Clincosm LogoSign in Get a demo

Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma

Sponsor
Pfizer (Industry)
Overall Status
Completed
CT.gov ID
NCT01763164
Collaborator
(none)
402
Enrollment
229
Locations
2
Arms
70.7
Actual Duration (Months)
1.8
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Two-arm, randomized, prospective, open-label, multi-center, phase III study to compare the efficacy and safety of MEK162 (45 mg BID) versus dacarbazine (1000 mg/m2 IV every 3 weeks) in patients with advanced (Stage IIIC) unresectable or metastatic (Stage IV) NRAS Q61 mutation-positive cutaneous or unknown primary melanoma. The mutation analysis will be performed at a central laboratory. Only those patients with Q61 mutation per central laboratory and meet all eligibility criteria will be randomized. A total of 393 patients will be randomized 2:1 to receive either MEK162 or dacarbazine. Patients will be stratified according to AJCC stage (IIIC, IVM1a, and IVM1b versus IVM1c), ECOG Performance status (0 versus 1) and any prior number of lines of immunotherapy (immunotherapies versus none). This study will use an Interactive Response Technology (IRT). The primary end point of the study is progression-free survival. Key secondary end point is overall survival

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
402 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
The NEMO Trial (NRAS Melanoma and MEK Inhibitor):A Randomized Phase III, Open Label, Multicenter, Two-arm Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Patients With Advanced Unresectable or Metastatic NRAS Mutation-positive Melanoma
Actual Study Start Date :
Jul 12, 2013
Actual Primary Completion Date :
Dec 1, 2015
Actual Study Completion Date :
Jun 4, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: MEK162

Drug: MEK162
MEK162 will be administered as a fixed dose of 45 mg (3 x 15 mg tablets) BID, with a glass of water and taken with or without food.
Active Comparator: Dacarbazine

Drug: Dacarbazine
Patients randomized to dacarbazine will receive an IV infusion of dacarbazine 1000 mg/m2 over the course of 1 hour on day 1 and then every three weeks.

Outcome Measures

Primary Outcome Measures

  1. Progression-Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [From the date of randomization to the date of the first documented PD or death, whichever occurred first (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)]

    PFS: time from randomization to first documented PD or death due to any cause, whichever occurred first. RECIST 1.1, PD: >=20% increase in sum of diameter of target lesions (TLs) taking as reference the smallest sum on study (including baseline sum), sum must also be an absolute increase of >=5 mm; unequivocal progression of existing non-TLs; appearance of >=1 lesion. Complete response (CR): disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs. Partial response (PR): >=30% decrease in sum of diameter of all TLs, referring baseline sum of diameters. Stable disease (SD): neither sufficient shrinkage to qualify for PR nor increase in lesions qualified for PD referring smallest sum diameter. With no event at time of analysis cut-off or at start of any new anti-neoplastic therapy, PFS censored at date of last adequate tumor assessment of CR, PR or SD.

Secondary Outcome Measures

  1. Overall Survival (OS) [From the date of randomization to the date of death (maximum up to 107 weeks for binimetinib arm; maximum up to 88 weeks for dacarbazine arm)]

    Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a participant was not known to have died, overall survival was censored at the date of last known date participant alive.

  2. Overall Response Rate (ORR) [From date of randomization until first documented response of CR or PR (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)]

    ORR: percentage of participants with best overall response (BOR) of CR or PR. BOR: best response recorded from start of treatment until CR or PR. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter of all TLs, taking as reference baseline sum of diameters. ORR is reported for confirmed and unconfirmed responses. Confirmed CR or PR = at least 2 determinations of CR or PR at least 4 weeks apart before PD. PD: >=20% increase in sum of diameter of all measured target lesions, taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non TLs. Appearance of at least 1 new lesion.

  3. Time to Response (TTR) [From date of randomization until first documented response of CR or PR (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)]

    TTR: time between date of randomization until first documented response of CR or PR. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter (dia) of all TLs, referring baseline sum of dia; c) PD: >=20% increase in sum of diameter of all measured TLs taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non-TLs. Appearance of >=1 new lesion. Participants who did not achieve PR or CR censored at last adequate tumor assessment date when they did not have PFS event (time from date of randomization to date of first documented PD or death due to any cause, whichever occur first) or at maximum follow-up when they had PFS event.

  4. Duration of Objective Response (DOR) [From the date of first documented response (CR or PR) to the first documented progression or death (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)]

    DOR: time from date of first documented response (CR or PR) to first documented progression or death due to underlying cancer. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter (dia) of all TLs, referring baseline sum of dia; c) PD: >=20% increase in sum of diameter of all measured target lesions taking as reference smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion. If a participant with a CR or PR had no PD or death due to underlying cancer, participants was censored at date of last adequate tumor assessment.

  5. Disease Control Rate (DCR) [From date of randomization until first documented response of CR, PR, SD or non-CR/non-PD (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)]

    DCR was calculated as the percentage of participants with a BOR of CR, PR, SD RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters; c) SD: neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD taking as reference the smallest sum diameters; d) PD: >=20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion.

  6. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [From baseline up to 219.4 weeks for binimetinib arm; From baseline up to 123.9 weeks for dacarbazine arm]

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. SAE was defined as one of the following: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE was defined as an AE with onset date occurring during the on-treatment period. AEs included all SAEs and non-SAEs.

  7. Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 [From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm]

    Clinically notable shifts are defined as worsening by at least 2 grades or to >= grade 3. Severity was graded as 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 AE.

  8. Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 [From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm]

    Clinically notable shifts are defined as worsening by at least 2 grades or to >= grade 3. Severity was graded as 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 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 AE.

  9. Number of Participants With Clinically Notable Vital Signs [From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm]

    Abnormalities criteria included: low/high pulse rate (beats per minute [bpm]):<=50bpm with decrease from baseline >=15bpm/>=120bpm with increase from baseline >=15bpm; Low/high systolic blood pressure (millimeters of mercury [mmHg]): <=90mmHg with decrease from baseline >=20mmHg/>=160mmHg with increase from baseline >=20mmHg; Low/high diastolic blood pressure [mmHg]: <=50mmHg with decrease from baseline >=15mmHg/>=100mmHg with increase from baseline >=15mmHg; Low/high body weight (kilogram [kg]): >=20% decrease from baseline / >=10% increase from baseline; Low/high body temperature (degree Celsius [°C]): <=36°C / >= 37.5°C

  10. Number of Participants With Notable Electrocardiogram (ECG) Values [From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm]

    Criteria for notable ECG values were as follow: QT interval (in millisecond [msec]) new (newly occurring post-baseline value) greater than (>) 450, 480, 500, increase from baseline >30, increase from baseline >60; corrected QT interval by Fredericia formula (QTcF) in msec new (newly occurring post-baseline value) > 450, 480, 500, increase from baseline >30, increase from baseline >60; corrected QT interval by Bazett's formula (QTcB) in msec new (newly occurring post-baseline value) > 450, 480, 500, increase from baseline >30, increase from baseline >60; heart rate in bpm new (newly occurring post-baseline value) <60 and >100.

  11. Number of Participants With Adverse Events of Special Interest: Cardiac Events [From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm]

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. 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 AE. Here, in this outcome measure data is reported for events falling in any of the grades.

  12. Number of Participants With Clinically Significant Findings in Physical Examination [From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm]

    A complete physical examination included the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological systems. If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and pelvic examinations were performed. Clinical significance in physical examination was reported as adverse events.

  13. Number of Participants With Adverse Events of Special Interest: Ocular Events [From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm]

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. 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 ADL; Grade 3: Severe or medically significant but not immediately sight threatening; Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) in the affected eye. Here, in this outcome measure data is reported for events falling in any of the grades.

  14. Plasma Concentration of Binimetinib [Day 1 of Week 1: Pre-dose, 1, 1.5, 2, 10 hours post-dose; Day 1 of Weeks 4, 7: Pre-dose, 1.5 hours post-dose; Day 1 of Weeks 10, 13: Pre-dose]

  15. Time to Definitive 10% Deterioration in Global Health Status Score of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) [From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm]

    The time to definitive 10% deterioration was defined as the time from the date of randomization to the date of event, which was defined as death due to any cause or at least 10% worsening of the corresponding scale score, relative to baseline, with no later improvement above this threshold observed during the course of the study or death due to any cause. If a participant had no event prior to analysis cut-off or start of another anticancer therapy, time to deterioration was censored at the date of the last adequate health related quality of life (HRQoL) evaluation. EORTC QLQ-C30: 5 functional scales (physical, role, cognitive, emotional, and social), a global health status scale, 3 symptom scales (nausea/vomiting, pain, fatigue) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single-item measures range =0 to 100. High score for global health status = high quality of life.

  16. Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 [Both arms: Baseline, Day 1 Treatment Week (TW) 4,7,13,19,25,34,43,52; Post-treatment follow-up Visit (FUV) 1 to 6; Binimetinib: Day 1 TW61,70; End of treatment (EOT= TW73); Safety FUV=30 days post TW73; Dacarbazine: EOT=TW 57;Safety FUV=30 days post TW57]

    EORTC QLQ-C30: 5 functional scales (physical, role, cognitive, emotional, and social), a h global health status scale, 3 symptom scales (nausea/vomiting, pain, fatigue) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single-item measures range =0 to 100. High score for global health status = high quality of life. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.

  17. Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 [Both arms: Baseline, Day 1 Treatment Week (TW) 4,7,13,19,25,34,43,52; Post-treatment follow-up Visit (FUV) 1 to 6; Binimetinib: Day 1 TW61,70; End of treatment (EOT= TW73); Safety FUV=30 days post TW73; Dacarbazine: EOT=TW 57;Safety FUV=30 days post TW57]

    EQ-5D-5L, is a standardized measure of health utility that provides a single index value for one's health status. EQ-5D-5L contained 1 item for each of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Index score: participant responses to the 5 dimensions reflected a specific health state that corresponded to a population preference weight for that state on a continuous scale of 0 (death) to 1 (perfect health). Higher index scores = better health state. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.

