to Grade 1 post-baseline
0
0%
5
4.3%
0
0%
WBC (Total) decreased: Grade 1 baseline to Grade 2 post-baseline
0
0%
1
0.9%
1
4%
WBC (Total) decreased: Grade 2 baseline to Grade 1 post-baseline
1
2.4%
2
1.7%
0
0%
WBC (Total) decreased: Grade 2 baseline to Grade 2 post-baseline
0
0%
1
0.9%
1
4%
WBC (Total) increased: Grade 0 baseline to Grade 0 post-baseline
40
97.6%
117
100%
24
96%
WBC (Total)- increased: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
9. Secondary Outcome
Title Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Chemistries)
Description Albumin(G1:<30,G2:<30-20,G3:<20[g/L], G4:life-threatening, G5:death);Alkaline phosphatase(G1:>2.5,G2:>2.5-5.0,G3:>5.0-20.0, G4:>20.0[*ULN]);Creatine kinase(G1:>2.5,G2:>2.5-5,G3:>5-10,G4:>10[*ULN]);Creatinine(CT) clearance(G1:<LLN-60,G2:59-30,G3:29-15,G3:<15[ml/min/1.73m^2], G5:death);CT (G1:>1.5,G2:>1.5-3.0,G3:>3.0-6.0,G4:>6.0[*ULN]);Hypomagnesemia(G1:<0.5,G2:<0.5-0.4,G3:<0.4-0.3,G4:<0.3[mmol/L],G5:death);Hypermagnesemia(G1:>1.23,G3:>1.23-3.30, G4:>3.30[mmol/L],G5:death);Hypophosphatemia(G1:<0.8,G2:<0.8-0.6,G3:<0.6-0.3,G4:<0.3[mmol/L], G5:death);Hypokalemia(G1:<3.0,G2:<3.0,G3:<3.0-2.5,G4:<2.5[mmol/L],G5:death);Hyperkalemia(G1:>5.5,G2:>5.5-6.0,G3:>6.0-7.0, G4:>7.0[mmol/L],G5:death);AST(G1:>3.0,G2:>3.0-5.0,G3:>5.0-20.0,G4:>20.0[*ULN]); ALT(G1:>3.0,G2:>3.0-5.0,G3:>5.0-20.0,G4:>20.0[*ULN]);Hyponatremia(G1:<130,G3:<130-120,G4:<120[mmol/L],G5:death);Hypernatremia(G1:150,G2:>150-155,G3:>155-160,G4:>160[mmol/L],G5:death);High blood bilirubin (G1:>1.5,G2:>1.5-3.0,G3:>3.0-10.0,G4:>10.0[*ULN]).
Time Frame Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who had received at least one dose of study drug and had at least one valid post-baseline safety assessment.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
Albumin: Grade 0 baseline to Grade 0 post-baseline
14
34.1%
43
36.8%
11
44%
Albumin: Grade 0 baseline to Grade 1 post-baseline
13
31.7%
41
35%
4
16%
Albumin: Grade 0 baseline to Grade 2 post-baseline
4
9.8%
19
16.2%
2
8%
Albumin: Grade 0 baseline to Grade 3 post-baseline
0
0%
0
0%
1
4%
Albumin: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Albumin: Grade 1 baseline to Grade 1 post-baseline
0
0%
2
1.7%
1
4%
Albumin: Grade 1 baseline to Grade 2 post-baseline
4
9.8%
3
2.6%
5
20%
Albumin: Grade 2 baseline to Grade 0 post-baseline
1
2.4%
0
0%
0
0%
Albumin: Grade 2 baseline to Grade 2 post-baseline
1
2.4%
3
2.6%
0
0%
Albumin: Grade 2 baseline to Grade 3 post-baseline
2
4.9%
1
0.9%
0
0%
Albumin: 'Missing' baseline to Grade 0 post-baseline
0
0%
3
2.6%
0
0%
Albumin: 'Missing' baseline to Grade 1 post-baseline
1
2.4%
1
0.9%
0
0%
Albumin: 'Missing' baseline to Grade 2 post-baseline
0
0%
1
0.9%
0
0%
Alkaline phosphatase, serum: Grade 0 baseline to Grade 0 post-baseline
0
0%
44
37.6%
0
0%
Alkaline phosphatase, serum: Grade 0 baseline to Grade 1 post-baseline
0
0%
21
17.9%
0
0%
Alkaline phosphatase, serum: Grade 0 baseline to Grade 2 post-baseline
0
0%
2
1.7%
0
0%
Alkaline phosphatase, serum: Grade 0 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Alkaline phosphatase, serum: Grade 1 baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Alkaline phosphatase, serum: Grade 1 baseline to Grade 1 post-baseline
0
0%
7
6%
0
0%
Alkaline phosphatase, serum: Grade 1 baseline to Grade 2 post-baseline
0
0%
3
2.6%
0
0%
Alkaline phosphatase, serum: Grade 1 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Alkaline phosphatase, serum: Grade 2 baseline to Grade 1 post-baseline
0
0%
1
0.9%
0
0%
Alkaline phosphatase, serum: Grade 2 baseline to Grade 2 post-baseline
0
0%
1
0.9%
0
0%
Alkaline phosphatase, serum: Grade 3 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Alkaline phosphatase, serum: 'Missing' baseline to Grade 0 post-baseline
0
0%
2
1.7%
3
12%
Alkaline phosphatase, serum: 'Missing' baseline to Grade 1 post-baseline
0
0%
1
0.9%
1
4%
Alkaline phosphatase, serum: 'Missing' baseline to 'Missing' post-baseline
41
100%
31
26.5%
21
84%
Creatine Kinase: Grade 0 baseline to Grade 0 post-baseline
10
24.4%
20
17.1%
3
12%
Creatine Kinase: Grade 0 baseline to Grade 1 post-baseline
11
26.8%
34
29.1%
6
24%
Creatine Kinase: Grade 0 baseline to Grade 2 post-baseline
6
14.6%
27
23.1%
4
16%
Creatine Kinase: Grade 0 baseline to Grade 3 post-baseline
4
9.8%
13
11.1%
6
24%
Creatine Kinase: Grade 0 baseline to Grade 4 post-baseline
1
2.4%
9
7.7%
1
4%
