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

Metastatic or Unresectable Cutaneous Melanoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01763164
• Other study ID #: CMEK162A2301
• Secondary ID: C42110022012-003
• Status: Completed
• Phase: Phase 3
• Start date: July 12, 2013
• Est. completion date: June 4, 2019

Study information

• Verified date: March 2021
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 402
• Est. completion date: June 4, 2019
• Est. primary completion date: December 1, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Melanoma
• Metastatic or Unresectable Cutaneous Melanoma

Intervention

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.
• 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.

Locations

Country	Name	City	State
Argentina	Fundacion CIDEA	Buenos Aires
Argentina	Sanatorio de La Providencia	Buenos Aires	Ciudad Autónoma DE Buenosaires
Argentina	Centro Oncologico de Rosario	Rosario	Santa FE
Argentina	Centro de Investigación Clínica ? Clínica Viedma	Viedma	RÍO Negro
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Chris O'Brien Lifehouse Hospital	Camperdown	New South Wales
Australia	Lake Macquarie Private Hospital	Gateshead	New South Wales
Australia	Melanoma Institute Australia	North Sydney	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Austria	LKH-Universitätsklinikum Klinikum Graz	Graz	Steiermark
Austria	Universitätsklinikum Innsbruck	Innsbruck	Tirol
Austria	Salzburger Landeskliniken	Salzburg
Austria	Allgemeines Krankenhaus der Stadt Wien	Vienna
Belgium	UZ Gasthuisberg	Leuven
Belgium	CHU Sart Tilman	Liege
Belgium	Sint-Augustinuskliniek	Wilrijk	Antwerpen
Brazil	Hospital de Clinicas de Passo Fundo	Passo Fundo	RIO Grande DO SUL
Brazil	Hospital Moinhos de Vento	Porto Alegre	RIO Grande DO SUL
Brazil	Hospital Moinhos de Vento	Porto Alegre	RIO Grande DO SUL
Brazil	INCA Instituto Nacional de Cancer	Rio de Janeiro
Brazil	Hospital São José	Sao Paulo
Canada	Alberta Health Services - Cross Cancer Institute	Edmonton	Alberta
Canada	London Regional Cancer Program	London	Ontario
Canada	McGill University Health Center / Royal Victoria Hospital	Montreal	Quebec
Canada	CHU de Quebec - L'Hotel-Dieu de Quebec	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	Sunnybrook Research Institute Centre	Toronto	Ontario
Czechia	Mou/Mmci - Ppds	Brno	Jihomoravský KRAJ
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Fakultni nemocnice Kralovske Vinohrady	Praha 10
Czechia	Vseobecna Fakultni Nemocnice V Praze	Praha 2
France	CHU Angers	Angers	Maine-et-loire
France	Hôpital Saint-André	Bordeaux
France	Centre Hospitalier Universitaire Ambroise Pare	Boulogne Billancourt
France	Centre Hospitalier Le Mans	Le Mans
France	CHRU de Lille - Hôpital Huriet	Lille	Nord
France	Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer Rhône Alpes	Lyon	Rhône
France	Hopitaux de La Timone	Marseille
France	Groupe Hospitalier Archet I Et II	Nice
France	Hôpital Saint Louis	Paris
France	Service de PneumologieCHU Lyon Sud	Pierre Benite
France	Hôpital Robert Debré	Reims
France	Centre Hospitalier Universitaire Hopitaux de Rouen	Rouen
Germany	Charite Campus Mitte	Berlin	Schleswig-holstein
Germany	Elben Klinken Stade Buxtehude	Buxtehude	Niedersachsen
Germany	Universitätsklinikum Carl Gustav Carus an der TU Dresden	Dresden
Germany	Helios Klinikum Erfurt	Erfurt	Thüringen
Germany	Universitätsklinikum Essen	Essen
Germany	Institut für Diagnostische und Interventionelle Radiologie Frankfurt	Frankfurt	Hessen
Germany	Universitätsklinikum Frankfurt	Frankfurt	Hessen
Germany	Universitaetsklinikum Freiburg	Freiburg im Breisgau	Baden-württemberg
Germany	SRH Wald-Klinikum Gera GmbH	Gera
Germany	Medizinische Hochschule Hannover (Hannover Medical School)	Hannover
Germany	University Clinic Heidelberg - PPDS	Heidelberg
Germany	Universitatsklinikum Schleswig-Holstein	Kiel
Germany	Uniklinik Köln	Koeln
Germany	Universitatsklinikum Leipzig	Leipzig	Sachsen
Germany	Universitatsklinikum Schleswig-Holstein	Lübeck
Germany	Klinikum Mannheim Universitätsklinikum gGmbH	Mannheim	Baden-württemberg
Germany	Johannes Wesling Klinikum Minden	Minden	Nordrhein-westfalen
Germany	LMU Klinikum der Universität München	München	Bayern
Germany	Fachklinik Hornheide	Münster
Germany	Klinikum Nuernberg Nord	Nürnberg
Germany	Klinikum Dorothea Christiane Erxleben Quedlinburg GmbH	Quedlinburg	Sachsen-anhalt
Germany	University Clinic Regensburg - PPDS	Regensburg	Bayern