  18. Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) [From baseline up to 73 weeks 3 days for binimetinib arm; From baseline up to 57 weeks 3 days for dacarbazine arm]

    ECOG PS was used to assess the physical health of participants, and ranged from 0 (most active) to 5 (dead). ECOG PS grades: 0= fully active, able to carry on all pre-disease performance without restriction, 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work, 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, confined to bed or chair more than 50% of waking hours, 4=completely disabled. cannot carry on any selfcare. Totally confined to bed or chair and 5= dead. Definitive deterioration is defined as on treatment death due to any cause or decrease in ECOG PS by at least one category from baseline score.

  19. Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) [For both arms: Baseline, Weeks 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55 and 30-day Follow-up For binimetinib only: Weeks 58, 61, 64, 67, 70, 73]

    ECOG PS was used to assess the physical health of participants, and ranged from 0 (most active) to 5 (dead). ECOG PS grades: 0= fully active, able to carry on all pre-disease performance without restriction, 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work, 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, 4=completely disabled. cannot carry on any selfcare. Totally confined to bed or chair confined to bed or chair more than 50% of waking hours and 5= dead. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.

  20. Number of Participants With Neuroblastoma RAS Viral (V-ras) Oncogene Homolog (NRAS) Mutation Status at Baseline [Baseline]

    Number of participants with NRAS mutation status at baseline were reported.

Eligibility Criteria

Criteria

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

  • Diagnosis of locally advanced, unresectable or metastatic cutaneous or melanoma of unknown primary AJCC Stage IIIC or IV (uveal and mucosal melanoma are excluded)

  • Presence of NRAS Q61 mutation in tumor tissue prior to randomization as determined by a Novartis designated central laboratory

  • Naïve untreated patients or patients who have progressed on or after any number of prior lines of immunotherapy for unresectable locally advanced or metastatic melanoma

  • Evidence of at least one measurable lesion as detected by radiological or photographic methods

  • Adequate bone marrow, organ function, cardiac and laboratory parameters

  • Normal functioning of daily living activities

Exclusion Criteria:

  • Any untreated CNS metastases

  • Uveal or mucosal melanoma

  • History of or current evidence of retinal vein occlusion (RVO) or risk factors of RVO

  • Patients with washout period < 6 weeks from the last dose of ipilimumab or other immunotherapy.

  • Previous systemic chemotherapy for unresectable locally advanced or metastatic melanoma.

  • History of Gilbert's syndrome

  • Prior therapy with a MEK- inhibitor

  • Impaired cardiovascular function or clinically significant cardiovascular diseases

  • Uncontrolled arterial hypertension despite medical treatment

  • HIV positive or active Hepatitis A or B

  • Impairment of gastrointestinal function

  • Patients who have undergone major surgery or radiotherapy ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure;

  • Patients with neuromuscular disorders that are associated with elevated CK.