Creatine Kinase: Grade 0 baseline to 'Missing' post-baseline
2
4.9%
0
0%
1
4%
Creatine Kinase: Grade 1 baseline to Grade 3 post-baseline
2
4.9%
2
1.7%
0
0%
Creatine Kinase: Grade 1 baseline to Grade 4 post-baseline
1
2.4%
2
1.7%
0
0%
Creatine Kinase: Grade 2 baseline to Grade 1 post-baseline
0
0%
1
0.9%
0
0%
Creatine Kinase: Grade 2 baseline to Grade 4 post-baseline
0
0%
1
0.9%
0
0%
Creatine Kinase: Grade 3 baseline to Grade 4 post-baseline
0
0%
0
0%
1
4%
Creatine Kinase: 'Missing' baseline to Grade 1 post-baseline
2
4.9%
4
3.4%
0
0%
Creatine Kinase: 'Missing' baseline to Grade 2 post-baseline
1
2.4%
0
0%
2
8%
Creatine Kinase: 'Missing' baseline to Grade 3 post-baseline
1
2.4%
3
2.6%
0
0%
Creatine Kinase: 'Missing' baseline to 'Missing' post-baseline
0
0%
1
0.9%
1
4%
Creatinine Clearance: Grade 0 baseline to Grade 0 post-baseline
22
53.7%
57
48.7%
16
64%
Creatinine Clearance: Grade 0 baseline to Grade 1 post-baseline
5
12.2%
17
14.5%
4
16%
Creatinine Clearance: Grade 0 baseline to Grade 2 post-baseline
2
4.9%
7
6%
0
0%
Creatinine Clearance: Grade 0 baseline to Grade 3 post-baseline
0
0%
1
0.9%
1
4%
Creatinine Clearance: Grade 0 baseline to Grade 4 post-baseline
0
0%
1
0.9%
0
0%
Creatinine Clearance: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Creatinine Clearance: Grade 1 baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Creatinine Clearance: Grade 1 baseline to Grade 1 post-baseline
6
14.6%
12
10.3%
0
0%
Creatinine Clearance: Grade 1 baseline to Grade 2 post-baseline
1
2.4%
7
6%
2
8%
Creatinine Clearance: Grade 2 baseline to Grade 1 post-baseline
2
4.9%
0
0%
0
0%
Creatinine Clearance: Grade 2 baseline to Grade 2 post-baseline
1
2.4%
6
5.1%
0
0%
Creatinine Clearance: Grade 2 baseline to 'Missing' post-baseline
1
2.4%
0
0%
0
0%
Creatinine Clearance: 'Missing' baseline to 'Missing' post-baseline
0
0%
8
6.8%
1
4%
Creatinine: Grade 0 baseline to Grade 0 post-baseline
9
22%
12
10.3%
4
16%
Creatinine: Grade 0 baseline to Grade 1 post-baseline
27
65.9%
91
77.8%
16
64%
Creatinine: Grade 0 baseline to Grade 2 post-baseline
1
2.4%
9
7.7%
0
0%
Creatinine: Grade 0 baseline to Grade 3 post-baseline
0
0%
0
0%
1
4%
Creatinine: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Creatinine: Grade 1 baseline to Grade 0 post-baseline
1
2.4%
0
0%
0
0%
Creatinine: Grade 1 baseline to Grade 1 post-baseline
1
2.4%
4
3.4%
2
8%
Creatinine: Grade 1 baseline to Grade 2 post-baseline
1
2.4%
1
0.9%
1
4%
Hypomagnesemia: Grade 0 baseline to Grade 0 post-baseline
30
73.2%
78
66.7%
22
88%
Hypomagnesemia: Grade 0 baseline to Grade 1 post-baseline
4
9.8%
21
17.9%
2
8%
Hypomagnesemia: Grade 0 baseline to Grade 2 post-baseline
0
0%
1
0.9%
0
0%
Hypomagnesemia: Grade 0 baseline to 'Missing' post-baseline
2
4.9%
0
0%
1
4%
Hypomagnesemia: Grade 1 baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Hypomagnesemia: Grade 1 baseline to Grade 1 post-baseline
1
2.4%
8
6.8%
0
0%
Hypomagnesemia: Grade 1 baseline to Grade 2 post-baseline
0
0%
1
0.9%
0
0%
Hypomagnesemia: 'Missing' baseline to Grade 0 post-baseline
3
7.3%
5
4.3%
0
0%
Hypomagnesemia: 'Missing' baseline to Grade 1 post-baseline
1
2.4%
1
0.9%
0
0%
Hypomagnesemia: 'Missing' baseline to 'Missing' post-baseline
0
0%
1
0.9%
0
0%
Hypermagnesemia: Grade 0 baseline to Grade 0 post-baseline
35
85.4%
108
92.3%
22
88%
Hypermagnesemia: Grade 0 baseline to Grade 1 post-baseline
0
0%
1
0.9%
2
8%
Hypermagnesemia: Grade 0 baseline to 'Missing' post-baseline
2
4.9%
0
0%
1
4%
Hypermagnesemia: Grade 3 baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Hypermagnesemia: 'Missing' baseline to Grade 0 post-baseline
4
9.8%
6
5.1%
0
0%
Hypermagnesemia: 'Missing' baseline to 'Missing' post-baseline
0
0%
1
0.9%
0
0%
Hypophosphatemia (Inorganic Phosphorus): Grade 0 baseline to Grade 0 post-baseline
36
87.8%
79
67.5%
20
80%
Hypophosphatemia (Inorganic Phosphorus): Grade 0 baseline to Grade 1 post-baseline
1
2.4%
6
5.1%
0
0%
Hypophosphatemia (Inorganic Phosphorus): Grade 0 baseline to Grade 2 post-baseline
0
0%
7
6%
0
0%
Hypophosphatemia (Inorganic Phosphorus): Grade 0 baseline to Grade 3 post-baseline
0
0%
4
3.4%
1
4%
Hypophosphatemia (Inorganic Phosphorus): Grade 0 baseline to 'Missing' post-baseline
2
4.9%
0
0%
1
4%
Hypophosphatemia (Inorganic Phosphorus): Grade 1 baseline to Grade 0 post-baseline
1
2.4%
3
2.6%
1
4%
Hypophosphatemia (Inorganic Phosphorus): Grade 1 baseline to Grade 2 post-baseline