Germany	Universitätsklinikum Tübingen	Tübingen
Germany	Universit*ätsklinikum Ulm	Ulm
Germany	Universitätsklinikum Würzburg	Würzburg	Bayern
Greece	Laiko General Hospital of Athens	Athens
Hungary	Magyar Honvédség Egészségügyi Központ	Budapest
Hungary	Orszagos Onkologiai Intezet	Budapest
Hungary	Somogy Megyei Kaposi Mór Oktató Kórház	Kaposvár
Hungary	Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet	Szolnok
Israel	Rambam Medical Center - PPDS	Haifa
Israel	Hadassah Medical Center - PPDS	Jerusalem
Israel	Sheba Medical Center - PPDS	Ramat Gan
Italy	IRCCS Giovanni Paolo II Istituto Oncologico	Bari
Italy	ASST Papa Giovanni XXIII - Azienda Ospedaliera Papa Giovanni XXIII	Bergamo
Italy	ASST degli Spedali Civili di Brescia - Spedali Civili di Brescia	Brescia	Lombardia
Italy	IRCCS Az. Osp. Universitaria San Martino- IST	Genova
Italy	Fondazione IRCCS 'Istituto Nazionale dei Tumori' di Milano	Milano
Italy	Ospedale San Raffaele S.r.l. - PPDS	Milano
Italy	AOU dell'Università degli Studi della Campania Luigi Vanvitelli	Napoli	Campania
Italy	Istituto Nazionale per lo studio e la cura dei tumori Fondazione Giovanni Pascale	Napoli	Naples
Italy	Istituto Oncologico Veneto - I.R.C.C.S.	Padova	Veneto
Italy	Istituto Dermopatico dell'Immacolata IRCCS	Roma	Lazio
Italy	Istituto Nazionale Tumori Regina Elena	Roma
Italy	Azienza Ospedaliera Universitaria Senese	Siena
Italy	A.O.U. Città della Salute e della Scienza di Torino - Presidio S. Lazzaro	Torino
Japan	National Cancer Center Hospital	Chuo-ku
Japan	Kansai Medical University Hospital	Hirakata-city
Japan	Shinshu University Hospital	Matsumoto	Nagano
Korea, Republic of	Asan Medical Center - PPDS	Seoul
Korea, Republic of	Samsung Medical Center - PPDS	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System - PPDS	Seoul
Netherlands	Het Nederlands Kanker Instituut Antoni Van Leeuwenhoek Ziekenhuis	Amsterdam	Noord-holland
Netherlands	Leids Universitair Medisch Centrum	Leiden	Zuid-holland
Netherlands	Radboud University Nijmegen Medical Centre	Nijmegen	Gelderland
Netherlands	Isala Klinieken	Zwolle
Poland	Centrum Medyczne MAVIT Sp. z o.o.	Warszawa	Mazowieckie
Poland	Centrum Onkologii Instytut im. Marii Sklodowskiej-Curie	Warszawa
Poland	Lux Med	Warszawa
Portugal	Hospital Garcia de Orta*E.P.E.	Almada
Portugal	Centro Hospitalar Lisboa Norte, E.P.E. - Hospital de Santa Maria	Lisboa
Portugal	Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.	Lisbon	Lisboa
Portugal	Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS	Porto
Russian Federation	Russian Oncology Research Center n a N N Blokhin	Moscow
Russian Federation	Ryazan Regional Clinical Oncology Dispensary	Ryazan
Russian Federation	Scientific Research Institute of Oncology n.a. N.N. Petrov	St. Petersburg
Slovakia	Narodny onkologicky ustav	Bratislava
South Africa	University of The Free State	Bloemfontein	FREE State
South Africa	Sandton Oncology Medical Group	Johannesburg	Gauteng
South Africa	Sandton Oncology Medical Research	Johannesburg	Gauteng
South Africa	Mary Potter Oncology Centre	Pretoria	Gauteng
South Africa	Steve Biko Academic Hospital	Pretoria	Gauteng
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebrón - PPDS	Barcelona
Spain	ICO l'Hospitalet - Hospital Duran i Reynals	Barcelona
Spain	Complejo Hospitalario Universitario Insular - Materno Infantil	Gran Canaria
Spain	ICO l'Hospitalet - Hospital Duran i Reynals	L'Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitario A Coruña	La Coruna
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario Fundacion Jimenez Diaz	Madrid
Spain	Hospital Universitario HM Sanchinarro - CIOCC	Madrid
Spain	MD Anderson Cancer Center	Madrid
Spain	Hospital Regional Universitario de Malaga Hospital General	Malaga	Málaga
Spain	Clinica Universidad Navarra	Pamplona	Navarra
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Virgen de La Salud	Toledo
Spain	Consorcio Hospital General Universitario de Valencia	Valencia
Spain	Fundacion Instituto Valenciano de Oncologia	Valencia
Sweden	Skanes Universitetssjukhus Lund	Lund	Skane LAN
Sweden	Skanes Universitetssjukhus Lund	Lund
Switzerland	Hôpitaux Universitaires de Genève	Genève
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	Universitätsspital Zürich	Zurich	Zürich (DE)
Turkey	Adana Ba?kent Hastanesi K??la Yerle?kesi	Adana
Turkey	Baskent University Medical Faculty Ankara Hospital	Ankara
Turkey	Hacettepe University Medical Faculty	Ankara
Turkey	Ege University Medical Faculty	Bornova	Izmir