  • Pregnant or nursing (lactating) women

  • Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study

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
2 Highlands Oncology Group Rogers Arkansas United States 72758
3 Florida Cancer Specialists Altamonte Springs Florida United States 32701
4 Florida Cancer Specialists Bonita Springs Florida United States 34135
5 Florida Cancer Specialists Bradenton Florida United States 34209
6 Florida Cancer Specialists Brandon Florida United States 33511
7 Florida Cancer Specialists Cape Coral Florida United States 33914
8 Florida Cancer Specialists Clearwater Florida United States 33756
9 Florida Cancer Specialists Clearwater Florida United States 33761
10 Florida Cancer Specialists Fort Myers Florida United States 33905
11 Florida Cancer Specialists Fort Myers Florida United States 33908
12 Florida Cancer Specialists Gainesville Florida United States 32605
13 Florida Cancer Specialists Hudson Florida United States 34667
14 Florida Cancer Specialists Inverness Florida United States 34453
15 Florida Cancer Specialists Largo Florida United States 33770
16 Florida Cancer Specialists Largo Florida United States 33777
17 Florida Cancer Specialists Naples Florida United States 34102
18 Florida Cancer Specialists Naples Florida United States 34119
19 Florida Cancer Specialists New Port Richey Florida United States 34655
20 Florida Cancer Specialists Orange City Florida United States 32763
21 Florida Cancer Specialists Orlando Florida United States 32806
22 Florida Cancer Specialists Port Charlotte Florida United States 33980
23 Florida Cancer Specialists Saint Petersburg Florida United States 33705
24 Florida Cancer Specialists Saint Petersburg Florida United States 33707
25 Florida Cancer Specialists Sarasota Florida United States 34232
26 Florida Cancer Specialists Sarasota Florida United States 34236
27 Florida Cancer Specialists Spring Hill Florida United States 34608
28 Florida Cancer Specialists Tampa Florida United States 33607
29 Florida Cancer Specialists Tampa Florida United States 33613
30 Florida Cancer Specialists Tavares Florida United States 32778
31 Florida Cancer Specialists Venice Florida United States 34285
32 Florida Cancer Specialists Venice Florida United States 34292
33 Oncology Specialists, SC Niles Illinois United States 60714
34 Oncology Specialists, SC Park Ridge Illinois United States 60068
35 Goshen Center For Cancer Care Goshen Indiana United States 46526
36 Eastern Maine Medical Center Bangor Maine United States 04401
37 Harry and Jeannette Weinberg Cancer Institute @Franklin Square Baltimore Maryland United States 21237
38 Massachusetts General Hospital Boston Massachusetts United States 02114
39 Brigham and Women's Hospital Boston Massachusetts United States 02115
40 Dana Farber Cancer Institute Boston Massachusetts United States 02215
41 Kresge Eye Institute Bingham Farms Michigan United States 48025
42 Barbara Ann Karmanos Cancer Institute Detroit Michigan United States 48201
43 Kresge Eye Institute Detroit Michigan United States 48201
44 Karmanos Cancer Institute of Farmington Hills Farmington Hills Michigan United States 48334
45 Nebraska Methodist Hospital Omaha Nebraska United States 68114
46 Hackensack University Medical Center Hackensack New Jersey United States 07601
47 John Theurer Cancer Center at Hackensack University Medical Center Hackensack New Jersey United States 07601
48 Cooper University Hospital Voorhees New Jersey United States 08043
49 The Ohio State University James Cancer Hospital Columbus Ohio United States 43210
50 The Ohio State University Martha Morehouse Medical Plaza Columbus Ohio United States 43221
51 OHSU Knight Cancer Institute Portland Oregon United States 97201
52 Kaiser Permanente Northwest Region Oncology/Hematology Portland Oregon United States 97227
53 OHSU Center for Health and Healing Portland Oregon United States 97239
54 OHSU Portland Oregon United States 97239
55 Oregon Health and Science University Portland Oregon United States 97239
56 Cancer Center Associates - Medical Oncology Allentown Pennsylvania United States 18104
57 St. Luke's Cancer Center - Allentown Campus Allentown Pennsylvania United States 18104
58 St. Luke's Hospital - Allentown Campus Allentown Pennsylvania United States 18104
59 Cancer Center Associates - Medical Oncology Bethlehem Pennsylvania United States 18015
60 St. Luke's University Hospital - Bethlehem Campus Bethlehem Pennsylvania United States 18015
61 St. Luke's Cancer Center - Anderson Campus Easton Pennsylvania United States 18045
62 Penn State Milton S. Hershey Medical Center Hershey Pennsylvania United States 17033
63 Hospital of the University of Pennsylvania, Perelman Center for Advanced Medicine Philadelphia Pennsylvania United States 19104
64 Thomas Jefferson Medical Oncology Philadelphia Pennsylvania United States 19107
65 Thomas Jefferson University Philadelphia Pennsylvania United States 19107
66 St. Luke's Hospital - Quakertown Campus Quakertown Pennsylvania United States 18951
67 Sarah Cannon Research Institute Nashville Tennessee United States 37203
68 Texas Oncology-Austin Central Austin Texas United States 78731
69 Elliot J. Ginchansky, MD, PA Dallas Texas United States 75230
70 Dennis B. Kay Dallas Texas United States 75231
71 Parkland Memorial Hospital Dallas Texas United States 75235
72 UT Southwestern University Hospital- St. Paul Dallas Texas United States 75235
73 Texas Oncology-Baylor Charles A. Sammons Cancer Center Dallas Texas United States 75246
74 UT Southwestern Medical Center at Dallas Dallas Texas United States 75390
75 UT Southwestern University Hospital - Zale Lipshy Dallas Texas United States 75390
76 US Oncology Fort Worth Texas United States 76177-3204
77 US Oncology The Woodlands Texas United States 77380
78 Sanatorio de La Providencia Buenos Aires Ciudad Autónoma DE Buenosaires Argentina C1050AAK
79 Centro de Investigación Clínica ? Clínica Viedma Viedma RÍO Negro Argentina 08500
80 Centro Oncologico de Rosario Rosario Santa FE Argentina S2000KZE
81 Fundacion CIDEA Buenos Aires Argentina C1125ABE
82 Chris O'Brien Lifehouse Hospital Camperdown New South Wales Australia 2050
83 Lake Macquarie Private Hospital Gateshead New South Wales Australia 02290
84 Melanoma Institute Australia North Sydney New South Wales Australia 2060
85 Princess Alexandra Hospital Woolloongabba Queensland Australia 4102
86 Royal Adelaide Hospital Adelaide South Australia Australia 05000
87 LKH-Universitätsklinikum Klinikum Graz Graz Steiermark Austria 08036
88 Universitätsklinikum Innsbruck Innsbruck Tirol Austria 06020
89 Salzburger Landeskliniken Salzburg Austria 05020
90 Allgemeines Krankenhaus der Stadt Wien Vienna Austria 01090
91 Sint-Augustinuskliniek Wilrijk Antwerpen Belgium 2610
92 UZ Gasthuisberg Leuven Belgium 03000
93 CHU Sart Tilman Liege Belgium 04000
94 Hospital de Clinicas de Passo Fundo Passo Fundo RIO Grande DO SUL Brazil 99010-260
95 Hospital Moinhos de Vento Porto Alegre RIO Grande DO SUL Brazil 90035-903
96 Hospital Moinhos de Vento Porto Alegre RIO Grande DO SUL Brazil 90560-030
97 INCA Instituto Nacional de Cancer Rio de Janeiro Brazil 20220410
98 Hospital São José Sao Paulo Brazil 01321-001
99 Alberta Health Services - Cross Cancer Institute Edmonton Alberta Canada T6G 1Z2
100 London Regional Cancer Program London Ontario Canada N6A 4L6
101 Sunnybrook Research Institute Centre Toronto Ontario Canada M4N 3M5
102 Princess Margaret Cancer Centre Toronto Ontario Canada M5G 2M9
103 McGill University Health Center / Royal Victoria Hospital Montreal Quebec Canada H4A 3J1
104 CHU de Quebec - L'Hotel-Dieu de Quebec Quebec Canada G1R 2J6
105 Mou/Mmci - Ppds Brno Jihomoravský KRAJ Czechia 656 53
106 Fakultni nemocnice Ostrava Ostrava Czechia 708 52
107 Fakultni nemocnice Kralovske Vinohrady Praha 10 Czechia 100 34
108 Vseobecna Fakultni Nemocnice V Praze Praha 2 Czechia 128 08
109 CHU Angers Angers Maine-et-loire France 49033
110 CHRU de Lille - Hôpital Huriet Lille Nord France 59037
111 Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer Rhône Alpes Lyon Rhône France 69373
112 Hôpital Saint-André Bordeaux France 33000