0
0%
1
0.9%
0
0%
Hypophosphatemia (Inorganic Phosphorus): Grade 2 baseline to Grade 0 post-baseline
0
0%
8
6.8%
1
4%
Hypophosphatemia (Inorganic Phosphorus): Grade 2 baseline to Grade 2 post-baseline
0
0%
7
6%
1
4%
Hypophosphatemia (Inorganic Phosphorus): Grade 2 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Hypophosphatemia (Inorganic Phosphorus): 'Missing' baseline to Grade 0 post-baseline
1
2.4%
1
0.9%
0
0%
Hypokalemia: Grade 0 baseline to Grade 0 post-baseline
33
80.5%
93
79.5%
18
72%
Hypokalemia: Grade 0 baseline to Grade 2 post-baseline
3
7.3%
19
16.2%
6
24%
Hypokalemia: Grade 0 baseline to Grade 3 post-baseline
1
2.4%
0
0%
0
0%
Hypokalemia: Grade 0 baseline to Grade 4 post-baseline
1
2.4%
0
0%
0
0%
Hypokalemia: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Hypokalemia: Grade 2 baseline to Grade 0 post-baseline
1
2.4%
1
0.9%
0
0%
Hypokalemia: Grade 2 baseline to Grade 2 post-baseline
0
0%
3
2.6%
0
0%
Hypokalemia: Grade 2 baseline to Grade 4 post-baseline
1
2.4%
1
0.9%
0
0%
Hyperkalemia: Grade 0 baseline to Grade 0 post-baseline
35
85.4%
104
88.9%
21
84%
Hyperkalemia: Grade 0 baseline to Grade 1 post-baseline
3
7.3%
6
5.1%
1
4%
Hyperkalemia: Grade 0 baseline to Grade 2 post-baseline
0
0%
2
1.7%
1
4%
Hyperkalemia: Grade 0 baseline to Grade 3 post-baseline
0
0%
0
0%
1
4%
Hyperkalemia: Grade 0 baseline to Grade 4 post-baseline
0
0%
1
0.9%
0
0%
Hyperkalemia: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Hyperkalemia: Grade 1 baseline to Grade 0 post-baseline
0
0%
4
3.4%
0
0%
Hyperkalemia: Grade 1 baseline to Grade 1 post-baseline
1
2.4%
0
0%
0
0%
Hyperkalemia: Grade 2 baseline to Grade 0 post-baseline
1
2.4%
0
0%
0
0%
AST: Grade 0 baseline to Grade 0 post-baseline
11
26.8%
33
28.2%
5
20%
AST: Grade 0 baseline to Grade 1 post-baseline
24
58.5%
67
57.3%
13
52%
AST: Grade 0 baseline to Grade 2 post-baseline
0
0%
5
4.3%
1
4%
AST: Grade 0 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
AST: Grade 0 baseline to Grade 4 post-baseline
0
0%
0
0%
1
4%
AST: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
AST: Grade 1 baseline to Grade 0 post-baseline
1
2.4%
0
0%
0
0%
AST: Grade 1 baseline to Grade 1 post-baseline
1
2.4%
6
5.1%
3
12%
AST: Grade 1 baseline to Grade 2 post-baseline
2
4.9%
2
1.7%
0
0%
AST: Grade 1 baseline to Grade 3 post-baseline
0
0%
1
0.9%
1
4%
AST: Grade 2 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
AST: Grade 3 baseline to Grade 3 post-baseline
1
2.4%
0
0%
0
0%
AST: 'Missing' baseline to Grade 1 post-baseline
0
0%
1
0.9%
0
0%
ALT: Grade 0 baseline to Grade 0 post-baseline
20
48.8%
58
49.6%
15
60%
ALT: Grade 0 baseline to Grade 1 post-baseline
17
41.5%
39
33.3%
5
20%
ALT: Grade 0 baseline to Grade 2 post-baseline
0
0%
5
4.3%
0
0%
ALT: Grade 0 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
ALT: Grade 0 baseline to Grade 4 post-baseline
0
0%
0
0%
1
4%
ALT: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
ALT: Grade 1 baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
ALT: Grade 1 baseline to Grade 1 post-baseline
3
7.3%
7
6%
2
8%
ALT: Grade 1 baseline to Grade 2 post-baseline
0
0%
4
3.4%
1
4%
ALT: Grade 1 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
ALT: Grade 2 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Hyponatremia: Grade 0 baseline to Grade 0 post-baseline
25
61%
92
78.6%
17
68%
Hyponatremia: Grade 0 baseline to Grade 1 post-baseline
7
17.1%
11
9.4%
3
12%
Hyponatremia: Grade 0 baseline to Grade 3 post-baseline
1
2.4%
5
4.3%
0
0%
Hyponatremia: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Hyponatremia: Grade 1 baseline to Grade 0 post-baseline
3
7.3%
5
4.3%
2
8%
Hyponatremia: Grade 1 baseline to Grade 1 post-baseline
4
9.8%
2
1.7%
2
8%
Hyponatremia: Grade 1 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Hyponatremia: Grade 3 baseline to Grade 3 post-baseline
0
0%
1
0.9%
0
0%
Hypernatremia: Grade 0 baseline to Grade 0 post-baseline
37
90.2%
101
86.3%
24
96%
Hypernatremia: Grade 0 baseline to Grade 1 post-baseline
2
4.9%
14
12%
0
0%
Hypernatremia: Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Hypernatremia: Grade 1 baseline to Grade 0 post-baseline
1
2.4%
2
1.7%
0
0%
Bilirubin (total) increased: Grade 0 baseline to Grade 0 post-baseline
36
87.8%
105
89.7%
22
88%
Bilirubin (total) increased: Grade 0 baseline to Grade 1 post-baseline
1
2.4%
7
6%
0
0%
Bilirubin (total) increased: Grade 0 baseline to Grade 2 post-baseline