Turkey	Istanbul University Cerrahpasa Medical Faculty Hospital	Istanbul
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	The Royal Sussex County Hospital	Brighton	EAST Sussex
United Kingdom	Bristol Haematology and Oncology Centre	Bristol	Bristol, CITY OF
United Kingdom	Broomfield Hospital	Chelmsford	Essex
United Kingdom	St James s Institute of Clinical Oncology	Leeds
United Kingdom	Royal Marsden Hospital - Surrey	London	London, CITY OF
United Kingdom	Royal Preston Hospital	Preston	Lancashire
United Kingdom	Singleton Hospital - PPDS	Swansea	Glamorgan
United Kingdom	Royal Cornwall Hospital	Truro	Cornwall
United Kingdom	Clatterbridge Hospital	Wirral
United States	Cancer Center Associates - Medical Oncology	Allentown	Pennsylvania
United States	St. Luke's Cancer Center - Allentown Campus	Allentown	Pennsylvania
United States	St. Luke's Hospital - Allentown Campus	Allentown	Pennsylvania
United States	Florida Cancer Specialists	Altamonte Springs	Florida
United States	Texas Oncology-Austin Central	Austin	Texas
United States	Harry and Jeannette Weinberg Cancer Institute @Franklin Square	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Cancer Center Associates - Medical Oncology	Bethlehem	Pennsylvania
United States	St. Luke's University Hospital - Bethlehem Campus	Bethlehem	Pennsylvania
United States	Kresge Eye Institute	Bingham Farms	Michigan
United States	Florida Cancer Specialists	Bonita Springs	Florida
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Florida Cancer Specialists	Bradenton	Florida
United States	Florida Cancer Specialists	Brandon	Florida
United States	Florida Cancer Specialists	Cape Coral	Florida
United States	Florida Cancer Specialists	Clearwater	Florida
United States	Florida Cancer Specialists	Clearwater	Florida
United States	The Ohio State University James Cancer Hospital	Columbus	Ohio
United States	The Ohio State University Martha Morehouse Medical Plaza	Columbus	Ohio
United States	Dennis B. Kay	Dallas	Texas
United States	Elliot J. Ginchansky, MD, PA	Dallas	Texas
United States	Parkland Memorial Hospital	Dallas	Texas
United States	Texas Oncology-Baylor Charles A. Sammons Cancer Center	Dallas	Texas
United States	UT Southwestern Medical Center at Dallas	Dallas	Texas
United States	UT Southwestern University Hospital - Zale Lipshy	Dallas	Texas
United States	UT Southwestern University Hospital- St. Paul	Dallas	Texas
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Kresge Eye Institute	Detroit	Michigan
United States	St. Luke's Cancer Center - Anderson Campus	Easton	Pennsylvania
United States	Karmanos Cancer Institute of Farmington Hills	Farmington Hills	Michigan
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	Florida Cancer Specialists	Fort Myers	Florida
United States	Florida Cancer Specialists	Fort Myers	Florida
United States	US Oncology	Fort Worth	Texas
United States	Florida Cancer Specialists	Gainesville	Florida
United States	Goshen Center For Cancer Care	Goshen	Indiana
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Florida Cancer Specialists	Hudson	Florida
United States	Florida Cancer Specialists	Inverness	Florida
United States	Florida Cancer Specialists	Largo	Florida
United States	Florida Cancer Specialists	Largo	Florida
United States	Florida Cancer Specialists	Naples	Florida
United States	Florida Cancer Specialists	Naples	Florida
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Florida Cancer Specialists	New Port Richey	Florida
United States	Oncology Specialists, SC	Niles	Illinois
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Florida Cancer Specialists	Orange City	Florida
United States	Florida Cancer Specialists	Orlando	Florida
United States	Oncology Specialists, SC	Park Ridge	Illinois
United States	Hospital of the University of Pennsylvania, Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania
United States	Thomas Jefferson Medical Oncology	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Florida Cancer Specialists	Port Charlotte	Florida
United States	Kaiser Permanente Northwest Region Oncology/Hematology	Portland	Oregon
United States	OHSU	Portland	Oregon
United States	OHSU Center for Health and Healing	Portland	Oregon
United States	OHSU Knight Cancer Institute	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	St. Luke's Hospital - Quakertown Campus	Quakertown	Pennsylvania
United States	Highlands Oncology Group	Rogers	Arkansas
United States	Florida Cancer Specialists	Saint Petersburg	Florida