113 Centre Hospitalier Universitaire Ambroise Pare Boulogne Billancourt France 92100
114 Centre Hospitalier Le Mans Le Mans France 72037
115 Hopitaux de La Timone Marseille France 13385
116 Groupe Hospitalier Archet I Et II Nice France 06202
117 Hôpital Saint Louis Paris France 75010
118 Service de PneumologieCHU Lyon Sud Pierre Benite France 69495
119 Hôpital Robert Debré Reims France 51092
120 Centre Hospitalier Universitaire Hopitaux de Rouen Rouen France 76031
121 Universitaetsklinikum Freiburg Freiburg im Breisgau Baden-württemberg Germany 79104
122 Klinikum Mannheim Universitätsklinikum gGmbH Mannheim Baden-württemberg Germany 68135
123 LMU Klinikum der Universität München München Bayern Germany 80337
124 University Clinic Regensburg - PPDS Regensburg Bayern Germany 93053
125 Universitätsklinikum Würzburg Würzburg Bayern Germany 97080
126 Institut für Diagnostische und Interventionelle Radiologie Frankfurt Frankfurt Hessen Germany 60590
127 Universitätsklinikum Frankfurt Frankfurt Hessen Germany 60590
128 Elben Klinken Stade Buxtehude Buxtehude Niedersachsen Germany 21614
129 Johannes Wesling Klinikum Minden Minden Nordrhein-westfalen Germany 32429
130 Klinikum Dorothea Christiane Erxleben Quedlinburg GmbH Quedlinburg Sachsen-anhalt Germany 06484
131 Universitatsklinikum Leipzig Leipzig Sachsen Germany 04103
132 Charite Campus Mitte Berlin Schleswig-holstein Germany 10117
133 Helios Klinikum Erfurt Erfurt Thüringen Germany 99089
134 Universitätsklinikum Carl Gustav Carus an der TU Dresden Dresden Germany 01307
135 Universitätsklinikum Essen Essen Germany 45147
136 SRH Wald-Klinikum Gera GmbH Gera Germany 07548
137 Medizinische Hochschule Hannover (Hannover Medical School) Hannover Germany 30625
138 University Clinic Heidelberg - PPDS Heidelberg Germany 69120
139 Universitatsklinikum Schleswig-Holstein Kiel Germany 24105
140 Uniklinik Köln Koeln Germany 50937
141 Universitatsklinikum Schleswig-Holstein Lübeck Germany 23538
142 Fachklinik Hornheide Münster Germany 48157
143 Klinikum Nuernberg Nord Nürnberg Germany 90419
144 Universitätsklinikum Tübingen Tübingen Germany 72076
145 Universit*ätsklinikum Ulm Ulm Germany 89081
146 Laiko General Hospital of Athens Athens Greece 115 27
147 Magyar Honvédség Egészségügyi Központ Budapest Hungary 01062
148 Orszagos Onkologiai Intezet Budapest Hungary H-1122
149 Somogy Megyei Kaposi Mór Oktató Kórház Kaposvár Hungary 07400
150 Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet Szolnok Hungary 05004
151 Rambam Medical Center - PPDS Haifa Israel 3109601
152 Hadassah Medical Center - PPDS Jerusalem Israel 91120
153 Sheba Medical Center - PPDS Ramat Gan Israel 5262100
154 AOU dell'Università degli Studi della Campania Luigi Vanvitelli Napoli Campania Italy 80138
155 Istituto Dermopatico dell'Immacolata IRCCS Roma Lazio Italy 00167
156 ASST degli Spedali Civili di Brescia - Spedali Civili di Brescia Brescia Lombardia Italy 25123
157 Istituto Nazionale per lo studio e la cura dei tumori Fondazione Giovanni Pascale Napoli Naples Italy 80131
158 Istituto Oncologico Veneto - I.R.C.C.S. Padova Veneto Italy 35128
159 IRCCS Giovanni Paolo II Istituto Oncologico Bari Italy 70126
160 ASST Papa Giovanni XXIII - Azienda Ospedaliera Papa Giovanni XXIII Bergamo Italy 24129
161 IRCCS Az. Osp. Universitaria San Martino- IST Genova Italy 16132
162 Ospedale San Raffaele S.r.l. - PPDS Milano Italy 20132
163 Fondazione IRCCS 'Istituto Nazionale dei Tumori' di Milano Milano Italy 20133
164 Istituto Nazionale Tumori Regina Elena Roma Italy 00144
165 Azienza Ospedaliera Universitaria Senese Siena Italy 53100
166 A.O.U. Città della Salute e della Scienza di Torino - Presidio S. Lazzaro Torino Italy 10126
167 Shinshu University Hospital Matsumoto Nagano Japan 390-8621
168 National Cancer Center Hospital Chuo-ku Japan 1040045
169 Kansai Medical University Hospital Hirakata-city Japan 573-1191
170 Asan Medical Center - PPDS Seoul Korea, Republic of 05505
171 Samsung Medical Center - PPDS Seoul Korea, Republic of 06351
172 Seoul National University Hospital Seoul Korea, Republic of 110-744
173 Severance Hospital Yonsei University Health System - PPDS Seoul Korea, Republic of 3722
174 Radboud University Nijmegen Medical Centre Nijmegen Gelderland Netherlands 6525 GA
175 Het Nederlands Kanker Instituut Antoni Van Leeuwenhoek Ziekenhuis Amsterdam Noord-holland Netherlands 1066 CX
176 Leids Universitair Medisch Centrum Leiden Zuid-holland Netherlands 2333ZA
177 Isala Klinieken Zwolle Netherlands 8025 AB
178 Centrum Medyczne MAVIT Sp. z o.o. Warszawa Mazowieckie Poland 01-673
179 Lux Med Warszawa Poland 02-676
180 Centrum Onkologii Instytut im. Marii Sklodowskiej-Curie Warszawa Poland 02-781
181 Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E. Lisbon Lisboa Portugal 1099-023
182 Hospital Garcia de Orta*E.P.E. Almada Portugal 2801-951
183 Centro Hospitalar Lisboa Norte, E.P.E. - Hospital de Santa Maria Lisboa Portugal 1649-035
184 Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS Porto Portugal 4200-072
185 Russian Oncology Research Center n a N N Blokhin Moscow Russian Federation 115478
186 Ryazan Regional Clinical Oncology Dispensary Ryazan Russian Federation 390011
187 Scientific Research Institute of Oncology n.a. N.N. Petrov St. Petersburg Russian Federation 197758
188 Narodny onkologicky ustav Bratislava Slovakia 833 01
189 University of The Free State Bloemfontein FREE State South Africa 09301
190 Sandton Oncology Medical Group Johannesburg Gauteng South Africa 02196
191 Sandton Oncology Medical Research Johannesburg Gauteng South Africa 02199
192 Steve Biko Academic Hospital Pretoria Gauteng South Africa 00002
193 Mary Potter Oncology Centre Pretoria Gauteng South Africa 00027
194 ICO l'Hospitalet - Hospital Duran i Reynals L'Hospitalet de Llobregat Barcelona Spain 08907
195 Hospital Regional Universitario de Malaga Hospital General Malaga Málaga Spain 29010
196 Clinica Universidad Navarra Pamplona Navarra Spain 31008
197 Hospital Universitario Vall d'Hebrón - PPDS Barcelona Spain 08035
198 Hospital Clinic de Barcelona Barcelona Spain 08036
199 ICO l'Hospitalet - Hospital Duran i Reynals Barcelona Spain 08907
200 Complejo Hospitalario Universitario Insular - Materno Infantil Gran Canaria Spain 35001
201 Hospital Universitario A Coruña La Coruna Spain 15006
202 Hospital General Universitario Gregorio Maranon Madrid Spain 28009
203 MD Anderson Cancer Center Madrid Spain 28033
204 Hospital Universitario Fundacion Jimenez Diaz Madrid Spain 28040
205 Hospital Universitario HM Sanchinarro - CIOCC Madrid Spain 28050
206 Hospital Universitario Virgen Macarena Sevilla Spain 41009
207 Hospital Virgen de La Salud Toledo Spain 45004
208 Fundacion Instituto Valenciano de Oncologia Valencia Spain 46009
209 Consorcio Hospital General Universitario de Valencia Valencia Spain 46014
210 Skanes Universitetssjukhus Lund Lund Skane LAN Sweden
211 Skanes Universitetssjukhus Lund Lund Sweden 221 85
212 Universitätsspital Zürich Zurich Zürich (DE) Switzerland 08091
213 Hôpitaux Universitaires de Genève Genève Switzerland 01211
214 Centre Hospitalier Universitaire Vaudois Lausanne Switzerland 01011
215 Ege University Medical Faculty Bornova Izmir Turkey 35100
216 Adana Ba?kent Hastanesi K??la Yerle?kesi Adana Turkey 01230
217 Hacettepe University Medical Faculty Ankara Turkey 06100
218 Baskent University Medical Faculty Ankara Hospital Ankara Turkey 06490
219 Istanbul University Cerrahpasa Medical Faculty Hospital Istanbul Turkey 34098
220 Bristol Haematology and Oncology Centre Bristol Bristol, CITY OF United Kingdom BS2 8ED
221 Royal Cornwall Hospital Truro Cornwall United Kingdom TR1 3LJ
222 The Royal Sussex County Hospital Brighton EAST Sussex United Kingdom BN2 5BE
223 Broomfield Hospital Chelmsford Essex United Kingdom CM1 7ET
224 Singleton Hospital - PPDS Swansea Glamorgan United Kingdom SA2 8QA
225 Royal Preston Hospital Preston Lancashire United Kingdom PR2 9HT
226 Royal Marsden Hospital - Surrey London London, CITY OF United Kingdom SW3 6JJ
227 Queen Elizabeth Hospital Birmingham United Kingdom B15 2TH
228 St James s Institute of Clinical Oncology Leeds United Kingdom LS9 7TF
229 Clatterbridge Hospital Wirral United Kingdom CH63 4JY