0
0%
0
0%
1
4%
Bilirubin (total) increased: Grade 0 baseline to Grade 3 post-baseline
0
0%
2
1.7%
0
0%
Bilirubin (total) increased: Grade 0 baseline to Grade 4 post-baseline
0
0%
1
0.9%
0
0%
Bilirubin (total) increased: Grade 0 baseline to 'Missing' post-baseline
2
4.9%
0
0%
1
4%
Bilirubin (total) increased: Grade 1 baseline to Grade 0 post-baseline
1
2.4%
1
0.9%
1
4%
Bilirubin (total) increased: Grade 1 baseline to Grade 1 post-baseline
1
2.4%
1
0.9%
0
0%
10. Secondary Outcome
Title Number of Participants With Shift From Baseline in Vital Signs Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Blood Pressure)
Description Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP).
Time Frame Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who had received at least one dose of study drug and had at least one valid post-baseline safety assessment.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
Sitting SBP (millimeters of mercury): Grade 0 baseline to Grade 0 post-baseline
4
9.8%
6
5.1%
0
0%
Sitting SBP (millimeters of mercury): Grade 0 baseline to Grade 1 post-baseline
7
17.1%
14
12%
6
24%
Sitting SBP (millimeters of mercury): Grade 0 baseline to Grade 2 post-baseline
1
2.4%
8
6.8%
0
0%
Sitting SBP (millimeters of mercury): Grade 0 baseline to Grade 3 post-baseline
0
0%
2
1.7%
0
0%
Sitting SBP (millimeters of mercury): Grade 1 baseline to Grade 0 post-baseline
2
4.9%
1
0.9%
1
4%
Sitting SBP (millimeters of mercury): Grade 1 baseline to Grade 1 post-baseline
10
24.4%
29
24.8%
6
24%
Sitting SBP (millimeters of mercury): Grade 1 baseline to Grade 2 post-baseline
7
17.1%
23
19.7%
6
24%
Sitting SBP (millimeters of mercury): Grade 1 baseline to Grade 3 post-baseline
2
4.9%
10
8.5%
2
8%
Sitting SBP (millimeters of mercury): Grade 1 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Sitting SBP (millimeters of mercury): Grade 2 baseline to Grade 1 post-baseline
0
0%
4
3.4%
1
4%
Sitting SBP (millimeters of mercury): Grade 2 baseline to Grade 2 post-baseline
3
7.3%
8
6.8%
1
4%
Sitting SBP (millimeters of mercury): Grade 2 baseline to Grade 3 post-baseline
2
4.9%
5
4.3%
0
0%
Sitting SBP (millimeters of mercury): Grade 2 baseline to 'Missing' post-baseline
1
2.4%
0
0%
0
0%
Sitting SBP (millimeters of mercury): Grade 3 baseline to Grade 2 post-baseline
0
0%
3
2.6%
1
4%
Sitting SBP (millimeters of mercury): Grade 3 baseline to Grade 3 post-baseline
1
2.4%
4
3.4%
0
0%
Sitting DBP (millimeters of mercury): Grade 0 baseline to Grade 0 post-baseline
9
22%
14
12%
2
8%
Sitting DBP (millimeters of mercury): Grade 0 baseline to Grade 1 post-baseline
7
17.1%
23
19.7%
6
24%
Sitting DBP (millimeters of mercury): Grade 0 baseline to Grade 2 post-baseline
5
12.2%
8
6.8%
4
16%
Sitting DBP (millimeters of mercury): Grade 0 baseline to Grade 3 post-baseline
3
7.3%
6
5.1%
2
8%
Sitting DBP (millimeters of mercury): Grade 0 baseline to 'Missing' post-baseline
1
2.4%
0
0%
0
0%
Sitting DBP (millimeters of mercury): Grade 1 baseline to Grade 0 post-baseline
1
2.4%
1
0.9%
0
0%
Sitting DBP (millimeters of mercury): Grade 1 baseline to Grade 1 post-baseline
5
12.2%
19
16.2%
1
4%
Sitting DBP (millimeters of mercury): Grade 1 baseline to Grade 2 post-baseline
5
12.2%
17
14.5%
5
20%
Sitting DBP (millimeters of mercury): Grade 1 baseline to Grade 3 post-baseline
1
2.4%
10
8.5%
2
8%
Sitting DBP (millimeters of mercury): Grade 1 baseline to 'Missing' post-baseline
1
2.4%
0
0%
1
4%
Sitting DBP (millimeters of mercury): Grade 2 baseline to Grade 0 post-baseline
0
0%
1
0.9%
0
0%
Sitting DBP (millimeters of mercury): Grade 2 baseline to Grade 1 post-baseline
0
0%
3
2.6%
0
0%
Sitting DBP (millimeters of mercury): Grade 2 baseline to Grade 2 post-baseline
1
2.4%
9
7.7%
1
4%
Sitting DBP (millimeters of mercury): Grade 2 baseline to Grade 3 post-baseline
1
2.4%
4
3.4%
1
4%
Sitting DBP (millimeters of mercury): Grade 3 baseline to Grade 2 post-baseline
0
0%
1
0.9%
0
0%
Sitting DBP (millimeters of mercury): Grade 3 baseline to Grade 3 post-baseline
1
2.4%
1
0.9%
0
0%
11. Secondary Outcome
Title Number of Participants With Markedly Abnormal Vital Sign Values: Sitting Pulse Rate
Description Pre-defined criteria of markedly abnormal vital signs abnormalities was defined as increase or decrease from baseline (>=15 beats per minute) in pulse rate of >=120 beats per minute or less than or equal to (<=) 50 beats per minute.