United States	Florida Cancer Specialists	Saint Petersburg	Florida
United States	Florida Cancer Specialists	Sarasota	Florida
United States	Florida Cancer Specialists	Sarasota	Florida
United States	Florida Cancer Specialists	Spring Hill	Florida
United States	Florida Cancer Specialists	Tampa	Florida
United States	Florida Cancer Specialists	Tampa	Florida
United States	Florida Cancer Specialists	Tavares	Florida
United States	US Oncology	The Woodlands	Texas
United States	Florida Cancer Specialists	Venice	Florida
United States	Florida Cancer Specialists	Venice	Florida
United States	Cooper University Hospital	Voorhees	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Czechia,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Poland,  Portugal,  Russian Federation,  Slovakia,  South Africa,  Spain,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	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.	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)
Secondary	Overall Survival (OS)	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.	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)
Secondary	Overall Response Rate (ORR)	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.	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)
Secondary	Time to Response (TTR)	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.	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)
Secondary	Duration of Objective Response (DOR)	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.	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)
Secondary	Disease Control Rate (DCR)	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.	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)
Secondary	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	From baseline up to 219.4 weeks for binimetinib arm; From baseline up to 123.9 weeks for dacarbazine arm
Secondary	Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03	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.	From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm
Secondary	Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03	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.	From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm
Secondary	Number of Participants With Clinically Notable Vital Signs	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	From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm
Secondary	Number of Participants With Notable Electrocardiogram (ECG) Values	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.	From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm
Secondary	Number of Participants With Adverse Events of Special Interest: Cardiac Events	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.	From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm
Secondary	Number of Participants With Clinically Significant Findings in Physical Examination	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.	From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm
Secondary	Number of Participants With Adverse Events of Special Interest: Ocular Events	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.	From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm
Secondary	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
Secondary	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)	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.	From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm
Secondary	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	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.	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
Secondary	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	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.	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
Secondary	Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)	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.	From baseline up to 73 weeks 3 days for binimetinib arm; From baseline up to 57 weeks 3 days for dacarbazine arm
Secondary	Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)	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.	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
Secondary	Number of Participants With Neuroblastoma RAS Viral (V-ras) Oncogene Homolog (NRAS) Mutation Status at Baseline	Number of participants with NRAS mutation status at baseline were reported.	Baseline