Sponsors and Collaborators

  • Pfizer

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT01763164
Other Study ID Numbers:
  • CMEK162A2301
  • C4211002
  • 2012-003593-51
First Posted:
Jan 8, 2013
Last Update Posted:
Mar 22, 2021
Last Verified:
Mar 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Pfizer
Melanoma
Cutaneous melanoma
Skin disease
Skin cancer
Skin Neoplasms
Neoplasm Metastasis
Additional relevant MeSH terms:
Melanoma
Dacarbazine

Study Results

Participant Flow

Recruitment Details Participants randomized were with previously untreated, advanced unresectable or metastatic Neuroblastoma RAS viral oncogene homolog (NRAS) mutation-positive melanoma as confirmed by central assessment.
Pre-assignment Detail
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Period Title: Treatment Phase
STARTED 269 133
Treated/Safety Set 269 114
Full Analysis Set 269 133
COMPLETED 0 0
NOT COMPLETED 269 133
Period Title: Treatment Phase
STARTED 200 78
COMPLETED 3 3
NOT COMPLETED 197 75

Baseline Characteristics

Arm/Group Title Binimetinib (MEK162) Dacarbazine Total
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Total of all reporting groups
Overall Participants 269 133 402
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
63.6
(12.28)
60.6
(13.35)
62.6
(12.71)
Sex: Female, Male (Count of Participants)
Female
103
38.3%
48
36.1%
151
37.6%
Male
166
61.7%
85
63.9%
251
62.4%

Outcome Measures

1. Primary Outcome
Title Progression-Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Description PFS: time from randomization to first documented PD or death due to any cause, whichever occurred first. RECIST 1.1, PD: >=20% increase in sum of diameter of target lesions (TLs) taking as reference the smallest sum on study (including baseline sum), sum must also be an absolute increase of >=5 mm; unequivocal progression of existing non-TLs; appearance of >=1 lesion. Complete response (CR): disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs. Partial response (PR): >=30% decrease in sum of diameter of all TLs, referring baseline sum of diameters. Stable disease (SD): neither sufficient shrinkage to qualify for PR nor increase in lesions qualified for PD referring smallest sum diameter. With no event at time of analysis cut-off or at start of any new anti-neoplastic therapy, PFS censored at date of last adequate tumor assessment of CR, PR or SD.
Time Frame From the date of randomization to the date of the first documented PD or death, whichever occurred first (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Outcome Measure Data

Analysis Population Description
FAS consisted of all randomized participants.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 133
Median (95% Confidence Interval) [Months]
2.83
1.51
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Binimetinib (MEK162), Dacarbazine
Comments Hazard ratio was obtained from the stratified unadjusted Cox model. P-value was obtained from the one-sided stratified log-rank test.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value < 0.001
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.47 to 0.80
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Overall Survival (OS)
Description Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a participant was not known to have died, overall survival was censored at the date of last known date participant alive.
Time Frame From the date of randomization to the date of death (maximum up to 107 weeks for binimetinib arm; maximum up to 88 weeks for dacarbazine arm)

Outcome Measure Data

Analysis Population Description
FAS consisted of all randomized participants.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 133
Median (95% Confidence Interval) [Months]
10.97
10.09
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Binimetinib (MEK162), Dacarbazine
Comments Hazard ratio was obtained from the stratified unadjusted Cox model. P-value was obtained from the one-sided stratified log rank test.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.499
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Confidence Interval (2-Sided) 95%
0.75 to 1.33
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Overall Response Rate (ORR)
Description ORR: percentage of participants with best overall response (BOR) of CR or PR. BOR: best response recorded from start of treatment until CR or PR. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter of all TLs, taking as reference baseline sum of diameters. ORR is reported for confirmed and unconfirmed responses. Confirmed CR or PR = at least 2 determinations of CR or PR at least 4 weeks apart before PD. PD: >=20% increase in sum of diameter of all measured target lesions, taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non TLs. Appearance of at least 1 new lesion.
Time Frame From date of randomization until first documented response of CR or PR (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Outcome Measure Data

Analysis Population Description
FAS consisted of all randomized participants.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 133
Confirmed ORR
15.2
5.7%
6.8
5.1%
Confirmed + Unconfirmed: ORR
22.7
8.4%
9.8
7.4%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Binimetinib (MEK162), Dacarbazine
Comments Confirmed ORR: The p-value (2-sided) was computed from stratified Cochran-Mantel-Haenszel chi-square test statistic.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.015
Comments
Method Cochran-Mantel-Haenszel
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Binimetinib (MEK162), Dacarbazine
Comments Confirmed ORR + Unconfirmed ORR: The p-value (2-sided) was computed from stratified Cochran-Mantel-Haenszel chi-square test statistic.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.002
Comments
Method Cochran-Mantel-Haenszel
Comments
4. Secondary Outcome
Title Time to Response (TTR)
Description TTR: time between date of randomization until first documented response of CR or PR. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter (dia) of all TLs, referring baseline sum of dia; c) PD: >=20% increase in sum of diameter of all measured TLs taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non-TLs. Appearance of >=1 new lesion. Participants who did not achieve PR or CR censored at last adequate tumor assessment date when they did not have PFS event (time from date of randomization to date of first documented PD or death due to any cause, whichever occur first) or at maximum follow-up when they had PFS event.
Time Frame From date of randomization until first documented response of CR or PR (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all randomized participants and who had at least once CR or PR.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 61 13
Median (95% Confidence Interval) [Months]
1.45
2.79
5. Secondary Outcome
Title Duration of Objective Response (DOR)
Description DOR: time from date of first documented response (CR or PR) to first documented progression or death due to underlying cancer. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter (dia) of all TLs, referring baseline sum of dia; c) PD: >=20% increase in sum of diameter of all measured target lesions taking as reference smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion. If a participant with a CR or PR had no PD or death due to underlying cancer, participants was censored at date of last adequate tumor assessment.
Time Frame From the date of first documented response (CR or PR) to the first documented progression or death (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all randomized participants and who had confirmed responses (CR or PR).
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 41 9
Median (95% Confidence Interval) [Months]
6.87
NA
6. Secondary Outcome
Title Disease Control Rate (DCR)
Description DCR was calculated as the percentage of participants with a BOR of CR, PR, SD RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters; c) SD: neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD taking as reference the smallest sum diameters; d) PD: >=20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion.
Time Frame From date of randomization until first documented response of CR, PR, SD or non-CR/non-PD (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Outcome Measure Data

Analysis Population Description
FAS consisted of all randomized participants.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 133
Number (95% Confidence Interval) [Percentage of participants]
58.4
21.7%
24.8
18.6%
7. Secondary Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. SAE was defined as one of the following: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE was defined as an AE with onset date occurring during the on-treatment period. AEs included all SAEs and non-SAEs.
Time Frame From baseline up to 219.4 weeks for binimetinib arm; From baseline up to 123.9 weeks for dacarbazine arm

Outcome Measure Data

Analysis Population Description
The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 114
AEs
269
100%
104
78.2%
SAEs
95
35.3%
26
19.5%
8. Secondary Outcome
Title Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03
Description Clinically notable shifts are defined as worsening by at least 2 grades or to >= grade 3. Severity was graded as 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 AE.
Time Frame From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Outcome Measure Data