Time Frame Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Here "Overall number of participants analyzed" signifies participants evaluable for this outcome measure.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 39 116 24
Sitting pulse (High only) (beats per minute)
1
2.4%
2
1.7%
1
4%
Sitting pulse (Low only) (beats per minute)
1
2.4%
6
5.1%
1
4%
Sitting pulse (High and Low) (beats per minute)
0
0%
0
0%
0
0%
12. Secondary Outcome
Title Number of Participants With Markedly Abnormal Vital Sign Values: Weight
Description Vital signs included assessment of body weight. Body weight (in kilograms) measurements included high and low. Pre-defined criteria of markedly abnormal vital signs abnormalities was defined as increase or decrease from baseline in weight of >=10%.
Time Frame Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Here "Overall number of participants analyzed" signifies participants evaluable for this outcome measure.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 39 117 24
Weight (High)
6
14.6%
11
9.4%
8
32%
Weight (Low)
2
4.9%
8
6.8%
0
0%
13. Secondary Outcome
Title Number of Participants With Notable Electrocardiogram (ECG) Values
Description ECG findings included maximum value of >450 millisecond (msec), >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval corrected using Fridericia's formula (QTcF); maximum value of >450 msec, >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval corrected using Bazett's formula (QTcB); maximum value of >450 msec, >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval; RR decrease >25% and to a VR >100, RR increase >25% and to a VR <50 beats per minute for VR interval; an increase >25% and to a value >200 msec for PR interval; an increase >25% and to a value >110 msec for QRS interval.
Time Frame Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
QTcF (millisecond): New >450
5
12.2%
15
12.8%
3
12%
QTcF (millisecond): New >480
1
2.4%
4
3.4%
0
0%
QTcF (millisecond): New >500
0
0%
0
0%
0
0%
QTcF (millisecond): Increase from baseline >30
4
9.8%
24
20.5%
5
20%
QTcF (millisecond): Increase from baseline >60
1
2.4%
1
0.9%
0
0%
QTcB (millisecond): New >450
4
9.8%
26
22.2%
6
24%
QTcB (millisecond): New >480
3
7.3%
7
6%
2
8%
QTcB (millisecond): New >500
0
0%
3
2.6%
1
4%
QTcB (millisecond): Increase from baseline >30
6
14.6%
29
24.8%
6
24%
QTcB (millisecond): Increase from baseline >60
0
0%
2
1.7%
3
12%
QT (millisecond): New >450
6
14.6%
13
11.1%
1
4%
QT (millisecond): New >480
2
4.9%
4
3.4%
0
0%
QT (millisecond): New >500
1
2.4%
1
0.9%
0
0%
QT (millisecond): Increase from baseline >30
14
34.1%
54
46.2%
9
36%
QT (millisecond): Increase from baseline >60
3
7.3%
13
11.1%
3
12%
VR (beats per minute): RR decrease >25% & to a VR >100
2
4.9%
6
5.1%
2
8%
VR (beats per minute): RR increase >25% & to a VR <50
3
7.3%
8
6.8%
2
8%
PR (millisecond): Increase >25% & to a value >200
1
2.4%
6
5.1%
0
0%
QRS (millisecond): Increase >25% & to a value >110
1
2.4%
5
4.3%
1
4%
14. Secondary Outcome
Title Number of Participants With Change From Baseline in Abnormal Ophthalmoscopy Values- by Fundoscopy
Description Fundoscopy examination included an examination of the retina, vitreous, macula, optic nerve, optic nerve pallor, choroid and other new abnormalities in either or both eyes. New abnormalities were identified where the baseline assessment showed no abnormalities in a particular eye, but at the post-dose time point an abnormality was observed. New abnormalities at any time point were reported and included unscheduled assessments.
Time Frame Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
Retina: New abnormalities (At any time)
10
24.4%
43
36.8%
13
52%
Vitreous: New abnormalities (At any time)
2
4.9%
4
3.4%
1
4%
Macula: New abnormalities (At any time)
7
17.1%
39
33.3%
9
36%
Optic Nerve: New abnormalities (At any time)
1
2.4%
5
4.3%
1
4%
Optic Nerve Pallor: New abnormalities (At any time)
0
0%
2
1.7%
0
0%
Choroid: New abnormalities (At any time)
1
2.4%
5
4.3%
2
8%
Other: New abnormalities (At any time)
0
0%
6
5.1%
1
4%
15. Secondary Outcome
Title Number of Participants With Change From Baseline in Abnormal Ophthalmoscopy Values- by Slit Lamp Examination
Description Slit lamp examination included an examination of the conjunctiva, cornea, iris, lens, anterior chamber, lids and other new abnormalities in either or both eyes. New abnormalities were identified where the baseline assessment showed no abnormalities in a particular eye, but at the post-dose time point an abnormality was observed. New abnormalities at any time point were reported and included unscheduled assessments.
Time Frame Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 41 117 25
Conjunctiva: New abnormalities (At any time)
4
9.8%
25
21.4%
7
28%
Cornea: New abnormalities (At any time)
3
7.3%
8
6.8%
5
20%
Iris: New abnormalities (At any time)
0
0%
1
0.9%
0
0%
Lens: New abnormalities (At any time)
5
12.2%
17
14.5%
3
12%
Anterior chamber: New abnormalities (At any time)
0
0%
1
0.9%
0
0%
Lids: New abnormalities (At any time)
6
14.6%
25
21.4%
5
20%
Other: New abnormalities (At any time)
1
2.4%
8
6.8%
16. Secondary Outcome
Title Area Under the Curve From Time Zero to End of Dosing Interval at Steady-State (AUCtau) of Binimetinib
Description
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
Pharmacokinetic (PK) analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
1606.73
(42.55)
1704.80
(20.37)
1587.47
(42.49)
Cycle 1, Day 15
2438.22
(NA)
2051.70
(32.63)
2637.48
(22.04)
17. Secondary Outcome
Title Maximum Plasma Concentration (Cmax) of Binimetinib
Description
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
445.8
(45.8)
471.6
(34.4)
542.5
(29.6)
Cycle 1, Day 15
385.2
(50.1)
479.7
(41.1)
531.3
(44.0)
18. Secondary Outcome
Title Time to Reach Maximum Observed Plasma Concentration (Tmax) of Binimetinib
Description
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
0.68
1.50
0.75
Cycle 1, Day 15
1.50
1.48
1.42
19. Secondary Outcome
Title Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-last) of Binimetinib
Description
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
1318.38
(47.38)
1447.07
(21.34)
1622.66
(37.46)
Cycle 1, Day 15
1806.28
(40.86)
1832.06
(30.71)
2263.46
(39.84)
20. Secondary Outcome
Title The Last Time Point of the Last Quantifiable Concentration (Tlast) of Binimetinib
Description
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
7.23
7.98
7.00
Cycle 1, Day 15
7.50
8.00
7.50
21. Secondary Outcome
Title Trough Plasma Concentration (Ctrough) of Binimetinib
Description Ctrough refers to plasma concentration of Binimetinib observed just before treatment administration.
Time Frame Pre-dose (0 hour) on Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here "Overall number of participants analyzed" signifies participants evaluable for this outcome measure.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 25 65 20
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]
127.0
(69.6)
102.3
(79.1)
136.1
(67.2)
22. Secondary Outcome
Title Apparent Total Body Clearance (CL/F) of Binimetinib
Description Drug clearance was defined as a quantitative measure of the rate at which a drug substance was removed from the plasma. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed.
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
28.01
(46.90)
26.40
(20.98)
37.80
(30.48)
Cycle 1, Day 15
18.46
(NA)
20.50
(26.73)
21.17
(24.18)
23. Secondary Outcome
Title Area Under the Curve From Time Zero to End of Dosing Interval at Steady-State (AUCtau) of Binimetinib's Metabolite
Description
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
257.73
(7.43)
170.11
(12.96)
248.82
(18.33)
Cycle 1, Day 15
253.93
(NA)
322.21
(NA)
24. Secondary Outcome
Title Maximum Plasma Concentration (Cmax) of Binimetinib's Metabolite
Description
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
56.37
(39.22)
49.42
(26.49)
56.71
(47.62)
Cycle 1, Day 15
32.31
(78.98)
33.55
(58.34)
25.47
(76.76)
25. Secondary Outcome
Title Time to Reach Maximum Observed Plasma Concentration (Tmax) of Binimetinib's Metabolite
Description
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
1.50
1.50
1.50
Cycle 1, Day 15
2.50
1.50
1.50
26. Secondary Outcome
Title Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-last) of Binimetinib's Metabolite
Description
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
197.29
(46.15)
181.60
(29.22)
189.37
(50.78)
Cycle 1, Day 15
157.35
(63.36)
129.13
(62.80)
87.11
(79.73)
27. Secondary Outcome
Title The Last Time Point of the Last Quantifiable Concentration (Tlast) of Binimetinib's Metabolite
Description
Time Frame Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here 'number analyzed' signifies participants with available data for each specified category.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 37 105 23
Cycle 1, Day 1
7.23
7.98
7.00
Cycle 1, Day 15
7.50
8.00
7.25
28. Secondary Outcome
Title Trough Plasma Concentration (Ctrough) of Binimetinib's Metabolite
Description Ctrough refers to plasma concentration of Binimetinib's metabolite observed just before treatment administration.