Analysis Population Description
The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 114
Activated partial thromboplastin time prolonged
7
2.6%
2
1.5%
Hemoglobin decreased
17
6.3%
13
9.8%
Prothrombin international normalized ratio increased
9
3.3%
0
0%
Lymphocytes increased
20
7.4%
0
0%
Lymphocytes decreased
35
13%
19
14.3%
Neutrophils decreased
8
3%
21
15.8%
Platelets decreased
3
1.1%
17
12.8%
Leukocytes increased
0
0%
0
0%
Leukocytes decreased
6
2.2%
26
19.5%
9. Secondary Outcome
Title Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03
Description Clinically notable shifts are defined as worsening by at least 2 grades or to >= grade 3. Severity was graded as 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 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 AE.
Time Frame From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Outcome Measure Data

Analysis Population Description
The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 114
Albumin decreased
27
10%
5
3.8%
Alkaline phosphatase
8
3%
2
1.5%
Alanine aminotransferase
14
5.2%
4
3%
Aspartate aminotransferase
20
7.4%
1
0.8%
Bilirubin
1
0.4%
1
0.8%
Corrected Calcium increased
2
0.7%
4
3%
Corrected Calcium decreased
2
0.7%
0
0%
Creatinine
9
3.3%
2
1.5%
Gamma-glutamyl transferase
9
3.3%
7
5.3%
Glucose serum fasting increased
13
4.8%
5
3.8%
Glucose serum fasting decreased
6
2.2%
0
0%
Potassium increased
13
4.8%
3
2.3%
Potassium decreased
14
5.2%
1
0.8%
Magnesium increased
1
0.4%
0
0%
Magnesium decreased
1
0.4%
0
0%
Phosphate decreased
17
6.3%
5
3.8%
Sodium increased
23
8.6%
4
3%
Sodium decreased
4
1.5%
0
0%
10. Secondary Outcome
Title Number of Participants With Clinically Notable Vital Signs
Description Abnormalities criteria included: low/high pulse rate (beats per minute [bpm]):<=50bpm with decrease from baseline >=15bpm/>=120bpm with increase from baseline >=15bpm; Low/high systolic blood pressure (millimeters of mercury [mmHg]): <=90mmHg with decrease from baseline >=20mmHg/>=160mmHg with increase from baseline >=20mmHg; Low/high diastolic blood pressure [mmHg]: <=50mmHg with decrease from baseline >=15mmHg/>=100mmHg with increase from baseline >=15mmHg; Low/high body weight (kilogram [kg]): >=20% decrease from baseline / >=10% increase from baseline; Low/high body temperature (degree Celsius [°C]): <=36°C / >= 37.5°C
Time Frame From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Outcome Measure Data

Analysis Population Description
The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation. Here, "number analyzed" signifies participants evaluable for this outcome measure for specified rows.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 114
Sitting Pulse Rate - High
4
1.5%
1
0.8%
Sitting Pulse Rate - Low
3
1.1%
1
0.8%
Sitting systolic blood pressure - High
43
16%
8
6%
Sitting systolic blood pressure -Low
2
0.7%
4
3%
Sitting diastolic blood pressure - High
28
10.4%
4
3%
Sitting diastolic blood pressure - Low
2
0.7%
1
0.8%
Weight - High
16
5.9%
1
0.8%
Weight - Low
0
0%
0
0%
Body temperature - High
15
5.6%
6
4.5%
Body temperature - Low
90
33.5%
24
18%
11. Secondary Outcome
Title Number of Participants With Notable Electrocardiogram (ECG) Values
Description Criteria for notable ECG values were as follow: QT interval (in millisecond [msec]) new (newly occurring post-baseline value) greater than (>) 450, 480, 500, increase from baseline >30, increase from baseline >60; corrected QT interval by Fredericia formula (QTcF) in msec new (newly occurring post-baseline value) > 450, 480, 500, increase from baseline >30, increase from baseline >60; corrected QT interval by Bazett's formula (QTcB) in msec new (newly occurring post-baseline value) > 450, 480, 500, increase from baseline >30, increase from baseline >60; heart rate in bpm new (newly occurring post-baseline value) <60 and >100.
Time Frame From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Outcome Measure Data

Analysis Population Description
The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation. Here, "number analyzed" signifies participants evaluable for this outcome measure for specified rows.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 114
QT - New > 450 msec
32
11.9%
8
6%
QT - New > 480 msec
7
2.6%
1
0.8%
QT - New > 500 msec
5
1.9%
0
0%
QT - Increase from baseline > 30 msec
109
40.5%
33
24.8%
QT - Increase from baseline > 60 msec
28
10.4%
5
3.8%
QTcF - New > 450 msec
29
10.8%
15
11.3%
QTcF - New > 480 msec
10
3.7%
1
0.8%
QTcF - New > 500 msec
5
1.9%
1
0.8%
QTcF - Increase from baseline > 30 msec
52
19.3%
25
18.8%
QTcF - Increase from baseline > 60 msec
9
3.3%
5
3.8%
QTcB - New > 450 msec
65
24.2%
26
19.5%
QTcB - New > 480 msec
24
8.9%
8
6%
QTcB - New > 500 msec
6
2.2%
6
4.5%
QTcB - Increase from baseline > 30 msec
76
28.3%
36
27.1%
QTcB - Increase from baseline > 60 msec
11
4.1%
9
6.8%
Heart rate - New < 60 bpm
85
31.6%
13
9.8%
Heart rate - New > 100 bpm
18
6.7%
16
12%
12. Secondary Outcome
Title Number of Participants With Adverse Events of Special Interest: Cardiac Events
Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. 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 AE. Here, in this outcome measure data is reported for events falling in any of the grades.
Time Frame From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Outcome Measure Data

Analysis Population Description
The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 114
Count of Participants [Participants]
35
13%
2
1.5%
13. Secondary Outcome
Title Number of Participants With Clinically Significant Findings in Physical Examination
Description A complete physical examination included the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological systems. If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and pelvic examinations were performed. Clinical significance in physical examination was reported as adverse events.
Time Frame From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Outcome Measure Data

Analysis Population Description
No data was collected and analyzed for this outcome measure, any clinically significant physical examination findings were counted as adverse events and reported in safety section.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 0 0
14. Secondary Outcome
Title Number of Participants With Adverse Events of Special Interest: Ocular Events
Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. 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 ADL; Grade 3: Severe or medically significant but not immediately sight threatening; Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) in the affected eye. Here, in this outcome measure data is reported for events falling in any of the grades.
Time Frame From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Outcome Measure Data

Analysis Population Description
The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 114
Count of Participants [Participants]
6
2.2%
0
0%
15. Secondary Outcome
Title Plasma Concentration of Binimetinib
Description
Time Frame Day 1 of Week 1: Pre-dose, 1, 1.5, 2, 10 hours post-dose; Day 1 of Weeks 4, 7: Pre-dose, 1.5 hours post-dose; Day 1 of Weeks 10, 13: Pre-dose

Outcome Measure Data

Analysis Population Description
The pharmacokinetic analysis set (PAS) consisted of all participants who received at least one dose of binimetinib and had at least one evaluable post-baseline binimetinib concentration measurement. Here, "Overall Number of Participants Analyzed" = number of participants evaluable for this outcome measure. This outcome was planned to be evaluated only for binimetinib arm. Here, "number analyzed" signifies participants evaluable for this outcome measure for specified timeframes.
Arm/Group Title Binimetinib (MEK162)
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 264
Week 1 Day 1, Pre-dose
64.4
(1132.3)
Week 1 Day 1, 1 hour (hr) Post-dose
182
(237.6)
Week 1 Day 1, 1.5 hr Post-dose
313
(71.6)
Week 1 Day 1, 2 hr Post-dose
321
(64.4)
Week 1 Day 1, 10 hr Post-dose
153
(52.6)
Week 4 Day 1, Pre-dose
101
(100.8)
Week 4 Day 1, 1.5 hr Post-dose
418
(51.9)
Week 7 Day 1, Pre-dose
101
(97.7)
Week 7 Day 1, 1.5 hr Post-dose
372
(63.4)
Week 10 Day 1, Pre-dose
92.9
(60.6)
Week 13 Day 1, Pre-dose
93.9
(89.8)
16. Secondary Outcome
Title Time to Definitive 10% Deterioration in Global Health Status Score of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)
Description The time to definitive 10% deterioration was defined as the time from the date of randomization to the date of event, which was defined as death due to any cause or at least 10% worsening of the corresponding scale score, relative to baseline, with no later improvement above this threshold observed during the course of the study or death due to any cause. If a participant had no event prior to analysis cut-off or start of another anticancer therapy, time to deterioration was censored at the date of the last adequate health related quality of life (HRQoL) evaluation. EORTC QLQ-C30: 5 functional scales (physical, role, cognitive, emotional, and social), a global health status scale, 3 symptom scales (nausea/vomiting, pain, fatigue) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single-item measures range =0 to 100. High score for global health status = high quality of life.
Time Frame From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Outcome Measure Data

Analysis Population Description
FAS consisted of all randomized participants.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 133
Median (95% Confidence Interval) [Months]
2.79
4.27
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Binimetinib (MEK162), Dacarbazine
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.43
Confidence Interval (2-Sided) 95%
0.96 to 2.13
Parameter Dispersion Type:
Value:
Estimation Comments
17. Secondary Outcome
Title Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6
Description EORTC QLQ-C30: 5 functional scales (physical, role, cognitive, emotional, and social), a h global health status scale, 3 symptom scales (nausea/vomiting, pain, fatigue) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single-item measures range =0 to 100. High score for global health status = high quality of life. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.
Time Frame Both arms: Baseline, Day 1 Treatment Week (TW) 4,7,13,19,25,34,43,52; Post-treatment follow-up Visit (FUV) 1 to 6; Binimetinib: Day 1 TW61,70; End of treatment (EOT= TW73); Safety FUV=30 days post TW73; Dacarbazine: EOT=TW 57;Safety FUV=30 days post TW57