Time Frame Pre-dose (0 hour) on Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description
PK analysis set included all participants who had at least one blood sample providing evaluable PK data. Here "Overall number of participants analyzed" signifies participants evaluable for this outcome measure.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 25 65 20
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]
12.85
(80.44)
11.63
(123.41)
16.10
(104.21)
29. Secondary Outcome
Title Percent Change From Baseline in Histological Score (H-score) for Phosphorylated Extracellular Signal-Regulated Kinase (pERK) From Tumor Samples of Cytoplasmic and Nuclear Cellular Compartment
Description Percent change from baseline in H-score for pERK from tumor samples was assessed and summarized. The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors.
Time Frame Baseline up to maximum duration of up to 33 months

Outcome Measure Data

Analysis Population Description
The full analysis set included all randomized participants who received at least one dose of study drug. Here "Overall number of participants analyzed" signifies participants evaluable for this outcome measure.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 3 8 4
Cytoplasmic: Percent change from baseline
-10.90
(26.460)
-50.11
(22.576)
-9.85
(59.566)
Nuclear: Percent change from baseline
195.19
(219.585)
-66.83
(47.524)
-32.35
(83.258)
30. Secondary Outcome
Title Percent Change From Baseline in Delta CT Values for Dual Specificity Phosphatase 6 (DUSP6) Expression From Tumor Samples
Description The percentage change in DUSP6 gene expression was derived from the Relative Expression Ratio (RER) computed via the Delta Ct method. DUSP6, a protein coding gene was used as a biomarker of inhibition of the mitogen-activated protein kinase (MEK) pathway.
Time Frame Baseline up to maximum duration of up to 33 months

Outcome Measure Data

Analysis Population Description
The full analysis set included all randomized participants who received at least one dose of study drug. Here "Overall number of participants analyzed" signifies participants evaluable for this outcome measure.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
Measure Participants 3 8 3
Mean (Standard Deviation) [percent change]
-50.25
(12.069)
-30.82
(42.836)
29.48
(73.145)

Adverse Events

Time Frame From Baseline up to 30 days after last dose (up to 33 months)
Adverse Event Reporting Description Same event may appear as both an AE and Serious Adverse Events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Analysis performed on safety set.
Arm/Group Title Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Arm/Group Description Participants with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug. Participants with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Participants were followed up to 30 days after last dose of study drug.
All Cause Mortality
Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 5/41 (12.2%) 18/117 (15.4%) 3/25 (12%)
Serious Adverse Events
Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 11/41 (26.8%) 35/117 (29.9%) 9/25 (36%)
Blood and lymphatic system disorders
Anaemia 0/41 (0%) 0/117 (0%) 1/25 (4%)
Lymphadenopathy 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Cardiac disorders
Cardiomyopathy 0/41 (0%) 0/117 (0%) 1/25 (4%)
Supraventricular tachycardia 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Eye disorders
Retinal vein occlusion 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Retinopathy 0/41 (0%) 0/117 (0%) 1/25 (4%)
Gastrointestinal disorders
Abdominal pain 0/41 (0%) 0/117 (0%) 1/25 (4%)
Ascites 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Diarrhoea 1/41 (2.4%) 2/117 (1.7%) 0/25 (0%)
Diarrhoea haemorrhagic 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Enteritis 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Gastritis 1/41 (2.4%) 0/117 (0%) 2/25 (8%)
Ileus paralytic 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Nausea 0/41 (0%) 1/117 (0.9%) 1/25 (4%)
Pancreatitis 0/41 (0%) 0/117 (0%) 1/25 (4%)
Small intestinal perforation 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Vomiting 1/41 (2.4%) 1/117 (0.9%) 1/25 (4%)
General disorders
Face oedema 1/41 (2.4%) 0/117 (0%) 0/25 (0%)
General physical health deterioration 1/41 (2.4%) 3/117 (2.6%) 1/25 (4%)
Malaise 1/41 (2.4%) 0/117 (0%) 0/25 (0%)
Non-cardiac chest pain 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Performance status decreased 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Hepatobiliary disorders
Acute hepatic failure 0/41 (0%) 0/117 (0%) 1/25 (4%)
Hepatic pain 1/41 (2.4%) 0/117 (0%) 0/25 (0%)
Liver injury 0/41 (0%) 0/117 (0%) 1/25 (4%)
Infections and infestations
Erysipelas 0/41 (0%) 4/117 (3.4%) 1/25 (4%)
Gastrointestinal viral infection 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Pneumonia 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Pneumonia pseudomonas aeruginosa 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Skin infection 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Injury, poisoning and procedural complications
Femur fracture 1/41 (2.4%) 0/117 (0%) 0/25 (0%)
Investigations
Aspartate aminotransferase increased 0/41 (0%) 1/117 (0.9%) 1/25 (4%)
Blood creatine phosphokinase increased 0/41 (0%) 2/117 (1.7%) 0/25 (0%)
Gamma-glutamyltransferase increased 0/41 (0%) 1/117 (0.9%) 1/25 (4%)
Heart rate irregular 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
International normalised ratio increased 0/41 (0%) 0/117 (0%) 1/25 (4%)
Troponin T increased 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Metabolism and nutrition disorders
Dehydration 1/41 (2.4%) 2/117 (1.7%) 0/25 (0%)
Hyperglycaemia 1/41 (2.4%) 0/117 (0%) 1/25 (4%)
Hypoglycaemia 0/41 (0%) 0/117 (0%) 1/25 (4%)
Hypokalaemia 2/41 (4.9%) 0/117 (0%) 0/25 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Back pain 1/41 (2.4%) 1/117 (0.9%) 0/25 (0%)
Intervertebral disc protrusion 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain 0/41 (0%) 0/117 (0%) 1/25 (4%)
Tumour pain 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Nervous system disorders
Convulsion 1/41 (2.4%) 0/117 (0%) 0/25 (0%)
Grand mal convulsion 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Headache 1/41 (2.4%) 0/117 (0%) 1/25 (4%)
Presyncope 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Pregnancy, puerperium and perinatal conditions
Retained placenta or membranes 1/41 (2.4%) 0/117 (0%) 0/25 (0%)
Renal and urinary disorders
Renal failure 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Renal failure acute 0/41 (0%) 0/117 (0%) 1/25 (4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea 1/41 (2.4%) 1/117 (0.9%) 0/25 (0%)
Haemoptysis 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Laryngeal oedema 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Lung disorder 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Pleural effusion 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Pneumothorax 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Pulmonary haemorrhage 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Respiratory distress 1/41 (2.4%) 0/117 (0%) 0/25 (0%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform 1/41 (2.4%) 0/117 (0%) 0/25 (0%)
Pruritus 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Skin lesion 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Vascular disorders
Haematoma 0/41 (0%) 1/117 (0.9%) 1/25 (4%)
Hypertensive crisis 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Hypotension 0/41 (0%) 1/117 (0.9%) 0/25 (0%)
Other (Not Including Serious) Adverse Events
Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 40/41 (97.6%) 117/117 (100%) 25/25 (100%)
Blood and lymphatic system disorders
Anaemia 4/41 (9.8%) 17/117 (14.5%) 3/25 (12%)
Eye disorders
Retinopathy 1/41 (2.4%) 12/117 (10.3%) 9/25 (36%)
Chorioretinopathy 0/41 (0%) 16/117 (13.7%) 1/25 (4%)
Periorbital oedema 3/41 (7.3%) 10/117 (8.5%) 3/25 (12%)
Retinal detachment 2/41 (4.9%) 11/117 (9.4%) 1/25 (4%)
Gastrointestinal disorders
Diarrhoea 18/41 (43.9%) 57/117 (48.7%) 13/25 (52%)
Nausea 10/41 (24.4%) 36/117 (30.8%) 12/25 (48%)
Vomiting 4/41 (9.8%) 20/117 (17.1%) 9/25 (36%)
Constipation 3/41 (7.3%) 23/117 (19.7%) 4/25 (16%)
Abdominal pain 1/41 (2.4%) 12/117 (10.3%) 4/25 (16%)
Abdominal pain upper 1/41 (2.4%) 9/117 (7.7%) 1/25 (4%)
Dyspepsia 1/41 (2.4%) 6/117 (5.1%) 3/25 (12%)
Stomatitis 1/41 (2.4%) 8/117 (6.8%) 1/25 (4%)
General disorders
Oedema peripheral 17/41 (41.5%) 57/117 (48.7%) 14/25 (56%)
Fatigue 12/41 (29.3%) 39/117 (33.3%) 12/25 (48%)
Pyrexia 5/41 (12.2%) 17/117 (14.5%) 1/25 (4%)
Face oedema 5/41 (12.2%) 11/117 (9.4%) 4/25 (16%)
Asthenia 2/41 (4.9%) 10/117 (8.5%) 0/25 (0%)
Infections and infestations
Rash pustular 0/41 (0%) 11/117 (9.4%) 1/25 (4%)
Investigations
Blood creatine phosphokinase increased 12/41 (29.3%) 60/117 (51.3%) 14/25 (56%)
Aspartate aminotransferase increased 2/41 (4.9%) 20/117 (17.1%) 2/25 (8%)
Alanine aminotransferase increased 1/41 (2.4%) 18/117 (15.4%) 2/25 (8%)
Blood alkaline phosphatase increased 0/41 (0%) 10/117 (8.5%) 3/25 (12%)
Ejection fraction decreased 0/41 (0%) 10/117 (8.5%) 1/25 (4%)
Metabolism and nutrition disorders
Decreased appetite 5/41 (12.2%) 18/117 (15.4%) 3/25 (12%)
Musculoskeletal and connective tissue disorders
Arthralgia 3/41 (7.3%) 9/117 (7.7%) 6/25 (24%)
Myalgia 2/41 (4.9%) 12/117 (10.3%) 4/25 (16%)
Pain in extremity 3/41 (7.3%) 14/117 (12%) 1/25 (4%)
Nervous system disorders
Dysgeusia 9/41 (22%) 8/117 (6.8%) 1/25 (4%)
Headache 3/41 (7.3%) 7/117 (6%) 4/25 (16%)
Dizziness 3/41 (7.3%) 6/117 (5.1%) 3/25 (12%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea 2/41 (4.9%) 11/117 (9.4%) 1/25 (4%)
Cough 5/41 (12.2%) 5/117 (4.3%) 1/25 (4%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform 15/41 (36.6%) 63/117 (53.8%) 8/25 (32%)
Rash 16/41 (39%) 24/117 (20.5%) 5/25 (20%)
Pruritus 4/41 (9.8%) 21/117 (17.9%) 3/25 (12%)
Dry skin 1/41 (2.4%) 18/117 (15.4%) 5/25 (20%)
Alopecia 3/41 (7.3%) 15/117 (12.8%) 2/25 (8%)
Erythema 4/41 (9.8%) 8/117 (6.8%) 2/25 (8%)
Vascular disorders
Hypertension 2/41 (4.9%) 24/117 (20.5%) 5/25 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

Name/Title Pfizer ClinicalTrials.gov Call Center
Organization Pfizer Inc.
Phone 1-800-718-1021
Email ClinicalTrials.gov_Inquiries@pfizer.com
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT01320085
Other Study ID Numbers:
  • CMEK162X2201
  • C4211001
  • 2010-023412-13
First Posted:
Mar 22, 2011
Last Update Posted:
Nov 22, 2021
Last Verified:
Nov 1, 2021