Outcome Measure Data

Analysis Population Description
FAS consisted of all randomized participants. Here, "Number analyzed" signifies number of participants evaluable at specified time points.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 133
Baseline
68.35
(23.463)
70.50
(21.823)
Week 4 Day 1
-5.75
(22.285)
-1.81
(17.512)
Week 7 Day 1
-8.63
(22.562)
0.00
(15.691)
Week 13 Day 1
-8.28
(19.659)
-1.34
(16.955)
Week 19 Day 1
-8.05
(21.053)
-3.26
(22.296)
Week 25 Day 1
-10.58
(21.775)
-3.47
(13.036)
Week 34 Day 1
-6.25
(18.755)
3.57
(20.893)
Week 43 Day 1
-11.36
(20.841)
-6.94
(23.224)
Week 52 Day 1
-1.52
(20.006)
-8.33
(11.785)
Week 61 Day 1
-10.00
(18.066)
Week 70 Day 1
-20.83
(5.893)
End of Treatment
-12.20
(22.512)
-6.74
(21.536)
30-day safety follow-up
-8.10
(21.361)
-9.62
(14.372)
Post treatment follow-up 1
-5.95
(19.211)
-8.59
(21.218)
Post treatment follow-up 2
0.00
(NA)
Post treatment follow-up 3
16.67
(NA)
Post treatment follow-up 4
25.00
(11.785)
Post treatment follow-up 5
25.00
(11.785)
Post treatment follow-up 6
33.33
(NA)
18. Secondary Outcome
Title Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6
Description EQ-5D-5L, is a standardized measure of health utility that provides a single index value for one's health status. EQ-5D-5L contained 1 item for each of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Index score: participant responses to the 5 dimensions reflected a specific health state that corresponded to a population preference weight for that state on a continuous scale of 0 (death) to 1 (perfect health). Higher index scores = better health state. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.
Time Frame Both arms: Baseline, Day 1 Treatment Week (TW) 4,7,13,19,25,34,43,52; Post-treatment follow-up Visit (FUV) 1 to 6; Binimetinib: Day 1 TW61,70; End of treatment (EOT= TW73); Safety FUV=30 days post TW73; Dacarbazine: EOT=TW 57;Safety FUV=30 days post TW57

Outcome Measure Data

Analysis Population Description
FAS consisted of all randomized participants. Here, "Number analyzed" signifies number of participants evaluable at specified time points.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 133
Baseline
0.7780
(0.22464)
0.7657
(0.23003)
Week 4 Day 1
-0.0422
(0.18291)
0.0110
(0.12135)
Week 7 Day 1
-0.0397
(0.19154)
0.0132
(0.14084)
Week 13 Day 1
-0.0773
(0.17543)
0.0198
(0.15236)
Week 19 Day 1
-0.0576
(0.22503)
0.0257
(0.18052)
Week 25 Day 1
-0.1563
(0.32142)
0.0657
(0.16052)
Week 34 Day 1
-0.0801
(0.11141)
0.0617
(0.15254)
Week 43 Day 1
-0.0170
(0.22978)
0.1060
(0.15033)
Week 52 Day 1
-0.0389
(0.24609)
0.0000
(0.00000)
Week 61 Day 1
0.0690
(0.21080)
Week 70 Day 1
0.0120
(0.14001)
End of Treatment
-0.0978
(0.23931)
-0.0540
(0.19164)
30-day safety follow-up
-0.1165
(0.24410)
-0.0740
(0.17682)
Post treatment follow-up 1
-0.0820
(0.11993)
-0.0438
(0.25374)
Post treatment follow-up 2
-0.2480
(NA)
Post treatment follow-up 3
-0.1210
(NA)
Post treatment follow-up 4
0.1115
(0.15768)
Post treatment follow-up 5
0.1730
(0.24466)
Post treatment follow-up 6
0.2230
(NA)
19. Secondary Outcome
Title Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
Description ECOG PS was used to assess the physical health of participants, and ranged from 0 (most active) to 5 (dead). ECOG PS grades: 0= fully active, able to carry on all pre-disease performance without restriction, 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work, 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, confined to bed or chair more than 50% of waking hours, 4=completely disabled. cannot carry on any selfcare. Totally confined to bed or chair and 5= dead. Definitive deterioration is defined as on treatment death due to any cause or decrease in ECOG PS by at least one category from baseline score.
Time Frame From baseline up to 73 weeks 3 days for binimetinib arm; From baseline up to 57 weeks 3 days for dacarbazine arm

Outcome Measure Data

Analysis Population Description
The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation. Here, "Overall Number of Participants Analyzed" = number of participants evaluable for this outcome measure.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 262 105
Median (95% Confidence Interval) [Months]
NA
NA
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Binimetinib (MEK162), Dacarbazine
Comments Log-rank test and Cox PH model were stratified by American joint committee on cancer stage, prior line immunotherapy and ECOG performance status. P-value was one tailed and was based on the log-rank score test. Hazard ratio and 95% CI was based on a Wald test from Cox model.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.995
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 2.20
Confidence Interval (2-Sided) 95%
1.19 to 4.06
Parameter Dispersion Type:
Value:
Estimation Comments
20. Secondary Outcome
Title Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
Description ECOG PS was used to assess the physical health of participants, and ranged from 0 (most active) to 5 (dead). ECOG PS grades: 0= fully active, able to carry on all pre-disease performance without restriction, 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work, 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, 4=completely disabled. cannot carry on any selfcare. Totally confined to bed or chair confined to bed or chair more than 50% of waking hours and 5= dead. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.
Time Frame For both arms: Baseline, Weeks 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55 and 30-day Follow-up For binimetinib only: Weeks 58, 61, 64, 67, 70, 73

Outcome Measure Data

Analysis Population Description
The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation. Here, "Number Analyzed" signifies number of participants evaluable for specified rows.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 114
Baseline : Grade 0
193
71.7%
82
61.7%
Baseline: Grade 1
76
28.3%
31
23.3%
Baseline : Grade 2
0
0%
1
0.8%
Week 4 Day 1: Grade 0
146
54.3%
66
49.6%
Week 4 Day 1: Grade 1
101
37.5%
27
20.3%
Week 4 Day 1: Grade 2
6
2.2%
4
3%
Week 4 Day 1: Grade 3
3
1.1%
0
0%
Week 7 Day 1: Grade 0
138
51.3%
51
38.3%
Week 7 Day 1: Grade 1
84
31.2%
26
19.5%
Week 7 Day 1: Grade 2
10
3.7%
3
2.3%
Week 7 Day 1: Grade 3
3
1.1%
0
0%
Week 7 Day 1: Grade 4
1
0.4%
0
0%
Week 10 Day 1: Grade 0
118
43.9%
34
25.6%
Week 10 Day 1: Grade 1
72
26.8%
15
11.3%
Week 10 Day 1: Grade 2
8
3%
2
1.5%
Week 10 Day 1: Grade 3
3
1.1%
0
0%
Week 13 Day 1: Grade 0
93
34.6%
29
21.8%
Week 13 Day 1: Grade 1
62
23%
14
10.5%
Week 13 Day 1: Grade 2
11
4.1%
0
0%
Week 13 Day 1: Grade 3
1
0.4%
0
0%
Week 16 Day 1: Grade 0
70
26%
24
18%
Week 16 Day 1: Grade 1
48
17.8%
5
3.8%
Week 16 Day 1: Grade 2
5
1.9%
1
0.8%
Week 16 Day 1: Grade 4
1
0.4%
0
0%
Week 19 Day 1: Grade 0
53
19.7%
19
14.3%
Week 19 Day 1: Grade 1
43
16%
7
5.3%
Week 19 Day 1:Grade 2
4
1.5%
2
1.5%
Week 22 Day 1: Grade 0
42
15.6%
17
12.8%
Week 22 Day 1: Grade 1
26
9.7%
5
3.8%
Week 22 Day 1: Grade 2
3
1.1%
0
0%
Week 22 Day 1: Grade 3
1
0.4%
0
0%
Week 25 Day 1: Grade 0
37
13.8%
13
9.8%
Week 25 Day 1: Grade 1
19
7.1%
6
4.5%
Week 25 Day 1: Grade 2
1
0.4%
0
0%
Week 25 Day 1: Grade 3
1
0.4%
0
0%
Week 28 Day 1: Grade 0
28
10.4%
9
6.8%
Week 28 Day 1: Grade 1
15
5.6%
2
1.5%
Week 28 Day 1: Grade 2
2
0.7%
0
0%
Week 28 Day 1: Grade 5
1
0.4%
0
0%
Week 31 Day 1: Grade 0
22
8.2%
7
5.3%
Week 31 Day 1: Grade 1
11
4.1%
2
1.5%
Week 31 Day 1: Grade 2
1
0.4%
0
0%
Week 34 Day 1: Grade 0
20
7.4%
9
6.8%
Week 34 Day 1: Grade 1
7
2.6%
1
0.8%
Week 34 Day 1: Grade 2
2
0.7%
0
0%
Week 37 Day 1: Grade 0
16
5.9%
7
5.3%
Week 37 Day 1: Grade 1
4
1.5%
1
0.8%
Week 40 Day 1: Grade 0
15
5.6%
6
4.5%
Week 40 Day 1: Grade 1
0
0%
1
0.8%
Week 43 Day 1: Grade 0
12
4.5%
5
3.8%
Week 43 Day 1: Grade 1
1
0.4%
0
0%
Week 43 Day 1: Grade 2
1
0.4%
0
0%
Week 46 Day 1: Grade 0
11
4.1%
4
3%
Week 46 Day 1: Grade 1
2
0.7%
0
0%
Week 46 Day 1: Grade 2
1
0.4%
0
0%
Week 49 Day 1: Grade 0
9
3.3%
1
0.8%
Week 49 Day 1: Grade 1
2
0.7%
0
0%
Week 52 Day 1: Grade 0
10
3.7%
2
1.5%
Week 52 Day 1: Grade 1
1
0.4%
1
0.8%
Week 55 Day 1: Grade 0
9
3.3%
1
0.8%
Week 55 Day 1: Grade 1
1
0.4%
1
0.8%
Week 58 Day 1: Grade 0
7
2.6%
Week 58 Day 1: Grade 1
1
0.4%
Week 61 Day 1: Grade 0
5
1.9%
Week 64 Day 1: Grade 0
4
1.5%
Week 67 Day 1: Grade 0
3
1.1%
Week 70 Day 1: Grade 0
2
0.7%
Week 73 Day 1: Grade 0
1
0.4%
Safety Follow up Visit: Grade 0
42
15.6%
24
18%
Safety Follow up Visit: Grade 1
41
15.2%
16
12%
Safety Follow up Visit: Grade 2
14
5.2%
4
3%
Safety Follow up Visit: Grade 3
4
1.5%
0
0%
Safety Follow up Visit: Grade 4
4
1.5%
0
0%
21. Secondary Outcome
Title Number of Participants With Neuroblastoma RAS Viral (V-ras) Oncogene Homolog (NRAS) Mutation Status at Baseline
Description Number of participants with NRAS mutation status at baseline were reported.
Time Frame Baseline

Outcome Measure Data

Analysis Population Description
FAS consisted of all randomized participants. Here, "number analyzed" signifies participants evaluable for this outcome measure for specified rows.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Measure Participants 269 133
Wild Type
0
0%
1
0.8%
Mutant: Q61K
100
37.2%
51
38.3%
Mutant: Q61L
32
11.9%
17
12.8%
Mutant: Q61R
137
50.9%
64
48.1%

Adverse Events

Time Frame From baseline up to 219.4 weeks for binimetinib arm; From baseline up to 123.9 weeks for dacarbazine arm
Adverse Event Reporting Description Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another participant or 1 participant may have experienced both serious and non-serious event during study. Safety analysis set population included all participants who have received at least one dose of the study drug and had at least one valid post-baseline safety assessment.
Arm/Group Title Binimetinib (MEK162) Dacarbazine
Arm/Group Description Participants received oral binimetinib 45 milligram (mg) (3*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first. Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
All Cause Mortality
Binimetinib (MEK162) Dacarbazine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN)
Serious Adverse Events
Binimetinib (MEK162) Dacarbazine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 95/269 (35.3%) 26/114 (22.8%)
Blood and lymphatic system disorders
ANAEMIA 2/269 (0.7%) 0/114 (0%)
FEBRILE NEUTROPENIA 0/269 (0%) 1/114 (0.9%)
NEUTROPENIA 0/269 (0%) 1/114 (0.9%)
PANCYTOPENIA 0/269 (0%) 2/114 (1.8%)
THROMBOCYTOPENIA 1/269 (0.4%) 0/114 (0%)
IRON DEFICIENCY ANAEMIA 0/269 (0%) 1/114 (0.9%)
Cardiac disorders
ATRIAL FIBRILLATION 1/269 (0.4%) 0/114 (0%)
TACHYARRHYTHMIA 1/269 (0.4%) 1/114 (0.9%)
ANGINA PECTORIS 1/269 (0.4%) 0/114 (0%)
ATRIAL FLUTTER 1/269 (0.4%) 0/114 (0%)
ATRIOVENTRICULAR BLOCK 1/269 (0.4%) 0/114 (0%)
ATRIOVENTRICULAR BLOCK FIRST DEGREE 1/269 (0.4%) 0/114 (0%)
MITRAL VALVE DISEASE 1/269 (0.4%) 0/114 (0%)
Eye disorders
RETINAL VEIN OCCLUSION 4/269 (1.5%) 0/114 (0%)
RETINAL DETACHMENT 1/269 (0.4%) 0/114 (0%)
RETINAL VEIN THROMBOSIS 2/269 (0.7%) 0/114 (0%)
Gastrointestinal disorders
DIARRHOEA 2/269 (0.7%) 0/114 (0%)
VOMITING 3/269 (1.1%) 0/114 (0%)
MOUTH ULCERATION 1/269 (0.4%) 0/114 (0%)
CONSTIPATION 2/269 (0.7%) 0/114 (0%)
NAUSEA 2/269 (0.7%) 0/114 (0%)
ABDOMINAL PAIN 1/269 (0.4%) 1/114 (0.9%)
ABDOMINAL PAIN LOWER 1/269 (0.4%) 0/114 (0%)
ABDOMINAL PAIN UPPER 1/269 (0.4%) 0/114 (0%)
ASCITES 1/269 (0.4%) 0/114 (0%)
AUTOIMMUNE PANCREATITIS 1/269 (0.4%) 0/114 (0%)
COLITIS ISCHAEMIC 1/269 (0.4%) 0/114 (0%)
DUODENAL PERFORATION 1/269 (0.4%) 0/114 (0%)
HAEMORRHOIDS 1/269 (0.4%) 0/114 (0%)
INTESTINAL PERFORATION 1/269 (0.4%) 0/114 (0%)
INTUSSUSCEPTION 1/269 (0.4%) 0/114 (0%)
LARGE INTESTINAL OBSTRUCTION 1/269 (0.4%) 0/114 (0%)
MESENTERIC VEIN THROMBOSIS 1/269 (0.4%) 0/114 (0%)
SUBILEUS 1/269 (0.4%) 0/114 (0%)
General disorders
MALAISE 0/269 (0%) 1/114 (0.9%)
PYREXIA 1/269 (0.4%) 3/114 (2.6%)
GENERAL PHYSICAL HEALTH DETERIORATION 10/269 (3.7%) 0/114 (0%)
AXILLARY PAIN 1/269 (0.4%) 0/114 (0%)
FATIGUE 1/269 (0.4%) 0/114 (0%)
MULTIPLE ORGAN DYSFUNCTION SYNDROME 1/269 (0.4%) 0/114 (0%)
OEDEMA PERIPHERAL 1/269 (0.4%) 0/114 (0%)
Hepatobiliary disorders
HEPATIC FAILURE 1/269 (0.4%) 0/114 (0%)
CHOLECYSTITIS 1/269 (0.4%) 0/114 (0%)
CHOLESTASIS 0/269 (0%) 1/114 (0.9%)
Infections and infestations
SEPTIC SHOCK 1/269 (0.4%) 0/114 (0%)
SKIN INFECTION 3/269 (1.1%) 0/114 (0%)
LOWER RESPIRATORY TRACT INFECTION 0/269 (0%) 1/114 (0.9%)
CELLULITIS 2/269 (0.7%) 0/114 (0%)
ERYSIPELAS 2/269 (0.7%) 0/114 (0%)
PYELONEPHRITIS ACUTE 2/269 (0.7%) 0/114 (0%)
SEPSIS 2/269 (0.7%) 2/114 (1.8%)
SOFT TISSUE INFECTION 2/269 (0.7%) 0/114 (0%)
UROSEPSIS 2/269 (0.7%) 0/114 (0%)
ABSCESS LIMB 1/269 (0.4%) 0/114 (0%)
DERMO-HYPODERMITIS 1/269 (0.4%) 0/114 (0%)
HERPES ZOSTER 1/269 (0.4%) 0/114 (0%)
OSTEOMYELITIS 1/269 (0.4%) 0/114 (0%)
PNEUMOCOCCAL SEPSIS 1/269 (0.4%) 0/114 (0%)
PNEUMONIA 1/269 (0.4%) 1/114 (0.9%)
VIRAL INFECTION 1/269 (0.4%) 0/114 (0%)
LUNG INFECTION 0/269 (0%) 1/114 (0.9%)
PERINEAL ABSCESS 0/269 (0%) 1/114 (0.9%)
Injury, poisoning and procedural complications
MUSCLE INJURY 1/269 (0.4%) 0/114 (0%)
FEMORAL NECK FRACTURE 1/269 (0.4%) 0/114 (0%)
SUBDURAL HAEMATOMA 1/269 (0.4%) 0/114 (0%)
TIBIA FRACTURE 1/269 (0.4%) 0/114 (0%)
Investigations
BLOOD CREATINE PHOSPHOKINASE INCREASED 3/269 (1.1%) 0/114 (0%)
ALANINE AMINOTRANSFERASE INCREASED 1/269 (0.4%) 0/114 (0%)
ASPARTATE AMINOTRANSFERASE INCREASED 1/269 (0.4%) 0/114 (0%)
EJECTION FRACTION DECREASED 1/269 (0.4%) 0/114 (0%)
ELECTROCARDIOGRAM QT PROLONGED 1/269 (0.4%) 0/114 (0%)
HAEMOGLOBIN DECREASED 1/269 (0.4%) 0/114 (0%)
INTRAOCULAR PRESSURE INCREASED 1/269 (0.4%) 0/114 (0%)
BLOOD PRESSURE INCREASED 1/269 (0.4%) 0/114 (0%)
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS WORSENED 1/269 (0.4%) 0/114 (0%)
GENERAL PHYSICAL CONDITION ABNORMAL 1/269 (0.4%) 0/114 (0%)
Metabolism and nutrition disorders
DIABETIC METABOLIC DECOMPENSATION 1/269 (0.4%) 0/114 (0%)
DECREASED APPETITE 2/269 (0.7%) 0/114 (0%)
Musculoskeletal and connective tissue disorders
MUSCULAR WEAKNESS 2/269 (0.7%) 0/114 (0%)
RHABDOMYOLYSIS 1/269 (0.4%) 0/114 (0%)
INTERVERTEBRAL DISC PROTRUSION 2/269 (0.7%) 0/114 (0%)
INTERVERTEBRAL DISC COMPRESSION 1/269 (0.4%) 0/114 (0%)
OSTEONECROSIS 1/269 (0.4%) 0/114 (0%)
PATHOLOGICAL FRACTURE 1/269 (0.4%) 0/114 (0%)
BACK PAIN 0/269 (0%) 2/114 (1.8%)
FLANK PAIN 0/269 (0%) 1/114 (0.9%)
PAIN IN EXTREMITY 0/269 (0%) 1/114 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR HAEMORRHAGE 0/269 (0%) 1/114 (0.9%)
CANCER PAIN 1/269 (0.4%) 0/114 (0%)
MALIGNANT ASCITES 1/269 (0.4%) 0/114 (0%)
Nervous system disorders
MYASTHENIC SYNDROME 1/269 (0.4%) 0/114 (0%)
PERIPHERAL SENSORIMOTOR NEUROPATHY 1/269 (0.4%) 0/114 (0%)
LETHARGY 0/269 (0%) 1/114 (0.9%)
SPINAL CORD COMPRESSION 2/269 (0.7%) 0/114 (0%)
CEREBRAL HAEMORRHAGE 1/269 (0.4%) 0/114 (0%)
DROPPED HEAD SYNDROME 1/269 (0.4%) 0/114 (0%)
HAEMORRHAGE INTRACRANIAL 1/269 (0.4%) 0/114 (0%)
MOTOR DYSFUNCTION 1/269 (0.4%) 0/114 (0%)
SCIATICA 1/269 (0.4%) 0/114 (0%)
SUBARACHNOID HAEMORRHAGE 1/269 (0.4%) 1/114 (0.9%)
TRANSIENT ISCHAEMIC ATTACK 1/269 (0.4%) 0/114 (0%)
BRAIN OEDEMA 0/269 (0%) 1/114 (0.9%)
CEREBROVASCULAR ACCIDENT 0/269 (0%) 1/114 (0.9%)
DEMENTIA 0/269 (0%) 1/114 (0.9%)
ENCEPHALOPATHY 0/269 (0%) 1/114 (0.9%)
PROGRESSIVE SUPRANUCLEAR PALSY 0/269 (0%) 1/114 (0.9%)
Psychiatric disorders
CONFUSIONAL STATE 2/269 (0.7%) 0/114 (0%)
ABNORMAL BEHAVIOUR 1/269 (0.4%) 0/114 (0%)
Renal and urinary disorders
ACUTE KIDNEY INJURY 1/269 (0.4%) 0/114 (0%)
RENAL FAILURE 2/269 (0.7%) 0/114 (0%)
NEPHROLITHIASIS 1/269 (0.4%) 0/114 (0%)
Respiratory, thoracic and mediastinal disorders
PNEUMONITIS 2/269 (0.7%) 0/114 (0%)
PULMONARY EMBOLISM 4/269 (1.5%) 0/114 (0%)
DYSPNOEA 3/269 (1.1%) 2/114 (1.8%)
LUNG DISORDER 1/269 (0.4%) 0/114 (0%)
ASPIRATION 1/269 (0.4%) 0/114 (0%)
HAEMOPTYSIS 1/269 (0.4%) 0/114 (0%)
PLEURAL EFFUSION 1/269 (0.4%) 0/114 (0%)
RESPIRATORY ARREST 1/269 (0.4%) 0/114 (0%)
PNEUMOTHORAX 0/269 (0%) 1/114 (0.9%)
Skin and subcutaneous tissue disorders
HYPERHIDROSIS 0/269 (0%) 1/114 (0.9%)
DERMATITIS ACNEIFORM 1/269 (0.4%) 0/114 (0%)
PSORIASIS 1/269 (0.4%) 0/114 (0%)
RASH MACULO-PAPULAR 1/269 (0.4%) 0/114 (0%)
Vascular disorders
HYPERTENSIVE CRISIS 2/269 (0.7%) 0/114 (0%)
HAEMORRHAGE 2/269 (0.7%) 0/114 (0%)
AORTIC DILATATION 1/269 (0.4%) 0/114 (0%)
DEEP VEIN THROMBOSIS 1/269 (0.4%) 0/114 (0%)
EMBOLISM 1/269 (0.4%) 0/114 (0%)
Other (Not Including Serious) Adverse Events
Binimetinib (MEK162) Dacarbazine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 266/269 (98.9%) 100/114 (87.7%)
Blood and lymphatic system disorders
ANAEMIA 19/269 (7.1%) 11/114 (9.6%)
LYMPHOPENIA 7/269 (2.6%) 7/114 (6.1%)
NEUTROPENIA 4/269 (1.5%) 21/114 (18.4%)
THROMBOCYTOPENIA 2/269 (0.7%) 17/114 (14.9%)
LEUKOPENIA 0/269 (0%) 8/114 (7%)
Eye disorders
RETINAL DETACHMENT 35/269 (13%) 0/114 (0%)
EYELID OEDEMA 28/269 (10.4%) 0/114 (0%)
VISION BLURRED 20/269 (7.4%) 1/114 (0.9%)
SUBRETINAL FLUID 19/269 (7.1%) 0/114 (0%)
MACULAR OEDEMA 17/269 (6.3%) 0/114 (0%)
PERIORBITAL OEDEMA 14/269 (5.2%) 0/114 (0%)
Gastrointestinal disorders
DIARRHOEA 109/269 (40.5%) 15/114 (13.2%)
NAUSEA 85/269 (31.6%) 35/114 (30.7%)
VOMITING 58/269 (21.6%) 15/114 (13.2%)
CONSTIPATION 39/269 (14.5%) 22/114 (19.3%)
ABDOMINAL PAIN 24/269 (8.9%) 8/114 (7%)
DRY MOUTH 22/269 (8.2%) 1/114 (0.9%)
ABDOMINAL PAIN UPPER 16/269 (5.9%) 3/114 (2.6%)
General disorders
OEDEMA PERIPHERAL 97/269 (36.1%) 5/114 (4.4%)
FATIGUE 68/269 (25.3%) 38/114 (33.3%)
ASTHENIA 44/269 (16.4%) 19/114 (16.7%)
PYREXIA 34/269 (12.6%) 16/114 (14%)
PERIPHERAL SWELLING 15/269 (5.6%) 2/114 (1.8%)
FACE OEDEMA 14/269 (5.2%) 0/114 (0%)
Infections and infestations
RASH PUSTULAR 18/269 (6.7%) 0/114 (0%)
NASOPHARYNGITIS 17/269 (6.3%) 5/114 (4.4%)
ERYSIPELAS 15/269 (5.6%) 0/114 (0%)
Investigations
BLOOD CREATINE PHOSPHOKINASE INCREASED 119/269 (44.2%) 3/114 (2.6%)
ASPARTATE AMINOTRANSFERASE INCREASED 39/269 (14.5%) 5/114 (4.4%)
EJECTION FRACTION DECREASED 35/269 (13%) 2/114 (1.8%)
ALANINE AMINOTRANSFERASE INCREASED 23/269 (8.6%) 8/114 (7%)
INTRAOCULAR PRESSURE INCREASED 19/269 (7.1%) 0/114 (0%)
WEIGHT DECREASED 13/269 (4.8%) 6/114 (5.3%)
GAMMA-GLUTAMYLTRANSFERASE INCREASED 8/269 (3%) 7/114 (6.1%)
PLATELET COUNT DECREASED 2/269 (0.7%) 11/114 (9.6%)
NEUTROPHIL COUNT DECREASED 1/269 (0.4%) 8/114 (7%)
Metabolism and nutrition disorders
DECREASED APPETITE 34/269 (12.6%) 19/114 (16.7%)
Musculoskeletal and connective tissue disorders
MYALGIA 28/269 (10.4%) 3/114 (2.6%)
BACK PAIN 19/269 (7.1%) 6/114 (5.3%)
ARTHRALGIA 18/269 (6.7%) 3/114 (2.6%)
NECK PAIN 17/269 (6.3%) 2/114 (1.8%)
MUSCULAR WEAKNESS 16/269 (5.9%) 0/114 (0%)
PAIN IN EXTREMITY 11/269 (4.1%) 6/114 (5.3%)
Nervous system disorders
DYSGEUSIA 21/269 (7.8%) 2/114 (1.8%)
HEADACHE 18/269 (6.7%) 9/114 (7.9%)
DIZZINESS 17/269 (6.3%) 3/114 (2.6%)
Psychiatric disorders
INSOMNIA 17/269 (6.3%) 8/114 (7%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA 27/269 (10%) 5/114 (4.4%)
COUGH 20/269 (7.4%) 10/114 (8.8%)
Skin and subcutaneous tissue disorders
DERMATITIS ACNEIFORM 106/269 (39.4%) 1/114 (0.9%)
RASH 96/269 (35.7%) 2/114 (1.8%)
DRY SKIN 37/269 (13.8%) 2/114 (1.8%)
PRURITUS 27/269 (10%) 2/114 (1.8%)
SKIN FISSURES 26/269 (9.7%) 0/114 (0%)
ALOPECIA 24/269 (8.9%) 3/114 (2.6%)
RASH MACULO-PAPULAR 23/269 (8.6%) 0/114 (0%)
ERYTHEMA 17/269 (6.3%) 2/114 (1.8%)
Vascular disorders
HYPERTENSION 36/269 (13.4%) 4/114 (3.5%)

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:
NCT01763164
Other Study ID Numbers:
  • CMEK162A2301
  • C4211002
  • 2012-003593-51
First Posted:
Jan 8, 2013
Last Update Posted:
Mar 22, 2021
Last Verified:
Mar 1, 2021